Atlas of Clinical Endocrinology and Metabolism

Atlas of Clinical Endocrinology
and Metabolism
This updated text is a pictorial atlas of endocrine and metabolic disorders. Each chapter focuses on pro-
viding multiple illustrations as well as a thorough discussion of the diagnosis and management of a variety
of endocrine diseases with their appropriate treatment plans. Using updated guidelines, it provides a com-
prehensive discussion of the latest therapies, including diabetes technology. Presenting a large number
of clinical images, including imaging of thyroid ultrasounds, DXA images, bone scans, and new tech-
nologies in diabetes mellitus, this atlas aims to provide the reader with the information needed to make
accurate diagnoses, making it an updated source of highly illustrated information for endocrinologists,
clinicians, residents, fellows, and trainees. With new chapters on transgender medicine and obesity, this
textbook will be a valuable resource for the contemporary endocrine practitioner.
• Features new chapters such as transgender medicine and inborn errors of metabolism
• Aims to be an invaluable aid for endocrinologists, internal medicine specialists, family practice
clinicians, residents, fellows, and trainees
• Explores diabetes technology with updated guidelines
Atlas of Clinical Endocrinology
and Metabolism
Edited by
Pauline Camacho
Cover images provided by author.
First edition published 2024

by CRC Press
6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742
and by CRC Press

4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN
CRC Press is an imprint of Taylor & Francis Group, LLC
© 2024 Taylor & Francis Group, LLC
This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to
publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors
or omissions that may be made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors,
authors or contributors are personal to them and do not necessarily reflect the views/opinions of the publishers. The information or guid-
ance contained in this book is intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement
to the medical or other professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions
and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages,
procedures or diagnoses should be independently verified. The reader is strongly urged to consult the relevant national drug formulary
and the drug companies’ and device or material manufacturers’ printed instructions, and their websites, before administering or utilizing
any of the drugs, devices or materials mentioned in this book. This book does not indicate whether a particular treatment is appropriate or
suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own professional
judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted to trace the copyright holders
of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained.
If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint.
Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by
any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in
any information storage or retrieval system, without written permission from the publishers.
For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the Copyright Clearance
Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are not available on CCC please contact
mpkbookspermissions@tandf.co.uk
Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and expla-
nation without intent to infringe.
Library of Congress Cataloging‑in‑Publication Data

Names: Camacho, Pauline M., editor.
Title: Atlas of clinical endocrinology and metabolism / edited by Pauline
Camacho.
Description: First edition. | Boca Raton, FL : CRC Press, 2024. | Includes
bibliographical references and index.
Identifiers: LCCN 2023022854 (print) | LCCN 2023022855 (ebook) | ISBN
9780367608354 (hardback) | ISBN 9780367608330 (paperback) | ISBN
9781003100669 (ebook)
Subjects: MESH: Endocrine System Diseases--diagnostic imaging | Endocrine
System Diseases--therapy | Metabolic Diseases--diagnostic imaging |
Metabolic Diseases--therapy | Atlas
Classification: LCC RB147 (print) | LCC RB147 (ebook) | NLM WK 17 | DDC
616.3/900222--dc23/eng/20231030
LC record available at https://lccn.loc.gov/2023022854
LC ebook record available at https://lccn.loc.gov/2023022855
ISBN: 9780367608354 (hbk)

ISBN: 9780367608330 (pbk)
ISBN: 9781003100669 (ebk)
DOI: 10.1201/9781003100669
Typeset in Times
by Deanta Global Publishing Services, Chennai, India
Contents
Editor vi
Contributors vii
1 Thyroid Disorders
Thyrotoxicosis, Hypothyroidism, Thyroid Nodules 1
Jason L. Gaglia and Jeffrey R. Garber
Thyroid Cancer27
Louis G. Portugal and Alexander J. Langerman
2 Diabetes Mellitus 40
Alalah Mazhari, Mary Ann Emanuele, and Gerald Charnogursky
3 Obesity 74
Marriam Ali and Sobia Sadiq
4 Metabolic Bone Disorders 90

Natasha S. Kadakia, Caroline Poku, Rod Marianne Arceo-Mendoza, and
Pauline Camacho
5 Hypothalamic-Pituitary Disorders 124

S. Sethu K. Reddy, Pruthvi Goparaju, and Maria Fleseriu
6 Adrenal Disorders 147

Sarah Kanbour, Reza Pishdad, Ezra Baraban, and Amir H. Hamrahian
7 Male and Female Reproductive Disorders 192

Rhoda H. Cobin, MD
8 Lipid Disorders 249

Fatima Kazi and Francis Q. Almeda
9 Neuroendocrine Tumors and Genetic Endocrine Disorders: Multiple Endocrine

Neoplasia Type 1 270
Norma Lopez, Ikram Haque, and Shanika Samarasinghe
10 Endocrinologic Care of Transgender Patients 301

Pranav Gupta, Mark Walsh, Howa Yeung, and Mary O. Stevenson
Index 309
v
Editor
Dr. Pauline Camacho is a professor of medicine at Loyola University Medical Center and directs the
Loyola University Osteoporosis and Metabolic Bone Disease Center. She is also the program director for
the endocrinology fellowship at Loyola.
She obtained her medical degree from the University of the Philippines College of Medicine and
completed her internal medicine residency at Rush University Medical Center and endocrinology fellow-
ship at Loyola University Medical Center.
Her clinical practice and research focus on osteoporosis and other metabolic bone diseases such as
vitamin D deficiency, primary hyperparathyroidism, and other calcium and mineral disorders. She has
been on the editorial board of endocrine journals and has published numerous papers and five endocrinol-
ogy textbooks. She is the lead author of the 2020 AACE/ACE Postmenopausal Osteoporosis Treatment
Guidelines. Camacho is a past president of the American Association of Clinical Endocrinologists
(AACE) and past chancellor of the American College of Endocrinology.
She lives in Chicago with her husband and has three daughters.
vi
Contributors
Marriam Ali, MD Maria Fleseriu

Assistant Professor Professor Medicine and Neurological Surgery
Division of Endocrinology Director Pituitary Center
Loyola Medicine Oregon Health & Science University
Maywood, Illinois Portland, Oregon
Jason L. Gaglia, MD, MMSc

Francis Q. Almeda, MD Associate Professor of Medicine
Chief of Cardiology Joslin Diabetes Center
Non-Invasive Cardiology Boston, Massachusetts
UChicago Medicine Ingalls Memorial
Harvey, Illinois Jeffrey R. Garber, MD
Associate Professor of Medicine
Harvard Medical School
Rod Marianne Arceo-Mendoza, MD and
Associate Professor of Medicine Chief of the Division of Endocrinology
Division of Endocrinology Atrius Health
Loyola University Medical Center Boston, Massachusetts
Loyola Stritch School of Medicine
Maywood, Illinois Pruthvi Goparaju
Central Michigan University
Ezra Baraban, MD Mount Pleasant, Michigan
Assistant Professor of Pathology Pranav Gupta, MD
Department of Pathology Pediatric Endocrinologist
Johns Hopkins Hospital Division of Pediatric Endocrinology
Baltimore, Maryland Emory University School of Medicine
Atlanta, Georgia
Gerald Charnogursky, MD
Amir H. Hamrahian, MD
Professor of Medicine
Associate Professor of Medicine
Director, Division of Endocrinology and
Division of Endocrinology, Diabetes and
Metabolism
Metabolism
Loyola University Medical Center
Johns Hopkins University
Maywood, Illinois
Baltimore, Maryland
Rhoda H. Cobin, MD Ikram Haque, MD

Clinical Professor of Medicine Endocrinology Fellow
The Icahn School of Medicine at Mount Sinai Division of Endocrinology and Metabolism
New York, New York Loyola University Medical Center
Maywood, Illinois
Mary Ann Emanuele, MD Natasha S. Kadakia, DO

Professor of Medicine Endocrinology Fellow
Loyola University Medical Center Loyola University Medical Center
Maywood, Illinois Maywood, Illinois
vii
viii Contributors
Sarah Kanbour, MD Louis G. Portugal, MD

Endocrinology Fellow Professor of Surgery
Division of Endocrinology, Diabetes and University of Chicago
Metabolism Chicago, Illinois
Johns Hopkins University
Baltimore, Maryland S. Sethu K. Reddy
Professor of Medicine
Fatima Kazi, MD Division of Endocrinology and Metabolism
Endocrinologist Central Michigan University
Franciscan Physician Network Mount Pleasant, Michigan
Munster, Indiana
Sobia Sadiq, MD
Alexander J. Langerman, MD Assistant Professor
Associate Professor Division of Endocrinology and Metabolism
Otolaryngology, Head and Neck Surgery Loyola University Medical Center
Vanderbilt University Medical Center Maywood, Illinois
Nashville, Tennessee
Shanika Samarasinghe, MD
Norma Lopez, MD Professor
Professor of Medicine Division of Endocrinology and Metabolism
Division of Endocrinology Loyola University Medical Center
Loyola University Medical Center Maywood, Illinois
Maywood, Illinois
Mary O. Stevenson, MD
Alalah Mazhari, DO Division of Endocrinology, Metabolism and Lipids
Professor of Medicine Emory University School of Medicine
Loyola University Medical Center Atlanta, Georgia
Maywood, Illinois
Mark Walsh, MD
Reza Pishdad, MD Division of Plastic and Reconstructive Surgery
Clinical Fellow Emory University School of Medicine
Johns Hopkins University School of Medicine Atlanta, Georgia
Baltimore, Maryland
Howa Yeung, MD, MSc
Caroline Poku, MD Division of Dermatology
Endocrinology Section, Medical Service Emory University School of Medicine
Edward Hines VA Hospital Atlanta, Georgia
Hines, Illinois
and
Assistant Professor of Medicine
Loyola University Health Care System
Maywood, Illinois
Thyroid Disorders
1
ABSTRACT
Thyroid disorders are characterized by either abnormal function or structure. The first section is an over-
view of thyrotoxicosis, hypothyroidism, and thyroid nodules, most of which are benign. The latter section
is devoted to thyroid malignancy.
THYROTOXICOSIS, HYPOTHYROIDISM,
THYROID NODULES
Jason L. Gaglia and Jeffrey R. Garber
Normal Thyroid
Anatomy
During development, the thyroid gland originates as an outpouching of the floor of the pharynx. It grows
downward, anterior to the trachea, with the course of its downward migration marked by the thyroglossal
duct. The thyroid sits like a saddle over the trachea with the two lateral lobes of the thyroid connected by
a thin isthmus, which sits just below the cricoid cartilage. Normally, each lobe is pear shaped, 2.5–4 cm
in lengthlong, 1.5–2 cm in widthwide, and 1–1.5 cm in thickness; the gland typically weighs 10–20 g in an
adult depending upon body size and iodine supply. A pyramidal lobe may extend upward from the isthmus
on the surface of the thyroid cartilage and is a remnant of the thyroglossal duct.
The thyroid gland has a rich blood supply with the two superior thyroid arteries arising from the
common or external carotid arteries, the two inferior thyroid arteries from the thyrocervical trunk of the
subclavian arteries, and a small thyroid ima artery from the brachiocephalic artery at the aortic arch.
The venous drainage is via multiple surface veins that coalesce into superior, lateral, and inferior thyroid
veins. Blood flow is about 5 mL/g/min, but in hyperthyroidism, this may increase 100-a hundredfold.
Other important anatomic considerations include the relative proximity to the parathyroid glands and the
recurrent laryngeal nerves.
Thyroglossal duct cysts can occur during the embryologic descent of the primordial thyroid through
the foramen cecum of the tongue and through the thyroglossal duct near the hyoid bone to its final posi-
tion in the midline pretracheal inferior neck. Thyroglossal duct cysts may present as a midline neck
mass that elevates with tongue protrusion due to the extrinsic action of the genio-glossus muscle, which
inserts muscle fibers into the hyoid bone (see Figure 1.1). Surgical excision of thyroglossal duct cysts often
requires removal of a portion of the hyoid bone.
DOI: 10.1201/9781003100669-1 1
2 Atlas of Clinical Endocrinology and Metabolism
FIGURE 1.1 Thyroglossal duct cysts may present as a midline mass that elevates with tongue protrusion due
to the extrinsic action of the genio-glossus muscle, which inserts muscle fibers into the hyoid bone.
FIGURE 1.2 Normal thyroid. The thyroid gland consists of a collection of follicles where thyroid hormones
are produced and stored. Each follicle consists of a central colloid surrounded by one layer of follicular cells.
(Courtesy of Dr. James Connolly.)
Histology
The thyroid gland consists of a collection of follicles of varying sizes. These follicles contain a protein-
aceous material called colloid and are surrounded by a single layer of thyroid epithelium (Figure 1.2).
These follicle cells synthesize thyroglobulin, which is extruded into the lumen of the follicle. The bio-
synthesis of thyroid hormones occurs at the cell–colloid interface. Here thyroglobulin is hydrolyzed to
release thyroid hormones. In addition to the follicular cells are other light-appearing cells, often found
in clusters between the follicles, called C-cells (Figure 1.3). These cells are derived from the neural crest
via the ultimobranchial body and secrete calcitonin. In adults, the C-cells represent about 1% of the cell
population of the thyroid.
Thyroid Hormone
Thyroid hormone synthesis requires iodide, the glycoprotein thyroglobulin, and the enzyme thyroid
microsomal peroxidase (TPO). Synthesis involves several steps including: (1) active transport of I– into the
cell via the Na/I symporter; (2) iodide trapping with oxidation of iodide and iodination of tyrosyl residues
1 • Thyroid Disorders 3
FIGURE 1.3 C-cell is demonstrated in the classic parafollicular location with calcitonin staining in brown.
(Courtesy of Dr. James Connolly.)
in thyroglobulin catalyzed by TPO, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT); (3) cou-
pling of iodotyrosine molecules to form triiodothyronine (T3) from one MIT and one DIT molecule, and
thyroxine (T4) from two DIT molecules; (4) proteolysis of thyroglobulin; (5) deiodination of iodotyrosines
with conservation of liberated iodide; and (6) intrathyroidal 5′-deiodination of T4 to T3, particularly in
situations of iodide deficiency or hormone overproduction.
Thyroid hormones are transported in the serum bound to carrier proteins. It is the much smaller free
fraction that is responsible for hormonal activity (typically 0.03% for T4 and 0.3% for T3). The three major
thyroid hormone transport proteins are thyroxine-binding globulin, albumin, and transthyretin (thyrox-
ine-binding prealbumin), which carry 70%, 15%, and 10%, respectively. A number of conditions and
medications can affect carrier protein concentration or binding (Table 1.1). Peripheral deiodinases convert
T4 to the more active T3 or inactive reverse T3.
TABLE 1.1 Factors Influencing Total Thyroid Hormones Levels

Increased Binding Globulin
• Congenital
• Hyperestrogen states (pregnancy, ERT, SERMs, OCPs)
• Drugs: methadone, heroin, 5-fluouracil, mitotane
• Illness: acute hepatitis, hypothyroidism (minor)
Decreased Binding Globulin
• Congenital
• Drugs: androgens, glucocorticoids
• Illness: protein malnutrition, nephrotic syndrome, cirrhosis, hyperthyroidism (minor)
Drugs Affecting Binding
• Phenytoin
• Salicylates
• Furosemide
• Heparin (via increased free fatty acids)
ERT, estrogen replacement therapy; OCP, oral contraceptive pill; SERM, selective estrogen receptor modulator.
The production of thyroid hormone is normally controlled by the hypothalamic–pituitary–thyroid

axis. Thyrotropin-releasing hormone (TRH) produced in the hypothalamus reaches the thyrotrophs in
the anterior pituitary via the hypothalamic–hypophysial portal system and stimulates the synthesis and
release of thyroid-stimulating hormone (TSH). TSH acts upon the thyroid to increase thyroid hormone
production. Negative feedback, primarily via T3 (which may be locally generated from T4 via type 2
iodothyronine deiodinase), inhibits TRH and TSH secretion.
Thyrotoxicosis
Definition
Thyrotoxicosis occurs when increased levels of thyroid hormone lead to biochemical excess of the hor-
mone at the tissue level. Increased levels of thyroid hormone leading to thyrotoxicosis may result from
the overproduction of thyroid hormone (termed ‘hyperthyroidism’), leakage of stored hormone from the
gland, or exogenous thyroid hormone administration.
Etiology
Many cases of thyrotoxicosis are from autoimmune antibody-mediated stimulation (Graves’ disease), gland
destruction (thyroiditis), or autonomous nodular disease. Other less frequent causes of thyrotoxicosis include
stimulation of the TSH receptor by high human chorionic gonadotropin (hCG) levels, TSH-secreting pitu-
itary adenomas, pituitary-specific thyroid hormone resistance, struma ovarii, functional metastatic thyroid
carcinoma, thyrotoxicosis factitia, neonatal Graves’ disease, and congenital hyperthyroidism.
Iodine-containing drugs, such as iodinated contrast agents, or iodine-rich foods, such as kelp, may
precipitate thyrotoxicosis in susceptible individuals, especially in iodine-deficient areas, and is termed
Jod–Basedow disease. Amiodarone may precipitate thyrotoxicosis via iodine excess (type 1) or a drug-
induced destructive thyroiditis (type 2).
Clinical Presentation
Common symptoms of thyrotoxicosis include palpitations, nervousness, shakiness, insomnia, difficulty
concentrating, irritability, emotional lability, increased appetite, heat intolerance, fatigue, weakness, exer-
tional dyspnea, hyperdefecation, decreased menses, and brittle hair. Although weight loss is more typical,
approximately 10% of affected individuals gain weight likely due to a mismatch between increased meta-
bolic demand and polyphagia. Due to changes in adrenergic tone, older individuals with thyrotoxicosis
may lack many of the overt symptoms seen in younger individuals and instead present with what has been
termed ‘apathetic thyrotoxicosis’. Often weight loss, fatigue, and irritability are the major complaints in
this age group. They may be depressed and have constipation rather than frequent stools. Atrial fibrilla-
tion, crescendo angina, and congestive heart failure are also not uncommon in this population.
Signs of thyrotoxicosis include tremors, warm moist skin, tachycardia, flow murmurs, hyperreflexia
with rapid relaxation phase, and eye signs. Lid retraction or ‘thyroid stare’ may be seen with any cause of
thyrotoxicosis and is attributed to increased adrenergic tone. True ophthalmopathy is unique to Graves’
disease and may include proptosis, conjunctival injection, and periorbital edema. Patients with Graves’
disease also typically have a goiter and may have a thyroid bruit from increased intrathyroidal blood flow,
while patients with autonomous adenoma(s) frequently have palpable nodule(s).
Diagnosis/Investigations
Measurement of serum TSH followed by free T4 or T4 index are the initial laboratory studies when
thyrotoxicosis is suspected. If free T4 (or T4 index) is normal and TSH is undetectable, a T3 level
should be checked to evaluate for T3 thyrotoxicosis. Other laboratory findings that may be associ-
ated with thyrotoxicosis include mild leukopenia, normocytic anemia, transaminitis, elevated alka-
line phosphatase (particularly from bone, but liver alkaline phosphatase may also be elevated), mild
hypercalcemia, low albumin, and low cholesterol. Several medications including dopamine and cor-
ticosteroids may decrease TSH but should not be confused with thyrotoxicosis, as the free T4 and/or
T3 are not elevated.
Once biochemical thyrotoxicosis is confirmed, the underlying etiology is usually determined by clini-
cal findings or functional and/or structural assessment of the gland. A quantitative assessment of func-
tional status may be obtained with radioactive iodine uptake. An inappropriately high uptake (uptake
should normally be suppressed in the setting of a suppressed TSH) confirms hyperthyroidism, whereas
a low uptake may be seen with the thyrotoxic phase of thyroiditis, exogenous thyroid hormone ingestion,
or thyroid hormone production from an area outside of the neck. A scan with 123I or 99mTc pertechnetate
can be used to obtain further functional information with images depicting the distribution of trapping
within the thyroid gland. Uniform distribution in a hyperthyroid patient most often suggests Graves’ dis-
ease (Figure 1.4). Activity corresponding to a nodule with suppression of the rest of the thyroid suggests
a toxic adenoma. A patchy distribution may be seen in toxic multinodular goiter. Structural information
may be obtained with physical examination and thyroid ultrasound (Figures 1.5 and 1.6). This should be
correlated with functional data to ensure that another concurrent process such as thyroid cancer is not
overlooked.
Although the cause of thyrotoxicosis can usually be determined by history, physical examination,
and radionuclide studies, in unclear situations the measurement of circulating thyroid autoantibodies may
be helpful. A low thyroglobulin level may be useful in differentiating thyrotoxicosis factitia from other
etiologies.
Management/Treatment
Complications of untreated hyperthyroidism may include atrial fibrillation, cardiomyopathy, and osteo-
porosis. Regardless of the etiology of the thyrotoxicosis, beta-blockers, most commonly propranolol,
may be used for heart rate control and symptomatic relief. Rate control is particularly important in indi-
viduals who have developed an arrhythmia or a rate-related cardiomyopathy. Once a euthyroid state is
FIGURE 1.4 123 I scan showing increased and homogenous uptake of radioiodine in Graves’ disease.
FIGURE 1.5–1.6 Right sagittal thyroid ultrasound 123I scan correlation of Figure 1.5. The superior and middle
nodules (circled) on ultrasound correlate with the areas of increased uptake on the scan (arrows) while the
inferior nodule (dotted circle) corresponds to a relatively photopenic area and warrants further evaluation
(arrowhead). (Courtesy of Dr. Susan Mandel.)
achieved, the beta-blocker is often stopped. Thyroiditis resulting in thyrotoxicosis is usually self-limiting
and often requires no additional therapy, but does carry the potential for subsequent hypothyroidism. In
cases of destructive thyroiditis such as amiodarone-induced thyrotoxicosis type 2, steroid therapy may be
employed to decrease inflammation. Steroids can also inhibit conversion of T4 to T3.
Thionamides are the major class of drugs used in the treatment of thyrotoxicosis caused by Graves’
disease or for usually brief periods in those with multinodular goiter and autonomous adenomas.
Commonly utilized forms include propylthiouracil, methimazole, and carbimazole. These agents pro-
duce effective intrathyroidal iodine deficiency by inhibiting the oxidation and organic binding of thyroid
iodine. Large doses of propylthiouracil may also impair the peripheral conversion of T4 to T3 by type 1
deiodinase. Since these agents inhibit the synthesis but not the release of hormones, they are not useful
if there is thyroid hormone leakage from the gland without excess hormone production and also have a
latent period before a clinical response is seen. Thionamides may cause hypothyroidism, particularly if
given in excessive doses over longer periods of time. Potential adverse reactions include rash, arthralgia,
myalgia, neuritis, agranulocytosis, hepatitis, ANCA-positive vasculitis (hepatitis and vasculitis are more
common with propylthiouracil), cholestasis (which may also lead to hepatitis and is more common with
methimazole), thrombocytopenia, and taste disturbance. Rash may occur in as many as 10% of patients,
while agranulocytosis occurs in fewer than 1% of patients. Agranulocytosis most frequently, but not exclu-
sively, occurs within the first few weeks or months of treatment and is often accompanied by fever and
sore throat. Surgery or radioactive iodine may be considered for more definitive therapy depending upon
the etiology, clinical situation, and patient preference.
Subclinical Hyperthyroidism
Subclinical hyperthyroidism is characterized by a subnormal serum TSH level and normal free T4 and
T3. Subclinical hyperthyroidism is most often asymptomatic and discovered on screening. Several studies
report a prevalence of <2% in adult populations. It is generally accepted that once a suppressed TSH with
normal free T4 and T3 are detected, this should be reassessed, typically in 2–4 months, to determine if it
is persistent or transient, and that all patients with subclinical hyperthyroidism should undergo periodic
clinical and laboratory assessment. Beyond this, there currently is no consensus as to the management of
subclinical hyperthyroidism, but its treatment may be warranted in several subpopulations.
The three major concerns with subclinical hyperthyroidism are (1) progression to overt hyperthyroid-
ism, (2) cardiac effects, and (3) skeletal effects. In individuals with subclinical hyperthyroidism attribut-
able to nodular disease, there is a high rate of conversion to clinical hyperthyroidism and thus treatment
is often considered in this population. In elderly individuals, subclinical hyperthyroidism increases the
relative risk of atrial fibrillation threefold, and other adverse cardiac effects including impaired ventricu-
lar ejection fraction response to exercise have been reported. Prolonged subclinical hyperthyroidism may
be associated with decreased bone mineral density, particularly in postmenopausal women. These risks
are considered in developing an individualized treatment plan. In most other individuals, treatment may
be unnecessary, and for individuals in which treatment is deferred, thyroid tests are typically performed
every 6 months.
Graves’ Disease
Definition/Overview
Graves’ disease, or as it is known in parts of Europe, von Basedow’s disease, is an autoimmune disor-
der in which stimulatory autoantibodies directed against the TSH receptor (TSHRAbs) result in TSH-
independent stimulation of the thyroid gland causing production and secretion of thyroid hormone.
Histologically, hyperplastic columnar epithelium is evident (Figure 1.7). Extrathyroidal manifestations
may include ophthalmopathy, pretibial myxedema, and, rarely, thyroid acropachy. Thyroid enlargement
with hormone excess is typical, but any of the components, thyroid disease, infiltrative orbitopathy and
ophthalmopathy, or infiltrative dermopathy may occur and often run largely independent courses.
Epidemiology/Etiology
Graves’ disease has an incidence of between 0.3 and 1.5 cases per 1,000 population per year with a
female-to-male ratio of between 5 and 10 to 1. The typical age of presentation is between 30 and 60 years.
Although it is by far the most common cause of hyperthyroidism in individuals younger than age 40, it is
very uncommon in children under 10 years old. Smoking has been associated with a greater propensity
to develop ophthalmopathy and the worsening of ophthalmopathy with antigen release after radioactive
iodine therapy.
FIGURE 1.7 Graves’ disease. (A) At lower power, hyperplastic columnar epithelium with increased infold-
ing is noted. (B) At higher power, clear vacuoles in the colloid are evident with the increased activity of the
epithelium from increased thyroid hormone production leading to scalloping of the colloid. (Courtesy of Dr.
James Connolly.)
The thyroid component of Graves’ disease is genetically related to autoimmune thyroiditis, particu-
larly Hashimoto’s disease, with both often occurring within the same families. The frequency of other
autoimmune disorders including type 1 diabetes, pernicious anemia, myasthenia gravis, Addison’s dis-
ease, Sjögren’s syndrome, lupus erythematosus, rheumatoid arthritis, and idiopathic thrombocytopenic
purpura is also increased in Graves’ disease patients and their families. There have been reports that
in susceptible individuals SARS-CoV-2 infection or vaccination may worsen or precipitate autoimmune
thyroid disease.
Although the TSH receptor is the primary autoantigen of Graves’ disease, autoantibodies against
TPO and thyroglobulin are also common. Thyroid-directed T-cell-mediated autoimmunity can also be
shown. Extrathyroidal TSH receptor messenger ribonucleic acid (mRNA) and receptor protein have
been reported in many other tissues including retro-orbital adipocytes, muscle cells, and fibroblasts,
and may play a role in the extrathyroidal manifestations not seen in other forms of thyrotoxicosis. The
expression may trigger lymphocyte migration into affected tissues. TSHRAbs may be stimulating,
blocking, or neutral. Stimulating TSHRAbs bind to the TSH receptor activating adenylate cyclase,
inducing thyroid growth, increasing vascularity, and increasing thyroid hormone production and secre-
tion. Changes in the balance between blocking and stimulating antibodies may lead to fluctuations in
thyroid hormone levels.
Most patients with Graves’ disease have a diffuse goiter. The gland is frequently enlarged two to three
times more than normal but may be much larger. This enlargement is usually symmetric and there is a
smooth or lobular surface to the gland. The consistency of the gland may vary from soft to firm and rub-
bery, but is often more spongy than that seen in Hashimoto’s disease. In more ‘severe’ cases, a bruit or
thrill may be present with increased intrathyroidal blood flow, which is more common with a larger goiter.
Although thyroid-associated ophthalmopathy is closely associated with Graves’ hyperthyroidism,
either condition may exist without the other; it may predate (20%), coincide with (40%), or follow success-
ful treatment of hyperthyroidism (40%). Thyroid-associated ophthalmopathy results from enlargement of
the extraocular muscles and intraorbital fat with an increase in retro-ocular pressure, caused by lympho-
cytic infiltration, edema, and later fibrosis. This results in proptosis and impairment of extraocular muscle
function. As a result, ophthalmoplegia, diplopia, chemosis, papilledema, or corneal ulceration may occur
(Figures 1.8–1.12).
FIGURE 1.8 Normally, the upper lid is located 1–1.5 mm below the superior limbus, and the lower lid is
located at the inferior limbus. This figure demonstrates upper lid retraction (Dalrymple sign) with temporal
flare and scleral show in Graves’ ophthalmopathy. (Courtesy of Dr. Richard Dallow.)
FIGURE 1.9 Marked periorbital edema and chemosis are demonstrated. (Courtesy of Dr. Richard Dallow.)
FIGURE 1.10 Ophthalmoplegia with downward gaze is shown. (Courtesy of Dr. Richard Dallow.)
Thyroid-associated dermopathy is seen in 5%–10% of patients with Graves’ disease and is closely
associated with ophthalmopathy. It is generally over the shin (pretibial myxedema) but can be seen over
the toes, forehead, neck, or in areas of trauma (Figures 1.13 and 1.14). It presents as painless thickening of
the skin in hyperpigmented nodules or plaques. Thyroid acropachy, (clubbing of the digits and periosteal
bone formation) is seen in less than 1% of patients and is usually associated with longstanding disease
(Figures 1.15–1.17). Almost all patients with acropachy also have thyroid-associated ophthalmopathy and
dermopathy. Generalized lymphadenopathy, occasionally with splenic and thymic enlargement, may also
be seen.
Differential Diagnosis
The diffuse goiter of Graves’ disease may be confused with the goiter of other thyroid diseases but can
often be differentiated based on laboratory studies or radioactive iodine uptake. Mild bilateral exophthal-
mos may be familial and also sometimes occurs in patients with Cushing’s syndrome, cirrhosis, uremia,
chronic obstructive pulmonary disease, or superior vena cava syndrome. Unilateral exophthalmos, even
when associated with thyrotoxicosis, should raise consideration of another local cause, including orbital
FIGURE 1.11 Lid retraction with proptosis and conjunctival injection is shown. (Courtesy of Dr. Richard
Dallow.)
FIGURE 1.12 Orbital CT demonstrating the classic findings in Graves’ ophthalmopathy with thickened recti
muscles but sparing of the tendons. Exophthalmos with bilateral anterior displacement of the globes is also
shown.
FIGURE 1.13–1.14 Skin changes. Subtle findings of pretibial myxedema with painless thickening of the skin
over the shin are shown. (Courtesy of Dr. Pamela Hartzband.) Thyroid-associated dermopathy is evident as skin
thickening after a skin biopsy. (Courtesy of Dr. Arturo Rolla.)
FIGURE 1.15–1.17 Thyroid acropachy. Thyroid acropachy is characterized by clubbing of the fingers and toes
often with soft tissue swelling over the distal small joints. Soft tissue swelling with periosteal or endocortical
thickening or subperiosteal reaction may be seen on radiographs. (Courtesy of Drs. A. Rolla and P. Hartzband.)
Soft tissue swelling with periosteal or endocortical thickening or subperiosteal reaction seen on MRI. (Courtesy
of Drs. A. Rolla and P. Hartzband.) Soft tissue swelling with periosteal or endocortical thickening or subperi-
osteal reaction seen on bone scan. (Courtesy of Drs. A. Rolla and P. Hartzband.)
neoplasm, carotid–cavernous sinus fistulae, cavernous sinus thrombosis, orbital pseudotumor, or other
infiltrative disorders.
Thyroid tests in Graves’ disease are consistent with thyrotoxicosis, usually with a suppressed TSH and
elevated free T4. Often there is a proportionally greater increase in T3 than T4 concentrations in Graves’
disease (this can also be seen with autonomous nodules). If free T4 levels are unexpectedly normal, T3
should be measured to evaluate for T3 thyrotoxicosis.
Measurement of radioactive iodine uptake may be useful in differentiating Graves’ disease, where
uptake is inappropriately normal or high, from painless thyroiditis, where uptake is low during the thy-
rotoxic phase.
Measurement of TSHRAbs is usually not necessary in hyperthyroid patients with Graves’ disease
with an intact thyroid gland as thyrotoxicosis already serves as an internal bioassay of autoantibody activ-
ity. In individuals with possible euthyroid Graves’ ophthalmopathy, measurement of TSHRAbs may aid
in diagnosis, especially if eye findings are unilateral. Similarly, in pregnant women with a prior history of
Graves’ disease and thyroid ablation, who therefore do not have an internal bioassay of activity, maternal
TSHRAbs may be useful in predicting neonatal thyrotoxicosis.
The mainstay of pharmacologic therapy for Graves’ disease is the thionamides. As described in the thy-
rotoxicosis section, these drugs inhibit thyroid hormone production. Thionamide drugs may also directly
decrease the autoimmunity in Graves’ disease by both decreasing antigen expression and cytokine release
from the thyroid as well as potential nonspecific immunosuppression leading to decreased lymphocytic
infiltration and antigen presentation. Up to 40% of patients previously treated with thionamides remain
euthyroid 10 years after discontinuation of antithyroid therapy. Individuals with persistently high levels of
TSHRAbs or a T3 to T4 ratio of greater than 20 are more likely to relapse after cessation of antithyroidal
drugs.
Radioactive iodine is often considered the preferred treatment for patients with Graves’ disease in
North America and is particularly attractive for those who have relapsed after discontinuation of antithy-
roid drugs, who would not tolerate a relapse, or are at increased risk of atrial fibrillation due to comorbid
conditions or age. Radioactive iodine treatment is contraindicated in pregnant women and those who
are breastfeeding. It can induce worsening ophthalmopathy, particularly in smokers, but this risk can be
reduced with high-dose glucocorticoid therapy (for example, 30–40 mg of prednisone daily, with a taper
over weeks to months).
Treatment regimens may vary from center to center and include administering either an ablative dose
or a calculated smaller dose of radioiodine. If used, antithyroid drugs are stopped 3–4 days before radio-
iodine to allow for its effective uptake and may be resumed 3–4 days after in individuals at high risk for
radiation thyroiditis. Since it is radioprotective, pretreatment with propylthiouracil is generally avoided
or a higher dose of radioactive iodine is used at the time of treatment. Typically, a response is seen within
3 months, but since radioiodine may work slowly, it is usual to wait 6 months before giving another dose
for persistent hyperthyroidism. By 1 year, permanent hypothyroidism occurs in the vast majority of those
given high-dose radioiodine, while those given a lower dose may develop hypothyroidism later and are at
higher risk for recurrent hyperthyroidism.
Subtotal thyroidectomy may be preferred in patients with a large goiter, a coexistent thyroid nodule
not proven to be benign, or when rapid control is required such as therapy-resistant Graves’ disease dur-
ing pregnancy. Preferably, the patient is treated with antithyroidal agents until euthyroid and an appropri-
ate beta-blockade are instituted. Inorganic iodide may be administered for 7–10 days prior to surgery to
decrease the vascularity of the gland.
During pregnancy, TSHRAbs, blocking or stimulating, may cross the placenta and affect fetal thyroid
function. Regular fetal monitoring for evidence of fetal thyrotoxicosis or goiter is therefore important in
cases where the mother has a history of Graves’ disease, whether or not there has been prior maternal
thyroidectomy or ablation.
Treatment of Graves’ ophthalmopathy, thyroid eye disease, may include applying cool compresses to
the eyes or using lubricating eye drops or gel to help maintain moisture. Sunglasses may help protect the
eyes from the sun and wind. Elevating the head of the bed may help reduce swelling and pressure on the
eyes. The use of prisms may aid with double vision. Medical treatments include steroids or teprotumumab,
an insulin-like growth factor-1 receptor antagonist antibody. Surgical treatments include surgical reposi-
tioning of the eyelid(s) to help reduce irritation, eye muscle surgery, and orbital decompression surgery.
Hypothyroidism
Definition
Hypothyroidism results from thyroid hormone deficiency in target tissues. Primary hypothyroidism is
defined as decreased secretion of thyroid hormone by factors affecting the thyroid gland itself. Central
hypothyroidism is due to factors interfering with TSH release from the pituitary (secondary hypothyroid-
ism) or TRH release from the hypothalamus (tertiary hypothyroidism). In rare instances, thyroid hormone
resistance may lead to hypothyroidism despite normal or elevated thyroid hormone levels. Hypothyroidism
is a graded phenomenon, which in its most severe form can result in myxedema.
The most common causes of hypothyroidism are autoimmune thyroid disease, hypothyroidism after sur-
gery, or radioactive iodine. Primary hypothyroidism is relatively common and affects 4%–8% of the gen-
eral population. Hypothyroidism is much more common in women than men with a female-to-male ratio
of up to 8–10 to 1. The mean age of diagnosis is mid-50s.
Central hypothyroidism is causal 1 in 20 to 1 in 200 individuals with hypothyroidism, frequently after
damage to the hypothalamus or pituitary by tumor, trauma, or an infiltrative disease. Thyroid hormone
resistance syndromes are seldom the cause of hypothyroidism with only approximately 1,000 registered
patients worldwide. Hypothyroidism may also be caused by iodine deficiency (decreased substrate for
synthesis) or transiently by iodine excess via the Wolff–Chaikoff effect (inhibition of iodide organifica-
tion by inorganic iodide excess). Many drugs, including lithium, interferon, amiodarone, and antithyroid
agents, may cause hypothyroidism. Rare causes of hypothyroidism include infiltrative diseases such as
sarcoidosis, cystinosis, hemochromatosis, progressive systemic sclerosis, amyloidosis, Riedel’s thyroiditis
with fibrosis, infectious diseases, thyroid dysgenesis, and consumptive hypothyroidism (excessive type 3
iodothyronine deiodinase activity).
The symptoms of hypothyroidism are often nonspecific and include fatigue, cold intolerance, depression,
mild weight gain, weakness, joint aches, constipation, dry skin, hair loss, and menstrual irregularities.
Common signs of moderate to severe hypothyroidism include diastolic hypertension, bradycardia, coarse
hair, diffuse hair loss (especially the outer third of the eyebrows), dry brittle nails, periorbital swelling,
carpal tunnel syndrome, and a delayed relaxation phase of deep tendon reflexes. Other less common pre-
sentations may include yellowing of the skin (carotenoderma), myxedema (pale, waxy, edematous skin
without pitting), acropachy, ventricular arrhythmias, and congestive heart failure (particularly in associa-
tion with underlying cardiac disease). Retarded growth and delayed bone age may be seen in hypothyroid
children. In primary hypothyroidism, the thyroid usually has a firm consistency. Its size can be quite
variable.
When myxedema coma occurs, it is usually in elderly patients with hypothyroidism and a superim-
posed precipitating event. Hypothermia, bradycardia, and hypoventilation are common. Ileus is usually
present, and pericardial, pleural, and peritoneal effusions may be seen. Central nervous system (CNS)
manifestations may include confusion, seizures, or coma.
TSH is elevated in individuals with primary gland failure but may be normal or low in individuals with
central hypothyroidism. Although central hypothyroidism is relatively uncommon, the free T4 or T4 index
should also be checked if this is suspected. Other laboratory findings associated with hypothyroidism may
include normochromic, normocytic anemia or iron deficiency anemia in the setting of excessive menstrual
bleeding, hyponatremia, hypercholesterolemia, and elevated creatine phosphokinase.
The standard treatment for hypothyroidism is thyroid hormone replacement, usually with oral levothy-
roxine (LT4). In primary hypothyroidism, therapy is titrated to a normal TSH (typical goals are 0.3–3.0
μIU/mL) unless otherwise indicated (for example, those with a history of thyroid cancer may have a lower
TSH goal). In an adult, the full replacement dose is often around 1.6 μg/kg/day. Elderly patients or those
with known or suspected cardiac disease are often started on lower doses of LT4 (typically 25 μg/day) and
increased slowly until TSH is normal. In central hypothyroidism, trough free T4 or T4 index levels should
be followed instead and therapy adjusted as needed to keep troughs in the middle of the normal range.
Since the bioavailability of different thyroid hormone brand name preparations are often not equivalent,
brand changes should not be made without retitrating the dose. Even if a bioequivalent substitution is
made, consider rechecking the TSH in 8 weeks. In general, it takes 6–8 weeks for TSH levels to reach
equilibrium after a dose adjustment.
If myxedema coma is diagnosed or suspected, the treatment includes rapid repletion of thyroid
hormone deficit, stress doses of glucocorticoids (at least until adrenal function can be evaluated), and
treatment of any precipitants. Initially, treatment with intravenous levothyroxine is usually employed,
as absorption may be variable in the setting of associated gut edema. An intravenous loading dose of
200–500 μg of levothyroxine is commonly recommended, followed by daily intravenous administration
of 50–100 μg. Lower daily doses are used in elderly patients and for those in whom myocardial ischemia
is likely. The role of intravenous T3 remains controversial and is usually reserved for individuals with low
cardiovascular risk with some practitioners advocating additional intravenous T3 at 10 μg every 8 hours
for such patients.
Untreated or inadequately treated hypothyroidism during pregnancy may increase maternal and
fetal complications including fetal death. Even mild, asymptomatic maternal hypothyroidism may affect
the cognitive function of the offspring. TSH measurement should be performed before pregnancy or as
early as possible during the first trimester for those with known thyroid disease. Since thyroid hormone
requirements often increase during the first and second trimesters of pregnancy, in women with known
hypothyroidism one strategy has been to increase thyroid hormone dose by about 30% when pregnancy
is confirmed and then to follow the serum TSH level every 6 weeks during pregnancy to ensure that the
requirement for levothyroxine has not changed.
Subclinical Hypothyroidism
Subclinical hypothyroidism is characterized by a mildly increased TSH in the setting of normal free T4
and T3. Subclinical hypothyroidism is most often asymptomatic and discovered on screening. The preva-
lence has been estimated at between 1% and 10% of the adult population.
The major concerns with subclinical hypothyroidism are (1) progression to overt hypothyroidism, (2)
cardiovascular effects, (3) hyperlipidemia, and (4) neuropsychiatric effects. Individuals with TSH levels
>10 μIU/mL or with TSH levels between 5 and 10 μIU/mL and goiter and/or positive antithyroid per-
oxidase antibodies have the highest rates of progression to overt hypothyroidism and are therefore often
treated with levothyroxine. Beyond this, treatment of subclinical hypothyroidism remains controversial.
Thyroiditis
Thyroiditis rather broadly refers to inflammation of the thyroid gland and comprises a large group of
diverse conditions. Since these disorders may be grouped in various ways and there may be multiple
names for the same conditions, these conditions may at first seem confusing. Many of the commonly
used names are listed in Table 1.2; the major syndromes are described in the following and summarized
in Table 1.3.
In postpartum thyroiditis, painless thyroiditis, and subacute thyroiditis, inflammatory destruction
of the thyroid may lead to transient thyrotoxicosis, as preformed thyroid hormone is released from the
damaged gland. Due to the destructive nature of these processes, thyrotoxicosis may be preceded by a
significant increase in serum thyroglobulin. Reflecting the ratio of stored hormone in the gland, serum
T4 concentrations are often elevated proportionally higher than T3 concentrations in contrast to Graves’
disease or autonomous adenomas in which T3 may be preferentially elevated. As thyroid hormone stores
TABLE 1.2 Forms of Thyroiditis

TYPE OTHER NAMES OR SUBTYPES
Hashimoto’s thyroiditis Chronic lymphocytic thyroiditis, chronic autoimmune thyroiditis, lymphadenoid
goiter, struma lymphomatosa
Postpartum thyroiditis Painless postpartum thyroiditis, subacute lymphocytic thyroiditis
Silent thyroiditis Painless (sporadic) thyroiditis, subacute lymphocytic thyroiditis
Subacute thyroiditis Painful subacute thyroiditis, de Quervain’s thyroiditis (subacute) granulomatous
thyroiditis, giant cell thyroiditis
Suppurative thyroiditis Infectious thyroiditis, pyogenic thyroiditis, bacterial thyroiditis, acute
(suppurative) thyroiditis
Riedel’s thyroiditis Reidel’s struma
Thyroiditis Fibrous thyroiditis
Drug-induced Amiodarone, lithium, interferon-alpha, interleukin 2, sunitinib, checkpoint
inhibitors
Other Radiation-induced, traumatic
are depleted and destruction continues, there may be progression to overt hypothyroidism. Hashimoto’s
thyroiditis, painless thyroiditis, and postpartum thyroiditis all have an autoimmune basis.
Hashimoto’s Thyroiditis
Hashimoto’s thyroiditis often begins clinically with gradual enlargement of the thyroid gland and eventual
development of hypothyroidism. If untreated, the goiter may slowly increase in size. The goiter is diffuse
and firm with the gland variably being normal to four times the normal size at diagnosis. Associated pain
and tenderness are unusual but may be present. In addition to the symptoms of hypothyroidism, about
one-quarter of patients with Hashimoto’s thyroiditis develop other musculoskeletal complaints including
chest pain, fibrositis, or arthritis.
Antithyroid autoantibodies are detectable in more than 95% of patients with Hashimoto’s thyroiditis,
with high serum TPO antibodies present in 90% of patients and high serum thyroglobulin antibodies
detectable in 50%–80% of patients. Elevated antibodies may also be detected in 5%–15% of the gen-
eral population, the majority of whom have normal thyroid function. The ultrasound appearance of the
gland is remarkable for a heterogeneous echotexture often with multiple ill-defined hypoechoic patches
or pseudonodules. Histology often reveals lymphocytic infiltration with germinal center formation and
fibrosis (Figure 1.18). A radioactive iodine (RAI) scan contributes little to the diagnosis. Uptake may be
low, normal, or elevated with an irregular pattern.
With the institution of LT4 treatment, goiter size often decreases within months, whether the patient
is euthyroid or hypothyroid. This is especially true in younger individuals, as there is likely less fibrosis
present. If the goiter is small and the patient is euthyroid and asymptomatic, no treatment is required.
Although controversial, some physicians consider therapy if the TSH is elevated and free T4 is normal
since the eventual onset of hypothyroidism is likely in such patients (estimated at 2%–5% per year).
Antibody levels may spontaneously dissipate and up to 20% of initially hypothyroid patients will later
recover and have normal thyroid function if thyroid hormone withdrawal is attempted.
Postpartum and Painless Thyroiditis

Postpartum thyroiditis is most common in women with a high serum TPO antibody concentration in the
first trimester of pregnancy or immediately after delivery. Women with type 1 diabetes are at particular
risk with up to 25% developing postpartum thyroiditis. Thyrotoxicosis typically is noted by 3–4 months
after delivery and lasts 1–2 months. This may be followed by a hypothyroid phase lasting 4–6 months.
TABLE 1.3 Overview of Thyroiditis Syndromes
16
HASHIMOTO’S POSTPARTUM SILENT SUBACUTE SUPPURATIVE

CHARACTERISTIC THYROIDITIS THYROIDITIS THYROIDITIS THYROIDITIS THYROIDITIS RIEDEL’S THYROIDITIS
Thyroid pain No No No Yes Yes No
Typical neck exam Firm symmetric Small, nontender Small, nontender Tender and swollen Tender thyroid Rock-hard, fixed,
goiter gland gland gland mass painless gland
Sex ratio (F:M) 8–15:1 — 2:1 5:1 1:1 3–4:1
Cause Autoimmune Autoimmune Autoimmune ? Viral Infectious Unknown
Associations HLA DR3, HLA DR3, HLA DR3 HLA Bw-35 Pre-existing thyroid Systemic fibrosis;
DR4, DR5 DR5 disease immune- hypoparathyroidism
compromised; from fibrosis
structural
abnormalities
Temporal course Chronic Episodic: 70% Episodic: Episodic: <2%–4% May be fatal if Progressive
recurrence with recurrence rate recurrence rate untreated
pregnancy unknown
ESR Normal Normal Normal Elevated Elevated Normal
TPO antibodies Elevated Elevated Elevated Transient mild Absent Elevated in 2/3 of
Atlas of Clinical Endocrinology and Metabolism
increase patients
Thyroid hormonal Hypothyroid or Thyrotoxic, Thyrotoxic, Thyrotoxic, Usually euthyroid Euthyroid but may
status euthyroid hypothyroid, or hypothyroid, or hypothyroid, or progress to hypothyroid
both both both
Histology Lymphocytic Lymphocytic Lymphocytic Giant cells, Abscess Dense fibrosis
infiltrate, infiltrate infiltrate granulomas
germinal centers,
fibrosis
Typical treatments Levothyroxine or Observation/ Observation/ NSAIDs or Surgical abscess Surgery, glucocorticoids,
observation variable variable glucocorticoids drainage and tamoxifen, methotrexate
antibiotics
NSAID, nonsteroidal anti-inflammatory drug.
FIGURE 1.18 Hashimoto’s thyroiditis. There is a profuse mononuclear infiltrate with germinal center forma-
tion. Thyroid follicles are small and reduced in number. (Courtesy of Dr. Tad Wieczorek.)
There is recovery of normal thyroid function within a year in 80% of women; however, 50% of affected
women develop chronic hypothyroidism within 7 years. There is about a 70% chance of recurrence with
subsequent pregnancies.
Other than the lack of a temporal relationship with pregnancy, the presentation and clinical course of
painless thyroiditis are similar to that of postpartum thyroiditis. About 50% of individuals with painless
thyroiditis will have a small, firm, nontender gland, and about 20% of affected individuals will develop
chronic hypothyroidism. An elevated serum TPO antibody titer is detectable in about 50% of individuals
with painless thyroiditis at the time of presentation. The titers are on average lower than those seen in
Hashimoto’s thyroiditis but cannot be used to distinguish the two on an individual basis. A low or unde-
tectable radioactive iodine uptake (RAIU) can usually differentiate thyroiditis from other forms of thyro-
toxicosis with suppressed TSH; however, during the recovery phase of thyroiditis, RAIU may be normal
or elevated and can be potentially misleading if not correlated with TSH and thyroid hormone levels. On
ultrasound, the gland is usually hypoechogenic with normal to low vascularity. Histology is remarkable
for a lymphocytic infiltrate.
If thyrotoxicosis is present, beta-blockers may be used for symptomatic relief. Since there is not an
actual increase in thyroid hormone production but instead a release of thyroid hormone with damage
to the gland, thionamides should not be used. If chronic hypothyroidism develops, LT4 therapy may be
required. Transient hypothyroidism usually does not require additional therapy.
Painful Subacute Thyroiditis

Subacute thyroiditis frequently follows a viral upper respiratory tract infection or sore throat and begins
with a prodrome of generalized myalgia, pharyngitis, low-grade fever, and fatigue. Mumps, influenza,
COVID-19 (SARS-CoV-2), and other viral infections have been implicated. Interestingly, subacute thy-
roiditis has also been reported after vaccination for SARS-CoV-2 or influenza. With the development
of subacute thyroiditis, fever and severe neck pain often with swelling are noted. Approximately half of
affected individuals develop symptomatic thyrotoxicosis, which may last several weeks, and hypothyroid-
ism may subsequently develop. Five percent of patients develop chronic hypothyroidism, usually mild,
while the rest have normalization over 6–12 months. The recurrence rate is estimated to be between 2%
and 4%. On histology and cytology, giant cells and granulomas may be seen (Figure 1.19). As SARS-
CoV-2 has been identified as a potential viral trigger, checking for SARS-CoV-2 infection should be
considered in patients with subacute thyroiditis.
FIGURE 1.19 Subacute thyroiditis cytology. (A) Giant cell; (B) granuloma. (Courtesy of Dr. Tad Wieczorek.)
The treatment for painful subacute thyroiditis is designed to provide symptomatic relief. Nonsteroidal
anti-inflammatory agents can frequently be used to control mild thyroid pain. For more severe pain or
significant thyrotoxicosis, high-dose glucocorticoids (prednisone 40 mg/day) can provide relief and are
usually tapered over 4–6 weeks.
Suppurative Thyroiditis
The thyroid gland is normally highly resistant to infection. This has been attributed to its location and
encapsulation, high vascularity, high iodide content, the generation of hydrogen peroxide during synthesis
of thyroid hormone, and extensive lymphatic drainage. Suppurative thyroiditis is most likely to occur in
individuals with congenital anomalies such as a pyriform sinus fistula or persistent thyroglossal duct,
those with preexisting thyroid disease such as a degenerating thyroid nodule, or those who are otherwise
immunocompromised or debilitated including individuals with acquired immunodeficiency syndrome
(AIDS) or cancer.
Patients with suppurative bacterial thyroiditis usually present with fever, dysphagia, dysphonia, ante-
rior neck pain, and local lymphadenopathy, and have a tender erythematous thyroid mass. The patient is
very uncomfortable and may sit with a flexed neck to avoid pressure on the thyroid. In children, suppurative
thyroiditis affecting the left lobe of the thyroid is most commonly a result of direct extension from a pyri-
form sinus fistula (this tract rarely develops on the right), while a midline infection raises the possibility
of a persistent thyroglossal duct. In adults, symptoms may not be as obvious as in children and they may
instead present with a vague, slightly painful mass in the thyroid region, often without fever. This pre-
sentation is more common with fungal infections, parasitic infections, and mycobacterial thyroiditis. Fine
needle aspiration (FNA) under ultrasound guidance with gram’s stain and culture is the diagnostic test of
choice when suppurative thyroiditis is suspected and may also provide therapeutic drainage. Treatment
includes surgical drainage and appropriate antibiotics.
Reidel’s Thyroiditis
Patients with Reidel’s thyroiditis often present with a painless, extremely hard, fixed goiter that is often
described as ‘rock-hard’ or ‘wood-like’; malignancy is often initially suspected. They may have dyspnea,
hoarseness, aphonia, or dysphagia from tracheal or esophageal compression. Most patients are initially
euthyroid at presentation, and the disease may remain stable over many years or progress slowly to hypo-
thyroidism. Hypoparathyroidism from fibrosis of adjacent parathyroid glands may also be present.
An open biopsy is usually required to diagnose Reidel’s thyroiditis. The firmness of the gland and
paucity of thyroid follicular cells often leads to an inadequate FNA biopsy. For this reason and to dif-
ferentiate from the fibrotic changes associated with anaplastic thyroid carcinoma, a surgical biopsy is
preferred for diagnosis.
The management of Reidel’s thyroiditis depends upon the clinical features of the disease and has
been largely empiric. In more advanced cases, surgical intervention may be required to relieve compres-
sion. With less advanced disease, corticosteroids and tamoxifen have both been used successfully, either
alone or in combination. Steroids may reduce inflammation and decrease the actions of fibrinogenic cyto-
kines, while it is believed that the response to tamoxifen is due to the inhibition of fibroblast proliferation
by transforming growth factor (TGF)-beta as opposed to antiestrogen effects. Methotrexate is usually
reserved for those with progressive Reidel’s thyroiditis not responsive to other therapies. Since one-third
of patients with Reidel’s thyroiditis will develop an extracervical manifestation of multifocal fibrosclerosis
such as retroperitoneal fibrosis, mediastinal fibrosis, or sclerosing cholangitis, screening for these other
conditions should also be considered.
Drug-Induced Thyroiditis
A number of drugs, including amiodarone, interferon-alpha, lithium, and interleukin-2 (IL-2), can cause
thyroiditis, which may present with hypothyroidism or thyrotoxicosis. Interferon-alpha and IL-2 have
both been associated with painless lymphocytic thyroiditis. This is likely through an enhancement of
underlying autoimmune processes, as induction of and increased anti-TPO antibody titers have been
detected with exposure.
Tyrosine kinase inhibitors, especially sunitinib, may cause a destructive thyroiditis. Immune check-
point inhibitors are also associated with thyroiditis. PD-1 inhibitors are associated with greater risk of
thyroid dysfunction relative to CTLA-4 inhibitors, although the highest risk occurs with combined anti-
CTLA-4 and anti-PD-1 treatment.
Lithium and amiodarone cause thyroid dysfunction via multiple different mechanisms. For example,
amiodarone can cause iodine-induced disease or a destructive thyroiditis (Table 1.4). For differentiating
between types 1 and 2 amiodarone-induced thyrotoxicosis, RAIU, IL-6 levels, and Doppler ultrasound for
vascularity have all been proposed, but in clinical practice, it often remains difficult to distinguish between
the two. As such, some clinicians treat both concurrently using a combination of thionamide and steroids.
Those with type 2 disease typically have a more rapid response to this strategy than those with type 1
disease, allowing tailoring of therapy to the underlying etiology based upon response. Thyroidectomy
may be advisable for some patients.
TABLE 1.4 Amiodarone-Induced Thyroid Dysfunction

TYPE 1 TYPE 2 HYPOTHYROID
Mechanism Iodine excess Destructive thyroiditis Iodine excess
Presentation Thyrotoxicosis Thyrotoxicosis Hypothyroidism
Thyroid antibodies Absent or present Usually initially absent Often present
RAI uptake Low in iodine-sufficient areas <5% Low in iodine-sufficient
Variable in iodine-deficient areas
areas
Doppler Hypervascular Reduced blood flow Variable
ultrasound
IL-6 Normal to mild elevation Markedly elevated Normal
Preferred Thionamides (possible Glucocorticoids Levothyroxine
treatment potassium perchlorate and/or
surgery)
Thyroid Nodules
Definition/Overview
Although the normal thyroid gland is fairly homogeneous, nodules are not infrequent with about 5% of
women and 1% of men in iodine-sufficient areas having palpable thyroid nodules. In autopsy series, thy-
roid nodules are detected in 19%–67% of the population, with higher frequencies noted in women and the
elderly. The main clinical concern with thyroid nodules is that of thyroid cancer, which occurs in 5%–10%
of nodules, although it is estimated that only 1 in 15 cases of thyroid cancer are diagnosed premortem.
Approximately 1 in 10 to 1 in 20 solitary nodules are autonomous, with this being more common in
Europe than in the USA. Thyrotoxicity is related to the amount of autonomous tissue and is more common
in nodules over 3 cm in diameter. In some individuals, multiple autonomous nodules may be present, and
such a toxic adenomatous goiter is sometimes referred to as Plummer’s disease.
Thyroid nodules are often asymptomatic, and it is not unusual for them to go unrecognized by the patient,
instead being noted by an acquaintance or family member, on routine examination, or incidentally on
an unrelated radiologic study. When patients identify nodules themselves, it is often in the setting of
increased awareness of the neck such as after a sore throat or cough. Occasionally, a painful, rapid expan-
sion may be seen, which may be due to acute hemorrhage.
Large goiters, particularly those with substernal components, may cause venous congestion or tra-
cheal compression (Figures 1.20–1.22). Patients may present with difficulty breathing, particularly when
lying flat, or experience a feeling of worsening asthma symptoms. Patients with venous congestion
may note facial fullness when they extend their arms above their head, referred to as Pemberton’s sign
(Figures 1.23 and 1.24). Pemberton’s sign is caused by clavicular motion during arm elevation that com-
presses major venous structures within a narrowed thoracic inlet against a relatively fixed and enlarged
thyroid, much like the movement of a nutcracker (Figure 1.25).
Patients with toxic adenomas may not have thyrotoxic symptoms at presentation. Those with symp-
tomatic toxic adenomas tend to be older than individuals with Graves’ disease, and the onset of thyrotoxi-
cosis is generally slower than in Graves’ patients. When autonomy is longstanding, the normal thyroid
tissue that surrounds the nodule is often atrophic.
FIGURE 1.20 (A) A man with retrosternal goiter causing venous congestion. (B) Six months after resection,
venous congestion has resolved. (From Le Goitre by F. de Quervain, 1923.)
FIGURE 1.21 Goiter with multiple visible thyroid nodules. (From Le Goitre by F. de Quervain, 1923.)
The differential of thyroid mass is quite broad, as adenomas, carcinomas, thyroid cysts, hemiagenesis,
thyroiditis, parathyroid lesions (including cysts, adenomas, and carcinomas), thyroid sarcoma, thyroid
lymphoma, and metastatic cancer may also present as a thyroid mass on exam or ultrasound.
Current diagnostic algorithms in the evaluation of thyroid nodules focus on the risk of malignancy, evi-
dence of autonomy, and symptoms of compression or obstruction. Factors that increase the likelihood
of thyroid malignancy include age younger than 20 or older than 60 years, prior exposure to ionizing
FIGURE 1.22 Large pendulous cystic nodule. (From Le Goitre by F. de Quervain, 1923.)
FIGURE 1.23 The goiter is shown exposed during resection. (Courtesy of Dr. Sareh Parangi.)
FIGURE 1.24 Goiter. On physical exam there is venous engorgement with arms raised above the head
(Pemberton’s sign). (Courtesy of Dr. Sareh Parangi.)
FIGURE 1.25 Pemberton’s sign: Caused by clavicular motion during arm elevation that compresses major
venous structures within a narrowed thoracic inlet against a relatively fixed and enlarged thyroid. (From Werner
& Ingbar's The Thyroid: A Fundamental and Clinical Text, 11th Edition, 2021 (Wolters Kluwer), Page 261, Figure
16-2.)
radiation to the head or neck, family history of medullary or papillary thyroid cancer, and stigmata or
family history of familial predisposing syndromes such as Gardner’s syndrome (colonic polyps, osteo-
mas, and soft tissue tumors), Carney complex (cardiac myxomas and spotty pigmentation), and Cowden’s
syndrome (hamartomas and neoplasia). Physical findings suggestive of malignancy include a hard, non-
tender nodule, fixed to adjacent tissue, and local lymphadenopathy.
Serum TSH should be measured in all patients with nodular disease. In most instances, serum TSH is
normal and then further diagnostic evaluation is performed with ultrasound and FNA biopsy. If the TSH
is low, isotopic scanning with 131I or 123I is often performed to determine if there is evidence of autonomy.
Although not commonly performed, if the TSH is not suppressed but there is a high index of suspicion for
autonomy, exogenous thyroid hormone can be administered prior to imaging to demonstrate nonsuppress-
ibility (Figure 1.26). Nodules that exhibit evidence of autonomous function have a low risk of malignancy,
although there have been reports of malignancy in autonomous nodules, particularly in those found to be
a follicular variant of papillary cancer.
Thyroid ultrasound can be used as an adjunct to physical examination for screening high-risk indi-
viduals (for example, those with hereditary syndromes or prior radiation exposure), or for guidance of
FNA. Ultrasonography more accurately detects the presence, location, and size of nodules within the
thyroid gland than examination alone, as 40%–60% of thyroid nodules between 1 and 2 cm in diameter
are not palpable on examination. Thyroid ultrasound can provide information including consistency, echo-
genicity, patterns of calcification, and Doppler blood flow. Nodules that are principally solid, hypoechoic,
have irregular margins, contain microcalcifications, lack a halo, are taller than wide, or have increased
vascular flow are of more concern for malignancy, but ultrasound characteristics alone are usually not
sensitive or specific enough for diagnostic purposes.
FNA biopsy is considered the most accurate test (diagnostic accuracy exceeding 90%) for the diag-
nosis of thyroid nodules. Biopsy is usually performed with a 27- or 25-gauge needle with sampling
FIGURE 1.26 Thyroid scintigraphy (suppression scan). RAO, anterior, and LAO views are shown. In the top
panel, 123I thyroid scintigraphy shows iodine uptake by the thyroid. In the lower panel, after treatment with
exogenous thyroid hormone, an autonomous area becomes apparent in the right inferior portion of the gland
as the normal surrounding tissue is suppressed.
performed via capillary action or gentle aspiration, preferably under ultrasound guidance. Typical thyroid
cytology findings include thyroid epithelial cells arranged in macrofollicles (Figure 1.27A) and microfol-
licles (Figure 1.27B). FNA results are usually categorized into one of the following diagnostic categories:
benign (negative), suspicious (indeterminate), malignant (positive), or unsatisfactory (nondiagnostic or
insufficient). Although follicular neoplasm (microfollicular lesion) can be diagnosed by cytology, the dis-
tinction between follicular adenoma and carcinoma requires pathologic evaluation of a surgical specimen.
Since it is difficult to differentiate between thyroid and parathyroid tissue on FNA, if it is unclear
on ultrasound if the area is a thyroid nodule or parathyroid adenoma, then the serum calcium should be
checked and the aspirate evaluated for parathyroid hormone on washout. Parathyroid adenomas are typi-
cally extrathyroidal and hypoechoic on ultrasound. If the fluid removed from a cyst is clear and waterlike,
then it may be a parathyroid cyst. The diagnosis can be confirmed by analyzing the fluid for parathyroid
hormone level; although it is infrequent for parathyroid cysts to cause hyperparathyroidism, serum cal-
cium should still be checked in this setting.
Although more expensive than ultrasound, computed tomography (CT) or magnetic resonance imag-
ing (MRI) can help evaluate substernal goiters and define the relationship of nodules to surrounding struc-
tures. This is most helpful if there is evidence of venous obstruction or difficulty breathing. Chest X-ray,
barium swallow, and pulmonary function tests with flow volume loop may also be used to determine the
extent of obstruction.
Nodules with malignant or indeterminate aspirates are usually treated surgically with the extent of sur-
gery and follow-up therapy, if any, based on the clinical situation. Various surgical specimens are shown
in Figures 1.28–1.31. Obstructive goiters are generally treated surgically, although radioactive iodine
treatment has been used in a limited fashion. Autonomous nodules without TSH suppression are often
observed and may involute, stay the same, or grow. Once there is evidence of thyrotoxicosis, autonomous
nodules are generally treated with radioiodine or surgery.
FIGURE 1.27 (A) Macrofollicle. (B) Microfollicle. (Courtesy of Dr. Tad Wieczorek.)
FIGURE 1.28 Papillary carcinoma. (Courtesy of Dr. Tad Wieczorek.)

FIGURE 1.29 Follicular carcinoma. (Courtesy of Dr. Tad Wieczorek.)
FIGURE 1.30 Follicular adenoma. (Courtesy of Dr. Tad Wieczorek.)
FIGURE 1.31 Anaplastic carcinoma histology. (Courtesy of Dr. Tad Wieczorek.)

THYROID CANCER
Louis G. Portugal and Alexander J. Langerman
Definition/Overview
In the USA, there are approximately 40,000 new cases of thyroid cancer diagnosed yearly, about 2% of
all malignancies, although this rate has been increasing due in part to more sensitive diagnostic methods
resulting in earlier diagnosis. Fortunately, thyroid cancer is a very treatable disease, with only 1,500
disease-specific deaths occurring per year. Females are three times more likely to present with a thyroid
nodule to be evaluated for cancer, but a thyroid nodule in a male is more suspicious for malignancy. A
history of radiation exposure or positive family history, as well as physical examination findings, such as
associated lymphadenopathy, also increase the likelihood of cancer. Even though most thyroid nodules
encountered by clinicians will be benign, a prompt workup is necessary to ensure early and appropriate
treatment can be instituted for those with malignancy.
Etiology
The primary risk factors for thyroid carcinoma are a family history of thyroid cancer or related genetic
syndromes and a personal history of radiation exposure. In the 1940s and 1950s, low-dose irradiation was
commonly used to treat acne, adenotonsillar hypertrophy, thymus enlargement, and other conditions. As
reports of childhood thyroid cancer emerged, the practice was largely abandoned. Any patient with a his-
tory of radiation to the face, neck, or chest is at increased risk of developing thyroid neoplasms. Patients
with this type of radiation exposure have up to a 50% chance of harboring cancer in a thyroid nodule and
have a higher chance of cervical metastasis. The most common histology of postradiation thyroid cancer
is papillary.
In 1986, a reactor at the nuclear power plant in Chernobyl suffered a meltdown and explosion result-
ing in extensive radiation exposure to the surrounding area. Located in the northern part of what is now
Ukraine, Chernobyl is close to the Ukraine–Belarus border and Belarus actually received the majority
of the fallout. In the months following the explosion, radioactivity was detected as far away as the United
Kingdom. Local children exposed to the fallout had a 60-fold increase in thyroid carcinoma. A connec-
tion has been made between exposure to this disaster and a particular gene rearrangement (RET/PTC) in
papillary thyroid cancers.
The full spectrum of genetic abnormalities resulting in thyroid cancer is actively being investigated.
Certain familial syndromes such as Gardner’s (autosomal dominant syndrome of colonic polyps, osteo-
mas, and soft tissue tumors) and Cowden’s (autosomal dominant syndrome of multiple hamartomas) are
associated with well-differentiated thyroid cancer. The multiple endocrine neoplasia syndromes IIA and
IIB are associated with medullary thyroid cancer.
Pathophysiology
The pathophysiology of thyroid cancer is influenced by the specific histologic diagnosis.
Well-Differentiated Thyroid Cancer

Papillary Thyroid Cancer
Papillary thyroid cancer (PTC) is the most common histology, accounting for 80% of all thyroid cancers.
It has a bimodal distribution with peaks in the 20s–30s and 50–60s. PTC has a propensity for lymphatic
spread, and up to 80% of patients can present with microscopic disease in the lymph nodes. Indeed, the
finding of cystic or calcified cervical lymph nodes should raise immediate suspicion for PTC. There is
also a high incidence of multicentricity within the thyroid with up to 80% of thyroidectomy specimens
demonstrating additional foci of PTC in the contralateral lobe.
Histologically, PTC is made of malignant epithelium usually forming papillae with characteristic
nuclear clearing (‘Orphan Annie eyes’) and intranuclear inclusions and grooves (Figure 1.32). Concentric
calcifications called psammoma bodies are seen in roughly half of specimens. Other histologic variations
include the follicular type, whose behavior is more similar to follicular cell carcinoma, a diffuse scleros-
ing type with a lack of papillae but many psammoma bodies, and the more clinically aggressive tall and
columnar cell types.
Although there are no pathognomonic ultrasound findings, PTC is usually hypodense to surrounding
thyroid tissue and can be partially or entirely cystic (Figure 1.33). Microcalcifications, or eggshell-like
peripheral calcifications, while present in some benign processes, increase with the likelihood of PTC.
FNA is highly sensitive and specific for PTC (Figure 1.33), and most patients will proceed to surgery
knowing their diagnosis ahead of time (Figures 1.34–1.40).
Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is the term
now used for noninvasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). It is
now considered indolent or premalignant. Surgical excision is required for diagnosis and therapy, but total
thyroidectomy and radioactive iodine therapy are not.
FIGURE 1.32 Histology of papillary thyroid cancer demonstrating central nuclear clearing (Orphan Annie
eyes) and psammoma bodies.
FIGURE 1.33 Patient with papillary thyroid cancer of the thyroid isthmus presenting as an invasive anterior
neck mass that is firm and minimally mobile on physical exam.
FIGURE 1.34 Cytology from fine needle aspiration biopsy of a thyroid mass demonstrating papillary fronds
consistent with papillary thyroid cancer.
Follicular Cell Cancer

In most regions, follicular cell carcinoma represents 5%–15% of all thyroid cancers. This increases to
40% in areas that are endemic for goiter from iodine deficiency. The median age at diagnosis is 50.
Follicular cancer tends to spread hematogenously, with 10%–15% of patients presenting with systemic
metastasis, with lung being the most common site, followed by bone, liver, brain, and other sites. These
are iodine-avid tumors, with three-quarters able to concentrate iodine.
FIGURE 1.35 Surgical specimen of a total thyroidectomy (specimen in center) surrounded by bilateral neck
dissections demonstrating a metastatic papillary thyroid cancer that extensively involved both jugular lymph
node chains. This demonstrates the potential for thyroid cancer to present primarily with cervical metastasis
with minimal clinical changes in the thyroid gland.
FIGURE 1.36 Axial CT scan of a patient demonstrating the growth pattern of papillary thyroid cancer arising
from the isthmus and invading the strap muscles anteriorly.
For most follicular cancers, FNA can only make the diagnosis of a follicular lesion. The diagnosis of
cancer relies on features detected during permanent sectioning, namely, extracapsular spread or vascular
invasion (Figure 1.41). If a follicular lesion presents with local extrathyroid spread or regional or distant
metastasis, a preoperative diagnosis of follicular cancer can more assuredly be made. Minimally invasive
follicular cancer is defined as those nodules with only capsular invasion, and is believed to be similar in
prognosis and behavior to benign follicular adenomas. Moderately invasive follicular cancers are those
demonstrating vascular invasion, and widely invasive are those with spread beyond their capsules.
Hurthle Cell Cancer

Hurthle cell thyroid cancer is very similar to follicular cancer and indeed may be a variant thereof. The
hallmark is large, mitochondria-rich cells with eosinophilic cytoplasm. The presentation, reliance on
FIGURE 1.37 Surgical findings of the patient in Figure 1.36 demonstrating the growth pattern of papillary
thyroid cancer arising from the isthmus and invading the strap muscles anteriorly. The picture is oriented with
the superior part of the neck at the top.
FIGURE 1.38 Axial CT scan of a patient with calcifications within the right thyroid lobe harboring papillary
thyroid cancer. Papillary thyroid cancer should always be considered in patients demonstrating calcifications
within the thyroid gland on radiographic imaging.
permanent sectioning for diagnosis, and penchant for hematogenous spread are the same as follicular
cancer. However, some authors believe Hurthle cell cancer to be a more aggressive entity, demonstrating
up to one-third as multicentric and one-quarter with lymph node spread at diagnosis. Hurthle cell cancers
are less iodine avid than follicular cancers, but they do tend to produce thyroglobulin.
FIGURE 1.39 CT scan of the patient in Figure 1.41 at a higher axial plane in the neck. Findings include meta-
static thyroid cancer to the right cervical region manifesting as a cystic neck mass as well as neck mass with
calcifications. The differential diagnosis of any patient presenting with a cystic neck mass or lymph node with
calcification should always include metastatic papillary thyroid cancer.
FIGURE 1.40 Intraoperative findings of the patient in Figure 1.38 demonstrating the cystic neck mass just
medial to the right sternocleidomastoid. The picture is oriented with the superior part of the neck at the top.
FIGURE 1.41 Histology of follicular adenocarcinoma of the thyroid demonstrating angioinvasion (arrow).
Insular Thyroid Cancer

Insular thyroid cancer is a rare disease entity distinguished by the identification of small clusters of malig-
nant cells similar in appearance to pancreatic islet cells. Insular thyroid cancer can occur in association
with papillary or follicular cancer or as an independent process. Insular carcinoma arising independently
is associated with a more aggressive clinical course. These lesions are typically iodine avid.
Medullary Thyroid Cancer

Medullary thyroid cancer (MTC) arises from the parafollicular C-cells of neural crest origin. Approximately
two-thirds arise spontaneously, usually as a solitary nodule in patients in their sixth or seventh decade,
with equal distribution between females and males. The remaining third are associated with familial
autosomal dominant mutations of the RET protooncogene, either in isolation or as part of the syndromes
of multiple endocrine neoplasia (MEN) 2A and 2B. Familial MTC is associated with multicentricity.
Measurement of serum calcitonin can be useful in the diagnosis of MTC and can be used for post-
operative monitoring for recurrence. Up to half of patients will present with local or distant disease; the
favored sites of spread are cervical lymph nodes, then mediastinum, lung, liver, and bone. Some patients
may present with pain from local invasion. The overall clinical behavior is more aggressive than the afore-
mentioned differentiated thyroid cancers but less aggressive than anaplastic cancer.
Anaplastic Thyroid Cancer

Anaplastic thyroid cancer is an uncommon entity, accounting for less than 2% of thyroid cancers but caus-
ing the most deaths. The prognosis is grim, with fewer than 10% of patients surviving beyond 5 years, and
most patients only surviving 3–6 months after diagnosis. The typical presentation is a female in her 50s
FIGURE 1.42 Axial CT scan demonstrating invasive anaplastic thyroid cancer invading the larynx and encas-
ing the great vessels.
or 60s with a rapidly enlarging thyroid mass. Half of patients present with metastatic disease, primarily
mediastinum and lung, followed by bone and brain (Figures 1.42 and 1.43).
Respiratory symptoms are common, and airway management with a tracheotomy is often neces-
sary. In some patients, extensive tracheal invasion requires endoluminal stenting to alleviate asphyxiation.
Anaplastic cancer is believed to be on the far end of a spectrum of dedifferentiation of thyroid cells, as
evidenced by common genetic alterations, especially with papillary cancer. Most anaplastic cancers have
lost their ability to concentrate iodine or elaborate thyroglobulin.
Thyroid Lymphoma
Primary thyroid lymphoma is uncommon, accounting for approximately 2% of thyroid malignancies.
Many patients have a history of autoimmune thyroiditis, particularly Hashimoto’s, and 85% of thyroid
FIGURE 1.43 Axial CT scan demonstrating invasive anaplastic thyroid cancer encasing the tracheal airway.
lymphoma specimens have thyroiditis features present histologically. A typical presentation is enlarge-
ment of a previously existing goiter, or as a rapidly enlarging thyroid or cervical mass. ‘B’ symptoms such
as fever, weight loss, and night sweats can also be present.
Thyroid lymphomas are typically non-Hodgkin’s lymphomas of the B-cell type, though T-cell lym-
phomas can occur, particularly in human T-lymphotropic virus (HTLV)-endemic areas. Many patients
have laboratory evidence of longstanding hypothyroidism, with elevated TSH and antithyroid peroxi-
dase or thyroglobulin antibodies. Elevated immunoglobulins or lactate dehydrogenase can also be seen.
Traditionally, an incisional or excisional biopsy was needed to establish the diagnosis accurately, sent
fresh for lymphoma workup. However, advances in flow cytometry have made diagnosis by FNA more
reliable when performed by experienced clinicians.
The first discovery of a thyroid nodule is often made on physical examination or is an incidental find-
ing on imaging workup for another reason. Thyroid nodules are not uncommon, with studies reporting
30%–50% of individuals harboring incidental nodules. The vast majority of nodules will be benign, with
less than 10% representing malignancy. Certain features of the history and physical exam may suggest
a malignancy. As mentioned earlier, patients with a history of radiation exposure or family history are
at increased risk. In addition, a history of a rapidly enlarging mass is more suspicious for malignancy
(Figure 1.33); however, a rapidly enlarging, painful thyroid mass may represent hemorrhage into a benign
cyst. More aggressive thyroid cancers can manifest early with respiratory symptoms, due either to airway
compression, invasion of the trachea, or compression or invasion of the recurrent laryngeal nerves leading
to vocal cord dysfunction.
Most patients presenting with thyroid cancer are euthyroid. Symptoms of hyper- or hypothyroidism
do not rule out cancer but may prompt further workup for a benign cause.
Nodules that are greater than 1 cm can usually be palpated. Fixation to surrounding structures and
palpable cervical lymphadenopathy increase the suspicion of malignancy, though in particular, lymphade-
nopathy can occur in benign processes such as Graves’ and Hashimoto’s. History and physical examination
findings that are more indicative of a malignant process are summarized in Table 1.5. Well-differentiated
thyroid cancers (papillary, follicular, and Hurthle cell) can be staged using one of four grading systems:
AJCC, AGES, AMES, or MACIS. Again, depending on the histology, cancer of the thyroid has many
different presentations and behaviors.
TABLE 1.5 History and Physical Examination Findings Suggestive of Thyroid Cancer
History
Family history of multiple endocrine neoplasia, or medullary thyroid cancer
Personal history of head and neck irradiation or radiation exposure
Symptoms of airway compression or voice changes
Symptoms of hemoptysis
Rapid tumor growth
Physical Examination
Very firm or hard nodule
Fixation of nodule to surrounding structures
Regional lymphadenopathy including cystic neck mass
Distant metastases
Large nodule (>4 cm)
The primary differential diagnosis is between benign and malignant processes. Thyroid cancer typically
presents as a nodule and may not be able to be distinguished from a benign adenoma without surgical
excision. Metastases from renal cell, melanoma, breast, and lung cancer can also present as thyroid nod-
ules. Multinodular goiters usually represent benign processes, but large or suspicious nodules must be
investigated independently, as they carry the same risk for carcinoma. Diffuse thyroid enlargement may
be benign goiter, an inflammatory or infectious process, or neoplastic infiltration.
Diagnosis
Palpation of the thyroid, and appreciating the overall size and consistency of the thyroid as well as the
character of any nodules is the first step in diagnosis. Tenderness, fixation to surrounding structures, and
associated cervical lymphadenopathy should be appreciated (Table 1.5). A screening TSH can be ordered
to evaluate for functional nodules. FNA is the mainstay of the workup for a thyroid nodule. A 27-gauge
needle loaded on a syringe is inserted into a palpable nodule, while gentle suction is maintained with
backpressure on the syringe plunger. Several passes are made in different directions taking care to stay
within the nodule. The hub of the needle is watched for the return of serous material. Aspiration of blood
decreases the interpretability of the FNA, and if this occurs, the needle should be taken out, pressure
should be held, and the FNA should be reattempted with a fresh needle. Multiple samples should be taken
and spread among slides for both air-dry and cytologic fixation. Involvement of experienced clinicians in
the process of FNA increases the diagnostic yield. If the nodule is found to be cystic and fluid-filled, the
fluid should be sent for cytology. Bloody fluid may represent hemorrhage into a cyst or carcinoma. If a
lesion is found on imaging to have both solid and cystic components, an attempt should be made to sample
the solid component.
As mentioned earlier, FNA is highly sensitive and specific when diagnosing PTC. Follicular and
Hurthle cell nodules cannot be distinguished between benign and malignant on FNA alone. Anaplastic
cancer and thyroid lymphoma may require additional tissue from an incisional biopsy to make the diag-
nosis accurately. Nondiagnostic FNA should never be interpreted as negative for cancer.
Ultrasonography is very useful for evaluating the thyroid. It can detect additional nonpalpable nodes
or differentiate between nodules and lobar hypertrophy. Certain characteristics of nodules, such as cal-
cifications or cystic components, can increase the suspicion of cancer. Ultrasound can also be used to
evaluate regional lymphatics and can be used to guide FNA for nonpalpable nodules or for sampling the
solid component of a cystic nodule.
CT and MRI scans of the thyroid usually do not add much to the workup of thyroid cancer. For
patients with well-differentiated thyroid cancers who are being considered for postoperative radioactive
iodine therapy (see later), use of CT with iodinated contrast media is contraindicated because it delays
treatment for up to 3 months. If imaging must be obtained in these patients, such as for suspicion of tra-
cheal invasion or to evaluate substernal extension, MRI is preferred. Postoperatively, MRI is also better at
distinguishing recurrent disease from postoperative fibrosis. In patients who present with massive, rapidly
enlarging goiters suspicious for anaplastic carcinoma or lymphoma where tissue diagnosis or airway man-
agement is needed, a CT with contrast is appropriate for surgical planning.
Radionucleotide scanning with radioactive iodine is useful for assessing the functionality of a nodule
but is not useful in determining the risk for cancer. Nodules that fail to take up iodine on scan are referred
to as cold nodules. Traditionally, cold nodules have been considered higher risk for cancer. However, the
majority of patients with thyroid nodules are cold on scan, making radionucleotide ineffective in screen-
ing for cancer risk. Additionally, hyperfunctional or hot nodules have been traditionally considered to be
benign but numerous cases have been reported of hot nodules harboring thyroid cancer. The primary role
of radionucleotide scanning is for ablation and posttreatment surveillance.
Surgery is the primary treatment for most thyroid cancers. For some well-differentiated thyroid nodules,
there is controversy regarding the extent of surgical resection (lobectomy versus subtotal or total thyroid-
ectomy). However, the basic guiding principles are as follows:
• If a patient has no worrisome risk factors and a favorable histology (e.g., a young woman with
an isolated <4 cm papillary cancer without worrisome features with no extracapsular spread or
nodal involvement), a lobectomy may be appropriate and spares the patient a lifetime of thyroid
hormone replacement.
• If unfavorable features are seen in permanent histology after a lobectomy, such as vascular
invasion or diffuse infiltration of the thyroid, removal of the contralateral lobe is indicated.
• If there is high suspicion for multicentricity (e.g., large papillary thyroid cancers and familial
medullary thyroid cancer), or at least some disease in the contralateral lobe, an upfront total
thyroidectomy is indicated or removal of the contralateral lobe after unilateral lobectomy.
• If postoperative radioactive iodine is planned for aggressive histology or known extrathyroid
disease, a total thyroidectomy permits more effective detection and treatment of residual local
and distant microscopic disease (see later).
The standard surgical approach is through a small horizontal incision just above the clavicle. The strap
muscles are divided in the midline down to the gland. One lobe is removed at a time if both are being
taken, with care to preserve the parathyroid glands and recurrent laryngeal nerves.
In patients with clinically apparent nodal disease in the central compartment or lateral cervical lymph
node chains, a neck dissection is warranted to remove gross disease. En bloc lymphadenectomy is pre-
ferred in these situations over removal of individual nodes given the high incidence of microscopic dis-
ease. The role of neck dissection in the clinically negative neck is more controversial.
Radioactive iodine (131I) has proven a very effective treatment for microscopic and distant disease in
well-differentiated thyroid cancer (i.e., cancers able to uptake and concentrate the radioiodine). The typi-
cal sequence of treatment is total thyroidectomy, followed by a 4–6-week period of thyroid withdrawal
during which time the TSH level is allowed to rise to greater than 30 μIU/mL. Then, while maximal
stimulation of any remaining thyroid tissue is occurring, whole-body radioiodine scanning is performed,
followed the next day by 131I ablation (Figure 1.44). As an alternative to thyroid hormone withdrawal,
recombinant thyrotropin alfa may be used as an adjunctive treatment for radioiodine ablation of thyroid
tissue remnants in patients who have undergone a near-total or total thyroidectomy for well-differentiated
thyroid cancer and who do not have evidence of distant metastatic thyroid cancer.
After ablation, the patient is started on thyroid suppression therapy with levothyroxine to maintain a
low level of TSH through feedback mechanisms on the hypothalamus. The target level of TSH is deter-
mined by the aggressiveness of the cancer, with lower or undetectable levels desired for higher-risk patients.
Serum thyroglobulin (Tg) is followed for recurrence. Recombinant thyrotropin alfa may be used as an
adjunctive diagnostic tool to improve the sensitivity of Tg testing. In patients with antithyroglobulin (anti-
Tg) antibodies, Tg levels cannot be accurately followed with the standard assays, but Tg mass spectrometry
can be used. In these patients, the level of anti-Tg has been shown somewhat to correlate with recurrence.
In contrast to patients with well-differentiated thyroid cancer, chemotherapy and radiation are the
primary treatment modalities for patients with anaplastic cancer or thyroid lymphoma, and there is no
role for radioactive iodine. For lymphoma, the treatment regimen is driven by the specific types of cells
involved, but the most common for non-Hodgkin’s lymphoma is a combination of cyclophosphamide,
doxorubicin, and vincristine in combination with radiotherapy. Treatment for anaplastic cancer is largely
experimental, with some combination of chemotherapy, external beam radiation, and surgical debulking
performed as much for palliation as curative intent. The main role of surgery in both anaplastic cancer and
thyroid lymphoma is obtaining tissue for diagnosis and airway management with a tracheotomy.
FIGURE 1.44 Radioactive iodine uptake scan with 131I demonstrating metastatic papillary thyroid cancer. The
large starburst pattern in the lower part of the image is consistent with metastasis to the pelvic bone.
Patients with a family history of medullary thyroid cancer who are positive for the RET mutation
often undergo prophylactic thyroidectomy at a young age. Total thyroidectomy with central compartment
neck dissection is the minimum treatment for any patient presenting with clinically evident MTC. Further
neck dissection is based on clinical findings.
BIBLIOGRAPHY
Burch HB, Perros P, Bednarczuk T, Cooper DS, Dolman PJ, Leung AM, Mombaerts I, Salvi M, Stan MN.
Management of Thyroid Eye Disease: A Consensus Statement by the American Thyroid Association and the
European Thyroid Association. Thyroid 2022 December;32(12):1439–1470. doi: 10.1089/thy.2022.0251. Epub
2022 December 8. PMID: 36480280. PMCID: PMC9807259.
De Filippis EA, Sabet A, Sun MR, Garber JR. Pemberton's Sign: Explained Nearly 70 Years Later. J Clin Endocrinol
Metab 2014 June;99(6):1949–1954. doi: 10.1210/jc.2013-4240. Epub 2014 Mar 19. PMID: 24646105.
Duntas LH, Jonklaas J. COVID-19 and Thyroid Diseases: A Bidirectional Impact. J Endocr Soc 2021 April
27;5(8):bvab076. doi: 10.1210/jendso/bvab076. PMID: 34189381. PMCID: PMC8135350.
Ferrari SM, Fallahi P, Galetta F, Citi E, Benvenga S, Antonelli A. Thyroid Disorders Induced by Checkpoint
Inhibitors. Rev Endocr Metab Disord 2018 December;19(4):325–333. doi: 10.1007/s11154-018-9463-2. PMID:
30242549.
Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM,
Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L. 2015 American
Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated
Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and
Differentiated Thyroid Cancer. Thyroid 2016 January;26(1):1–133. doi: 10.1089/thy.2015.0020. PMID:
26462967. PMCID: PMC4739132.
Nikiforov YE, Seethala RR, Tallini G, Baloch ZW, Basolo F, Thompson LD, Barletta JA, Wenig BM, Al Ghuzlan
A, Kakudo K, Giordano TJ, Alves VA, Khanafshar E, Asa SL, El-Naggar AK, Gooding WE, Hodak SP,
Lloyd RV, Maytal G, Mete O, Nikiforova MN, Nosé V, Papotti M, Poller DN, Sadow PM, Tischler AS, Tuttle
RM, Wall KB, LiVolsi VA, Randolph GW, Ghossein RA. Nomenclature Revision for Encapsulated Follicular
Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors.
JAMA Oncol 2016 August 1;2(8):1023–1029. doi: 10.1001/jamaoncol.2016.0386. PMID: 27078145. PMCID:
PMC5539411.
Werner and Ingbar's the Thyroid. In: Braverman LE, Cooper DS, Kopp P, ed. A Fundamental and Clinical Text, 11th
edition, Philadelphia, PA: Wolters Kluwer, 2021.
Diabetes Mellitus
Alalah Mazhari, Mary Ann Emanuele,

2
and Gerald Charnogursky
INTRODUCTION
Diabetes mellitus is a disease that afflicts more than 400 million people worldwide. The areas most
affected are Africa, the eastern Mediterranean region, and Southeast Asia. Data from the National Health
Interview Survey (2016 and 2017) estimated the prevalence of diagnosed type 2 diabetes (T2DM) among
adults in the United States was 8.5%, and other national databases, such as the Centers for Disease Control
and Prevention Diabetes Surveillance System, reported a prevalence of diagnosed diabetes of approxi-
mately 7%. In the United States, the lifetime risk for developing diabetes in an individual born after 2000
is 33% for Caucasians and 50% for Hispanics. These numbers reflect the explosion of obesity in the US
and worldwide. Type 1 diabetes (T1DM), accounting for about 10% of people with diabetes mellitus, is
an autoimmune disease in which the insulin-producing β-cells of the pancreas are destroyed. Treatment
relies solely on the use of insulin.
T2DM, seen in almost 90% of the diabetic population, has several pathophysiologic loci. These
include insulin resistance at hepatic, skeletal muscle and adipocyte level, relative or absolute hypoinsu-
linemia, decreased GLP-1 secretion and increased resistance to GLP-1, and enhanced glucose absorption
from the proximal convoluted tubule in the kidney. Insulin resistance, in addition to participating in the
development of hyperglycemia, can also lead to hypertriglyceridemia, low HDL cholesterol, hypertension,
and truncal obesity, and this constellation of features is commonly referred to as metabolic syndrome.
The treatment of T2DM initially relies on the use of oral agents and subcutaneously injected medications
that augment insulin secretion, reduce excessively high glucagon levels, decrease insulin resistance, or
interrupt intestinal carbohydrate absorption. These agents may be used in combination with a variety of
insulins as pancreatic function wanes.
RETINOPATHY
Definition/Overview
Retinopathy is the most common microvascular complication of diabetes and accounts for 10,000 cases
of new blindness per year. This complication is seen in both T1DM and T2DM, but since the onset of
40 DOI: 10.1201/9781003100669-2
2 • Diabetes Mellitus 41
T2DM can be insidious, it may develop many years before diagnosis. There is evidence that retinopa-
thy may begin to develop 7–10 years before the clinical diagnosis of T2DM. Retinopathy is known to
initially worsen, and then improve as better glycemic control is instituted. It may also progress with
pregnancy, with improvement after delivery. Treatment protocols utilizing intravitreal anti–vascular
endothelial growth factor (anti-VEGF) therapies in retinal diseases continue to evolve. In the manage-
ment of neovascular age-related macular degeneration (nAMD), extending the treatment interval can
maintain significant visual acuity while reducing the treatment burden. For patients with diabetic reti-
nopathy (DR), early intervention with anti-VEGF therapies has reduced vision-threatening complica-
tions as well as slowed disease progression. The role of persistent subretinal and intraretinal fluid in
determining response to treatment in patients with nAMD must also be addressed and follow-up with a
retinal specialist is crucial.
Etiology
The major mechanism for the development of retinopathy is chronic hyperglycemia. Accumulation of
polyols and advanced glycosylation end products, oxidative stress, and protein kinase C activation may
mediate the effects of hyperglycemia. Excessive levels of intraocular vascular endothelial growth factor,
a deficiency of pigment epithelium-derived factor (a protein that inhibits neovascularization), and reduced
concentrations of transforming growth factor-β (a protein that may inhibit endothelial proliferation) may
play a role. Insulin-like growth factor 1 seems to be permissive in the development of retinopathy. In addi-
tion to these chemical factors, genetic factors seem to play a role, as genetic clustering of retinopathy has
been reported.
Pathophysiology
Diabetic retinopathy may be divided into pre-proliferative (or background) retinopathy and the more
serious proliferative retinopathy. First, there is the pre-proliferative phase. Because of the alterations
described in the preceding ‘Etiology’ section, there is loss of the vascular supporting cells, the pericytes,
which allow for the development of microaneurysms, small outpouching from the capillaries of the retina,
as well as dot intraretinal hemorrhages (Figure 2.2, compared to Figure 2.1, the normal fundus). There
may be a progressive increase in the number of hemorrhages as well as the development of cotton wool
spots, both manifestations of regional ischemia due to microvascular disease.
Proliferative retinopathy develops because of the formation of new blood vessels, the process of neo-
vascularization (Figure 2.2). This is likely due, at least in part, to the growth factor imbalance described
earlier, as well as to loss of pericytes, which may have a contractile function regulating retinal blood
flow. This dysregulation may lead to ischemia, an additional stimulus to neovascularization. The new and
fragile blood vessels grow into the vitreous where they may burst, with the vitreous hemorrhage causing
visual loss (Figure 2.4). Scarring in the hemorrhage attaching to the retina can then retract causing retinal
detachment and more visual problems.
Excess VEGF may cause disruption of the blood–retinal barrier. This can lead to macular edema,
which may result in substantial central visual loss. When the fluid elements of this macular edema reab-
sorb, the lipid and lipoprotein elements remaining cause hard exudates (Figure 2.3).
There is a progression from microaneurysms and dot hemorrhages to neovascularization (Figures 2.1–
2.3). After neovascularization, its attendant problems, vitreous hemorrhage, retinal detachment, and glau-
coma may follow (Figure 2.4). Macular edema can occur anywhere during the course of this progression.
FIGURE 2.1 Normal fundus. (Courtesy of Dr. Mark Dailey.)
FIGURE 2.2 Microaneurysms, flame hemorrhages, cotton wool spots, and neovascularization of the disc.
(Courtesy of Dr. Mark Dailey.)
Diagnosis
The traditional method of detection of diabetic retinopathy is by ophthalmoscopic physical examina-
tion, preferably through dilated pupils. However, a variety of photographic techniques may complement
FIGURE 2.3 Hard exudates. (Courtesy of Dr. Mark Dailey.)
FIGURE 2.4 Large preretinal hemorrhage. (Courtesy of Dr. Mark Dailey.)
physical examination or even replace it. Fluorescein angiography is a useful method for characterization
of the retinal vasculature (Figure 2.5).
Observational as well as interventional studies have shown that maintenance of good glycemic control
is of ocular benefit. Several prospective trials have documented the importance of good blood pressure
control in ocular protection and, in fact, there was a 47% reduced risk of deterioration in visual acuity in
the United Kingdom Prospective Diabetes Study.
FIGURE 2.5 Fluorescein angiogram showing vascular leakage. (Courtesy of Dr. Mark Dailey.)
In addition, several eye-specific treatments are effective. Panretinal scatter photocoagulation benefits
people with proliferative retinopathy or neovascular glaucoma. Focal photocoagulation may be used for
macular edema. Vitrectomy can be used for nonclearing vitreous hemorrhage or traction detachment of
the retina. Newer approaches, such as blockade of VEGF, are also very effective.
NEPHROPATHY
Definition/Overview
Diabetic nephropathy is the leading cause of renal failure in individuals on dialysis. It has been gener-
ally defined as the presence of more than 500 mg albumin in a 24-hour urine collection. This is overt
nephropathy. However, patients first go through stages of lesser protein spillage, termed microalbumin-
uria. Proteinuria occurs in 15%–40% of individuals with T1DM, the prevalence peaking at 15–20 years
of diabetes duration. The prevalence varies from 5% to 20% in patients with T2DM.
Etiology
At most, probably no more than 40% of diabetic people develop nephropathy. It is clear that there is
familial clustering of this complication, and, thus, genetic susceptibility plays a role in the development of
nephropathy in both T1DM and T2DM. On this background, several modifiable factors lead to the clinical
initiation and progression of nephropathy including hyperglycemia and hypertension. Other etiological
factors include glomerular hyperfiltration, proteinuria itself, smoking, dyslipidemia, and dietary factors
including protein and fat.
FIGURE 2.6 Glomerulus from a patient with advanced diabetic nephropathy stained with PAS. Nodular
mesangial expansion is seen (Kimmelstiel–Wilson nodules). (Courtesy of Dr. Maria Picken.)
Pathophysiology
The classic histological changes of diabetic nephropathy are increased glomerular basement membrane
(GBM) width and mesangial expansion (Figures 2.6 and 2.7). Not only is the GBM thickened, but it is
biochemically and functionally defective, allowing for albumin leakage into the urine. The defective
FIGURE 2.7 Glomerulus from a patient with advanced diabetic nephropathy stained with H&E. Nodular
mesangial expansion is seen (Kimmelstiel–Wilson nodules). (Courtesy of Dr. Maria Picken.)
function of the GBM coupled with increased transglomerular pressure (caused by excessive constriction
of the efferent glomerular arteriole compared to the afferent arteriole) leads to proteinuria. The expansion
of the mesangium decreases glomerular capillary luminal space and, thus, reduces glomerular filtration.
The mechanistic role of hyperglycemia in the pathophysiology is complex and mediated through an
increase in growth factors (such as transforming growth factor-β and vascular endothelial growth factor),
activation of protein kinase C, increase in oxidative stress, enhanced formation of advanced glycosylation
end products, and increased flux through the aldose reductase pathway.
If untreated, patients initially present with no evidence of renal disease but then progress from microalbu-
minuria to nephropathy to nephrotic syndrome and, finally, to dialysis-requiring end-stage renal disease.
In diabetic patients with impaired renal function and/or proteinuria, symptoms of urinary tract obstruc-
tion and systemic diseases other than diabetes (such as lupus or hepatitis B or C among others) should be
sought. Imaging or biopsy may be considered in selected cases.
Diagnosis
The diagnosis is easily made in long-term (>10 years) T1DM individuals with renal functional impairment
and proteinuria, especially if there is concurrent retinopathy, the retinal–renal syndrome. The diagnosis
may be less certain in people with T2DM since the actual time of onset of the disease is often not clear,
and about one in four patients may not have retinopathy.
A clinical diagnosis of diabetic kidney disease can be made if there is persistent albuminuria and/
or persistent decreased glomerular filtration rate (GFR). Screening for proteinuria is conveniently accom-
plished with a spot urine sample. Because of the well-known variability in day-to-day urinary albumin
excretion, the diagnosis should only be made if two specimens are abnormal. An additional diagnostic
caveat is that the presence of factors other than renal disease, which can elevate urinary albumin excre-
tion, must be ruled out. These include urinary tract infection, hematuria, acute febrile illness, uncontrolled
hypertension, heart failure, vigorous exercise, and short-term pronounced hyperglycemia. Decreased
GFR is defined as an eGFR <60 mL/min/1.73 m2 using a creatinine-based formula. Persistence of these
abnormalities for at least 3 months should be confirmed, because transient abnormalities, which can be
induced by a variety of unrelated disorders, are common.
It is important to note that albuminuria is not required to make a clinical diagnosis of diabetic
kidney disease. A substantial minority of patients with diabetes and decreased eGFR have <30 mg/g of
albuminuria, and such patients commonly have histopathologic findings consistent with diabetic kidney
disease.
Good glycemic control has been shown to protect kidney function and is a major part of therapy.
Equally important is blood pressure control. The goal is a blood pressure less than 140/90 (<125/75
if serum creatinine is elevated and proteinuria is >1 gram/24 hours). Therapy should be initiated with
angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, renin–angiotensin system

(RAS) blockade, or SGLT-2 inhibitors, and many patients will need three to four different agents to
achieve goals. Additionally, some GLP-1 receptor agonists have been shown to reduce the incidence of
a composite kidney endpoint (consisting of a new onset of albuminuria >300 mg/day, doubling of serum
creatinine, ESKD, or kidney death). Since SGL-2 inhibitors and GLP-1 receptor agonists also reduce the
rates of cardiovascular disease, they are important agents in diabetes management. There is data suggest-
ing that statin therapy may preserve kidney function, as may dietary protein restriction.
NEUROPATHY
Definition/Overview
Diabetic neuropathy can be subdivided into generalized symmetric polyneuropathies and focal/multifo-
cal mononeuropathies. Symmetric polyneuropathies include three distinct entities: acute sensory, chronic
sensorimotor, and autonomic neuropathies. Focal/multifocal neuropathies are further subcategorized
into cranial, truncal, focal limb, and diabetic amyotrophy. Chronic distal sensorimotor polyneuropathy
(DPN) and autonomic neuropathy (AN) are the two most common forms. A simple definition of DPN
is “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after
the exclusion of other causes”. DPN is the most common form of neuropathy. About half the time, DPN
is subclinical. AN may manifest itself in one or multiple organ systems. More than 50% of individuals
with diabetes may expect to develop a diabetic neuropathy. The duration of diabetes correlates well with
the development of neuropathy. Those with T1DM typically begin to develop neuropathies after 5 years,
while in individuals with T2DM, the neuropathy may begin prior to the clinical diagnosis of diabetes.
Etiology
The duration of diabetes, as well as the level of hyperglycemia, plays a central role in the development
of diabetic neuropathies. Other factors thought to play a role in the development of neuropathy include
hypertension, hyperlipidemia, obesity, tobacco use, and alcohol consumption.
Acute sensorimotor neuropathy, although rare, is thought to be a result of marked metabolic derange-
ment including ketoacidosis and rapid fluctuations in glycemic control.
Mononeuropathies have two distinct etiologies. The most common form is entrapment. This can be
seen in up to 30% of diabetic people. Microvascular infarcts, whose symptoms are self-limiting, also lead
to mononeuropathies and are rare in comparison.
Pathophysiology
Hyperglycemia in DPN and AN leads to the intracellular accumulation of sorbitol, via the actions of
the aldose reductase pathway. As a result, cellular osmolality is increased and myoinositol is decreased.
Hyperglycemia also leads to the development of advanced glycosylation end products. These factors,
coupled with the increased development of reactive oxygen species (multiple pathways) and the decrease
in available antioxidants, lead to a functional limitation in axonal transport, impairment of neurotro-
pism, and alteration of gene expression. Ischemia is also thought to play a role in the development of
FIGURE 2.8 Diabetic neuropathy in a sural nerve. Note the wedge-shaped areas with axonal loss and a mild
overall decrease in axonal number. (Courtesy of Dr. Henry Brown.)
polyneuropathies. Heightened expression of protein kinase C (PKC), PAI-1, transforming growth factor
beta (TGF-β), and VEGF in diabetes leads to increases in endothelial injury and micro-/macrovascular
occlusion. An example of diabetic neuronal loss in a sural nerve biopsy is shown in Figure 2.8.
DPN most frequently presents as paresthesia, hyperesthesia, deep aching pain, burning, or an electri-
cal sensation. These symptoms are typically worse at night. It is symmetric in distribution. The disease
typically affects the distal extremities; most commonly the feet and lower legs. It has a progressive sym-
metric distal-to-proximal course, leading to the classic stocking-glove distribution. In 50% of instances,
DPN is subclinical and may present with calluses or a painless foot ulcer. Acute sensorimotor neuropa-
thy presents with similar findings as DPN. The hallmark is the sudden onset, severity, and typical self-
limiting course.
ANs present in a variety of ways, dependent upon the organ systems that are affected. Cardiac AN
may present as decreased exercise tolerance, fatigue, weakness with exercise, postural hypotension, diz-
ziness, tachycardia, or overt syncope. In many instances, cardiac AN is silent. Esophageal motility dis-
turbances are not uncommon. These are manifested by either excessive peristaltic contractions (Figure
2.9) or absent contractions (Figure 2.10). The gastric presentation of AN is varied. It ranges from gastro-
paresis, abdominal pain, vomiting, belching, early satiety, and constipation to diarrhea and incontinence.
Genitourinary symptoms include vaginal dryness, erectile dysfunction, nocturia, urinary retention, uri-
nary incontinence, or increased urinary frequency, and striking examples of neurogenic bladders are
shown in Figures 2.11 and 2.12. Sudomotor symptoms associated with AN include hyperhidrosis, anhi-
drosis, heat intolerance, and dry skin.
Focal/multifocal mononeuropathies also have varied presentations. Patients with diabetic amyotro-
phy will present with unilateral or bilateral severe neuropathic pain. Physical findings include proximal
FIGURE 2.9 Tertiary contractions in the esophagus of a diabetic patient. (Courtesy of Dr. Laurie Lomasney.)
FIGURE 2.10 Absence of contractions in the esophagus of a diabetic patient. (Courtesy of Dr. Laurie
Lomasney.)
FIGURE 2.11 Neurogenic bladder. (Courtesy of Dr. Laurie Lomasney.)
FIGURE 2.12 Neurogenic bladder with diverticula. (Courtesy of Dr. Laurie Lomasney.)
thigh weakness and atrophy. Those with thoracic polyradiculopathy may present with severe pain in a
bandlike distribution about the chest or abdomen. Cranial mononeuropathies can affect the oculomotor,
trochlear, and abducens nerves, leading to ophthalmoplegia. Patients with diabetic ophthalmoplegia pres-
ent with unilateral pain, ptosis, and diplopia. Peripheral mononeuropathies may produce effects in the
median, ulnar, radial, and peroneal nerves. This has an acute onset and may result in symptoms such as
foot drop.
Chronic inflammatory demyelinating process (CIDP), B12 deficiency, spinal stenosis, hypothyroidism,
and uremia occur more frequently in the diabetic population. Imaging, laboratory workup, and neurology
referral should be used to elucidate the etiology of the neuropathy. In asymmetric polyneuropathies, the
diagnosis of systemic vasculitis should be entertained.
Diagnosis
DPN is a clinical diagnosis, and a complete history and physical are essential. Simple inspection of the
feet may reveal calluses or ulcerations of an insensate foot. Regularly checking pinprick, temperature
perception, vibratory sense (using a 128 Hz tuning fork), pressure sensation (using a 10 g monofilament),
and ankle reflexes are recommended. The combination of any two positive tests has an 87% sensitivity
for detecting DPN.
Detection of AN involves diverse testing based on the organ system involved, but the details are
beyond the scope of this chapter.
Focal/multifocal neuropathies can be diagnosed through a meticulous history and physical.
Electrophysiological studies may aid in the determination of the site of nerve entrapment or infarction.
There are numerous drugs used to treat DPN. The first goal of therapy (with all neuropathies) should be to
improve glycemic control. Regular inspection of the feet may prevent amputation by identifying early foot
lesions otherwise missed because of insensate feet. Subsequent therapy should be directed at appropri-
ately controlling blood pressure and following cholesterol guidelines. Medications for symptomatic relief
of pain include tricyclic drugs (e.g., amitriptyline), anticonvulsants (gabapentin and topiramate), prega-
balin, capsaicin cream, selective serotonin reuptake inhibitors, and duloxetine. Vasodilators have been
shown to have limited success. For refractory pain, the use of opioids or pain service consultation may
be necessary. Treatment of mononeuropathies may include surgical decompression of entrapped nerves.
Cardiac AN may respond to beta blockers, ACE inhibitors, and supervised exercise therapy. Postural
hypotension, after exclusion of other diseases, may respond to the use of midodrine or octreotide.
Gastroparesis, chronic abdominal pain, and vomiting may respond to frequent small meals, prokinetic
agents (metoclopramide and erythromycin), gastric pacing, pyloric Botox, or enteral feedings. Constipation
may be approached with high-fiber diets, bulking agents, and osmotic laxatives. Erectile dysfunction may
respond to phosphodiesterase 5 inhibitors (sildenafil, vardenafil, and tadalafil), prostaglandins, or a pros-
thesis. Bladder dysfunction can be treated with bethanechol or intermittent catheterization.
SKIN MANIFESTATIONS
Overview
Skin manifestations in diabetes mellitus are common. Many skin manifestations seen in association with
diabetes mellitus may also be seen in other conditions. These lesions may result from microangiopathy,
hyperinsulinemia, hyperlipidemia, reaction to treatments, or immune compromise leading to infections.
NECROBIOSIS LIPOIDICA DIABETICORUM
Definition/Overview
This disease is an uncommon finding affecting 0.3%–1.2% of patients. Necrobiosis is most commonly
seen in individuals with T1DM, although it manifests in those with T2DM and patients with insulin resis-
tance. About one in four patients with necrobiosis do not carry a diagnosis of diabetes. Women are three
times more likely to develop these lesions
Etiology
This skin lesion may be the result of diabetic microangiopathy, immune complex disease, abnormal pro-
duction of collagen, and impaired neutrophil migration. The lesions are commonly associated with poor
glycemic control, but there is no evidence that necrobiosis is prevented by good glycemic control.
Pathophysiology
Biopsy examination of necrobiosis reveals thinning central dermis, collagen degeneration, and granulo-
matous inflammation of the subcutaneous tissue, as well as blood vessel wall thickening.
The lesions are most common on the pretibial aspect of the leg and are generally bilateral in presenta-
tion (Figure 2.13). Less often they are found on the trunk, arms, and face. Initially, they are seen as
small red papules. These eventually coalesce to form a large circular lesion with a waxy yellow center.
Telangiectasias are seen in this area of the lesion (Figure 2.14). Mature lesions have been characterized
FIGURE 2.13 Necrobiosis lipoidica diabeticorum. (Courtesy of Drs. Anthony Peterson and David Eilers.)
FIGURE 2.14 Necrobiosis lipoidica diabeticorum with telangiectasia. (Courtesy of Drs. Anthony Peterson and
David Eilers.)
as having a ‘porcelain-like sheen’. The lesions may become ulcerative (35%) and direct trauma to the area
should be avoided. These lesions may spontaneously disappear in up to 19% of patients.
Differential diagnosis of this lesion includes granuloma annulare, necrobiotic xanthogranuloma (associ-
ated with paraproteinemia), rheumatoid arthritis nodules, sarcoidosis, stasis dermatitis, lichen sclerosus et
atrophicus, Hansen’s disease, and erythema nodosum.
Diagnosis
Diagnosis is through history and physical examination as well as familiarity with the lesion.
Both medical and surgical treatments of necrobiosis lipoidica have been of limited efficacy. In ulcerative
or complicated cases, surgery or split-thickness skin grafts have been used. Medical treatments have
included topical or intralesional corticosteroids, fibrinolytic agents, nicotinamide, tacrolimus, pentoxifyl-
line, heparin, antiplatelet agents, ticlopidine hydrochloride, tretinoin, cyclosporine, and thalidomide.
ACANTHOSIS NIGRICANS
Definition/Overview
Acanthosis nigricans is a papillomatosis and hyperkeratosis of the skin. The lesions are commonly asso-
ciated with T2DM and hyperinsulinemic states. This lesion may be seen in up to 36% of people with
T2DM. Acanthosis has a higher prevalence in Blacks, Hispanics, and Native Americans when compared
with Caucasians.
Etiology
Hyperinsulinemic states and obesity are commonly associated with acanthosis nigricans, suggesting that
insulin resistance may participate in the genesis of this lesion. The incidence of acanthosis in moderately
obese individuals may be as high as 27% and up to 54% in severe obesity.
Pathophysiology
Acanthosis nigricans is characterized as a dermal thickening with hyperpigmentation. Acanthosis is
thought to arise from insulin stimulation of insulin-like growth factor-1 receptors in keratinocytes leading
to epidermal hyperplasia.
The dermal thickening seen in acanthosis appears as dark, velvety areas (Figure 2.15). They are com-
monly distributed to the axilla, neck, back, and periumbilical areas. In diabetic dermopathy, groups of
small >5 mm red papules occur on the arms and legs of diabetic individuals. These lesions slowly develop
shallow centers and characteristically evolve into hyperpigmented scars.
Rapidly appearing lesions of acanthosis in elderly nonobese patients should prompt the clinician to search
for occult malignancy, as there is an association with paraneoplastic syndromes and cancer. Acanthosis
FIGURE 2.15 Acanthosis nigricans. (Courtesy of Mayo Clinic Proceedings. With permission.)
nigricans is also associated with polycystic ovarian syndrome, congenital adrenal hyperplasia, Cushing’s
disease, acromegaly, obesity, and Prader–Willi syndrome.
Diagnosis
Diagnosis is through history and physical examination as well as familiarity with the lesion. Groups of
small >5 mm red papules occur on the arms and legs of diabetics. These lesions slowly develop shallow
centers and characteristic hyperpigmentation.
Reduction of insulin resistance by weight loss and/or use of metformin or thiazolidinediones may lead to
amelioration or even disappearance of acanthosis.
CUTANEOUS INFECTIONS
Definition/Overview
Malignant otitis externa is predominantly seen in elderly patients with glucose intolerance or diabetes
mellitus. The most common causative bacterium is Pseudomonas aeruginosa though it may also, less
commonly, be secondary to Aspergillus, Staphylococcus, Proteus, Klebsiella, or Candida.
Mucormycosis, or zygomycosis, is a rare but rapidly growing infection by the class of fungi
Zygomycetes. They are common in nature and are aerosolized as spores. In diabetic patients or patients
with metabolic acidosis, the most common and devastating manifestation is rhinocerebral mucormycosis.
Almost three-quarters of all cases of rhinocerebral mucormycosis are associated with diabetes.
Pathophysiology
P. aeruginosa is not a common pathogen of the external ear. It is thought to be introduced by contami-
nation of water. Poor tissue perfusion, secondary to microangiopathy, and being immunocompromised
increase susceptibility to this infection. The infection may spread to the meninges, brain, or mastoid
process.
Rhinocerebral mucormycosis most likely begins with the inhalation of spores and the seeding of
the nares. The infection begins in the presence of hyperglycemia or metabolic acidosis. The presence of
ketone reductase allows the fungi to proliferate in acidic environments and hyperglycemic states.
Patients with malignant otitis media may present with fever and localized ear pain and drainage.
Development of meningitis or osteomyelitis may occur. The initial site of infection in diabetic patients
is the nasal turbinates. Presentation is consistent with acute sinusitis. Patients may rapidly develop fever,
sinus tenderness and pain, purulent discharge, and severe headaches. Spread is to contiguous areas.
Common sites include the orbits, palate, and brain. If the etiology of the infection is fungal, there may
be marked tissue destruction and angioinvasion. Nerve palsies, proptosis, facial swelling, and cyanosis of
overlying structures may be seen.
Squamous cell carcinoma of the external ear may mimic signs and symptoms of malignant otitis media.
Diagnosis
Diagnosis of malignant otitis externa is accomplished through history and physicals. Laboratory values
may indicate the presence of an infection. The erythrocyte sedimentation rate, although nonspecific, is
generally elevated. Biopsy of the ear is the only reliable mechanism to differentiate between squamous
cell carcinoma and malignant otitis externa. Culture will help determine the causative organism and
direct appropriate antimicrobial therapy.
Diagnosis of mucormycosis is via culture. The aggressive nature of the investigation warrants rapid
identification. Direct biopsy and staining of necrotic tissue are appropriate. Clinicians should treat patients
immediately if suspicion is high. CT scan or magnetic resonance imaging should be employed to deter-
mine the extent of the disease.
Malignant otitis externa may be treated with parenteral combination antibiotics or single-agent fluoroqui-
nolone. Current treatment of rhinocerebral mucormycosis includes aggressive and potentially disfiguring
debridement. Amphotericin B is the antifungal of choice.
DIABETIC DERMOPATHY
Definition/Overview
Diabetic dermopathy is a common finding in patients with long-standing diabetes mellitus and encom-
passes many types of skin lesions that are not explained by other classifications of skin lesions. It is a
diagnosis of exclusion.
Etiology
Diabetic dermopathy is associated with long-standing disease. The areas affected suggest a relationship
with local trauma.
For dermopathy, cutaneous infections and cancer must be ruled out.
There is no specific treatment for diabetic dermopathy.
OTHER INFECTIONS
A more common, though less dramatic, infection is intertrigo (Figure 2.16). This is an infectious or
noninfectious inflammatory condition of two closely opposed skin surfaces. Although, when infectious
in etiology, it may result from any of a variety of microorganisms; the most common cause is Candida.
Treatment consists of treating the predisposing factor (e.g., weight loss if possible), topical antifungals,
and drying agents.
Tinea infections are fairly common as well (Figure 2.17). They are caused by the organism
Pityrosporum orbiculare and are treated by topical antifungal agents.
FIGURE 2.16 Axillary intertrigo. (Courtesy of Dr. Eva Parker.)
FIGURE 2.17 Tinea. (Courtesy of Drs. Anthony Peterson and David Eilers.)
COMMON DRUG REACTIONS
Definition/Overview
A common finding of drug therapy in diabetes mellitus is localized skin reaction (Figure 2.18). Insulin
administration may lead to a variety of localized reactions. Hypersensitivity reactions, lipohypertrophy,
lipoatrophy, nodule formation, and cellulitis may be seen in patients administered insulin. The use of
sulfonylureas may lead to the development of a wide variety of skin manifestations. Thiazolidinediones,
metformin, alpha-glucosidase inhibitors, DPP-4 inhibitors, and SGLT-2 inhibitors have not been associ-
ated with significant cutaneous manifestations. GLP-1 agonists can be associated with local skin irritation
at the site of injection.
Etiology
Please refer to the following section ‘Pathophysiology’.
Pathophysiology
Lipohypertrophy likely results from the localized effects of insulin. Insulin in high concentration leads
to the inhibition of lipolysis locally. Lipoatrophy is a localized immunologic reaction to the impurities
found within the various insulin preparations. Impurities in insulin preparations may cause hypersensitiv-
ity reactions locally or systemically. With the use of indwelling catheters associated with insulin pumps,
direct skin trauma may lead to hard nodular formations. Additionally, these chronic sites may lead to a
port of entry for infections leading to localized cellulitis.
In patients with severe systemic allergic reactions, all medications should be evaluated thoroughly.
Vasculitis should be considered in patients with significant skin lesions.
FIGURE 2.18 Typical drug eruption. (Courtesy of Drs. Anthony Peterson and David Eilers.)
Diagnosis
Diagnosis of lipohypertrophy, lipoatrophy, and pump-related injury is by history, physical examination,
and familiarity with the character of the lesion. Deterioration in glycemic control in patients using the
insulin pump may indicate skin problems at the site. Localized cellulitis presents with an increasing area
of erythema, fever, and pain.
Sulfonylurea allergic reactions are related temporally to the initiation of therapy and are diagnosed
through a thorough history and physical. These reactions are typically erythema multiforme, erythema
nodosum, morbilliform rash, or simple pruritus. Reactions with the intake of alcohol result in an unpleas-
ant flushing sensation. Jaundice may accompany more severe reactions to sulfonylurea. Photoallergic
reactions to ultraviolet B radiation manifest as eruptions on the sun-exposed skin, typically the hands,
face, and neck.
Treatment of lipohypertrophy, nodules associated with insulin pumps and some GLP-1 agonists, and
lipoatrophy is simply to vary the site employed for insulin delivery. Patients utilizing insulin pumps
should avoid using single sites for greater than 72 hours at a time. Cellulitis should be treated with an
appropriate antibiotic regime. Withdrawal of the sulfonylurea is warranted for significant skin changes. In
severe reactions, such as Stevens–Johnson syndrome, hospitalization, and supportive care are necessary.
BULLAE
Bullae are rare and tend to appear spontaneously from normal skin (Figure 2.19). They are usually on
the lower extremities but sometimes on the arms, hands, and fingers. They may be intraepidermal or
subepidermal. Intraepidermal bullae are sterile and nonhemorrhagic and resolve spontaneously within a
few weeks. Subepidermal bullae may be hemorrhagic and may heal with scarring and atrophy. The only
therapy is local care to avoid local infection while the lesions resolve spontaneously.
FIGURE 2.19 Diabetic bullae. (Courtesy of Drs. Anthony Peterson and David Eilers.)
THE DIABETIC FOOT
Definition/Overview
A patient with diabetes can have serious foot complications, including ulcers and amputation, largely due
to the combined impact of neuropathy and peripheral vascular disease. Diabetic foot ulcers and lower-
extremity amputations are serious and expensive complications that may affect as many as 15% of people
with diabetes during their lifetime. Simple and inexpensive interventions may decrease the amputation
rate by up to 85%.
Etiology
Many etiologic and risk factors can participate in the development of the diabetic foot, especially ulcer-
ation. Primarily, diabetic foot disease is a culmination of the combined effects of peripheral neuropathy
and peripheral vascular disease. Other factors are associated with increased risk, however. These include
increasing duration of diabetes, age, male gender, poor glycemic control, and microvascular and macro-
vascular diabetic complications. There is a weak association with cigarette smoking (though it should be
avoided in any case), and alcohol consumption does not have a clear association with foot ulcerations.
Pathophysiology
Neuropathy leads to ulceration by several mechanisms. First, there is loss of sensation so an individual
may not recognize the development of ulceration early. Second, the motor component of neuropathy leads
to atrophy of the intrinsic muscles of the foot, resulting in a flexion deformity. This results in increased
pressure on the metatarsal heads and tips of toes, common places for ulceration (Figure 2.20). Third,
peripheral sympathetic autonomic neuropathy causes dyshidrosis and dry skin, which can readily crack,
allowing for the invasion of pathogenic bacteria. Autonomic neuropathy may also be involved with arte-
riovenous shunting leading to altered skin and bone perfusion. Neuropathy, because of sensory loss, can
also lead to the development of Charcot foot and attendant ulceration (Figures 2.21–2.23).
FIGURE 2.20 Ulcer secondary to chronic focal pressure callus. (Courtesy of Dr. Ronald Sage.)
FIGURE 2.21 Chronic Charcot feet with hammer toes. (Courtesy of Dr. Ronald Sage.)
FIGURE 2.22 Radiograph of a Charcot foot. (Courtesy of Dr. Laurie Lomasney.)
Another pathophysiologic factor is limited joint mobility because of glycosylation of the skin, soft tis-
sue, and joints. This limited joint mobility at the subtalar and first metatarsophalangeal joint causes higher
plantar pressures than in those with normal mobility and further aggravates the situation caused by the
flexion deformity. People with diabetes and neuropathy are more likely to have gait abnormalities making
them prone to suffer some kind of injury during ambulation. Calluses may further increase pressure, and
hemorrhages and early ulcers can form underneath calluses (Figure 2.24).
Peripheral vascular disease, highly prevalent in people with diabetes, is an infrequent precipitating
event but plays a major role in delayed wound healing and gangrene (Figures 2.25–2.27). Infection may
ultimately lead to osteomyelitis (Figures 2.28 and 2.29).
In the context of neuropathy, biomechanical problems, and peripheral vascular disease, a definable
precipitating event may start the process of ulceration. This is often poorly fitting footwear.
FIGURE 2.23 Neuropathic ulcer in Charcot foot. (Courtesy of Dr. Ronald Sage.)
FIGURE 2.24 Plantar focal pressure calluses, high risk for ulceration. (Courtesy of Dr. Ronald Sage.)
FIGURE 2.25 Extensive limb threatening ascending infection arising from first metatarsal ulcer secondary to
chronic focal pressure callus. (Courtesy of Dr. Ronald Sage.)
FIGURE 2.26 Distal ischemic ulcer. (Courtesy of Dr. Ronald Sage.)
FIGURE 2.27 Severe ischemic ulceration. (Courtesy of Dr. Ronald Sage.)
FIGURE 2.28 Ulcer with exposed bone and osteomyelitis. (Courtesy of Dr. Ronald Sage.)
FIGURE 2.29 Radiograph showing osteomyelitis. (Courtesy of Dr. Laurie Lomasney.)
In its most extreme form, patients with diabetic feet present with foot ulcerations, often infected. Short of
this, the presentation is that of peripheral neuropathy, peripheral vascular disease, flexion deformities of
the toes, interosseous muscle wasting, dry and cracked skin, and toenail deformities.
Diagnosis
A detailed discussion of the many modes of diagnosis of each of the component factors in the development
of the diabetic foot (e.g., neuropathy, biomechanical abnormalities, and peripheral neuropathy) is beyond
the scope of this chapter. However, in taking the history, attention should be given to classic symptoms
of peripheral neuropathy, especially numbness, and classical symptoms of peripheral vascular disease,
notably claudication. A previous history of ulceration is important as well. The physical exam includes a
foot inspection to assess for obvious foot deformities, dry skin, cracks in the skin, calluses, and toenail
deformities. A neurologic examination to ascertain whether there is sensory loss, and palpation of the
pulses should be part of the routine. More specialized procedures such as nerve conduction velocity test-
ing, Doppler, or angiograms may be necessary for some individuals and should be decided on a case-by-
case basis.
The old axiom that foot inspection prevents amputation remains true. A key part of management is to
make sure that the patient and/or a family member looks at the feet daily – top, bottom, and between the
toes. Patients should be advised to call their physicians immediately at any sign of infection or anything
unusual. The importance of daily self-examination should be reinforced by the physician doing this at
every clinic visit. Proper-fitting shoes are essential. Patients should be instructed to dry their feet thor-
oughly after bathing and use skin moisturizers liberally to keep the skin from getting dry and cracked.
The development of peripheral neuropathy can be delayed by good glycemic control, so that is part of
the management. Surgical debridement of calluses and good nail care is fundamental. Surgery to correct
bony deformities may be indicated. Claudication, a manifestation of peripheral vascular disease, can be
managed by a graded exercise program and, in some cases, vascular surgery. Fungal nail infections can
be treated with topical and systemic agents.
CARDIOVASCULAR DISEASE IN DIABETES
Definition/Overview
Diabetes mellitus is a well-established independent risk factor for the development and progression of
coronary heart disease (CHD), peripheral vascular disease (PVD), and atherosclerotic cardiovascular dis-
ease (CVD). CHD is two- to threefold more common in individuals with diabetes than in the general
population. Women with diabetes are at a greater risk for the development of CHD than men. The preva-
lence of symptomatic and silent CHD in this population after age 49 is estimated to be 30%. The cumula-
tive mortality from CHD is approximately 35% at age 55 in people with T1DM. Individuals with T2DM
without known coronary disease had a similar rate of developing a myocardial infarction (approximately
20%) compared with nondiabetic patients with a previous history of myocardial infarction. This was
independent of other traditional risk factors. Poor glycemic control is well correlated with the increase in
the prevalence of CHD and myocardial infarction. Carotid arterial disease development and progression
are directly correlated with glycemic control. Despite these relationships, no studies have clearly shown
that improved glycemic control prevents coronary or carotid disease in T2DM. Studies have suggested
that there might be a delayed macrovascular benefit from periods of antecedent good glycemic control
in T1DM. Duration of diabetes mellitus has a significant impact on the development and progression of
peripheral arterial disease. Although intensive glycemic control is always advocated, the relationship
between glycemic control and peripheral arterial disease treatment has not been well established and no
glycemic intervention has been shown to improve PVD.
Etiology
The primary defect in cardiovascular disease is the formation and progression of atherosclerotic plaques,
with resultant occlusive or thromboembolic disease. Common risk factors for its development include
diabetes mellitus, hypertension, hypercholesterolemia, chronic kidney disease, smoking, obesity, age, and
family history.
Pathophysiology
Atherosclerosis development is multifactorial. Central to development and progression is endothelial dys-
function. In some patients, there is likely a genetic predisposition to endothelial dysfunction. In other
patients, endothelial dysfunction is triggered by hyperglycemia, hypertension, hyperlipidemia, and the
products of smoking. At baseline, there appears to be a reduction in the production and release of nitric
oxide, a potent vasodilator that has antiatherosclerotic and antiplatelet properties. Dysfunctional endothe-
lial cells express adhesion molecules that trap circulating monocytes. These are then translocated into the
FIGURE 2.30 Coronary artery with atherosclerosis and calcification. (Courtesy of Dr. Henry Brown.)
vessel wall itself where they meet a highly oxidative environment. The environment converts the mono-
cytes to macrophages. LDL cholesterol particles also become oxidized within the vessel wall and this pro-
cess makes them more easily taken up by macrophages. These lipid-laden macrophages are called foam
cells and will eventually rupture leading to development of the earliest identifiable histological feature of
atherosclerosis: the fatty streak. The oxidized LDL-C particles additionally stimulate tissue macrophages
to release proinflammatory cytokines and adhesion molecules, self-perpetuating the inflammatory pro-
cess. Hyperglycemia further exacerbates inflammatory cytokine production and oxidative stress. With
60%–70% occlusion of a vessel, the patient is likely to experience symptoms. Plaque rupture results in
acute syndromes. This phenomenon is typically associated with plaques occluding less than 50% of the
vessel lumen. Plaques may additionally undergo remodeling and calcification. The pathology of plaque,
plaque rupture, and subsequent ischemic fibrosis is shown in Figures 2.30–2.32.
FIGURE 2.31 Ruptured atherosclerotic plaque. (Courtesy of Dr. Henry Brown.)

FIGURE 2.32 Postischemic subendocardial fibrosis. (Courtesy of Dr. Henry Brown.)
Cardiovascular disease diagnosis in the diabetic may present as both a straightforward diagnosis or with
an insidious onset resulting in disastrous consequences. For example, coronary disease can present as
sudden death.
PVD may initially present with the progression of hair loss in the lower extremities, worsening neu-
ropathy, an overall cold sensation in the feet, or claudication. Diabetics with pronounced PVD may be
predisposed to the development of ulceration and infection.
Patients with carotid and cerebrovascular disease present with headache, nausea, syncope, symptoms
of stroke, or an early harbinger of severe disease, the transient ischemic attack. A physical exam may
reveal carotid bruits and subtle neurological deficits.
Diagnosis
A physical examination can guide a clinician in the diagnosis and early treatment of vascular complica-
tions of diabetes mellitus. Although powerful imaging and laboratory testing are available, the art of the
physical examination remains the cornerstone in the diagnosis and stratification of cardiovascular disease.
Details of various diagnostic modalities are beyond the scope of this discussion.
Acute coronary, peripheral, and cerebral injuries related to arterial insults in diabetic patients should be
treated in an emergent fashion under the care of appropriate surgical and acute care physicians. Access
to interventional procedures should not be delayed in favor of medical management in patients with non-
ST segment elevation myocardial infarction. Patients should be initially treated with oxygen, nitrates,
antiplatelet agents, beta-blockers, and high-dose statins. Patients who have undergone revascularization
for CHD should avoid the use of the sulfonylurea glyburide, as in the periprocedural setting this sulfonyl-
urea may reduce the powerful myocardial protection afforded by ischemic preconditioning. Individuals
with hyperglycemia, both known diabetics and new onset, admitted to the hospital or intensive care set-
ting should be managed utilizing glycemic protocols. The use of insulin in hyperglycemic patients should
be advocated in this setting regardless of their previous medical regimen and regardless of whether the
patient has an antecedent history of diabetes. Decreased mortality and morbidity have been demonstrated
for cardiovascular patients in the surgical and medical intensive care units in many but not all studies with
good glycemic control achieved by insulin.
Therapy should also be directed at controlling cardiovascular risk factors over the long term. Positive
lifestyle changes and control of hypertension, microalbuminuria, and lipids should aggressively be insti-
tuted. Liberal use of SGLT-2 inhibitors should be instituted given the remarkable cardiovascular benefits
of these agents. If not contraindicated by gastrointestinal issues, GLP-1 agents should be frontline therapy
once discharged, as these agents also have demonstrated cardiovascular protection.
Secondary Causes of Diabetes

Although uncommon, it is important to not overlook secondary causes of diabetes associated with physi-
cal findings, where treatment could ameliorate the underlying insulin resistance and hyperglycemia.
These include acromegaly, excess cortisol states, and glucagonoma.
ACROMEGALY
Definition
Acromegaly is almost always caused by a growth hormone (GH)-secreting adenoma of the pituitary gland
and is associated with increased morbidity and mortality. Growth hormone excess that occurs before
fusion of the epiphyseal growth plates in a child or adolescent is called pituitary gigantism; when the
excess GH appears in an adult, soft tissue changes are the clinical clues leading to the diagnosis.
Etiology
Excess GH stimulates hepatic secretion of insulin-like growth factor-I (IGF-I), which causes most of the
clinical manifestations of the disease. The clinical diagnosis is often delayed because of the slow progres-
sion of the signs of acromegaly over a period of many years.
Pathophysiology
Serum GH concentrations and IGF-I concentrations are increased in virtually all patients with acromeg-
aly. The increases in serum IGF-I are often disproportionately greater than those in GH for two reasons:
GH secretion fluctuates more and GH stimulates the secretion of IGF binding protein-3 (IGFBP-3), the
major IGF-I binding protein in serum. Other rare causes of acromegaly include pituitary somatotroph
carcinoma, hypothalamic tumor secreting growth hormone-releasing hormone (GHRH), nonendocrine
tumor secreting GHRH, ectopic secretion of GH by a nonendocrine tumor, and excess growth factor
activity.
Clinical clues to acromegaly include visual field defects, cranial nerve palsy, acral enlargement includ-
ing thickness of soft tissue of hands and feet, prognathism, arthritis, proximal myopathy, hypertrophy of
frontal bones, skin tags, macroglossia, thyromegaly, hepatomegaly, and galactorrhea.
Diagnosis
A normal serum IGF-I concentration is strong evidence that the patient does not have acromegaly. If the
serum IGF-I concentration is high (or equivocal), serum GH should be measured after oral glucose admin-
istration. It is equally acceptable to proceed immediately to MRI after obtaining an elevated level of IGF-
I. If the MRI is normal, then studies to identify a GHRH- or GH-secreting tumor should be undertaken.
All patients with acromegaly have increased GH secretion. However, the random serum GH concentration
is often in the range of 2 to 10 ng/mL during much of the day, values that can be found in normal subjects.
Unlike normal subjects, the patient’s serum GH concentrations change little during the day or night, and
in most patients do not change in response to stimuli such as food or exercise. Nevertheless, because of
the variations in serum GH that occur in normal subjects and in patients with other disorders, a high value
cannot be interpreted without knowing when the blood sample was obtained and something about the
patient. To obviate these problems it is best not to obtain random measurements of serum GH.
The most specific dynamic test for establishing the diagnosis of acromegaly is an oral glucose toler-
ance test. In normal subjects, serum GH concentrations fall to 1 ng/mL or less within 2 hours after inges-
tion of 75 g glucose. In contrast, the post-glucose values are greater than 2 ng/mL in acromegaly.
Since acromegaly is associated with increased cardiovascular risk, almost all patients should be treated,
even those who are asymptomatic and those in whom the disorder does not seem to be progressing.
Selective transsphenoidal surgical resection is the treatment of choice for patients. Surgical resection may
be followed up with radiotherapy or medical treatment with analogs of somatostatin (growth hormone-
inhibitory hormone) that inhibit GH secretion more effectively than native somatostatin because of their
greater potency and longer plasma half-life. These are octreotide and lanreotide. Octreotide is available in
short- and long-acting forms; lanreotide is available in long-acting forms.
EXCESS CORTISOL STATES: CUSHING’S SYNDROME
Definition
Excess cortisol can be due to exogenous use (iatrogenic Cushing’s syndrome) or due to endogenous causes,
which include benign and malignant adrenal tumors, pituitary ACTH-dependent Cushing’s syndrome
(Cushing’s disease), and ectopic ACTH from other malignancies. It is crucial to determine the cause of
the excess glucocorticoids so that appropriate treatment can be rendered.
Etiology
Excess cortisol due to exogenous use (iatrogenic Cushing’s syndrome) is more common than any other
cause but is seldom reported. Cushing’s syndrome may also be caused by a benign adrenal adenoma, often
discovered incidentally in radiographic studies. While adrenal nodules are noted in up to 8.7% of adults,
they are usually not associated with any clinical adrenal disease. Excess glucocorticoid production, how-
ever, is the most common hormone overproduced. A very rare cause of Cushing’s syndrome is adrenal
carcinoma, which is estimated to be 0.2 to 2 per million per year. Pituitary ACTH-dependent Cushing’s
syndrome (Cushing’s disease) is due to the hypersecretion of pituitary ACTH by the pituitary cortico-
trophs and is associated with bilateral adrenocortical hyperplasia. It is five to six times more common
than Cushing’s syndrome caused by benign and malignant adrenal tumors combined, with women three
to eight times more likely than men to develop Cushing’s disease. Ectopic ACTH syndrome, although
often not diagnosed, can cause Cushing’s syndrome; about 1% of patients with small-cell lung cancer have
ectopic ACTH syndrome and small-cell lung carcinoma causes half of all cases of the syndrome.
Pathophysiology
ACTH-dependent Cushing’s syndrome is due to hypersecretion of pituitary ACTH by the corticotrophs
and is associated with bilateral adrenocortical hyperplasia. There is loss of synchrony between ACTH
and cortisol secretion, with hypersecretion of cortisol and the loss of normal circadian rhythm. Morning
plasma ACTH and serum cortisol concentrations may be normal, but late-evening concentrations are
high. Salivary cortisol concentrations reflect those of serum free cortisol. The increased cortisol secre-
tion is reflected by increased urinary excretion of cortisol. The pituitary adenoma cells function at a
higher than normal set point for cortisol feedback inhibition, and this characteristic is clinically impor-
tant because it permits the use of dexamethasone suppression to distinguish between pituitary and ecto-
pic ACTH secretion; the latter is usually very resistant to glucocorticoid negative feedback. Almost all
patients with Cushing’s disease have a pituitary adenoma, although the tumor is often not demonstrable
by imaging; the remainder have corticotroph hyperplasia. The tumors are usually microadenomas; only
about 5% are macroadenomas. Patients with macroadenomas are more likely to have high plasma ACTH
concentrations than those with microadenomas, and the concentrations are less likely to fall with high
doses of dexamethasone. Patients with ectopic ACTH secretion will have persistent cortisol elevation,
even with high-dose dexamethasone testing. Adrenal adenomas, which are almost always benign, can also
oversecrete cortisol, but the concomitant ACTH level will be suppressed.
Clinical clues to the diagnosis of Cushing’s disease are underlying centripetal obesity, facial plethora,
impaired glucose tolerance or type 2 diabetes, proximal muscle weakness, hypertension, easy bruising,
hirsutism, depression, oligomenorrhea, acne, abdominal striae, and edema.
Diagnosis
The diagnosis of Cushing’s disease involves suspecting it based on the patient’s symptoms and signs,
documenting the presence of hypercortisolemia, and determining its cause.
If a patient is taking exogenous steroids, discontinuation is recommended if this is possible. If a corti-
sol-producing adrenal adenoma is found, surgical removal should be curative. If a pituitary adenoma is
responsible (Cushing’s disease), then neurosurgical intervention is the procedure of choice often followed
by radiation therapy. If ectopic ACTH secretion is determined to be the source, treatment of the underly-
ing malignancy is needed.
GLUCAGONOMA
Definition
Glucagonomas are rare islet cell tumors of the pancreas that oversecrete glucagon. The systemic mani-
festations make it unique among islet cell tumors and provide visible clues that make early diagnosis
possible.
Etiology
Nearly all reported cases of glucagonoma syndrome have been associated with tumors originating in the
alpha cells of the pancreas. These tumors demonstrate the typical characteristics of islet cell tumors; they
are usually encapsulated, firm nodules, varying in size from 2 cm up to 25 cm, and occur most often in
the tail of the pancreas.
Pathophysiology
Glucagonomas consist of cords and nests of well-differentiated islet cells. Characteristic alpha cell gran-
ules may be seen on electron microscopy. Despite their benign histologic appearance, most pancreatic
glucagonomas are malignant, as defined by their propensity for metastasis, which is usually present at the
time of diagnosis.
Clinical Manifestations
Patients typically present in their fifth decade, with an even distribution between males and females. The
clinical syndrome classically associated with glucagonoma includes necrolytic migratory erythema, chei-
litis, diabetes mellitus, anemia, weight loss, venous thrombosis, and neuropsychiatric symptoms. Weight
loss and necrolytic migratory erythema are the most prevalent symptoms, occurring in approximately
65% to 70% of patients by the time of diagnosis. Necrolytic migratory characteristically begins as ery-
thematous papules or plaques involving the face, perineum, and extremities. Over the next 7 to 14 days,
the lesions enlarge and coalesce. Central clearing then occurs, leaving bronze-colored, indurated lesions.
A rash may occasionally appear, before the onset of systemic symptoms, but most patients with rash usu-
ally have weight loss, diarrhea, sore mouth, weakness, mental status changes, or diabetes mellitus. Venous
thrombosis occurs in up to 30% of patients with glucagonoma; this association with thromboembolism
appears to be unique among endocrine tumors. Neurologic symptoms associated with glucagonoma may
include ataxia, dementia, optic atrophy, and proximal muscle weakness. The prevalence of metastatic
disease at the time of diagnosis varies from 50% to 100%, with the most common site of metastasis being
the liver, followed by regional lymph nodes, bone, adrenal gland, kidney, and lung. Rarely, glucagonoma
may be associated with multiple endocrine neoplasia syndrome, type 1 (MEN 1); such patients typically
have a family history of pituitary, pancreatic islet cell, or parathyroid tumors.
Diagnosis
The characteristic skin lesions of glucagonoma syndrome are often the clue that leads to the correct
diagnosis, and the presence of necrolytic migratory erythema should prompt further workup. A serum
glucagon level should be obtained. It is important to recognize, however, that conditions other than glu-
cagonoma can induce ‘physiologic’ elevations in the serum glucagon concentration. These include hypo-
glycemia, fasting, trauma, sepsis, acute pancreatitis, abdominal surgery, Cushing’s syndrome, and renal
and hepatic failure. However, these conditions are associated with only moderate elevations of glucagon,
usually less than 500 pg/mL (upper limit of normal <100 pg/mL), while a glucagonoma is associated with
markedly elevated glucagon concentrations. This should be followed up with an abdominal CT. Since the
tumor is usually large by the time of diagnosis, it is localizable by CT in the majority of cases. Endoscopic
ultrasonography can detect pancreatic tumors as small as 2 to 3 mm, provides accurate information on
the local extent of disease, and is the modality of choice for detecting and biopsying islet cell tumors too
small for CT visualization. Finally, somatostatin receptor scintigraphy using radiolabeled octreotide is
very sensitive to glucagonomas, however, since these tumors are usually large by the time of diagnosis,
this is rarely required for diagnosis.
For the minority of cases in which the tumor remains localized at the time of diagnosis, resection of the
primary pancreatic tumor is indicated since it offers the chance of a complete cure. Whether a simple
enucleation, focal pancreatic resection, or Whipple procedure is performed is dictated by the site and
extent of the tumor. Because patients with glucagonoma syndrome suffer from a prolonged catabolic state,
nutritional support of some kind is an integral component of therapy. Treatment for metastatic disease
includes somatostatin analogs such as octreotide and lanreotide. Finally, interferon improves symptoms
of hormonal hypersecretion in 40% to 50% of patients with pancreatic islet cells.
Therapeutic Options for T2DM

Many options are available to clinicians caring for individuals with diabetes, and it is beyond the scope of
this book to review them. A very helpful algorithm is included with the recommendations of the American
Diabetes Association for managing outpatient diabetes.
BIBLIOGRAPHY
American Diabetes Association Position Statement Cardiovascular Disease and Risk Management, Diabetes Care
(2022), PMID 34964815/DOI 10.2337/dc22-S010
Bakris et al., Diabetes Care (2014), PMID 24558077/DOI 10.2337/dc13-1870
Boulton et al., Diabetes Care (2005), PMID 15793206/DOI 10.2337/diacare.28.4.956
Burke et al., Diabetes Care (1999), PMID 10526730/DOI 10.2337/diacare.22.10.1655
Cheung et al., Kidney International (2021), PMID 33637203/DOI 10.1016/j.kint.2020.10.026

Chronic Kidney Disease and Risk Management, Diabetes Care (2022), PMID 34964813/DOI 10.2337/dc22-er03
de Boer et al., Diabetes Care (2017), PMID 28830958/DOI 10.2337/dci17-0026
Finnerup et al., Lancet Neurology (2015), PMID 25575710/DOI 10.1016/s1474-4422(14)70251-0
Fong et al., Diabetes Care (2004), PMID 15451934/DOI 10.2337/diacare.27.10.2540
Freeman R, Lancet (2005), PMID 15811460/DOI 10.1016/S0140-6736(05)74815-7
Gross et al., Diabetes Care (2005), PMID 15616252/DOI 10.2337/diacare.28.1.164
KDIGO 2012 Clinical practice guideline for the evaluation and management of chronic kidney disease, Kidney
International Supplement (2013), 3(1) January 1, 2013.
KDIGO 2021 Clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney
International (2021), PMID 33637197/DOI 10.1016/j.kint.2020.11.003
McGuire et al., JAMA Cardiology (2021), PMID 33031522/DOI 10.1001/jamacardio.2020.4511
Palmer et al., British Medical Journal (2021), PMID 35044930/DOI 10.1136/bmj.o109
Passarella et al., Diabetes Spectrum (2018), PMID 30140137/DOI 10.2337/ds17-0085
Retinopathy, Neuropathy, and Foot Care. Diabetes Care (2022), PMID 34964887/DOI 10.2337/dc22-S012
Standards of Diabetes Care. Diabetes Care (2022), PMID 34964887/DOI 10.2337/dc22-S012, PMID 34964873/DOI
10.2337/dc22-S011, PMID 34964831/DOI 10.2337/dc22-S009, PMID 34964868/DOI 10.2337/dc22-S006
Vinik et al., Diabetes Care (2003), PMID 12716821/DOI 10.2337/diacare.26.5.1553
Waldfogel et al., Neurology (2017), PMID 28341643/DOI 10.1212.wnl.0000000000003882
Whelton et al., Hypertension (2018), PMID 29743247/DOI 10.1161/HYP.0000000000000076
Zelniker et al., Lancet (2019), PMID 30424892/DOI 10.1016/s0140-6736(18)32590-x
Obesity
Marriam Ali and Sobia Sadiq

3
ABSTRACT
Obesity is a disorder involving increased body fat and is associated with metabolic disease. The preva-
lence of obesity is steadily increasing across the globe with deleterious health implications. There are
several factors associated with obesity including genetics, metabolic syndromes, neuroendocrine dys-
regulation, as well as diet and lifestyle habits. Treatment includes prevention strategies, diet and lifestyle
modifications, medical pharmacotherapy and surgical interventions.
INTRODUCTION
Body weight is a physiologically regulated parameter; obesity is a derangement of this regulation.1 Obesity
is a major risk factor for the development of diabetes mellitus, cardiovascular diseases, and certain types
of cancer. The disease arises from a chronic positive energy balance that is often due to large caloric intake
and an increasingly sedentary lifestyle on the background of a genetic and epigenetic predisposition.2
Obesity is defined as a body mass index (BMI) of 30.0 or higher and is subdivided into the following
categories:3
Class 1: BMI of 30 to <35

Class 2: BMI of 35 to <40
Class 3: BMI of 40 or higher, also categorized as ‘severe’ obesity
EPIDEMIOLOGY
The prevalence of obesity is steadily increasing across the globe with deleterious health implications
worldwide. Obesity has been affecting Americans at an accelerated rate over the past two decades (Figure
3.1). From 1999–2000 to 2017–2018, the prevalence of obesity in the US increased from 30.5% to 42.4%.
During the same time, the prevalence of severe obesity nearly doubled from 4.7% to 9.2%.4
Data were collected through the Behavioral Risk Factor Surveillance System (BRFSS), an ongoing,
state-based, telephone interview survey conducted by state health departments with assistance from the
74 DOI: 10.1201/9781003100669-3
FIGURE 3.1 CDC’s Division of Nutrition, Physical Activity, and Obesity (DNPAO) State Adult Obesity Prevalence Map 2011–2018, Behavioral Risk Factor
Surveillance System. (Adapted from cdc.gov: https://www.cdc.gov/obesity/data /prevalence-maps.html#overall.)
3 • Obesity 75
Centers for Disease Control and Prevention (CDC). Height and weight data used in the BMI calculations
were self-reported.
Overweight and obesity are global health issues that affect 68.5% of the adult US population.5 In most
recent years, the category of extreme obesity has seen the greatest proportional change.5
PATHOPHYSIOLOGY
Obesity is a disease that involves a long-term positive energy balance in which energy intake is greater
than expenditure. Hormonal dysregulation plays an integral part in the pathogenesis and maintenance of
excess weight. The set point of the body changes to a higher setting resulting in difficulty maintaining
weight loss.1 The most impactful factor in the development of obesity is calorie intake. Consumption of
high-caloric, energy-dense diets promotes excess weight gain. Environmental factors ranging from socio-
economic status to exposure to endocrine disruptors to sedentary lifestyles confer further risks of obe-
sity.1,6 Epigenetic, genetic, and developmental risk factors are still being elucidated with ongoing research
(Figure 3.2).
Genetics
Obesity studies among twins, adoptees, and biological versus adoptive parents reveal the presence of
genetic factors7,8 Obesity has been historically divided into two categories: monogenic obesity and poly-
genic obesity (also known as common obesity) (Figure 3.3).
Common obesity is polygenic and reflects the collective interactions of various genetic predisposi-
tions with environmental factors. The FTO (fat mass- and obesity-associated) gene variant has the stron-
gest association hypothesized to be due to increased energy intake.
Monogenic obesity can be subdivided into autosomal dominant or recessive inherited forms.
Generally, monogenic forms possess abnormalities in leptin signaling.9 Chromosomal rearrangements
result in syndromic obesity like Prader–Willi syndrome, WAGR syndrome, SIM1 syndrome, and pleiotro-
pic syndromes (including Bardet–Biedl syndrome, fragile X syndrome, and Cohen syndrome).9
Neuroendocrine Dysregulation
The ventromedial hypothalamic nucleus (VMH) is regarded as the satiety center, whereas the lat-
eral hypothalamus (LH) is the hunger center.10 The hormonal signal of satiety and hunger come
largely from the adipose tissue, pancreas, and liver. Distention and satiety are signaled to the hind-
gut by peptide YY, GLP1 from the ileum, and cholecystokinin from the duodenum. The adipocyte,
anorexigenic hormone leptin plays a significant role in the relationship between obesity and energy
homeostasis. Leptin exerts its effects by inhibiting orexigenic neuropeptide Y/Agouti-related peptide
neurons and activating anorexigenic proopiomelanocortin (POMC)/cocaine amphetamine-related
transcript neurons in the arcuate nucleus, resulting in decreased food intake and increased energy
expenditure.9 Orexigenic ghrelin from the stomach increases with time after a meal. The develop-
ment of resistance to leptin and ghrelin, hormones that are crucial for the neuroendocrine control of
energy homeostasis, is a hallmark of obesity.2 A deficiency of leptin causes severe hyperphagia and
obesity in both humans and animals.1 Obese individuals have been found to have high levels of leptin
and exogenous administration of leptin has demonstrated a resistance to its anorexigenic effects
(Figures 3.4 and 3.5).11
FIGURE 3.2 Distinguishing underlying causes of obesity in adults based on clinical signs and symptoms (From van der Valk, E. S., et al., A Comprehensive
Diagnostic Approach to Detect Underlying causes of Obesity in Adults, Obes. Rev. 20, 795–804 (2019).)
3 • Obesity 77
FIGURE 3.3 Key features of monogenic and polygenic obesity (From Loos, R. J. F. & Yeo, G. S. H., The Genetics
of Obesity: From Discovery to Biology, Nat. Rev. Genet. 1–14 (2021) doi:10.1038/s41576-021-00414-z.)
FIGURE 3.4 Schematic representation of different anti-obesity therapies based on the use of leptin. (From
Izquierdo, A. G., Crujeiras, A. B., Casanueva, F. F. & Carreira, M. C. Leptin, Obesity, and Leptin Resistance:
Where Are We 25 Years Later? Nutrients 11, 2704 (2019).)
Development, Age, and Weight Gain

A large body of evidence has shown that intrauterine and early life events are influential in the develop-
ment of obesity.12 Multiple reports suggest that endocrine-disrupting chemicals (EDCs) can dysregulate
hormonal metabolic processes, particularly in early development, resulting in a propensity to gain weight
despite limiting caloric intake and increasing physical activity.6 An obesogenic perinatal environment
contributes to adulthood obesity, and particular maternal factors such as excessive weight gain during
pregnancy or preexisting maternal obesity and diabetes can also predispose a person to the development
of obesity in adulthood.13
Most women experience gestational weight gain and progressive weight gain with multiple pregnan-
cies. Pregnancy was associated with a threefold greater increase in visceral fat deposition compared to
non-childbearing women.14 For some women, this can lead to the development of obesity; women who are
overweight or obese at baseline are more likely to gain excessive weight during pregnancy.15
3 • Obesity 79
FIGURE 3.5 Schematic representation of leptin and ghrelin regulation in the body.
Aging is associated with weight gain in both genders, although females experience a higher rate of
weight gain than men.16,17 The current literature suggests weight gain in midlife women is due to aging
and lifestyle changes rather than menopause, however, estrogen deficiency does lead to an increase in total
body fat and a decrease in lean body mass.18
Dietary Factors
The availability of energy-dense foods and increased energy intake is sufficient to account for the increase
in the prevalence of obesity observed from the 1970s to the 2000s.19
Evaluation of dietary macronutrient composition has not shown conclusive evidence that diets high
in fats or carbohydrates are consistently associated with weight gain. However, specific food intake has
been shown to result in increased weight gain (e.g., french fries, processed red meat) or protection against
weight gain (e.g., whole grains and fresh fruit).20,21
Sedentary Lifestyles
A reduction in physical activity with aging results in reduced energy expenditure contributing to weight
gain. Increased levels of physical activity are associated with the primary prevention of obesity and long-
term weight maintenance after intentional weight loss.21
Sleep
A reduction in sleep duration has mirrored the obesity epidemic. Trials have shown that reduced sleep
leads to altered leptin and ghrelin levels, increased hunger, and a preference for calorie-dense, processed
carbohydrate foods.20,22 Furthermore, reduced sleep also leads to a lower rate of physical activity leading
to less energy expenditure.23
Drugs
A variety of drugs have been shown to cause weight gain (Table 3.1). Medications can affect energy
homeostasis mainly by promoting hunger or by decreasing resting metabolism.24
Endocrinopathies Leading to Obesity

Hypothyroidism
Studies have not shown a causal relationship between hypothyroidism and obesity.25 Overt hypothyroid-
ism does cause modest weight gain. However, subclinical hypothyroidism has not been shown to correlate
with weight gain. Current theories hypothesize that changes in TSH may be secondary to obesity. Treating
overt hypothyroidism with levothyroxine can cause a modest effect on inducing weight loss, but there is
no data supporting levothyroxine use in euthyroid obese patients.25
Cushing’s Syndrome
A common feature of Cushing’s syndrome is progressive central adiposity, fat accumulation in the face
and neck, and enlarged dorso- and supraclavicular fat pads with muscle wasting in the extremities.
Hypothalamic Obesity
Hypothalamic obesity is a syndrome resulting from damage to the ventromedial or paraventricular regions
of the hypothalamus or amygdala resulting in hyperphagia. It can be seen in patients with resected cranio-
pharyngioma, inflammatory processes such as tuberculosis and sarcoidosis, head trauma, or after cranial
irradiation.24
Growth Hormone Deficiency

Adults with growth hormone deficiency have an increased body weight compared to age-, sex-, and height-
matched adults due to increased fat and reduction in total body water.26,27
3 • Obesity 81
TABLE 3.1 Medications Associated with Weight Gain by Drug Class.

CATEGORY DRUG CLASS WEIGHT GAIN
Psychiatric agents Antipsychotic Clozapine
Risperidone
Olanzapine
Quetiapine
Haloperidol
Perphenazine
Quetiapine
Antidepressants/mood stabilizers: tricyclic Amitriptyline
antidepressants Doxepin
Imipramine
Nortriptyline
Trimipramine
Mirtazapine
Antidepressants/mood stabilizers: SSRIs Fluoxetine*
Sertraline*
Paroxetine
Fluvoxamine
Antidepressants/mood stabilizers: MAO Phenelzine
Inhibitors Tranylcypromine
Lithium
Neurologic agents Anticonvulsants Carbamazepine
Gabapentin
Valproate
Endocrinologic Diabetes drugs Insulin (weight gain differs with
agents type and regimen used)
Sulfonylureas
Thiazolidinediones
Sitagliptin*
Meglitinides
Gynecologic agents Oral contraceptives Progestational steroids
Hormonal contraceptives
containing progestational steroids
Endometriosis treatment Depot leuprolide acetate
Infectious disease Antiretroviral therapy Protease inhibitors
agents
General Steroid hormones Corticosteroids
Progestational steroids
NSAIDs
Antihistamines/anticholinergics Diphenhydramine*
Doxepin*
Cyproheptadine*
Source: Apovian CM, Aronne LJ, Bessesen DH, et al., Pharmacological Management of Obesity: An Endocrine Society
Clinical Practice Guideline, J. Clin. Endocrinol. Metab. 100:342 (2015).
* The data supporting the effects of these medications on weight gain are of low quality or conflicting.
TREATMENT
Guidelines for the management of obesity incorporate the presence and severity of weight-related com-
plications as the primary factors that influence the treatment modality. Therapies are aimed at both the
prevention and treatment of obesity and its complications through weight loss achieved by lifestyle,
pharmacological, and/or surgical interventions. Moderate weight loss, defined as a 5%–10% reduction
in baseline weight, is associated with meaningful impacts on obesity-related metabolic risk factors and
comorbidities.28
Prevention
Strategies aimed at the prevention of obesity include school-based and workplace interventions that focus
on learning positive behaviors concerning nutrition and physical activity. Successful interventions include
reducing the consumption of weight-promoting foods and refiguring the antiquated food pyramid for
plates with healthier proportions, such as adopting a Healthy Plate model in which fruits and vegetables
comprise 50% of one’s plate and the other half is divided among proteins and fiber-dense carbohydrates
(Figure 3.6). Strategies aimed to influence the obesity epidemic via nutrition, however, have been met
with several challenges including the expense of and limited access to healthful food options. Additional
strategies include improving access to healthful food options as well as encouraging an active lifestyle.
FIGURE 3.6 Healthy Plate Model: components and quantity of a balanced meal focused on 50% intake of
fruits and vegetables.
3 • Obesity 83
Managing Obesity with Diet, Exercise, and Lifestyle

The cornerstone of all dietary and lifestyle interventions is that energy balance must be negative in order
to lose weight. While multiple factors contribute to the degree of weight loss, a calorie deficit of 500 kcal/
day and adherence to a dietary program are recommended for successful weight loss. Approaches to
exercise include the incorporation of aerobic physical activity building to 150 minutes/week over 3 to 5
days and resistance training two to three times per week. Successful behavioral strategies accompanying
diet and exercise include self-monitoring of food intake and physical activity, stimulus control, and goal
setting.29
Medical Pharmacotherapy
The addition of pharmacotherapy yields greater weight loss and maintenance of weight loss compared
with lifestyle therapy alone. Pharmacologic therapies can be implemented in persons with an initial BMI
>30 kg/m2 or >27 kg/m2 and at least one comorbidity, such as type 2 diabetes mellitus (T2DM), hyperten-
sion, or dyslipidemia.4 The approach to pharmacotherapy should be individualized based on medication
efficacy, side effects, and the patient’s existing comorbidities. Multiple pharmacologic agents have been
approved by the US Food and Drug Administration (FDA) for the treatment of obesity and are reviewed
next (also see Figure 3.7).
Orlistat
Branded as Xenical, orlistat selectively inhibits pancreatic lipase, reducing intestinal digestion of fat. It
is associated with a maximal weight loss of about –6.65 kg and is the only medication approved by the
FDA for use in adolescents with obesity.30 Orlistat can reduce the absorption of fat-soluble vitamins, and
patients should be advised to take vitamin supplements. Rare reports of severe liver injury have been
reported, and patients should be monitored for jaundice, anorexia, or change in stool color. More com-
monly, diarrhea, flatulence, and bloating may occur.
Lorcaserin
Branded as Belviq, lorcaserin reduces food intake by targeting serotonin-2C receptors. It is associated
with a maximal weight loss of –5.39 kg (pooled metanalyses of five studies).5 These studies also demon-
strated an improvement in cardiovascular risk factors. Side effects include headache, sinusitis, depression,
and anxiety.
Liraglutide or Semaglutide
Branded as Saxenda and Wegovy, liraglutide and semaglutide are GLP-1 agonists administered as a daily
or weekly subcutaneous injection respectively. GLP-1 agonists are analogous to GLP-1 with a molecular
change that extends its half-life. They improve glycemic control and satiety and reduce body weight. In
cardiovascular outcome trials of patients with T2DM, GLP-1 agonists lowered the rate of the first occur-
rence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Side effects
include nausea, vomiting, and abdominal pain. GLP-1 agonists are contraindicated in patients with a fam-
ily history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 and should
not be prescribed in patients with a history of pancreatitis.
Phentermine/Topiramate
Branded as Qsymia, phentermine and topiramate decrease appetite by augmenting norepinephrine
and gamma-aminobutyric acid release. This combination produced larger weight loss than observed in
FIGURE 3.7 Chronic weight medical management selection.33 (Adapted from American Association of
Clinical Endocrinology.)
3 • Obesity 85
clinical trials with single drugs with a maximal weight loss of 15.6 kg.5,31 Improvements were also seen in
glycemic and blood pressure parameters. Contraindications include pregnancy (due to an increased risk
of cleft lip/palate in infants), glaucoma, hyperthyroidism, and monoamine oxidase inhibitors. Additional
concerns include an increased risk of kidney stones and tachycardia.
Naltrexone/Bupropion
Branded as Contrave, naltrexone and bupropion work together to reduce food intake by stimulating adren-
ergic and dopaminergic receptors, and inhibiting a feeding stimulus B-endorphin, respectively. Maximal
weight loss was –13.2 kg in a meta-analysis of six studies.5 Bupropion is approved as a single agent for
depression and smoking cessation, and thus may be a favorable choice should they coexist. Contraindications
include uncontrolled hypertension, seizure disorders, drug or alcohol withdrawal, and long-term opioid use.
Selection and Duration of Pharmacotherapy

Although there are few head-to-head trials comparing pharmacologic interventions, meta-analyses of ran-
domized trials have identified that all drug interventions were effective at weight loss when compared to
placebo and lifestyle therapy alone.32 Therefore, simultaneous initiation of lifestyle therapies and pharma-
cotherapy should be considered. Pharmacotherapy should be considered as chronic disease management,
as short-term treatment (under 6 months) did not demonstrate long-lasting health benefits.
Initiation of specific weight-loss pharmacotherapy for patients must include consideration of side
effects, mechanism of action, comorbidities, and contraindications. Therefore, selection must be individu-
alized, but a generalizable algorithm does not currently exist. A few disease-specific considerations are
reviewed next.
Hypertension
In patients with coexisting hypertension, orlistat, lorcaserin, phentermine/topiramate ER,
liraglutide, or semaglutide are preferred. Naltrexone/bupropion combinations are contraindi-
cated in uncontrolled hypertension.29
Diabetes
All weight-loss drugs should be considered in patients with coexisting diabetes. Liraglutide
and semaglutide may be preferred due to improved glucose-dependent insulin release and asso-
ciated glycemic outcomes.
Renal Impairment
Weight-loss medications should be avoided in advanced renal failure (GFR <30). However,
orlistat, liraglutide, or semaglutide can be considered with caution and discontinued in volume
depletion. Additionally, orlistat or phentermine/topiramate ER should not be utilized in patients
at risk of nephrolithiasis.29
Hepatic Impairment
All weight-loss medications should be avoided in severe hepatic impairment (Child–Pugh
score >9) with dose adjustments in hepatic impairment. Similarly, clinicians should have
awareness of the increased risk of cholelithiasis in patients undergoing weight-loss therapy,
particularly GLP-1 agonists.29
SURGICAL THERAPY
Bariatric surgery remains the most effective management option for severe obesity and the management or
resolution of comorbidities (Figures 3.8–3.10).34 The mechanisms by which various bariatric procedures
FIGURE 3.8 Adjustable gastric banding. An external ring with an inflatable balloon is placed around the
proximal stomach. The balloon can be adjusted to modulate gastric restriction. It is less effective than other
bariatric procedures, particularly in sustaining weight loss, and is thus falling out of favor.36
FIGURE 3.9 Sleeve gastrectomy. A tube-like stomach is created by excising a majority of the greater curva-
ture resulting in a marked reduction in gastric capacity. Emerging evidence supports neurohormonal modula-
tion and is associated with better weight loss and metabolic outcomes than purely restrictive approaches.9
3 • Obesity 87
FIGURE 3.10 Roux-en-Y gastric bypass (RYGB). The stomach is divided to create a small gastric pouch that
is connected through a gastrojejunostomy to a distal segment of the jejunum. The remainder of the stomach
drains into the bypassed portion of the bowel and continuity is resorted by a jejunojejunostomy. Along with
neurohormonal effects and impacts on nutrient signaling, RYGB involves an intrinsic malabsorptive and restric-
tive component.9 Patients should be followed by a nutritionist to replenish macronutrient and micronutrient
stores.
exert their benefits include primarily restrictive, malabsorptive, and/or neurohormonal effects. Indications
for surgical management of severe obesity include adults with an initial BMI >40 kg/m2 or >35 kg/
m2 with at least one serious comorbidity.35 Patients should also participate in a comprehensive program
focused on nutrition, behavior, and medical support, both preoperatively and on follow-up.
REFERENCES
1. Schwartz, M. W. et al. Obesity Pathogenesis: An Endocrine Society Scientific Statement. Endocr. Rev. 38(4),
267–296 (2017).
2. Cui, H., López, M. & Rahmouni, K. The Cellular and Molecular Bases of Leptin and Ghrelin Resistance in
Obesity. Nat. Rev. Endocrinol. 13(6), 338–351 (2017).
3. CDC. Defining Adult Overweight and Obesity. Centers for Disease Control and Prevention (2021). https://
www.cdc.gov/obesity/adult/defining.html.
4. Hales, C. M., Carroll, M.D., Fryar, C.D. & Ogden, C.L. Prevalence of Obesity and Severe Obesity Among
Adults: United States, 2017–2018. NCHS Data Brief 360, 1–8 (2020). PMID: 32487284.
5. Bray, G. A. et al. The Science of Obesity Management: An Endocrine Society Scientific Statement. Endocr.
Rev. 39(2), 79–132 (2018).
6. Heindel, J. J., Newbold, R. & Schug, T. T. Endocrine Disruptors and Obesity. Nat. Rev. Endocrinol. 11(11),
653–661 (2015).
7. Wardle, J., Carnell, S., Haworth, C. M. & Plomin, R. Evidence for a Strong Genetic Influence on Childhood
Adiposity despite the Force of the Obesogenic Environment. Am. J. Clin. Nutr. 87(2), 398–404 (2008).
8. Loos, R. J. F. & Yeo, G. S. H. The Genetics of Obesity: from Discovery to Biology. Nat. Rev. Genet. 1–14
(2021) doi:10.1038/s41576-021-00414-z.
9. Tirthani, E., Said, M. S. & Rehman, A. Genetics and Obesity. In: StatPearls (StatPearls Publishing, 2021).
10. Obradovic, M. et al. Leptin and Obesity: Role and Clinical Implication. Front. Endocrinol. 12, 585887 (2021).
11. Izquierdo, A. G., Crujeiras, A. B., Casanueva, F. F. & Carreira, M. C. Leptin, Obesity, and Leptin Resistance:
Where Are We 25 Years Later? Nutrients 11(11), 2704 (2019).
12. Fernandez-Twinn, D. S., Hjort, L., Novakovic, B., Ozanne, S. E. & Saffery, R. Intrauterine Programming of
Obesity and Type 2 Diabetes. Diabetologia 62(10), 1789–1801 (2019).
13. Josefson, J. L. et al. The Joint Associations of Maternal BMI and Glycemia with Childhood Adiposity. J. Clin.
Endocrinol. Metab. 105(7), 2177–2188 (2020).
14. Gunderson, E. P. et al. Childbearing May Increase Visceral Adipose Tissue Independent of Overall Increase in
Body Fat. Obes. Silver Spring Md 16(5), 1078–1084 (2008).
15. Mannan, M., Doi, S. A. R. & Mamun, A. A. Association between Weight Gain during Pregnancy and
Postpartum Weight Retention and Obesity: A Bias-Adjusted Meta-Analysis. Nutr. Rev. 71(6), 343–352 (2013).
16. Karvonen-Gutierrez, C. & Kim, C. Association of Mid-life Changes in Body Size, Body Composition and
Obesity Status with the Menopausal Transition. Healthcare (Basel) 4(3), 42 (2016).
17. Poehlman, E. T. et al. Physiological Predictors of Increasing Total and Central Adiposity in Aging Men and
Women. Arch. Intern. Med. 155(22), 2443–2448 (1995).
18. Kapoor, E., Collazo-Clavell, M. L. & Faubion, S. S. Weight Gain in Women at Midlife: A Concise Review of
the Pathophysiology and Strategies for Management. Mayo Clin. Proc. 92(10), 1552–1558 (2017).
19. Swinburn, B., Sacks, G. & Ravussin, E. Increased Food Energy Supply Is More than Sufficient to Explain the
US Epidemic of Obesity. Am. J. Clin. Nutr. 90(6), 1453–1456 (2009).
20. Mozaffarian, D., Hao, T., Rimm, E. B., Willett, W. C. & Hu, F. B. Changes in Diet and Lifestyle and Long-
Term Weight Gain in Women and Men (2011) doi:10.1056/NEJMoa1014296.
21. Hruby, A. et al. Determinants and Consequences of Obesity. Am. J. Public Health 106(9), 1656–1662 (2016).
22. Reutrakul, S. & Cauter, E. V. Sleep Influences on Obesity, Insulin Resistance, and Risk of Type 2 Diabetes.
Metab. Clin. Exp. 84, 56–66 (2018).
23. Ogilvie, R. P. & Patel, S. R. The Epidemiology of Sleep and Obesity. Sleep Health 3(5), 383–388 (2017).
24. van der Valk, E. S. et al. A Comprehensive Diagnostic Approach to Detect Underlying Causes of Obesity in
Adults. Obes. Rev. 20(6), 795–804 (2019).
25. Sanyal, D. & Raychaudhuri, M. Hypothyroidism and Obesity: An Intriguing Link. Indian J. Endocrinol.
Metab. 20(4), 554–557 (2016).
26. Binnerts, A., Deurenberg, P., Swart, G. R., Wilson, J. H. & Lamberts, S. W. Body Composition in Growth
Hormone-Deficient Adults. Am. J. Clin. Nutr. 55(5), 918–923 (1992).
27. Rosén, T., Bosaeus, I., Tölli, J., Lindstedt, G. & Bengtsson, B. A. Increased Body Fat Mass and Decreased
Extracellular Fluid Volume in Adults with Growth Hormone Deficiency. Clin. Endocrinol. (Oxf.) 38(1), 63–71
(1993).
28. Heymsfield, S. B. & Wadden, T. A. Mechanisms, Pathophysiology, and Management of Obesity (2017)
doi:10.1056/NEJMra1514009.
29. Garvey, W. T. et al. American Association of Clinical Endocrinologists and American College of Endocrinology
Comprehensive Clinical Practice Guidelines for Medical Care of Patients with Obesity. Endocr. Pract. 22,
1–203 (2016).
30. Dong, Z. et al. Comparative Efficacy of Five Long-Term Weight Loss Drugs: Quantitative Information for
Medication Guidelines. Obes. Rev. 18(12), 1377–1385 (2017).
31. Garvey, W. T. et al. Two-Year Sustained Weight Loss and Metabolic Benefits with Controlled-Release
Phentermine/Topiramate in Obese and Overweight Adults (SEQUEL): A Randomized, Placebo-Controlled,
Phase 3 Extension Study. Am. J. Clin. Nutr. 95(2), 297–308 (2012).
32. Khera, R. et al. Association of Pharmacological Treatments for Obesity With Weight Loss and Adverse Events:
A Systematic Review and Meta-Analysis. JAMA 315(22), 2424–2434 (2016).
33. Garvey, W. T. et al. American Association of Clinical Endocrinologists and American College of Endocrinology
Comprehensive Clinical Practice Guidelines for Medical Care of Patients with Obesity. Endocr. Pract. 22,
1–203 (2016).
34. Schauer, P. R. et al. Bariatric Surgery versus Intensive Medical Therapy for Diabetes – 3-Year Outcomes (2014)
doi:10.1056/NEJMoa1401329.
3 • Obesity 89
35. Mechanick, J. I. et al. Clinical Practice Guidelines for the Perioperative Nutritional, Metabolic, and Nonsurgical
Support of the Bariatric Surgery Patient – 2013 Update: Cosponsored by American Association of Clinical
Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery. Obes. Silver
Spring Md 21 S1 (2013).
36. Albaugh, V. L., Flynn, C. R., Tamboli, R. A. & Abumrad, N. N. Recent Advances in Metabolic and Bariatric
Surgery. F1000Research 5, 978 (2016).
Metabolic Bone
Disorders 4
Natasha S. Kadakia, Caroline Poku,
Rod Marianne Arceo-Mendoza, and Pauline Camacho
OSTEOPOROSIS
Definition/Overview
Osteoporosis is a chronic progressive disease characterized by low bone density, microarchitectural
bone deterioration, and decreased bone strength, leading to increased bone fragility and increased frac-
ture risk. In 1994, the World Health Organization (WHO) published criteria for the diagnosis of osteopo-
rosis based on bone mineral density (BMD). Normal BMD is defined as a BMD value within 1 standard
deviation of the young adult female reference mean and is designated as a T-score ≥−1. The young adult
female reference mean is calculated from the mean BMD of healthy females aged 20–29 of a single eth-
nicity. Low bone mass (osteopenia) is defined as a BMD that is between 1 and 2.5 standard deviations
below the young adult mean and is designated as a T-score <−1 and >−2.5. Osteoporosis is defined as a
BMD 2.5 standard deviations or more below the young adult mean designated as a T-score <−2.5. Last,
severe osteoporosis is defined as a BMD 2.5 standard deviations or more below the young adult mean
in the presence of one or more fragility fractures. The diagnosis of osteoporosis is based either upon
the aforementioned WHO criteria or the presence of fragility fractures. These types of fractures occur
with low-impact trauma, such as falling from a standing position, excluding fractures of the fingers, toes,
skull, and face.
In addition, per the 2020 guidelines of the American Association of Clinical Endocrinologists and
American College of Endocrinology (AACE/ACE), osteoporosis may also be diagnosed in patients who
have osteopenia with a high FRAX® (Fracture Risk Assessment Tool) score. FRAX uses clinical history
and, optionally, dual-energy X-ray absorptiometry (DXA) scores to calculate fracture risk. The AACE/
ACE diagnosis of osteoporosis in postmenopausal women includes a T-score of −2.5 or lower in the lum-
bar spine, femoral neck, total proximal femur, or 1/3 radius; low-trauma spine or hip fracture (regardless
of bone mineral density); or a T-score between −1.0 and −2.5 with a fragility fracture of the proximal
humerus, pelvis, or distal forearm.
90 DOI: 10.1201/9781003100669-4
4 • Metabolic Bone Disorders 91
Etiology
Osteoporosis is the most common bone disease in humans. Approximately 33.6 million Americans have
osteopenia or low bone mass, and 10 million have osteoporosis, of whom 80% are females and 20% are
males. The disease affects people of all ethnicities to varying degrees. Non-Hispanic White and Asian
people have the greatest incidence of osteoporosis followed by Hispanics and then non-Hispanic Blacks.
Osteoporosis is responsible for more than 1.5 million fractures annually. One in two women and one in
four men over the age of 50 will have an osteoporosis-related fracture during their lifetime. The national
health care costs for osteoporosis exceed $20 billion annually, with projected total costs of care in 2040 to
exceed $95 billion. Osteoporosis can be classified as either primary or secondary. Primary osteoporosis is
bone loss associated with menopause and the aging process. Secondary osteoporosis can occur as a result
of multiple conditions (Table 4.1).
Pathophysiology
Bone is dynamic. It is constantly undergoing formation and breakdown under the coordinated actions
of osteoblasts and osteoclasts. Approximately 5%–10% of the adult skeleton is replaced annually
through a process called remodeling. Remodeling occurs at focal sites termed ‘bone remodeling units’.
At these sites, osteoclasts and osteoblasts function in concert to replace old bone with new bone
(Figure 4.1).
The process begins with bone resorption by osteoclasts. Mononuclear cells proceed to line the resorp-
tion lacunae and deposit a cement line. Osteoprogenitor cells replace the mononuclear cells in the bone
remodeling unit. These cells differentiate into osteoblasts and begin to lay down the organic matrix. This
is then followed by the deposition of minerals. Osteoporosis occurs due to aberrancy in bone remodeling
in that there is an increase in osteoclast activity with a concomitant decrease in osteoblast activity. There
is also an increase in the total number of bone remodeling units. Therefore, bone resorption is occurring
at more sites than usual and in the presence of impaired bone formation. The actions occurring at the bone
remodeling unit are under the influence of multiple factors such as estrogen, testosterone, and cytokines.
Wnt/β-catenin signaling stimulates osteoblastic activity by promoting the progression of Osterix1 (Osx1)-
expressing cells to osteoblasts. In addition, the Wnt pathway prevents the cellular death of mature osteo-
blasts, thereby prolonging their lifespan. Wnt/β-catenin signaling also decreases osteoclast differentiation
by stimulating the production and secretion of osteoprotegerin (OPG), an antagonist of the receptor acti-
vator of nuclear factor-B ligand (RANKL). RANKL is secreted by osteocytes and is necessary for bone
resorption. During the process of osteoclast generation, RANKL and macrophage colony–stimulating
factors provide a very important step leading to osteoclast differentiation. Overall, if there is a deletion of
this Wnt/β-catenin signaling pathway, there is a subsequent increase in osteoclast number with an increase
in bone resorption, leading to a decrease in bone mass.
Osteoporosis is often called a ‘silent disease’ because bone loss occurs without symptoms. It usually
presents as either a fragility fracture or is discovered on radiographic imaging. There are several risk
factors associated with osteoporosis including advanced age, being female, an estrogen-deficient state or
early menopause, family history of osteoporosis, prior history of low-trauma fractures, cigarette smok-
ing, being thin, anorexia nervosa, low calcium intake, vitamin D deficiency, low testosterone, inactive
TABLE 4.1 Causes of Secondary Osteoporosis
HEMATOLOGIC
ENDOCRINE RHEUMATOLOGIC DRUGS GASTROINTESTINAL DISEASES OTHER
Hyperthyroidism Rheumatoid arthritis Glucocorticoids Celiac sprue Multiple myeloma Renal insufficiency
Primary SLE Anticonvulsants IBD Mastocytosis End-organ failure
hyperparathyroidism
Cushing’s syndrome Other malabsorptive Organ
syndromes transplantation
Hypogonadism Lithium Whipple procedure Malnutrition
Vitamin D deficiency Cytotoxic drugs Gastric bypass surgery Alcoholism
Calcium deficiency
Heparin HIV
Aromatase inhibitors COPD
Gonadotropin-releasing Prolonged non-
hormone agonist weight-bearing
states
Immunosup pressants
COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus; IBD, inflammatory bowel disease; SLE, systemic lupus erythematosus.
FIGURE 4.1 Photomicrograph of bone consisting of a bone remodeling unit composed of osteoclasts and
osteoblasts. (Courtesy of Dr. Susan Ott, http://courses.washington.edu/ bonephys/ophome.html.)
lifestyle, excessive use of alcohol, being Caucasian or Asian, chronic illness, and various medications. On
examination, the patient may have severe back pain, loss of height, or spinal deformities, such as kyphosis
or stooped posture. Other findings may point toward osteoporosis risk factors leading to further diagnostic
workup for osteoporosis.
Osteoporosis is associated with increased bone fragility and increased fracture risk. Hip fractures
are the most devastating complication of osteoporosis, and 90% of hip fractures occur in patients over the
age of 50. One out of every six Caucasian women will have a hip fracture during their lifetime. There is
a 30% excess mortality in the first year after a hip fracture. The diagnosis, treatment, and prevention of
osteoporosis result in a considerable decrease in the incidence of fractures and, therefore, a decrease in
mortality and morbidity.
The differential diagnosis for low bone mass and fractures includes osteomalacia, malignancy, and the
myriad of secondary causes of osteoporosis.
Diagnosis
A DXA scan of the lumbar spine and femoral neck is the most common way to diagnose osteoporosis.
Other imaging modalities include quantitative ultrasound, quantitative computed tomography (CT), and
radiography. Compared to DXA scanning, a quantitative ultrasound looks at the calcaneus as the pri-
mary site of measurement. In terms of fracture risk discrimination, this modality is equivalent to that of
DXA. However, ultrasonography cannot be used for monitoring skeletal changes or evaluating response
to therapy. Quantitative CT allows for selective assessment of both cortical and trabecular bone. This
is important since due to its high turnover rate, trabecular bone enables prediction of spinal fractures.
However, quantitative CT is more expensive and involves greater radiation exposure. Radiography is
less sensitive. DXA provides information regarding bone mineral density and using reference means can
FIGURE 4.2 Bone biopsies. (A) Normal trabecular bone, (B) osteoporosis. (Courtesy of Dr. Susan Ott, http://
courses.washington.edu / bonephys /ophome.html.)
provide both T-scores and Z-scores. Z-scores compare the individual’s bone density with age-matched
controls. In postmenopausal women and in men over age 50, T-scores have the greatest validity. In
premenopausal women and men under age 50, Z-scores have the most validity. The reference mean for
Z-scores should be age and ethnicity appropriate, particularly in children. The trabecular bone score,
or TBS, is an analytical tool that looks at measurements and trabecular bone architecture from lumbar
spine images.
Histopathologic findings in osteoporosis include cortical thinning, increased cortical porosity, and
thin trabeculae (Figure 4.2), and bone densitometry reveals decreased bone mineral density (Figures 4.3
and 4.4). Radiography may reveal compression fractures of the spine (Figure 4.5).
FIGURE 4.3 Dual-energy X-ray absorptiometry of the left and right hip from a patient with severe osteopo-
rosis. The regions are labeled. The total hip is the sum of the regions.
FIGURE 4.4 Dual-energy X-ray absorptiometry of the lumbar spine. The yellow and white lines are added to
the image to guide the scanner software in calculating the bone density.
FIGURE 4.5 Lateral radiograph of a patient with severe osteoporosis revealing kyphosis secondary to mul-
tiple vertebral fractures.
The treatment and prevention of osteoporosis begins with nonpharmacologic therapies. Daily calcium
and vitamin D intake should be optimized. In premenopausal women, the daily elemental calcium intake
should be 1,000 mg/d. At menopause that should be increased to 1,200 mg/d. Similarly, men should opti-
mize their elemental calcium intake to 1,000 mg/d until age 71 and then increase it to 1,200 mg/d. Current
AACE recommendations show an intake of at least 1,000–2,000 IU of vitamin D per day to maintain
optimal vitamin D levels. If patients have risk factors such as obesity or malabsorption, or are on medica-
tions affecting vitamin D metabolism, then they may need a higher dose. The optimal 25 OHD is 30–50
ng/ml.
Exercise is recommended in the treatment and prevention of osteoporosis. Weight-bearing exercise
helps to maintain or increase bone mass. Regular exercise improves strength and coordination, which
reduces the risk of falls. Fall prevention is important in reducing fall-related fractures. Interventions that
reduce the risk of falls are essential. Risk factors for falls include visual impairment, poor balance or gait,
neuromuscular and musculoskeletal disabilities, muscle weakness, postural hypotension, medications,
cognitive impairment, and environmental hazards. Cessation of habits such as cigarette smoking and
excessive alcohol consumption is suggested in the treatment and prevention of osteoporosis.
Indications for pharmacologic therapy are low T-score, high FRAX score, or a previous fragility frac-
ture. It is also important to risk-stratify these patients, as their fracture risk determines the initial choice of
therapy as well as the duration of treatment. Examples of very high fracture risk include recent fractures
(e.g., ≤12 months), fractures while on approved therapy, multiple fractures, fractures while on medications
causing skeletal harm, T-score <–3.0, high risk of falls, and high FRAX score.
Medications used in the treatment of osteoporosis include antiresorptive agents such as oral and
IV bisphosphonates, selective estrogen agonists/antagonists, estrogen/progesterone replacement therapy,
nasal calcitonin, denosumab, and anabolic agents, including teriparatide and abaloparatide. Lastly, romo-
sozumab, which is a humanized monoclonal antibody against osteocyte-derived sclerostin, has both ana-
bolic and anti-resorptive activity. The primary goal in the treatment of osteoporosis is to reduce the
incidence of fractures. A secondary goal is to maintain and, if possible, normalize the BMD.
When recommending pharmacologic therapy, one needs to stratify patients into those who are high
risk or those with very high risk for fractures. Examples of very high risk fractures include advanced
age, frailty, steroid use, very low T-scores, and increased fall risk. For patients who are high risk,
one can start with oral or IV bisphosphonate, or denosumab. For the initial treatment option for very
high risk patients, the recommendation is for abaloparatide, teriparatide, denosumab, zoledronate, or
romosozumab. Once started on therapy, the clinician is to reassess yearly for response to therapy and
fracture risk.
Bisphosphonates inhibit bone resorption by decreasing the number and activity of osteoclasts. Strong
clinical trial evidence supports the use of alendronate, risedronate, ibandronate, and zoledronic acid for
preventing fractures in women with postmenopausal osteoporosis and in men with osteoporosis. These
agents have been shown to reduce vertebral fractures by 50%–70% and hip fractures by 40% in postmeno-
pausal women. Per AACE guidelines, for oral bisphosphonates, consider a bisphosphonate holiday after 5
years of treatment if fracture risk is no longer high, but continue treatment up to an additional 5 years if
fracture risk remains high. If there is a very high fracture risk and if using oral bisphosphonate, consider a
bisphosphonate holiday after 6 to 10 years of stability. For IV zoledronic acid, consider a bisphosphonate
holiday after 3 years in high-risk patients or until fracture risk is no longer high, and continue for up to 6
years in very high risk patients.
Oral bisphosphonates are contraindicated in patients with esophageal irritation or stricture, hypocal-
cemia, hypersensitivity to bisphosphonates, the presence of gastrointestinal (GI) malabsorption (gastric
bypass procedures, celiac disease, Crohn’s disease, etc.), or renal insufficiency (creatinine clearance <30
mL/min). Rare adverse events of prolonged bisphosphonate therapy include osteonecrosis of the jaw and
atypical fractures of the femur. These occur at a rate of 1/10,000–100,000 patient-years. These adverse
events are mitigated by bisphosphonate holidays for risedronate.
Raloxifene is a selective estrogen receptor modulator that is approved for both the treatment and the
prevention of postmenopausal osteoporosis. In clinical studies, raloxifene has been shown to decrease
vertebral fractures by about 50%. However, no evidence is currently available for raloxifene that assesses
nonvertebral or hip fracture reduction. When raloxifene is discontinued, there is a loss of skeletal protec-
tion in the following 1–2 years.
The use of estrogen/progesterone replacement therapy remains controversial in the treatment of
osteoporosis. Estrogen alone or in combination with progesterone decreases bone turnover, bone loss,
and fractures. Due to the risks associated with estrogen/progesterone therapy, it is recommended that
other proven therapies are used in the treatment and prevention of osteoporosis. If estrogen/progesterone
therapy is desired, the lowest possible dose over the shortest possible time is suggested.
Calcitonin inhibits bone resorption by osteoclasts. It is usually administered as a nasal spray. In clini-
cal studies, nasal calcitonin has been shown to prevent bone loss and vertebral fractures, but not nonver-
tebral or hip fractures. Because of its modest effect on osteoporosis treatment and the absence of a BMD
increase (except for in the spine), this drug is mostly used as an alternative agent.
Teriparatide is a recombinant human parathyroid hormone (PTH) analog. It is a potent bone anabolic
agent that increases bone turnover. Studies show that teriparatide increases bone density, and reduces
vertebral fractures by 65% and nonvertebral fractures by 53%. Its use is recommended in postmenopausal
women with severe bone loss who are at high risk for fracture, as well as for the treatment of hypogo-
nadal or primary osteoporosis in men at high risk for fracture. It is also approved for the treatment of
glucocorticoid-induced osteoporosis. When treatment with teriparatide is stopped, there is a decline in
bone density in the following year. Fracture reduction may persist for 1 or 2 years after termination of
therapy. Use of bisphosphonates or denosumab after teriparatide therapy prevents bone mineral density
loss and may result in a further increase in BMD. Teriparatide should not be used in patients with a history
of bone malignancy, Paget’s disease of bone, unexplained hypercalcemia, skeletal radiation exposure, or
those younger than 18 years.
Abaloparatide, a modified PTH-related peptide 1–34, is an anabolic agent approved for the initial
treatment of women with postmenopausal osteoporosis who are at high risk of fracture or have failed/
developed an intolerance to other therapies. Just like teriparatide, it is contraindicated in patients with
Paget’s disease. When looking at data comparing abaloparatide to teriparatide, gains in BMD were greater
with abaloparatide, especially in the femoral neck, total hip, and 1/3 radius. Fracture reduction was also
greater with abaloparatide than with teriparatide. Side effects of both abaloparatide and teriparatide
include nausea, orthostatic hypotension, and leg cramps. Both abaloparatide and teriparatide have warn-
ings regarding the occurrence of osteosarcomas in rats treated with very high doses. Also, abaloparatide
and teriparatide are limited to no longer than 2 years in total duration. The initiation of alendronate after
discontinuation with abaloparatide has been studied with results showing an increase in BMD. Current
data shows that treatment with either teriparatide or abaloparatide should be followed by antiresorptive
therapy, typically with either a bisphosphonate or denosumab.
Denosumab is a humanized monoclonal antibody that works on reducing the rate of differentiation
of precursor cells into mature osteoclasts. It also decreases the survival of activated osteoclasts. In the
FREEDOM trial, which looked at postmenopausal women with osteoporosis, denosumab showed an anti-
fracture efficacy as early as 1 year after starting therapy. Studies showed persistent fracture protection
and a good safety profile with a duration of up to 10 years. It is important to note that when treatment is
stopped, after 2–8 years, BMD rapidly declines. There have also been case reports of multiple vertebral
fractures after stopping denosumab. Thus patients who are being discontinued from denosumab need to
be transitioned to an antiresorptive agent and closely watched. There have been cross-over studies with
exploratory analysis showing stable BMD 2 years posttransition from denosumab to oral bisphosphonates.
There are also studies showing stabilization of BMD with IV zoledronic acid.
Romosozumab is a humanized monoclonal antibody that inhibits sclerostin. This is a protein that
is secreted by osteocytes to reduce bone formation. This pharmacological agent was approved in April
2019. Its indication for use is in the postmenopausal population who are at high risk of fracture or who
have failed/developed an intolerance to other therapeutic agents. This therapy is limited to 12 months. The
FRAME trial looked at postmenopausal women and compared romosozumab to placebo and saw a 73%
lower risk of new vertebral fractures after 1 year of using romosozumab when compared to placebo. With
this medication, there is a risk of myocardial infarction, stroke, and cardiovascular death. It is contraindi-
cated in patients who had a myocardial infarction or stroke in the previous year prior to initiation of therapy.
Combination therapy with an anabolic and an antiresorptive therapy, shows some BMD benefit but no
fracture reduction data has been demonstrated yet. There is evidence to support sequential use of anabolic
followed by antiresorptive therapy, and conflicting evidence on combination therapy.
PRIMARY HYPERPARATHYROIDISM
Definition/Overview
Hyperparathyroidism is a disease defined by the overproduction of PTH. It can be classified as primary,
secondary, or tertiary. Primary hyperparathyroidism (PHP) is characterized by hypercalcemia due to
the autonomous overproduction of PTH, either as a result of parathyroid cell proliferation or impaired
calcium-sensing ability. Secondary hyperparathyroidism is the overproduction of PTH due to hypo-
calcemia and vitamin D deficiency. Tertiary hyperparathyroidism is the development of autonomous
parathyroid function manifested as hypercalcemia and elevated PTH in patients with long-standing sec-
ondary hyperparathyroidism. Recently there has been recognition, which has a high PTH level, and nor-
mal total serum calcium and ionized calcium. There is a risk of progression to hypercalcemic primary
hyperparathyroidism.
Etiology
PHP is present in about 1% of the adult population. The incidence of the disease increases to 2% or higher
after age 55. PHP is two to three times more common in women than in men, with postmenopausal
women having the highest incidence. Approximately 80%–85% of cases of PHP are caused by a single
parathyroid adenoma. The remainder is due to multiple gland hyperplasia affecting all parathyroid glands
(10% of cases), double adenomas (4% of cases), and rarely parathyroid carcinoma (1% of cases). PHP is
most commonly due to a sporadic parathyroid adenoma but may be inherited in endocrine syndromes
such as MEN type 1, MEN type 2A, familial hyperparathyroidism, and hyperparathyroidism jaw tumor
syndrome. Associated risk factors include neck irradiation and treatment with lithium.
Pathophysiology
Solitary parathyroid adenomas are monoclonal or oligoclonal tumors most frequently arising from
somatic or germline mutations in parathyroid precursor cells. Several genes that develop mutations in
PHP have been identified. The MEN type 1 gene is a tumor suppressor gene and the gene known to
most frequently have somatic mutations in both copies in parathyroid adenomas. Activating mutations
of the cyclin D1 gene resulting in the overexpression of the protein cyclin D1 have been identified in
parathyroid adenomas. Activating mutations in the RET protooncogene have also been identified in
parathyroid adenomas. Of note, although the calcium-sensing receptor and the vitamin D receptor
mediate inhibition of the parathyroid gland, no mutations of these genes have been isolated in parathy-
roid adenomas.
In secondary hyperparathyroidism, the elevated PTH is a physiologic response to hypocalcemia.
Hypocalcemia can be due to chronic renal disease. In chronic renal disease, hyperphosphatemia impairs
the ability of the kidneys to reabsorb calcium, resulting in hypercalciuria and hypocalcemia. Additionally,
there is impaired conversion of 25-hydroxyvitamin to 1,25-dihydroxyvitamin D in the diseased kidney,
the active form of vitamin D. It is a calcemic agent regulating calcium and phosphate transport as well as
a cell differentiating agent important for a number of cell types including the osteoclast, enterocyte, and
keratinocyte. Ultimately, a deficiency of 1,25-dihydroxyvitamin D results in hypocalcemia, which is a
stimulus to the parathyroid cells to produce PTH.
Hypocalcemia can also be due to vitamin D deficiency. Vitamin D, although termed a vitamin, is
in fact better described as a prohormone. The term ‘vitamin D’ includes a large group of closely related
secosteroids. Cholecalciferol is the form of vitamin D obtained when radiant energy from the sun strikes
the skin and converts 7-dehydrocholesterol into vitamin D3. Vitamin D deficiency can occur when there
is decreased exposure to the sun, decreased dietary intake of foods containing vitamin D, or decreased
absorption of vitamin D from the diet due to malabsorption syndromes such as celiac sprue. Whatever the
cause for the low vitamin D, as described earlier, it is essential for calcium homeostasis.
In the past, the classic clinical presentation of PHP consisted of ‘stones, moans, and groans’, i.e., neph-
rolithiasis, osteoporosis, fractures, gout, peptic ulcer disease, pancreatitis, fatigue, anxiety, depression,
and cognitive dysfunction. Other manifestations of PHP include muscle weakness, fatigue, renal insuf-
ficiency, hypomagnesemia, hypophosphatemia, hypertension, left ventricular hypertrophy, valvular calci-
fications, vascular stiffness, chondrocalcinosis, pseudogout, normochromic and normocytic anemia, and
band keratopathy (Figure 4.6). Essentially, clinical manifestations of PHP are all secondary to induced
hypercalcemia, hypercalciuria, and increased bone turnover. With the inclusion of total calcium on the
basic metabolic panel, most patients are diagnosed early in the course of PHP secondary to hypercalce-
mia. Consequently, if calcium levels increase over time, patients are often asymptomatic or have subtle
neurobehavioral symptoms such as fatigue and weakness.
As most patients with PHP are asymptomatic, the physical examination often fails to lead to a defini-
tive diagnosis. Careful examination may reveal proximal muscle weakness or illicit nonspecific symp-
toms, such as depression, lethargy, and vague aches and pains. Diagnosis is usually dependent upon
biochemical tests.
The differential diagnosis of hypercalcemia mainly includes cancer, milk-alkali syndrome, granuloma-
tous disease, hyperthyroidism, thiazide diuretics, lithium, and familial hypocalciuric hypercalcemia.
FIGURE 4.6 Band keratopathy in a patient with hyperparathyroidism. The name is derived from the distinc-
tive appearance of calcium deposition in a band across the central cornea. (Courtesy of Dr. Glen Sizemore.)
A normal or elevated PTH excludes malignancy, calcium and vitamin D toxicity, and granulomatous
diseases.
Diagnosis
The diagnosis of PHP requires the determination of serum total or ionized calcium and intact PTH. A
24-hour urinary calcium should be obtained to rule out familial hypocalciuric hypercalcemia, a disor-
der of the renal calcium-sensing receptor. A calcium-to-creatinine clearance ratio below 0.01 differen-
tiates patients with familial hypocalciuric hypercalcemia from those with PHP. Associated laboratory
abnormalities include decreased serum phosphate levels, high normal or increased serum chloride levels,
elevated levels of blood urea nitrogen, elevated levels of creatinine, and elevated levels of bone-specific
alkaline phosphatase. Patients with PHP should have a bone densitometry scan performed to ascertain
the presence or absence of osteopenia or osteoporosis. Parathyroid imaging has no role in the diagnosis
of PHP, but ultrasonography or sestamibi scanning of the parathyroid glands should be used for opera-
tive planning. Imaging can aid in localizing the parathyroid adenoma(s) to particular parathyroid glands
(Figure 4.7).
Patients may satisfy the diagnosis of normocalcemic PHP if they have elevated parathyroid hormone
but normal levels of serum and ionized calcium. To diagnose this, the clinician must rule out secondary
causes of elevated parathyroid hormone. These include primary hypercalciuria, malabsorption syndromes,
kidney disease, or medication induced (loop diuretics, bisphosphonates, or denosumab therapy). Elevated
serum parathyroid hormone with multiple values of normal albumin-adjusted calcium and ionized cal-
cium in the setting of a normal serum 25-hydroxyvitamin D, and appropriate renal function (eGFR >60
mL/min/1.73 m2) supports the diagnosis of normocalcemic PHP. Over time, normocalcemic PHP can
progress to primary hyperparathyroidism.
Histology of the parathyroid gland in hyperparathyroidism can distinguish between malignancy and
hypercellular causes such as adenoma and hyperplasia. Histologically, normal parathyroid tissue shows
a cell-to-fat ratio of 1:1. Hypercellular parathyroid tissue is typified by the loss of the normal amount of
fat. The classic radiographic findings in PHP include nephrolithiasis (Figure 4.8), subperiosteal resorption
(Figure 4.9), thinning of the distal third of the clavicle (Figure 4.10), and osteitis fibrosa cystica (Figure
4.11).
FIGURE 4.7 Sestamibi scan of a patient with a left lower parathyroid adenoma (arrow). The patient’s salivary
glands (parotid, submandibular, and sublingual) represent the bright areas around the jaw.
FIGURE 4.8 Abdominal radiograph showing nephrolithiasis in the right renal medulla in a patient with
hyperparathyroidism. (Courtesy of Dr. Glen Sizemore.)
FIGURE 4.9 Radiograph of the hands revealing subperiosteal bone resorption of the digits in a patient with
Surgery is the first-line treatment for PHP in symptomatic patients. The best management for asymp-
tomatic patients with PHP is more controversial. The 2016 Guidelines for the Management of Primary
Hyperparathyroidism as suggested by the American Association of Endocrine Surgery recommends sur-
gery for patients who fulfill the following criteria:
1. Serum calcium >1.0 mg/dl (0.25 mmol/l) above the upper limit of normal.
2. Creatinine clearance <60 mg/min, or 24-hour urine for calcium >400 mg/day and increased
stone risk by biochemical stone risk analysis, or nephrolithiasis or nephrocalcinosis on imaging
study.
3. T-score <–2.5 at any site and/or previous fracture fragility.
4. Age <50 years.
FIGURE 4.10 Radiograph of the shoulder revealing thinning of the distal third of the clavicle in a patient with
FIGURE 4.11 A photomicrograph of a bone biopsy revealing osteitis fibrosis. This occurs in patients with
hyperparathyroidism from increased osteoclastic resorption of calcified bone with replacement by fibrous tis-
sue resulting in softened and deformed bone that may develop cysts.
Preoperative localization is optional in patients without previous neck surgery. There is an improvement
in localization accuracy when combining thyroid ultrasonography with technetium 99m sestamibi imag-
ing, with sensitivities of 60%–70%. Intraoperative PTH monitoring (IPM) guides surgeons while doing
minimally invasive parathyroid surgeries. IPM provides a more focused approach with cure rates as high
as 97%–99%. Repeat surgery may be necessary for up to 5% of patients who develop persistent PHP due
to incomplete resection of tissue. In these patients, a diagnosis of familial hypocalciuric hypercalcemia
(FHH) should be ruled out before repeat surgery.
Medical management is used for those patients who do not meet surgical criteria or who refuse sur-
gery. BMD tests should be performed every 1–2 years and biochemical profiles should be assessed yearly.
Patients are instructed to maintain adequate hydration, avoid thiazide diuretics, and limit their dietary
intake of calcium to less than 1,000 mg/day. Several medications are of benefit in treating PHP. Based
on current guidelines, cinacalcet has been shown to lower serum calcium in patients with PHP. Calcium-
sensing receptor agonists act directly on parathyroid cells by way of the calcium-sensing receptor to
inhibit the secretion of PTH. It has not been shown to affect BMD, kidney stones, or quality of life. These
calcimimetic agents may prove beneficial in the treatment of PHP. Currently, they are approved for the
treatment of secondary hyperparathyroidism and parathyroid cancer.
Alternatively, bisphosphonates inhibit bone resorption, but a persistent lowering of serum calcium
has not been shown. Thus far, pharmacological treatment has not been shown to improve both BMD and
serum calcium levels. Estrogen/progesterone has been shown to increase bone density in postmenopausal
women with PHP, and some studies indicate that it can decrease serum calcium levels. However, the risks
of hormone therapy must be weighed against the benefits of the treatment of PHP. Estrogen/progesterone
are not first-line agents. In secondary hyperparathyroidism, the goal is to reduce PTH levels to appropriate
goals depending on kidney function. In vitamin D deficiency, treatment with ergocalciferol or cholecal-
ciferol usually results in the normalization of the vitamin D level and the concomitant normalization of
the calcium and PTH. In renal disease, the administration of calcium salts and 1,25-dihydroxyvitamin D3
or calcitriol usually results in the normalization of the serum calcium level. The calcium salts increase
the calcium available for absorption and also chelate the phosphate in the intestines. Calcitriol acts at the
kidneys, intestines, and bone to decrease calcium renal loss, increase calcium absorption, and increase
bone mobilization. As the calcium normalizes, the PTH level also normalizes. Calcimimetic agents, as
described earlier, are currently approved for treatment of secondary hyperparathyroidism. In some cases
of severe secondary hyperparathyroidism and tertiary hyperparathyroidism in renal failure, parathyroid-
ectomy may be required.
HYPOPARATHYROIDISM AND
PSEUDOHYPOPARATHYROIDISM
Definition/Overview
Hypoparathyroidism is a rare entity defined by reduced levels of parathyroid hormone, leading to hypocal-
cemia, hyperphosphatemia, and inappropriately low or normal PTH. Pseudohypoparathyroidism results
from resistance to parathyroid hormone resulting in similar biochemical features as hypoparathyroidism,
except the PTH is elevated.
Etiology
The most common cause of hypoparathyroidism is an injury to or removal of the parathyroid glands dur-
ing neck surgery, which accounts for about 75% of cases. The incidence of hypoparathyroidism after neck
surgery is about 8%. Postsurgical hypoparathyroidism may be transient, permanent, or even intermit-
tent. Other causes of hypoparathyroidism can be categorized by developmental defects in the parathyroid
gland, defects in the PTH molecule, defective regulation of PTH secretion, autoimmune hypoparathyroid-
ism, defects in the type 1 PTH receptor, or defects of the stimulatory guanine nucleotide-binding protein.
Pathophysiology
Defects in the PTH molecule have been shown to result in hypoparathyroidism. A few cases of familial
hypoparathyroidism have been described in which the cause is a mutation in the gene for PTH. The muta-
tion results in the synthesis of a defective PTH molecule and undetectable amounts of PTH in serum.
DiGeorge syndrome, the most common genetic etiology, is a congenital defect resulting in the agen-
esis of the parathyroid glands. DiGeorge syndrome is associated with rearrangements and microdeletions
affecting genes on the long arm of chromosome 22. This in turn affects the protein that is necessary for
the development of the thymus and parathyroids. The manifestations of this syndrome include conotrun-
cal cardiac defects, facial malformations, learning disability, and incomplete development of the brachial
arches, resulting in varying degrees of parathyroid and thymic hypoplasia.
Hypoparathyroidism can also arise from defective regulation of PTH secretion. Autosomal dominant
hypercalciuric hypocalcemia is caused by activating mutations of the parathyroid and renal calcium-
sensing receptors that result in hypocalcemia and hypercalciuria. The mutations cause excessive calcium-
induced inhibition of PTH secretion. The hypocalcemia is usually mild and asymptomatic.
Hypoparathyroidism can occur as a consequence of autoimmunity. Autoimmune polyglandular syn-
drome type 1 consists of hypoparathyroidism, mucocutaneous candidiasis, adrenal insufficiency, and pri-
mary hypogonadism, as well as the less common features of malabsorption, gastrointestinal disorders,
hypothyroidism, and diabetes. The syndrome is inherited as an autosomal recessive trait and is caused by
mutations in an autoimmune regulator (AIRE) gene. The mutation in AIRE is postulated to lead to a loss
of self-immune tolerance, thus leading to destruction of the parathyroids, adrenals, and other endocrine
glands.
Defects in the type 1 PTH receptor can result in low PTH levels. Jansen’s chondrodystrophy is caused
by activating mutations of the type 1 PTH receptor. It is characterized by short limbs, mild hypercalce-
mia, and low serum PTH concentrations. Since the serum calcium level is mildly elevated, it does not
fulfill the definition of hypoparathyroidism.
Pseudohypoparathyroidism occurs due to PTH resistance as a consequence of defects in the PTH
receptor-associated stimulatory guanine nucleotide-binding protein. It is characterized by hypocalcemia
and hyperphosphatemia due to resistance to PTH. There are several forms of pseudohypoparathyroid-
ism. Patients with type 1a have hypocalcemia, hyperphosphatemia, elevated PTH levels, hormone resis-
tance to thyrotropin and gonadotropins, and display characteristic physical features that are collectively
termed ‘Albright’s hereditary osteodystrophy (AHO)’. Maternal transmission of the mutation is required
for the manifestations of this mutation. Typically, patients have short stature, round facies, brachydactyly
(Figures 4.12 and 4.13), obesity, and ectopic soft tissue or dermal ossification(s). In the calvaria, this may
manifest as hyperostosis frontalis interna. Intracranial calcification(s) (Figure 4.14), cataracts, band kera-
topathy, subcutaneous calcifications, and dental hypoplasia (Figure 4.15) are also common but are likely
the consequences of long-standing hypocalcemia. Type 1b patients present predominantly with renal PTH
resistance and lack any features of AHO. Patients with type 1c present with both AHO and PTH resistance
FIGURE 4.12 Radiographs of a patient’s hands. A: Brachydactyly of the third and fourth digits; B: brachydac-
tyly of the fourth digit. (Courtesy of Dr. Glen Sizemore.)
FIGURE 4.13 Photograph of the feet of a patient revealing brachydactyly of the third and fourth digits.
(Courtesy of Dr. Glen Sizemore.)
FIGURE 4.14 Basal ganglia calcification of a patient with hypoparathyroidism. (Courtesy of Dr. Glen Sizemore.)
but have normal stimulatory guanine nucleotide-binding protein function. Type 2 patients present with
a normal urinary cyclic adenosine monophosphate (cAMP) response to PTH but lack a phosphaturic
response. Furthermore, they lack any signs of AHO or resistance to other hormones. Last, patients with
type 2 disease do not display a familial origin.
The clinical findings associated with hypoparathyroidism are primarily due to the level and rate of change
of serum calcium. When hypocalcemia occurs acutely, clinical manifestations include tetany, muscle
cramps, muscle spasms, myopathy, paresthesia, seizures, fatigue, anxiety, and lethargy. When hypocal-
cemia occurs more chronically, patients may have very few symptoms apart from a history of cataracts.
FIGURE 4.15 Dental hypoplasia in a patient with pseudohypoparathyroidism. (Courtesy of Dr. Glen Sizemore.)
The examination findings are also somewhat dependent upon the degree and duration of hypocalcemia.
Findings include hypotension, a positive Trousseau’s sign (carpal spasm with inflation of the blood pres-
sure cuff above systolic), a positive Chvostek’s sign (facial muscle contraction when the facial nerve is
tapped on the ipsilateral side anterior to the ear), papilledema, congestive heart failure, dry and coarse
skin and hair, and brittle hair and nails. The clinician should also look for any depigmentation in the
skin and any signs of fungal infection. One should always inspect the neck for any signs of anterior neck
surgery. Patients with pseudohypoparathyroidism present with the findings of hypoparathyroidism. Some
patients will also display the clinical findings of short stature, rounded face, foreshortened fourth meta-
carpals, obesity, and subcutaneous calcifications characteristic of AHO.
The differential diagnosis of hypoparathyroidism includes iatrogenic from neck surgery, infiltration of
the parathyroid as seen in hemochromatosis, Wilson’s disease, granulomas, metastatic cancer, idiopathy,
human immunodeficiency virus (HIV) infection, hypermagnesemia, and acute severe hypomagnesemia.
Diagnosis
Hypoparathyroidism is diagnosed based on biochemical tests with initial screening to include serum cal-
cium, blood urea nitrogen/creatinine, serum phosphate, and magnesium levels. In hypoparathyroidism,
serum calcium concentrations are decreased and serum phosphate levels are increased. Serum PTH is
inappropriately normal, low, or undetectable. Usually, serum 1,25-dihydroxyvitamin D is low. Alkaline
phosphatase activity is normal. Intestinal calcium absorption and bone resorption are both suppressed.
The renal filtered load of calcium is decreased, and the 24-hour urinary calcium excretion is reduced.
Renal tubular reabsorption of phosphate is elevated. A bone densitometry scan in patients with chronic
hypoparathyroidism shows defects in the mineralization of new bone and can help with determining the
onset of the disease. Abdominal imaging can also be used to look for nephrolithiasis or nephrocalcinosis.
In pseudohypoparathyroidism, diagnosis is generally made based on the measurement of low cAMP and
phosphate levels in the urine following an infusion of synthetic PTH (1–34). The exception is in pseudo-
hypoparathyroidism type 2 in which there is a normal increase in cAMP levels in response to synthetic
PTH but no phosphaturic response.
Treatment for hypoparathyroidism includes therapies targeted to the underlying cause when possible, as
well as the normalization of the serum calcium level. Calcium salts, 1,25-dihydroxyvitamin D, vitamin
D analogues, and magnesium are the mainstay of therapy. For patients with symptoms such as seizures,
tetany, and electrocardiographic changes, as well as those in which hypocalcemia suddenly develops,
intravenous calcium should be administered. Calcium gluconate is preferred and should be continued
until the patient is stabilized with monitoring of calcium every 4–6 hours. Oral treatment with calcium
salts is directed to maintain serum calcium in the low normal range to prevent hypercalciuria. In patients
with hypoparathyroidism, the PTH-dependent renal production of 1,25-dihydroxyvitamin D is impaired.
Therefore, patients require supplementation with calcitriol. Last, hypomagnesemia can contribute to
hypoparathyroidism. Therefore, in patients with hypoparathyroidism, hypomagnesemia, and normal
renal function, magnesium replacement should be initiated. Patients with hypoparathyroidism have been
successfully treated with recombinant human PTH (1–84); however, in September 2019 the drug was
recalled by the US Food and Drug Administration (FDA) due to a defect in the mechanism of delivery
of the medication. Treatment of pseudohypoparathyroidism is similar to that of hypoparathyroidism and
consists largely of calcium replacement and calcitriol. Requirements for vitamin D supplementation are
usually lower than in patients with hypoparathyroidism. Supplementation with 1,25-dihydroxyvitamin
D is ideal, but patients can be treated with vitamin D analogs as well. Patients with AHO may require
specific treatment for problems related to their developmental and skeletal abnormalities. Patients with
pseudohypoparathyroidism type 1a may require therapy for associated hypogonadism or hypothyroidism.
PAGET’S DISEASE
Definition/Overview
Paget’s disease is a metabolic disorder of the bone featuring aggressive osteoclast-mediated bone resorp-
tion and impaired osteoblast-mediated bone formation, resulting in disorganized skeletal remodeling
causing pain, deformities, and fractures.
Etiology
The estimated prevalence of Paget’s disease in the US is about 1% per the National Health and Nutrition
Examination Survey. It occurs most commonly in the countries of Great Britain, Australia, New Zealand,
North America, and Western Europe, where there is a prevalence of about 3%. It rarely affects Africans,
Asians, or people from the Indian subcontinent. Some studies suggest that there is a slight male preponder-
ance. It rarely occurs in individuals under the age of 20. The exact etiology of Paget’s disease is currently
unknown. Family history of Paget’s disease is identified in 15%–30% of patients, suggesting a possible
genetic component. Heterozygous mutations affecting either of two genes have been shown in affected
families to be linked to Paget’s disease. Most of these genes are involved in osteoclast differentiation and
function. The first group consists of 11 different mutations, all of which are clustered around the ubiquitin-
binding domain of the sequestosome 1 protein. This protein modulates activity of the NF-κ β pathway,
an important mediator of osteoclast function. The second group of mutations consists of domain-specific
defects within valosin-containing proteins that predispose to Paget’s disease in a rare syndrome also asso-
ciated with late-onset inclusion body myopathy and dementia. Further evidence of the heterogeneity of
the genetics of Paget’s disease has come from studies reporting linkage of the disease with candidate loci
at chromosome 5q31, chromosome 2, and chromosome 10. Once the genes associated with these loci are
identified, a fuller understanding of the pathogenesis of familial Paget’s disease should follow.
Another possible etiology for Paget’s disease comes from observational studies that suggest the
involvement of virus particles. Particles resembling paramyxovirus nucleocapsids, as well as antigens and
nucleic acid sequences of measles virus, canine distemper virus, and respiratory syncytial virus have been
identified in the nuclei and cytoplasm of pagetic osteoclasts.
Pathophysiology
Paget’s disease occurs as a result of overactive osteoclasts coupled with an increase in osteoblastic func-
tion in a focal manner (Figure 4.16). The woven bone that is formed at a fast rate is structurally weaker
and abnormal, increasing the risk of fracture. It typically involves just one bone or a few bones. The bones
most often involved include the axial skeleton: skull, pelvis, vertebra, femur, or tibia. Osteolytic fronts
progress approximately 1 cm yearly. The subsequent ‘mixed stage’ disease features cortical thickening,
disorganized coarse trabeculae, and bone expansion. In cases of advanced disease, bones are widened and
heterogeneously ossified. This pagetic process does not spread spontaneously to adjacent bones. However,
there currently is no cure.
Paget’s disease is usually asymptomatic and discovered incidentally. The prevalence of the signs and
symptoms of Paget’s disease is uncertain, but the disease usually manifests in the skeleton. The most com-
mon presenting symptom is bone pain, seen in approximately 40% of patients. Other symptoms include
bone deformity, warmth of the skin overlying an affected bone, secondary arthritis, and headaches or
hearing loss if Paget’s disease of bone affects the skull. If the disease involves the skull, jaw, clavicle, or a
long bone of the leg, then skeletal expansion or distortion may be obvious. Mild to moderate, deep, aching
bone pain characteristically begins late in the clinical course, persists throughout the day and at rest, and
seems worse at night. Weight bearing often intensifies the pain, especially if there are osteolytic lesions.
A sudden fracture, a new mass, or constant or worsening bone pain may herald malignant transformation.
Osteosarcomas, or other skeletal sarcomas, develop in less than 1% of patients with Paget’s disease but are
more common and aggressive than in age-matched controls. Several neurologic findings may be present.
FIGURE 4.16 Hematoxylin and eosin decalcified stained section from a bone biopsy revealing an active
lesion of Paget’s disease with large multinucleated osteoclasts as well as osteoblasts that are repairing bone
previously resorbed by the osteoclasts. The arrow points to a giant osteoclast. (Courtesy of Dr. Glen Sizemore.)
Hearing loss may result from skull involvement. Less commonly basilar impressions, hydrocephalus with
headache and dizziness, and cranial nerve deficits may occur. In the spine, compression or ischemia may
cause pain, dysesthesias, or paralysis.
The differential diagnosis includes Paget’s disease, bone metastases, fibrous dysplasia, renal osteodystro-
phy, fluorosis, mastocytosis, tuberous sclerosis, and osteomalacia.
Diagnosis
Paget’s disease is generally diagnosed using biochemical tests. Elevated serum total or bone-specific alka-
line phosphatase (ALP) levels are present in patients with Paget’s disease and reflect increased bone for-
mation. Gamma-glutamyl transferase (GGT) can be used to help further differentiate the source of ALP
and bone-specific ALP can confirm the diagnosis. Other less specific markers of bone formation include
osteocalcin. Markers of bone resorption such as serum and urinary c-telopeptide and n-telopeptide are
elevated in Paget’s disease. The disease can be confirmed using radiographs and bone scans, which can
also detect asymptomatic areas of disease. The radiographic features of Paget’s disease include osteolytic,
osteosclerotic, and mixed lesions.
Histologically, Paget’s disease can be divided into two phases. The active phase features disorga-
nized bone architecture. There are clusters of numerous, large, multinucleated osteoclasts adjacent to
many osteoblasts. The osteoblasts synthesize matrix so rapidly that collagen forms an immature woven or
lamellar pattern with faint cement lines. The stroma is vascular and fibrous. The late phase features thick
trabeculae with a mosaic pattern of prominent cement lines at the interfaces of the numerous past episodes
of bone resorption followed by bone formation (Figure 4.17). Osteoblast activity remains apparent with
pale osteoid deposition.
FIGURE 4.17 Polarized views of (A) normal bone and (B) pagetic bone. The normal bone has a highly orga-
nized lamellar structure, whereas the pagetic bone displays a chaotic picture of lamellar and woven bone with
disorganized structure, often termed the ‘mosaic pattern’. (Courtesy of Dr. Glen Sizemore.)
FIGURE 4.18 Radiograph of the tibia and fibula of a patient with Paget’s disease revealing an area of severe
osteolytic activity (arrow) associated with a small degree of bony expansion in the distal region of the tibia
(arrowheads). (Courtesy of Dr. Glen Sizemore.)
Radiographs of affected areas show cortical thickening and irregular areas of lucency and sclerosis
(Figures 4.18 and 4.19). Skull involvement in Paget’s disease is characterized by bony enlargement as
well as cotton wool areas (Figures 4.20 and 4.21). Involvement of the long bones often results in bowing
deformities (Figures 4.22 and 4.23). On a plain radiograph, the leading edge of an osteolytic front in the
appendicular bones often appears shaped like a flame, a letter V, or a blade of grass (Figure 4.24). Bone
scans in patients with Paget’s disease reveal intense uptake at pagetic areas. Usually, the bone scan reveals
lesions throughout the body, particularly in areas such as the pelvis, vertebra, and scapula (Figure 4.25).
FIGURE 4.19 Radiograph of the lateral spine of a patient with Paget’s disease revealing cortical thickening
(small arrows) and irregular areas of lucency (arrowheads) and sclerosis (large arrows). (Courtesy of Dr. Glen
Sizemore.)
FIGURE 4.20 Radiograph of the skull showing Paget’s disease as characterized by a large circumscribed area
of bone loss, termed ‘osteoporosis circumscripta’, a common finding in Paget’s disease. (Courtesy of Dr. Glen
Sizemore.)
FIGURE 4.21 Radiograph of the skull showing the late sclerotic phase of Paget’s disease as characterized
by tremendous thickening of the cranial vault with chaotic bone structure. (Courtesy of Dr. Glen Sizemore.)
FIGURE 4.22 Photograph of a Paget’s disease patient with bowing of the long bones of the leg. (Courtesy
of Dr. Glen Sizemore.)
FIGURE 4.23 Radiograph of the arm of a patient with Paget’s disease revealing bowing of the radius as well
as cortical thickening and irregular areas of lucency and sclerosis (arrow).
FIGURE 4.24 Radiograph of a long bone in a patient with Paget’s disease showing the leading edge of an
osteolytic front appearing shaped like a flame, a letter V, or a blade of grass. (Courtesy of Dr. Glen Sizemore.)
There is no cure for Paget’s disease. The severity of the disease is variable. Morbidity and mortality come
from the pain, deformity, fracture, and sarcomatous degeneration of pagetic bone. The goal of therapy
is to slow osteoclastic bone resorption. There are several indications for the treatment of patients with
Paget’s disease. Treat if (1) the serum alkaline phosphatase is at least three or four times the upper limit of
FIGURE 4.25 Bone scan of a patient with Paget’s disease revealing lesions throughout the body, particularly
in the pelvis, vertebra, long bones, and scapula.
normal; (2) there are fractures or pain in the pagetic bone; (3) there is skull involvement with hearing loss
or headaches; (4) there is monostotic disease of weight-bearing bones; (5) there is involvement of critical
sites that may lead to complications such as arthritis or fractures; and (6) there is a need to pretreat patients
prior to surgery to reduce hypervascularity and blood loss.
The most commonly used agents for the treatment of Paget’s disease are bisphosphonates. These
agents are synthetic analogs of inorganic pyrophosphate that are not biodegradable. They have skeletal
half-lives measured in years and adhere to mineralized surfaces. Osteoclasts selectively take up bisphos-
phonates resulting in the disruption of energy metabolism and specific enzymatic pathways. Both the oral
and intravenous agents have been proven effective, with intravenous zoledronic acid showing a superior
response rate and longer duration of remission. After a first course of treatment, these agents can normal-
ize markers of bone turnover in most patients with moderate to severe Paget’s disease. Furthermore, most
patients report relief from pain. After a single course, biochemical remission can persist for 6–18 months
with oral bisphosphonates and several years with zoledronic acid. A major side effect of oral bisphospho-
nates is upper gastrointestinal irritation. The Endocrine Society recommends a single 5 mg intravenous
dose of zoledronic acid as the treatment of choice. This is based on two clinical trials that compared
zoledronic acid with oral risedronate. At 6 months, therapeutic response, ALP levels, onset of action, pain
relief, and quality of life were significantly better in the zoledronic acid group.
Intravenous pamidronate or zoledronic acid avoids this side effect, but after an infusion, patients may
develop an acute phase reaction characterized by transient mild fever, myalgias, headache, and malaise
that lasts 1–3 days and is responsive to analgesics and antipyretics. This, however, is uncommon and is
not seen in more than 15% of patients. Transient iritis develops in some patients treated with intravenous
pamidronate. With all bisphosphonates, there is a risk for osteonecrosis of the jaw and atypical femur
fractures. Hypocalcemia may develop in patients treated with intravenous bisphosphonates. This risk can
be minimized by correcting vitamin D deficiency and calcium deficiency before the infusion. After treat-
ment, the patient should continue appropriate vitamin D and calcium supplementation.
Paget’s disease can be treated with subcutaneous calcitonin as a second-line agent. Treatment with
calcitonin remains an option if bisphosphonates are not tolerated or contraindicated. Calcitonin has been
shown to decrease markers of bone turnover by 50%. It also often decreases bone pain and warmth,
improves neurologic complications, and can heal osteolytic lesions. One drawback is that soon after cessa-
tion of therapy, disease reactivation is likely. About 25% of patients acquire resistance to calcitonin. Side
effects include nausea and flushing.
OSTEOMALACIA
Definition/Overview
‘Osteomalacia’ is a term that encompasses several disorders all of which are characterized by defective
bone matrix mineralization. The term ‘rickets’ is often used interchangeably with osteomalacia. Rickets
generally refers to defective bone matrix mineralization of the newly formed bone and growth plate carti-
lage present in children. Osteomalacia generally refers to defective bone matrix mineralization at the sites
of bone remodeling present in both children and adults.
Etiology
The prevalence of osteomalacia is dependent upon the criteria used for diagnosis, i.e., clinical, biochemi-
cal, bone histology, or quantitative bone histomorphometry. On a global scale, vitamin D deficiency is by
far the most common cause of osteomalacia. It can be assumed that osteomalacia is prevalent in regions
where nutritional rickets is common. It is difficult to approximate the prevalence since histological con-
firmation of osteomalacia in children and adolescents with rickets is lacking. In studies describing bone
histomorphometry of the femoral head or iliac crest biopsy in patients with hip fracture, the frequency
of osteomalacia was shown to range from none to more than 30%. Defective bone matrix mineralization
can be caused by (1) calcium deficiency (hypocalcemic osteomalacia), (2) phosphorous deficiency (hypo-
phosphatemic osteomalacia), or (3) primary defects in local bone processes (osteomalacia with normal
mineral homeostasis). Hypocalcemic osteomalacia is essentially due to vitamin D deficiency. Vitamin D
deficiency can occur as a result of inadequate nutritional intake, lack of exposure to sunlight, and intesti-
nal malabsorption syndromes such as celiac sprue or inflammatory bowel disease. Osteomalacia caused
by vitamin D deficiency is seen in three stages. Initially, patients will present with normal serum calcium
and phosphate levels with elevated alkaline phosphatase, serum PTH, and 1,25-dihydroxyvitamin D lev-
els. At this stage, bone histomorphometry reveals only the effects of excess PTH without a mineraliza-
tion defect. In the second stage, serum calcium levels tend to decline, and both serum PTH and alkaline
phosphatase values increase further. At this point, there is some evidence of impaired mineralization seen
on bone histomorphometry. In the third stage, hypocalcemia and hypophosphatemia are seen with further
exacerbation of secondary hyperparathyroidism and cessation of bone matrix mineralization.
Pseudovitamin D deficiency has also been described. It consists of two syndromes caused by congeni-
tal errors in vitamin D metabolism. Pseudovitamin D deficiency type I is an autosomal recessive disorder
resulting in a defect in renal tubular 25(OH)D-1-alpha hydroxylase and thereby 1,25-dihydroxyvitamin
D deficiency. Pseudovitamin D deficiency type II is a hereditary condition resulting in defects in the cal-
citriol receptor effector system leading to resistance to 1,25-dihydroxyvitamin D.
Hypophosphatemic rickets is an X-linked disorder that results in decreased renal tubular absorption of
phosphorus. The disease affects males and is characterized by hypophosphatemia, growth retardation, and
lower limb deformities. A milder case can occur in females who are heterozygous for the gene. Osteomalacia
with normal mineral homeostasis is seen in hypophosphatasia. This rare disorder results from decreased
tissue-specific alkaline phosphatase activity. Clinical presentation can vary and is generally more severe
during childhood than adulthood. Hypophosphatasia is characterized by low alkaline phosphatase levels,
normal or high calcium and phosphate levels, and high serum pyridoxal 5′-phosphate.
Pathophysiology
The causes of osteomalacia from vitamin D deficiency can be classified as extrinsic or intrinsic. Vitamin
D derived from endogenous production in the skin or absorbed from the gut is a prohormone. It is trans-
formed into its active form by two successive steps: hydroxylation in the liver to 25-hydroxyvitamin D
followed by Ι α-hydroxylation in the renal proximal tubule to 1,25-dihydroxyvitamin D. The 25-hydroxyl-
ation of vitamin D in the liver is not tightly regulated. The principal determinant of the rate of 25-hydrox-
ylation is the circulating level of vitamin D. In contrast, the renal Ι α-hydroxylase enzyme is under tight
regulation by PTH, calcitonin, 1,25-dihydroxyvitamin D, calcium, and phosphorus. Once in its active
form, the effects of 1,25-dihydroxyvitamin D are mediated via a high-affinity intracellular vitamin D
receptor. The vitamin D receptor acts as a ligand-modulated transcription factor that belongs to the ste-
roid, thyroid, and retinoic acid receptors gene family.
1,25-Dihydroxyvitamin D is the most powerful physiologic agent that stimulates the active transport
of calcium and to a lesser degree phosphorus and magnesium, across the small intestine. Disorders in
vitamin D action result in a decrease in the net flux of minerals to the extracellular compartment causing
hypocalcemia and secondary hyperparathyroidism. Prolonged vitamin D deficiency decreases serum cal-
cium, causing an increase in serum PTH levels. The increased PTH levels, which act on bone and kidney,
cause an increase in serum calcium levels toward normal. As such, elevated serum PTH levels can be con-
sidered a pathognomonic hallmark in many patients with vitamin D deficiency. Increased renal phosphate
clearance due to secondary hyperparathyroidism and reduced absorption of phosphorus due to deficient
1,25-dihydroxyvitamin D action on the gut result in hypophosphatemia. Low concentrations of calcium
and phosphorus in the extracellular fluid lead to defective mineralization of the organic bone matrix.
The clinical features of rickets are weakness, bone pain, bone deformity, and fragility fractures. The
most rapidly growing bones show the most striking abnormalities. Thus, the clinical features will depend
on the age of onset. Rickets is not present at birth, as calcium and phosphorus levels in fetal plasma are
sustained by placental transport from maternal plasma that is not regulated by the fetal vitamin D sys-
tem. Children with hereditary disorders of vitamin D action usually develop the characteristic features of
rickets within the first 2 years of life. The rib cage may be deformed, contributing to respiratory failure.
Dental eruption is delayed. Muscle weakness and hypotonia are severe and result in a protuberant abdo-
men and further contributing to respiratory failure. This may also cause the inability to walk without
support. After the first year of life with the acquisition of erect posture and rapid linear growth, the defor-
mities are most severe in the legs, causing the bowing of long bones of the lower extremities. The clinical
features of osteomalacia are subtle and may include bone pain or low back pain of varying severity. Severe
muscle weakness and hypotonia may be prominent features in adults with osteomalacia. Improvement
of myopathy occurs after very low doses of 1,25-dihydroxyvitamin D. The first clinical presentation of
osteomalacia may be an acute fracture of the long bones, pubic rami, ribs, or spine. Because of the reduc-
tion in the mineral content of the bones, fractures can occur in the axial and appendicular skeleton. The
clinical presentation of a pseudofracture can be diagnostic of osteomalacia.
In patients with rickets occurring before the age of 2 years, physical examination often reveals wid-
ened cranial sutures, frontal bossing, posterior flattening of the skull, widening of the wrists, bulging of
the costochondral junction, and indentation of the ribs at the diaphragmatic insertion. The teeth usually
show enamel hypoplasia. Bow legs and knock knee deformities as well as widening of the end of long
bones develop as the patient becomes weight bearing. Examination findings of patients with osteomalacia
are often more subtle. Patients often have bone pain, muscle weakness, hypotonia, and fractures.
The differential diagnosis includes osteoporosis, vitamin D deficiency, liver disease, renal disease or
renal osteodystrophy, 1-alpha hydroxylase deficiency, vitamin D resistance, X-linked hypophosphatemic
rickets, autosomal dominant hypophosphatemic rickets, renal phosphate loss, excessive antacid intake,
hereditary hypophosphatemic rickets with hypercalciuria, drug toxicities including anticonvulsants, cho-
lestyramine, glucocorticoids, fluoride, etidronate, parenteral aluminum, imatinib, hypophosphatasia, aci-
dosis, and oncogenic osteomalacia.
Diagnosis
Diagnosis is primarily made through biochemical evaluation. The underlying cause can usually be deter-
mined by measuring the 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, serum calcium, 24-hour uri-
nary calcium, serum phosphorus, intact PTH, urinary cAMP, urinary phosphate, bone-specific alkaline
phosphatase, and osteocalcin. The characteristic biochemical features of vitamin D deficiency are low
to low normal concentrations of serum calcium, low urinary calcium excretion, hypophosphatemia,
increased serum intact PTH levels, increased urinary cAMP excretion, and decreased tubular reabsorp-
tion of phosphate. Biochemical markers associated with increased osteoid production such as bone-spe-
cific alkaline phosphatase and osteocalcin will be elevated in states of rickets and osteomalacia. If unable
to make a definitive diagnosis based on the clinical and biochemical evaluation, then the most reliable way
to establish the diagnosis is with an undecalcified bone biopsy.
The characteristic histologic feature of rickets and osteomalacia is deficiency or lack of mineral-
ization of bone matrix (Figure 4.26). In clinical practice, the bone specimen obtained is from the iliac
crest. Therefore, the histologic picture is osteomalacia. Osteomalacia is defined as excess osteoid and a
quantitative dynamic proof of defective bone matrix mineralization obtained by analysis of time-spaced
tetracycline labeling.
The specific radiographic features of rickets reflect the failure of cartilage calcification and endochon-
dral ossification and, therefore, are best seen in the metaphysis of rapidly growing bones. The metaphyses
are widened, uneven, concave, or cupped, and because of the delay in or absence of calcification, the
metaphyses become partially or totally invisible (Figures 4.27–4.29). In more severe forms, rarefaction
and thinning of the cortex of the entire shaft, sparse bone trabeculation, and bone deformities will become
evident. Greenstick fractures may appear as well. The radiographic features of osteomalacia are either
FIGURE 4.26 Bone biopsy revealing osteomalacia as defined as excess osteoid (arrow) and defective bone
matrix mineralization (arrowhead). (Courtesy of Dr. Susan Ott, http://courses.washington.edu/ bonephys/oph-
ome.html.)
FIGURE 4.27 Radiograph of the lower extremity of a patient with rickets (A) before and (B) after treatment.
The metaphyses are widened, uneven, concave, or cupped and partially invisible (arrows). (Courtesy of Dr.
Glen Sizemore.)
FIGURE 4.28 Radiograph of the hand of a patient with rickets (A) before and (B) after treatment. The
metaphyses are widened, uneven, concave, or cupped and partially invisible (arrows). (Courtesy of Dr. Glen
Sizemore.)
FIGURE 4.29 Radiograph of the tibia and fibula of a patient with rickets. The metaphyses are widened,
uneven, concave, or cupped and partially invisible. (Courtesy of Dr. Glen Sizemore.)
mild, such as generalized, nonspecific osteopenia, or more specific, such as pseudofractures, commonly
seen at the medial edges of the shaft of long bones (Figure 4.30). In hypocalcemic osteomalacia, radio-
graphic features of secondary hyperparathyroidism, such as subperiosteal resorption and cysts of the long
bones, may exist.
Rickets and osteomalacia comprise a spectrum of diseases. The prognosis is dependent upon age at pre-
sentation and the severity of the disease. Patients with rickets often have lifelong morbidity and mortality.
In contrast, patients with asymptomatic osteomalacia in adulthood may have complete resolution of the
disease with treatment. Treatment depends in large part on the etiology of the osteomalacia. The goals
of therapy for vitamin D–deficiency osteomalacia are to ease the symptoms, foster an environment for
fracture healing, and improve bone strength, all while correcting any biochemical abnormalities. The goal
with treatment of vitamin D–deficiency osteomalacia is to maintain 25(OH)D levels >30 ng/ml. Typically,
treatment consists of replacement of vitamin D with ergocalciferol, cholecalciferol, or, in severe cases,
calcitriol. Because vitamin D is stored in fat and released slowly and the half-life of 25-hydroxyvitamin
D is 2–3 weeks, the vitamin can be given orally once a month, once every 6–12 months, or once a year
by injection. Calcitriol (1,25-dihydroxyvitamin D) is given in cases where there is impaired renal conver-
sion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, such as in 1-alpha hydroxylase deficiency or
when there is severe malabsorption and secondary hyperparathyroidism. Patients with hypophosphatemic
FIGURE 4.30 Radiograph of the left pelvis, hip, and proximal half of the lower extremity with a pseudofrac-
ture at the medial edges of the femur. (Courtesy of Dr. Glen Sizemore.)
rickets benefit from treatment with phosphorus and 1,25-dihdroxyvitamin D. In the case of drug-induced
osteomalacia, treatment is the discontinuation of the offending agent.
SCLEROTIC BONE DISORDERS
Definition/Overview
Sclerotic bone disorders consist of a group of illnesses characterized by impaired osteoclast resorption
and/or increased osteoblast-mediated bone formation, ultimately resulting in thickening of cortical and
lamellar bone.
Epidemiology and Etiology

Osteopetrosis is a heterogeneous group of sclerotic bone disorders defined by defects in proteins in dif-
ferentiated osteoclasts, resulting in impaired osteoclast resorption. They are rare and can be grouped into
three main variants: (1) the autosomal dominant benign form that occurs in adulthood, termed ‘osteo-
petrosis tarda’; (2) the autosomal recessive malignant form that occurs in infancy, termed ‘osteopetrosis
congenita’; and (3) the autosomal recessive intermediate form that occurs in childhood, termed ‘marble
bone disease’.
Sclerotic bone disease also occurs as a consequence of prostate and breast cancer bone metastases
that induce increased osteoblast activity. Bone metastases occur in up to 70% of patients with advanced
breast or prostate cancer. The exact incidence of bone metastasis is unknown, but it is estimated that
350,000 people die from bone metastases annually in the United States. Metastases to the bone are a poor
prognostic sign, as only 20% of patients with breast cancer are still alive 5 years after the discovery of
bone metastasis.
Pathophysiology
Osteopetrosis is characterized by impaired osteoclastic bone resorption. The osteoclast is a multinucle-
ated cell with a typical ruffled border that is capable of breaking down both the inorganic and organic
matrix of bone. Osteoclastic bone resorption requires the establishment of a pH gradient across the ruffled
membrane and the synthesis and release of lysosomal enzymes, in particular tartrate-resistant acid phos-
phatase (TRAP) and cysteine proteinases such as the cathepsins, which are capable of degrading collagen.
Multiple genes are involved in the etiology and pathophysiology of osteopetrosis. The gene mutations
range from autosomal recessive to autosomal dominant. The severity of the mutations ranges from mod-
erate to malignant. It should be noted that a substantial percentage of patients with osteopetrosis have no
identifiable gene defect.
The mechanisms of osteoblastic metastasis and the factors involved are unknown. Endothelin-1 has
been implicated in osteoblastic metastasis from breast cancer. It stimulates the formation of bone and the
proliferation of osteoblasts in bone organ cultures, and serum endothelin-1 levels are increased in patients
with osteoblastic metastasis from prostate cancer. In addition to endothelin-1, platelet-derived growth fac-
tor, a polypeptide produced by osteoblasts in the bone microenvironment, urokinase, and prostate-specific
antigen (PSA) may also be involved. Prostate cancer cells also release PSA, a kallikrein serine protease.
PSA can cleave PTH-related peptides at the N-terminus, which could block tumor-induced bone resorp-
tion. It may also activate osteoblastic growth factors released in the bone microenvironment during the
development of bone metastases.
Clinical history in sclerotic bone disease is dependent upon the etiology. Autosomal recessive osteope-
trosis presents in infancy and is associated with failure to thrive and growth retardation. This form of
osteopetrosis is very severe and usually results in death by 2 years of age. Proptosis, blindness, deaf-
ness, and hydrocephalus occur in these patients as bone encroaches on the cranial foramina. A critical
feature of autosomal recessive osteopetrosis is severe bone marrow failure resulting in pancytopenia.
Thrombocytopenia, leukoerythroblastic anemia, elevated serum acid, and alkaline phosphatase levels are
also usually present. Hypocalcemia may or may not be present. Death from autosomal recessive osteo-
petrosis occurs as a result of severe anemia, bleeding, and/or infection. In rare instances, patients survive
into adulthood. They present with severe anemia, recurrent fractures, growth retardation, deafness, blind-
ness, and massive hepatosplenomegaly.
Intermediate autosomal recessive osteopetrosis is not characterized by bone marrow failure and sur-
vival rates are better. Patients are usually of short stature and present with intracranial calcifications,
sensorineural hearing loss, and psychomotor retardation.
Autosomal dominant osteopetrosis is asymptomatic in about 50% of cases and detected by a family
history of bone disease or as an incidental radiologic finding. About 40% of patients present with fractures
related to brittle osteopetrotic bones or with osteomyelitis, especially of the mandible. There is sufficient
retention of the marrow cavity for normal hematopoiesis to occur in patients with autosomal dominant
osteopetrosis.
The consequences of bone metastases are often devastating. Patients with osteoblastic metastases
have bone pain and pathologic fractures because of the poor quality of bone produced by the osteoblasts.
The differential diagnosis of sclerotic bone disease includes malignant autosomal recessive osteopetrosis,
intermediate autosomal recessive osteopetrosis, autosomal dominant osteopetrosis, severe osteoclast poor
osteopetrosis, transient infantile osteopetrosis, osteopetrosis with renal tubular acidosis, osteopetrosis
with neuronal anomalies, osteopetrosis with anhidrotic ectodermal dysplasia, immunodeficiency, lymph-
edema, osteopetrosis with Glanzmann thrombasthenia, and metastatic breast or prostate cancer.
AFFECTED
SCLEROSING BONE SKELETAL
DISORDER ONSET (AGE) REGION TYPICAL FINDINGS
Osteopetrosis Autosomal dominant, Skull, long Symmetric increase in bone mass with
adulthood bones, spine a ‘bone within a bone’ appearance
Pycnodyostosis Early childhood Skull, long Recurrent fractures, disproportionate
bones, orbital short stature with narrow thorax and
region large cranium
Osteomalacia Middle-aged, more Spine and pelvis Coarsening of trabecular bone
predominant in resembling osteomalacia
males
Osteopoikilosis Childhood Long bones, Spotty and patchy texture
hands, feet
Paget’s disease Axial skeleton Coarse trabecular thickening with
bone enlargement
Diagnosis
The diagnosis of sclerotic bone disease is derived from a combination of clinical findings, as well as radio-
logic evidence of dense, deformed, and diffusely sclerotic bone. Generalized osteosclerosis is apparent
radiographically, often with a ‘bone within a bone’ appearance (Figure 4.31). Transverse radiolucent bands
may be observed, and it may be difficult to discern the marrow cavity. The decrease in osteoclast activ-
ity also affects the shape and structure of bone by altering its capacity to remodel during growth (Figure
4.32). In severely affected patients, the medullary cavity is filled with endochondral new bone, with little
space remaining for hematopoietic cells. Osteosclerosis in patients with prostate or breast metastases is
similar in appearance radiographically to that seen in osteopetrotic patients (Figure 4.33).
Few therapies have proven effective in sclerotic bone disease. Bone marrow transplantation has been
shown to be curative in autosomal recessive infantile osteopetrosis. It effectively treats both bone mar-
row failure and metabolic disturbances. Zoledronic acid, a potent inhibitor of osteoclast activity, dif-
ferentiation, and survival, has been shown to decrease the risk of skeletal complications in males with
androgen-independent prostate cancer and bone metastases. The efficacy of zoledronic acid may extend
to other metastatic cancers such as metastatic breast cancer. The remaining options include treatment of
FIGURE 4.31 Radiograph of the tibia with a sclerotic pseudofracture (arrow) as well as the typical ‘bone
within a bone’ appearance. (Courtesy of Dr. Glen Sizemore.)
FIGURE 4.32 Biopsy of sclerotic bone revealing increased new bone, increased disorganization, and
decreased marrow cellularity. (Courtesy of Dr. Susan Ott, http://courses.washington.edu/ bonephys/ophome
.html.)
associated symptoms. Current guidelines recommend calcium and vitamin D as first-line therapy for the
treatment of hypocalcemia and secondary hyperparathyroidism in patients with osteopetrosis. The lack of
published studies on noninfantile osteopetrosis makes the development of evidence-based guidelines for
the clinical management of these patients difficult.
FIGURE 4.33 Radiograph of the pelvis and hip revealing sclerotic osteoblastic metastatic prostate neoplasms
(arrows) involving the sacrum, right and left innominate bones, and the left greater trochanter.
REFERENCES
AACE/AAES Task Force on Primary Hyperparathyroidism. The American Association of Clinical Endocrinologists
and the American Association of Endocrine Surgeons position statement on the diagnosis and management of
primary hyperparathyroidism. Endocr Prac 2005;11(1):49–54.
Balemans W, Van Wesenbeeck L, Van Hul W. A clinical and molecular overview of the human osteopetroses.
Calcified TissueInt 2005;77:263–74.
Bastepe M, Juppner H. GNAS locus and pseudohypoparathyroidism. Hormone Res 2005;63:65–74.
Dawson-Hughes B, Gold DT, Rodbard HW, Bonner FJ Jr, Khosla S, Swift SS. Physician’s guide to the prevention
and treatment of osteoporosis. National Osteoporosis Foundation, 2003. www.nof.org/physguide/index.htm.
Leib ES, Lewiecki EM, Binkley N, Hamdy RC, International society for clinical densitometry: Official positions of
the International Society for clinical densitometry. J Clin Densit 2004;7:1–6.
Lyles KW, Siris ES, Singer FR, Meunier PJ. A clinical approach to the diagnosis and management of Paget’s disease
of bone. J Bone Min Res 2001;16:1379–87.
Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000;343(25):1863–75.
Mauck KF, Clarke BL. Diagnosis, screening, prevention, and treatment of osteoporosis. Mayo Clin Proc
2006;81(5):662–72.
Nelson HD, Helfand M, Woolf SH, Allan JD. Screening for postmenopausal osteoporosis: A review of the evidence
for the US preventive services task force. Ann Intern Med 2002;137:529–41.
NIH Consensus Development Panel. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;285:785–95.
Ott S. Osteoporosis and bone physiology. 2006. http://courses.washington.edu/ bonephys/ophome.html
Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004;350(16):1655–64.
Roodman GD, Windle JJ. Paget disease of the bone. J Clin Investig 2005;115(2):200–8.
Sambook P, Cooper C. Osteoporosis. Lancet 2006;367:2010–18.
Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP. A 10-year prospective study of primary hyperparathyroid-
ism with or without parathyroid surgery. N Engl J Med 1999;341(17):1249–55.
Tolar J, Teitelbaum SL, Orchard PJ. Osteopetrosis. N Engl J Med 2004;351(27):2839–49.
White MP. Paget’s disease of the bone. N Engl J Med 2006;355(6):593–600.
WHO. Scientific Group on the prevention and management of osteoporosis. Prevention and Management of
Osteoporosis: Report of a WHO Scientific Group. Publications of the World Health Organization, Geneva,
2003.
Hypothalamic-
Pituitary Disorders 5
S. Sethu K. Reddy, Pruthvi Goparaju, and Maria Fleseriu
INTRODUCTION
The pituitary gland is divided into two lobes: anterior (developed from Rathke’s pouch) and posterior
(developed as a diverticulum growing downward from the base of the hypothalamus). It weighs less than a
gram and sits in the sella turcica, which is surrounded by bony walls and floor and a roof made up of dura,
and then the optic chiasma, hypothalamus, and third ventricle. The optic chiasma may be anterior (15%),
above (80%), or behind the sella (5%). Laterally on each side are the cavernous sinus; internal carotid
artery; and cranial nerves III, IV, V1, V2, and VI.
The median eminence is an intensely vascular component at the base of the hypothalamus that forms
the floor of the third ventricle. The pituitary stalk arises from the median eminence. The hypothalamus
extends anteriorly to the optic chiasm and posteriorly to the mamillary bodies.
Most of the anterior pituitary hormones have associated stimulatory releasing hormones: luteinizing
hormone-releasing hormone (LHRH) for both luteinizing hormone (LH) and follicle-stimulating hor-
mone (FSH); corticotrophin-releasing hormone (CRH) for adrenocorticotrophic hormone (ACTH); thyro-
tropin-releasing hormone (TRH) for thyroid-stimulating hormone (TSH); and growth hormone-releasing
hormone (GHRH) for growth hormone (GH). Of note, prolactin (PRL) is under tonic inhibitory influence,
with dopamine acting as a PRL release-inhibiting factor (Table 5.1). Magnetic resonance imaging (MRI)
TABLE 5.1 Pituitary Hormones, Hypothalamic Hormones, and Other Regulatory Factors
PITUITARY HYPOTHALAMIC
HORMONE HORMONE OTHER REGULATORY FACTORS
Thyrotropin (TSH) TRH T4, T3, dopamine, Pit 1
ACTH CRH ADH, adrenaline, cortisol
LH LHRH Estrogen, progesterone, testosterone
FSH LHRH Activin, estrogen, inhibin, follistatin, testosterone
GH GHRH Somatostatin, estrogens, T4, Pit 1
PRL PRF Dopamine, TRH, Pit 1, estrogen, serotonin, vasoactive
intestinal peptide, GnRH-associated peptide
ACTH, adrenocorticotrophic hormone; CRH, corticotrophin-releasing hormone; FSH, follicle-stimulating hormone; GH,
growth hormone; GHRH, growth hormone-releasing hormone; GnRH, gonadotropin-releasing hormone; LH, lutein-
izing hormone; LHRH, luteinizing hormone-releasing hormone; PRF, prolactin-releasing factor; PRL, prolactin; TRH,
thyrotropin-releasing hormone.
124 DOI: 10.1201/9781003100669-5
5 • Hypothalamic-Pituitary Disorders 125
is the best method for visualization of hypothalamic–pituitary anatomy, optic chiasm, vascular structures,
and tumor extension to cavernous sinuses.
PITUITARY ADENOMAS
Definition/Overview
Pituitary adenomas are tumors that may present with either hypofunction or hyperfunction, as well as
symptoms directly related to mass effect (Table 5.2). Since the advent of computed tomography (CT),
microadenomas have been arbitrarily designated as equal or less than 10 mm (Figure 5.1) in diameter
and macroadenomas as greater than 10 mm in diameter (Figure 5.2). They are invariably benign, with no
sex predilection. Pituitary adenomas are rarely associated with parathyroid and pancreatic hyperplasia or
neoplasia as part of the multiple endocrine neoplasia type 1 (MEN1) syndrome. Pituitary carcinomas are
rare, but metastases from other solid malignancies (e.g., breast, lung most common) can occur more fre-
quently. The fifth edition of the WHO Classification of Endocrine and Neuroendocrine Tumors suggests
that pituitary adenomas should be labeled pituitary neuroendocrine tumors (PitNETs).
Etiology
About 50% of pituitary adenomas are prolactinomas, 15% GH-producing, 10% ACTH-producing, and
less than 1% secrete TSH. Nonfunctioning pituitary adenomas, or more appropriately named nonsecretory
TABLE 5.2 Clinical Manifestations of Pituitary Tumors

ENDOCRINE EFFECTS
MASS EFFECTS HYPERPITUITARISM HYPOPITUITARISM
Headaches GH: acromegaly GH: short stature in children;
Chiasmal syndrome PRL: hyperprolactinemia increased fat mass, decreased
Hypothalamic syndrome ACTH: Cushing disease strength, and well-being in adults
• Disturbances of thirst, Nelson’s syndrome PRL: failure of postpartum lactation
appetite, satiety, sleep, LH/FSH: gonadal dysfunction or ACTH: hypocortisolism
and temperature silent α-subunit secretion
regulation LH or FSH: hypogonadism
• Diabetes insipidus TSH: hypothyroidism TSH: hyperthyroidism
• SIADH
Obstructive hydrocephalus
Cranial nerves III, IV, V1, V2,
and VI dysfunction
Temporal lobe dysfunction
Nasopharyngeal mass
• CSF rhinorrhea
ACTH, adrenocorticotrophic hormone; CSF, cerebrospinal fluid; FSH, follicle-stimulating hormone; GH, growth hormone; LH,
luteinizing hormone; PRL, prolactin; SIADH, syndrome of inappropriate antidiuretic hormone secretion; TSH, thy-
roid-stimulating hormone.
FIGURE 5.1 Pituitary microadenoma. Scan of a 40-year-old male with a 4 mm hypodense lesion in the left
lateral pituitary. There was no evidence of any pituitary hypo- or hyperfunction. Pituitary adenomas tend to be
hypointense on T1-weighted images and more likely to be hyperintense on T2-weighted images. With gado-
linium contrast, the pituitary adenoma is initially hypointense and later hyperintense.
FIGURE 5.2 Pituitary macroadenoma. (A) Abnormal eroded sella, confirmed by (B) MRI image. The coronal
images, (C) precontrast and (D) postcontrast, show the true extent of the tumor with evidence of wrapping
around the carotid vessel.
FIGURE 5.3 GH-secreting adenoma. (A) Young male showing some prominence of the frontal sinus and
prognathism of lower jaw. Of note, one should always compare with historical images to confirm a change
over time. (B) Young male demonstrating herpetegenous forehead wrinkling and prognathism.
adenomas, represent about 25% of pituitary tumors. Most of these adenomas on morphologic examination
reveal granules containing hormones, typically components of glycoprotein hormones (Figure 5.3).
Impingement on the chiasma or its branches by pituitary pathology may result in visual field defects,
with the most common being bitemporal hemianopsia. Lateral extension of the pituitary mass to the cav-
ernous sinuses may result in diplopia, ptosis, or altered facial sensation. Among the cranial nerves, third
nerve palsy is the most common.
Autopsy studies suggest that up to 20% of normal individuals harbor incidental pituitary microad-
enomas that are pathologically similar in distribution to those that present clinically. The initial workup
should be limited and include serum prolactin and insulin-like growth factor-1 (IGF-1) levels. Other
screening tests may be performed depending on clinical features. The adenoma can be followed yearly by
MRI, with increasing duration between imaging studies, if the size is stable.
PROLACTINOMA
Definition/Overview
Hyperprolactinemia is the most common pituitary disorder. Observational studies in patients with micro-
adenomas indicate that serum PRL concentration or adenoma size increase in only a minority of patients
and, indeed, serum PRL decreases in the majority of cases over time. Estrogen therapy in the past has
been suggested as a cause of prolactinoma formation, but careful case–cohort studies have found no evi-
dence that oral contraceptives induce development of prolactinomas. Clonal analysis of tumor deoxyribo-
nucleic acid (DNA) indicates that prolactinomas are monoclonal in origin.
Pathophysiology and Clinical Presentation

Hyperprolactinemia impairs pulsatile gonadotropin release (LH and FSH), likely through alteration
in hypothalamic LHRH secretion. Women of reproductive age usually present with oligomenorrhea,
TABLE 5.3 Clinical Presentation of Hyperprolactinemia

MEN WOMEN
Early Irregular menses
Polycystic ovary syndrome
Reduced fertility
Galactorrhea
Late Hypogonadism Osteoporosis
Erectile dysfunction
Reduced energy
Galactorrhea
Headaches
Impaired visual field
Gynecomastia
amenorrhea, galactorrhea, and infertility. Those with long-standing amenorrhea are less likely to have
galactorrhea, likely secondary to long-standing estrogen deficiency. Men and postmenopausal women
usually seek medical attention because of mass effect such as headaches and visual field defects. Many
men with hyperprolactinemia do not report any sexual dysfunction, but once treated effectively for
hyperprolactinemia, the majority realizes the previous presence of problems including decreased libido
and erectile dysfunction (Table 5.3). Men with long-standing hypogonadism may have decreased facial
and body hair, and soft but usually normal-sized testicles (if hypogonadism starts before completion of
puberty, testicles will be small). Patients with microadenomas have a higher frequency of headaches com-
pared to control subjects.
Premenopausal women tend to present earlier with hyperprolactinemia than men or postmenopausal
women. Thus, the latter often present with macroadenomas and symptoms of anterior hormone deficiency
and local mass effect in the sella. Prolactinomas are four times more common in women.
It is critical to evaluate drug history carefully since some medications are associated with hyper-
prolactinemia, and their discontinuation (if possible) will avoid any further, often expensive, workup.
Other common conditions associated with elevated PRL levels include pregnancy and hypothyroidism
(Table 5.4).
Diagnosis
The PRL level usually correlates well with the size of the tumor. A serum PRL level above 200 μg/L is
almost always indicative of a PRL-producing pituitary tumor. Conversely, a serum PRL level below 200
μg/L in the presence of a large pituitary adenoma is usually suggestive of stalk compression. However,
one must be wary of the ‘hook effect’ phenomenon, which leads to modest elevations in PRL (below 200
μg/L) despite the presence of a large tumor. This occurs when extremely elevated levels of PRL interfere
with the assay by saturating both the capture and signal antibodies, thus preventing binding. If suspected,
the test should be repeated with a 1:100 dilution of the serum. Stimulatory tests, including TRH stimula-
tion tests, are nonspecific and rarely used at present.
TABLE 5.4 Differential Diagnosis of Hyperprolactinemia

PHYSIOLOGIC PATHOLOGIC PHARMACOLOGIC
Pregnancy Prolactinoma TRH
Postpartum Acromegaly (25%) Psychotropic medications
Newborn Hypothalamic disorders Phenothiazines
Stress Chiari–Frommel syndrome Reserpine
Hypoglycemia Craniopharyngioma Methyldopa
Sleep Metastatic disease Estrogen therapy
Postprandial Pituitary stalk secretion or Metoclopramide, cimetidine (especially
hypoglycemia compression intravenous)
Intercourse Hypothyroidism Opiates
Nipple stimulation Renal failure Verapamil
Liver disease Some SSRIs including fluoxetine and
fluvoxamine
Chest wall trauma (burns, shingles)
SSRI, selective serotonin reuptake inhibitor; TRH, thyrotropin-releasing hormone.
Medical therapy with dopamine agonists is now the first-line treatment, since surgical resection is curative
only in a minority of patients and is associated with risk of recurrence in all patients. Cabergoline twice
weekly, bromocriptine mesylate, and pergolide mesylate are potent inhibitors of PRL secretion and often
result in tumor shrinkage. Suppression of prolactin secretion by dopamine agonists depends on the num-
ber and affinity of dopamine receptors on lactotrope adenoma. There is usually a substantial decrease in
prolactinoma size even when serum PRL levels do not normalize. These medications should be slowly ini-
tiated, since side effects often occur at the beginning of treatment. The most common side effects include
nausea, headache, dizziness, nasal congestion, and constipation. It is important to remember that it may
take up to 6 months before testosterone increases and normal sexual function is restored in men success-
fully treated for prolactinomas. PRL appears to have an independent effect in men on libido, since exog-
enous testosterone works poorly in restoring libido in those who continue to have elevated PRL levels.
Although patients with microadenomas or patients without evidence of a pituitary tumor can some-
times be followed without therapy, patients with macroadenomas always need to be treated. Occasionally,
a patient with microadenoma or no definite pituitary tumor will have stable PRL levels after dopamine
agonist discontinuation. For this reason, it would be reasonable to try a ‘drug holiday’ after several years
of therapy with close follow-up.
Despite early concerns of cardiac valve disease with the use of pergolide and cabergoline, most
follow-up studies have not demonstrated an increase in valvular regurgitation. The clinician may order
an echocardiogram if clinically suspected. Medical therapy during pregnancy often stirs debate about
the continuation of bromocriptine. Tumor-related complications are seen in about 15% of pregnancies
and in only 5% of women with microadenomas. A sensible approach would be to stop bromocriptine
when pregnancy begins, and then follow the clinical status with MRI and visual field examinations. PRL
levels may be misleading in pregnancy. If there is significant worsening in clinical status, bromocriptine
could be reinstituted. A large review of over 2,500 pregnancies with bromocriptine use did not reveal any
increase in maternal or fetal complications related to therapy. In a follow-up study of over 900 children
exposed to bromocriptine in utero, there were no developmental delays observed. Macroprolactinomas are
more likely to worsen during pregnancy with symptomatic growth observed in up to 40% of pregnancies.
Breastfeeding has not been associated with tumor growth.
Even in the presence of mass effect symptoms such as visual field defects, dopamine agonists are
the first line of therapy, since a rapid improvement in symptoms is observed in the majority of patients.
Transsphenoidal resection is preferred and reserved for patients with disease refractory to medical ther-
apy. The main advantage of surgery is avoidance of chronic medical therapy. Radiation therapy may be
considered for patients who poorly tolerate dopamine agonists and will likely not be cured by surgery
(e.g., tumor invasion of cavernous sinuses).
ACROMEGALY
Definition/Overview
Acromegaly is a disease that results from excessive GH secretion usually from a pituitary tumor (Figure
5.4). It occurs at a rate of three to four cases per million per year with mean age at diagnosis of 40 years
in males and 45 years in females.
Etiology and Differential Diagnosis

Acromegaly is caused by GH-secreting pituitary tumors (95%) and, rarely, by ectopic GHRH secretion
by carcinoids or pancreatic islet cell tumors. Somatotrope adenomas are monoclonal in origin. A Gsp
mutation in a GspIα subunit in GH cells, leading to continuous GH secretion, has been shown to result in
acromegaly. Ectopic GH secretion has been documented in extracts of lung adenocarcinoma, and breast
and ovarian cancers. None of these conditions, except one case of pancreatic tumor, has been reported to
cause acromegaly.
FIGURE 5.4 Acromegaly due to a pituitary tumor. (Courtesy of Dr. Donald Gordon.)
The GH-secreting tumors tend to be more aggressive in younger patients. Classic clinical features include:
• Coarsening of facial features (Figure 5.5)

• Prominent jaw and frontal sinus (Figure 5.6)
• Broadening of hands and feet (Figures 5.7–5.9)
• Hyperhidrosis
• Macroglossia (Figure 5.5C)
• Signs of hypopituitarism
• Diabetes mellitus (10%–25%)
• Skin tags (screening for colonic polyps required)
• Hypertension (25%–30%)
• Cardiomyopathy (50%–80%)
• Carpal tunnel syndrome
• Sleep apnea (5%)
FIGURE 5.5 Coarse facies due to bone overgrowth in acromegaly. (Courtesy of Dr. Donald Gordon.)
FIGURE 5.6 Enlarged sinuses in acromegaly. (Courtesy of Dr. Donald Gordon.)
FIGURE 5.7 Hands in acromegaly: (A) thick fingers, (B) spade-like hands, (C) tufting of terminal phalanges.
(Courtesy of Dr. Donald Gordon.)
Other features include overgrowth of vertebrae (Figure 5.10), degenerative arthritis (Figure 5.11), and
acanthosis nigricans (Figure 5.12). Particular attention to early detection of cardiovascular disease is of
paramount importance. Patients with acromegaly have a 3.5-fold increased mortality rate, often due to
cardiovascular disease. In addition, acromegalic patients have an increased risk of colon polyps with the
potential for an increased risk of malignancy, affecting their life expectancy. For this reason, they should
FIGURE 5.8 Hand in acromegaly: thickening of fingers and palm. (Courtesy of Dr. Donald Gordon.)
FIGURE 5.9 Thick heel pad in acromegaly.
undergo a colonoscopy every 3–5 years until more data about the frequency of such screening tests are
available. It is not clear if more rigorous screening for a variety of cancers, including breast, lung, and
prostate cancer, is indicated in these patients.
Diagnosis
Random GH levels can overlap in acromegalic patients and controls, due to GH’s pulsatility. Therefore, a
single GH level is inadequate to establish the diagnosis. IGF-1 has a longer plasma half-life than GH and
is an excellent initial screening test for those suspected to have acromegaly. An elevated IGF-1 level in a
clinical setting suggestive of acromegaly almost always confirms the diagnosis. One should be aware that
concomitant poorly controlled diabetes or malnutrition could be associated with low IGF-1 levels. The
oral glucose tolerance test remains the gold standard test to confirm the diagnosis. Normal individuals
suppress their GH level to less than 1 μg/L (using chemiluminescent assays) within 2 hours after ingestion
of 100 g oral glucose solution.
In the case of ectopic acromegaly, elevated GHRH can be measured in blood to confirm the diag-
nosis (usually >300 ng/mL). In the rare patient with a hypothalamic GHRH-secreting tumor, peripheral
GHRH levels may be normal. In patients with a GH-secreting pituitary adenoma, the GHRH level is
FIGURE 5.10 Overgrowth of vertebrae in acromegaly. (Courtesy of Dr. Donald Gordon.)
FIGURE 5.11 Degenerative arthritis in acromegaly. (Courtesy of Dr. Donald Gordon.)
FIGURE 5.12 Acanthosis nigricans in acromegaly. (Courtesy of Dr. Donald Gordon.)

low or undetectable. About 70% of patients with acromegaly have been shown to display a paradoxical
GH response to TRH, but unfortunately, with the lack of availability of TRH, this test is no longer easily
accessible.
The primary aims of treatment include relieving the symptoms, reducing tumor bulk, normaliza-
tion of IGF-1 and GH dynamics, and preventing tumor regrowth. Medical treatment of acromegaly
has improved over the last three decades, since the limitations of radiation and surgical therapy have
become evident. Analogs of somatostatin are the most effective medical therapy available for acro-
megaly. Octreotide therapy has been shown to lower and normalize IGF-1 in 90% and 65% of patients,
respectively. It is usually given as a subcutaneous injection three times per day. Long-acting octreotide
(Sandostatin LAR) can be given monthly intramuscularly. Long-term observations of patients on soma-
tostatin analogues have shown no evidence of tachyphylaxis. Some degree of tumor shrinkage in up
to 50% of patients is expected, although in most cases there is less than 50% shrinkage in tumor size.
The most common side effects are gastrointestinal, including diarrhea, abdominal pain, and nausea.
The most serious side effect of Sandostatin analogues is cholelithiasis, seen in up to 25% of patients.
Its management is similar to those with cholelithiasis in the general population, and routine ultraso-
nographic screening is not indicated. This type of therapy may be quite useful as an adjunct to radio-
therapy since radiotherapy may take several years to significantly reduce GH levels. Recently, an oral
formulation of octreotide has been approved for use in those who have responded to GH reduction to
injectable octreotide or lanreotide.
Normalization of IGF-1 is seen in only 10%–15% of patients treated with dopamine agonists and is
more likely with pituitary tumors secreting both GH and PRL. Pegvisomant, a GH receptor antagonist,
is a novel addition to the list of pharmacologic agents for acromegaly. This is administered as a daily
subcutaneous injection. IGF-1 is significantly reduced and clinical symptoms improve; however, growth
of the tumor is not inhibited and rare cases of tumor enlargement have been reported. In refractory sce-
narios, a combination of somatostatin receptor ligands with GH receptor antagonists may be considered.
Cabergoline has also been used in doses higher than those used for prolactinomas.
The surgical approach is the treatment of choice in those presenting with pituitary microadenomas
or when the tumor is confined to sella, with a cure rate of up to 90%. For those with macroadenomas,
surgical cure is observed in less than 50% of cases. Even in those not cured by surgery, tumor debulking
usually results in the improvement of symptoms and lowering of IGF-1 levels. Radiation therapy almost
always induces a decrease in the size of the tumor and GH level, but often fails to normalize IGF-1 levels.
Given low efficacy, high risk of hypopituitarism, and lack of knowledge about long-term effects on neu-
ropsychiatric functions, radiation therapy should be reserved for those not responsive to other treatment
modalities. Radiosurgery (gamma knife) seems to be superior to conventional radiation therapy, but large
studies with strict cure criteria including the normalization of IGF-1 and long-term safety profile are lack-
ing. GH antagonists are currently being investigated.
CUSHING DISEASE AND ECTOPIC ACTH SYNDROME
Definition/Overview
Cushing disease and ectopic ACTH syndrome are associated with excess cortisol secretion caused by
ACTH from the pituitary or a nonpituitary tumor, respectively. ACTH-secreting pituitary adenoma is the
FIGURE 5.13 ACTH-producing adenoma resulting in adrenal hyperplasia in Cushing syndrome.
most common cause of endogenous Cushing syndrome (CS) (60%) with the rest being adrenal (25%) or
ectopic (15%) in origin (Figures 5.13 and 5.14).
The following findings are suggestive of a hypercortisolism state:
• Central obesity
• Muscle wasting with proximal muscle weakness
• Thinning of skin and connective tissue
• Osteopenia/osteoporosis
• Spontaneous ecchymosis
• Purplish wide striae (>1 cm) (Figure 5.15)
• Hypokalemia
Other findings, which are less helpful in discriminating patients with and without Cushing, are hyperten-
sion, abnormal glucose tolerance, menstrual irregularities, and psychiatric disturbances including depres-
sion. Women with Cushing disease typically have fine facial lanugo hair and may have acne and temporal
scalp hair loss secondary to increased adrenal androgen secretion. There is usually a 3- to 6-year delay
FIGURE 5.14 Small-cell carcinoma of lung with ectopic ACTH overproduction in Cushing syndrome.
FIGURE 5.15 Clinical features in Cushing syndrome: purple striae.
in diagnosis of patients with Cushing disease, and it may be possible to date the onset of the disease by
determining, which scars are pigmented due to excess secretion of ACTH and other melanotropins.
Diagnosis
Twenty-four–hour urinary free cortisol measurement is the single best test for diagnosis of CS. Because
of the significant overlap between normal individuals and those with Cushing, random serum cortisol has
no role in the diagnosis of Cushing syndrome. A 1 mg overnight dexamethasone suppression test with a
morning cortisol level below 1.8 μg/dL virtually rules out the disease but has an up to 40% false-positive
rate. The combination of a low-dose dexamethasone suppression test and CRH stimulation test has been
shown to have 100% diagnostic accuracy in a study by the National Institutes of Health (NIH). This test
may have a significant value in establishing the diagnosis in those with pseudo-Cushing and elevated
24-hour urinary free cortisol. Other tests useful in establishing the diagnosis of Cushing disease include
midnight serum and salivary cortisol (Figure 5.16).
5.16
Clinical 2 Equivocal LDDST/CRH test

suspicious 24 hr UFC Midnight serum or
for Cushing salivary cortisol
Suppressed Low normal

ACTH CRH test
ACTH-independent ACTH-dependent
(adrenal source) (ectopic vs.pituitary)
Pituitary MRI
Adrenal CT HDDST and/or CRH test
Conclusive Inconclusive
Chest CT scan TS surgery IPSS
HDDST: high-dose dexamethasone suppresion test; IPSS: inferior petrosal sinus sampling;
LDDST: low-dose dexamethasone suppresion test; TS: trans-sphenoidal; UFC: urinary free cortisol.
FIGURE 5.16 Cushing evaluation: workup algorithm.
Once the diagnosis of CS has been established, the next step is to find out whether it is ACTH depen-
dent (Figure 5.16). Whereas undetectable or low ACTH are consistent with adrenal etiology, low-normal
ACTH may be seen in both ectopic Cushing and those with an ACTH-secreting pituitary tumor. A CRH
stimulation test is used for differentiation between the two. Although ACTH levels tend to be higher in
those with ectopic CS compared to patients with pituitary disease, there is considerable overlap. High-
dose dexamethasone test and/or CRH stimulation test are helpful in the differentiation of the two. Cortisol
levels are not suppressed with the high-dose (8 mg) dexamethasone test in patients with ectopic ACTH
syndrome and CRH stimulation may not lead to a further rise in ACTH. The gold standard test to dif-
ferentiate pituitary Cushing from an ectopic ACTH-producing tumor is inferior petrosal sinus sampling.
This test should be performed by an experienced neuroradiologist and it is essential to note that it cannot
be used to make the diagnosis of CS.
Ectopic ACTH syndrome is the most frequent and best studied of the ectopic hormone syndromes.
Most tumors associated with ectopic ACTH syndrome are carcinomas and have a poor prognosis. They
usually present as a rapid onset syndrome (within 6 months) associated with profound muscle weakness,
hyperpigmentation, hypertension, hypokalemia, and edema. Hyperpigmentation is thought to be due to
cosecretion of β-melanocyte stimulating hormone (β-MSH), one of the byproducts of ACTH synthesis.
Some benign tumors, such as carcinoids or islet cell tumors, have been shown to cause ectopic ACTH
syndrome and are difficult to differentiate from pituitary causes of Cushing syndrome. This difficulty
is exaggerated by radiologic investigations of the sella that are often negative or show a microadenoma,
which is seen in up to 20% of autopsy series in normal individuals.
Surgical (transsphenoidal) removal of the ACTH-secreting pituitary tumor is the treatment of choice.
Availability of an experienced surgeon is crucial with an 80%–90% remission rate following surgery. An
undetectable cortisol level postoperatively off steroid is considered to be an excellent marker for long-term
cure. There is a period of temporary adrenal insufficiency following successful surgery, usually of 6–8
months, but may be as long as 2 years in duration. For those not cured by the surgery, other options include
a second operation and radiation therapy. Patients whose tumor is unresponsive to these therapies may
then be offered medical or surgical adrenalectomy. Ectopic ACTH-producing tumors should be resected
if possible. Octreotide may inhibit ectopic ACTH secretion. Mitotane is perhaps the most effective adre-
nolytic agent. Other medications, such as aminoglutethimide, ketoconazole, or metyrapone, are useful
as temporizing agents only. The glucocorticoid antagonist mifepristone has been US - FDA approved
therapy that appears to have few side effects. One difficulty is that one cannot rely on cortisol measure-
ments to follow the effect of mifepristone.
OTHER PITUITARY ADENOMAS
Nonfunctioning or Glycoprotein-Secreting
Tumors and TSH Adenomas
Definition/Overview
Nonfunctioning or glycoprotein-secreting tumors are usually clinically silent because they are inefficient
in secreting hormones and lack a clinically recognizable syndrome. TSH-secreting adenomas are the most
uncommon.
Glycoprotein (LH or FSH) secreting adenomas usually come to attention because of manifestations of
mass lesions including headache and visual field defect. Patients may present with varying degrees of
hypopituitarism due to mass effect. Rarely, an FSH adenoma may cause amenorrhea in a woman, or an
LH adenoma may cause precocious puberty in a boy.
The clinical picture in patients with TSH-secreting pituitary adenomas includes pituitary mass lesion,
hyperthyroidism, and goiter.
Diagnosis
Diagnosis of an LH or FSH adenoma is confirmed by measurement of either intact glycoprotein hormones
or their α and β subunits. Levels of the α subunit tend to be inappropriately elevated, compared with those
of the intact hormone itself. The most important biochemical feature of a TSH adenoma is the elevation
of thyroid hormone levels in the presence of normal or elevated TSH levels. For this reason, any patient
presenting with endogenous hyperthyroidism and an elevated or normal TSH should be further evaluated
for the presence of a TSH-secreting pituitary adenoma. Elevated serum PRL and α subunit are in favor of
a thyrotrope adenoma and against thyroid hormone resistance syndrome.
The transsphenoidal surgical approach is standard, especially if visual function is abnormal. Surgery is
rarely curative because of the size of the adenoma on presentation, and radiation therapy is usually needed
as an adjunct. Octreotide may help reduce hormone secretion, but further studies are required to assess if
it has any effect on tumor size. Dopamine agonists, such as bromocriptine, have been used in high doses,
but clinical responses (i.e., changes in tumor size or visual symptoms) occur in less than 10% of patients.
Long-acting gonadotropin-releasing hormone (GnRH) agonists and antagonists may reduce secretion of
FSH and LH by tumors but do not reduce tumor size. In summary, the efficacy of the medical therapy in
patients with nonfunctional or glycoprotein-secreting pituitary adenoma is not established but is used in
an attempt to reduce tumor hypersecretion and size following unsuccessful surgery.
Lymphocytic Hypophysitis
Definition/Overview
Lymphocytic hypophysitis is a disease characterized by lymphocytic infiltration of the pituitary gland
which may lead to hypopituitarism.
Etiology
Hypophysitis is usually an autoimmune phenomenon, but other etiologies include inflammation second-
ary to sella tumors or cysts, systemic diseases, and infection or drug-induced causes. More recently, other
etiologies, including immunoglobulin G4 (IgG4)-related disease, immunotherapy-induced hypophysitis,
and paraneoplastic pituitary-directed autoimmunity, have been described.
Pathophysiology
Lymphocytic infiltration leads to mass effect and eventually hypofunction of the pituitary.
This is often seen in females during or after pregnancy. The clinical manifestations are secondary to
hypopituitarism or adrenal insufficiency and/or due to a pituitary mass effect.
Diagnosis
Serum PRL is elevated in half of patients but may be decreased. Antipituitary antibodies are present
in some patients and other autoimmune endocrine disorders, including Hashimoto’s thyroiditis and
Addison’s disease have been seen in others. MRI and CT scans of the sella reveal a pituitary mass and,
in some cases, thickening of the stalk. MRI shows diffuse and homogeneous contrast enhancement of
the anterior pituitary area. Although the diagnosis may be suspected on clinical grounds in a pregnant or
postpartum woman, a surgical biopsy is occasionally needed for confirmation of the diagnosis.
Management
Some patients recover fully, while others may need selective hormone replacement. For this reason,
patients need to be assessed at regular intervals for the necessity of continued hormone replacement.
Empty Sella Syndrome

Definition/Overview
Empty sella syndrome is often a radiologic diagnosis and is manifest by a sella that may appear to be
empty to varying degrees (i.e., partial to complete) (Figures 5.17 and 5.18).
FIGURE 5.17 (A and B) Images depicting auricular calcification. This clinical finding may be seen with acro-
megaly, hyperparathyroidism, and adrenal insufficiency. This particular subject had secondary adrenal insuf-
ficiency secondary to an empty sella syndrome.
FIGURE 5.18 Coronal image demonstrating an enlarged empty sella. Note that the intrasellar content is the
same density as CSF in the lateral ventricles.
Etiology
Whereas the primary empty sella is the result of a congenital diaphragmatic defect, the secondary empty
sella may result from previous surgery, irradiation, or infarction of a preexisting tumor.
Diagnosis
The diagnosis of empty sella syndrome is increasingly made owing to the prevalence of CT and MRI.
Pituitary fossa enlargement is secondary to communication between the pituitary fossa and subarachnoid
space, which causes remodeling and enlargement of the sella. Most patients have no pituitary dysfunction,
but a wide spectrum of pituitary deficiencies have been described, especially in those with secondary
empty sella. Coexisting tumors may occur.
Management is usually with reassurance and hormone replacement, if necessary. Surgery is only neces-
sary if visual field defects occur or if there is cerebrospinal fluid rhinorrhea.
Hypopituitarism
Etiology
Pituitary adenomas are the most common cause of hypopituitarism, but other causes including parasellar
diseases, following pituitary surgery or radiation therapy, and head injury must also be considered. The
usual consequence of pituitary hormone deficiency secondary to a mass effect is in the following order:
GH, LH, FSH, TSH, ACTH, and PRL. PRL deficiency is uncommon except in those with pituitary infarc-
tion. Isolated deficiencies of various anterior pituitary hormones have also been described.
Clinical Presentation, Management, and

Treatment of Hormone Deficiencies
GH deficiency is now recognized as a pathologic state in adults as well as children and more patients
with GH deficiency undergo GH replacement. GH deficiency may contribute to increased mortality in
patients with hypopituitarism, with cardiovascular disease being the most common cause of mortality.
The symptoms of GH deficiency in adults are more subtle including decreased muscle strength and exer-
cise tolerance, and reduced sense of well-being (e.g., diminished libido, social isolation). Patients with
GH deficiency have increased body fat, particularly intra-abdominally, and decreased lean body mass in
comparison to normal adults. Some patients have decreased bone mineral density, which may improve
with GH replacement. A trial of GH replacement in adults with documented GH deficiency and symptoms
or metabolic abnormalities suggestive of GH deficiency is indicated. The most common side effects of GH
therapy include fluid retention, carpal tunnel syndrome, and arthralgia. These side effects are usually dose
related and improve with dose reduction.
Gonadotropin deficiency may be secondary to a pituitary defect; hypothalamic deficiency of LHRH;
or a functional abnormality, such as hyperprolactinemia, anorexia nervosa, and severe disease state. In
females, gonadotropin deficiency causes infertility and menstrual disorders including amenorrhea. It is
often associated with lack of libido and dyspareunia. In males, hypogonadism is diagnosed less often,
since decreased libido and impotence may be considered as a function of aging. Hypogonadism is often
diagnosed retrospectively when a patient presents with a mass effect. Osteopenia is a consequence of long-
standing hypogonadism and usually responds to hormone replacement therapy.
The symptoms of secondary adrenal insufficiency are similar to primary adrenal insufficiency with
one important difference. Mineralocorticoid secretion is mainly regulated by the renin and angiotensin
system, and is preserved in patients with pituitary disorders. For this reason, the symptoms are more
chronic in nature and commonly include malaise, loss of energy, and anorexia. Hyperkalemia is not a
feature of secondary adrenal insufficiency. An acute illness may precipitate vascular collapse, hypogly-
cemia, and coma.
TSH deficiency is relatively a late finding in patients with pituitary disorders, with symptoms being
similar to those with primary hypothyroidism including malaise, leg cramps, lack of energy, and cold
intolerance. The degree of hypothyroidism depends on the duration of thyrotropin deficiency.
PITUITARY APOPLEXY
Definition/Overview
Pituitary apoplexy is an endocrine emergency resulting from hemorrhagic infarction of the pituitary, usu-
ally associated with a preexisting pituitary tumor.
Etiology
A variety of predisposing conditions, including bleeding disorders, diabetes mellitus, pituitary radia-
tion, pneumoencephalography (of historical interest only), mechanical ventilation, and trauma, have been
described.
Diagnosis
Diagnosis is made when a patient presents with classic symptoms of headache, visual disturbance, and an
MRI or CT showing hemorrhage within a pituitary adenoma.
• Aneurysm of the internal carotid
• Basilar artery occlusion
• Hypertensive encephalopathy
• Acute expansion of intrasellar cyst or abscess
• Cavernous sinus thrombosis
The clinical manifestations of this syndrome are related to rapid expansion and compression of the
pituitary gland and the perisellar structures, leading to severe headaches, hypopituitarism, visual field
defects, and cranial nerve palsies. Extravasation of blood or necrotic tissue into the subarachnoid space
may cause clouding of consciousness, meningismus, autonomic dysfunction, fever, and, rarely, sudden
death.
Although secondary hypoadrenalism does not usually result in hypotension, acute loss of ACTH in
pituitary hemorrhage can result in shock. Other deficiencies of anterior pituitary hormones may be pres-
ent, but diabetes insipidus is seen only transiently in 4% of cases.
If pituitary apoplexy is suspected, anterior pituitary insufficiency should be presumed and the patient
must be treated accordingly. The glucocorticoid dose must be adequate for the degree of stress and
presumptive cerebral edema. Any evidence of sudden visual field defects, oculomotor palsies, hypotha-
lamic compression, or coma should lead to immediate surgical decompression. The recovery of a variety
of pituitary hormone deficiencies following surgery has been documented, and all patients should be
reevaluated for possible recovery of their pituitary hormone axes. The choice between initial medical
versus surgical management is debated, and more research on prognostic variables and clinical outcomes
is needed.
Sheehan’s syndrome is the result of ischemic infarction of a normal pituitary gland leading to hypo-
pituitarism secondary to postpartum hemorrhage and hypotension. Patients have a history of failure to
lactate postpartum, failure to resume menses, cold intolerance, or fatigue. Some women may have an
acute crisis mimicking apoplexy within 30 days postpartum. There is often subclinical central diabetes
insipidus (DI).
A patient with untreated hypopituitarism may decompensate acutely with stress, resulting in a coma.
This acute decompensation may mimic acute myocardial infarction, overwhelming sepsis, a cerebro-
vascular accident (CVA), or meningitis. Symptoms may be a blend of acute thyroid and adrenal insuf-
ficiency. Clinical clues might consist of a myxedematous or acromegalic appearance and/or decreased
body hair.
POSTERIOR PITUITARY
Introduction
The posterior pituitary is a storage site for antidiuretic hormone (ADH, vasopressin) and oxytocin.
Clinically, disorders of ADH are the most relevant (Table 5.5). ADH secretion is regulated by changes in
serum osmolality and/or plasma volume. Small increments in serum osmolality greater than 290 mOsm/
kg lead to prompt secretion of ADH. However, more than a 10% reduction in plasma volume will override
any osmolar stimulus. Pain, nicotine, and caffeine can increase ADH secretion. Native ADH is a potent
vasoconstrictor, but desmopressin (DDAVP), an ADH analogue, has pure antidiuretic action with little
vasoconstriction.
TABLE 5.5 Common ADH-Related Syndromes

CLINICAL PRESENTATION THIRST ADH SECRETION ADH ACTION DIAGNOSIS
Polyuria/polydipsia N ⇓ N Central DI
Polyuria/polydipsia N N ⇓ Nephrogenic DI
Polyuria/polydipsia ⇑ N N Primary polydipsia
⇑ Na+ ⇓ N N Hypodipsia
⇓ Na+ ⇓ ⇑ N SIADH
DI, diabetes insipidus; SIADH, syndrome of inappropriate antidiuretic hormone secretion.
CENTRAL DIABETES INSIPIDUS
Definition/Overview
Central DI (pituitary origin) is a polyuric syndrome secondary to inadequate ADH secretion and the
inability to concentrate urine. Patients have a normal response to administration of vasopressin. Maximum
urine output due to complete ADH deficiency is about 18 liters per day, and urine volume over this indi-
cates excess fluid intake.
Etiology
• Familial
• Idiopathic
• Trauma/postsurgical
• Granulomatous disease
• Tumors
• Craniopharyngioma (Figure 5.19)
• Pituitary tumors
• Metastatic cancer
• Infectious
• Vascular
• Aneurysms
• Sheehan’s syndrome
• Autoimmune
Diagnosis
Patients with DI who are conscious usually have sufficient thirst to maintain a normal serum sodium in
spite of polyuria. In this situation, a standard water deprivation test should be performed, during which
patients are allowed no fluid to drink and are closely monitored. When two consecutive voided urine
osmolalities differ by less than 30 mmol/L or when 5% of body weight is lost, 5 U of aqueous vasopressin
FIGURE 5.19 Craniopharyngioma with suprasellar mass. (A) Precoronal and (B) postcoronal T1-weighted
images. (Courtesy of Dr. Amir Hamrahian.)
(approximately 5 μg of DDAVP) is given intravenously with repeating urine osmolality measurements at

30 and 60 minutes.
Desmopressin administration following dehydration will elicit the following responses:
• Less than 9% increase in urine osmolality with maximal urine concentration during the test
– normal
• Greater than 50% rise in urine osmolality with inadequate urine concentration during the test
– central DI
• No rise in urine osmolality with inadequate urine concentration during the test – nephrogenic DI
The serum ADH level at the end of fast and before administration of vasopressin helps to differentiate
between partial central and nephrogenic DI, since both may have modest concentrations of urine with
dehydration and a more than 10% increase in urine osmolality in response to vasopressin.
Patients with psychogenic polydipsia have a diluted medullary concentrating gradient and partial neph-
rogenic DI may develop. Some of the conditions associated with nephrogenic DI include familial, tubu-
lointerstitial renal disease, electrolytes disorder (hypokalemia and hypercalcemia), drugs (e.g., lithium,
demeclocycline), and pregnancy.
The posterior pituitary enhances on MRI with gadolinium and is a ‘good assay’ of ADH reserve, keeping
in mind that up to 20% of normal individuals do not have a bright spot. Partial central DI may be treated
with chlorpropamide or thiazides, while complete central DI needs to be treated with desmopressin. The
drug is available via subcutaneous, oral, and nasal spray administration. The exact dosing and timing have
to be individualized.
COVID-19 and Pituitary Disease
Definition/Overview
Since 2020, the COVID-19 pandemic has dominated medicine. With the finding of ACE2 in hypotha-
lamic and pituitary tissue, these organs may be susceptible to direct COVID-19 infection and resulting
symptoms. Cases of pituitary apoplexy secondary to COVID-19, have also been described in those with
preexisting pituitary disease.
Diagnosis
Diagnosis will require a high index of suspicion in a patient with proven COVID-19 who is presenting with
symptoms that could be due to pituitary dysfunction. Very rarely, posterior pituitary dysfunction may occur.
Management is the same as for any other pituitary dysfunction. Special attention should be given to steroid
courses given for the actual COVID-19 infection. With regard to COVID-19 vaccinations for those with
hypopituitarism, most would not recommend stress-dosing of glucocorticoids at the time of vaccination.
Adrenal Disorders
Sarah Kanbour, Reza Pishdad,

6
Ezra Baraban, and Amir H. Hamrahian
ANATOMY AND PHYSIOLOGY OF THE

ADRENAL GLAND
The adrenal glands are paired retroperitoneal organs that lie within the perinephric fat, at the kidneys’
anterior, superior, and medial aspects. They weigh about 5 grams. The right adrenal gland is located
posterior to the inferior vena cava (Figure 6.1). The adrenal glands are pyramidal in shape with a narrow
apex and a broader base. In cross-section, they resemble an inverted Y with an anteromedial limb and two
posterolateral limbs (Figure 6.1). Each gland consists of an outer cortex and inner medulla, with distinct
embryologic origins, and produces different hormones.
FIGURE 6.1 Normal adrenal gland. The right adrenal gland is located posterior to the inferior vena cava (blue
arrow). In cross-section, they resemble an inverted Y with an anteromedial limb and two posterolateral limbs
(white arrows).
DOI: 10.1201/9781003100669-6 147

FIGURE 6.2 Normal adrenal cortex is arranged into three discrete layers. The periphery of the gland abutting
the retroperitoneum is at the top of the image. The glomerulosa (1), fasciculata (2), and reticularis (3) layers
are composed of blue, clear, and pink cells respectively, with the medulla (not pictured) situated deep to the
reticularis layer at the bottom. H&E, 200×.
The cortex mainly produces steroid hormones and is composed of three zones (Figure 6.2):
• The outer zona glomerulosa synthesizes aldosterone under the principal control of the renin–
angiotensin system and serum potassium concentration. The adrenocorticotropic hormone
(ACTH) has a minor effect on aldosterone secretion.
• The middle zona fasciculata secretes cortisol under the influence of ACTH.
• The inner zona reticularis is primarily involved in the synthesis of androgens (dehydroepian-
drosterone [DHEA], dehydroepiandrosterone sulfate [DHEAS], and androstenedione).
The adrenal medulla, located in the central portion of the gland, is part of the sympathetic nervous system
and produces catecholamines, mostly epinephrine.
ADRENAL INSUFFICIENCY
Definition
Adrenal insufficiency (AI) is a failure of the adrenal cortex to secrete enough glucocorticoids, mineralo-
corticoids, or both. It can be caused by a primary adrenal disorder or secondary to the pituitary and hypo-
thalamic diseases, or from adrenocorticotropic hormone suppression by drugs such as glucocorticoids
and opioids.
6 • Adrenal Disorders 149
TABLE 6.1 Causes of Primary Adrenal Insufficiency

Anatomic Destruction of the Gland (Acute or Chronic)
• Autoimmune adrenalitis (Addison’s disease); autoimmune polyendocrine syndromes (APS) type 1 and 2
• Infections (tuberculosis, fungi, HIV, CMV, syphilis)
• Metastatic cancer
• Infiltration (e.g., amyloid)
• Hemorrhage/infarction
Metabolic Failure in Hormone Production
• Congenital adrenal hyperplasia
• Medications (ketoconazole, metyrapone, megestrol, mitotane, etomidate, immune checkpoint
inhibitors)
Others
• Adrenoleukodystrophy/adrenomyeloneuropathy
• Congenital adrenal hypoplasia
• ACTH-resistant syndromes
Primary Adrenal Insufficiency
Primary adrenal insufficiency is a rare condition with the highest prevalence of 6–14 individuals per
100,000. It is less common than secondary and tertiary AI. It is caused by an intrinsic adrenal gland
pathology such as autoimmune destruction of the adrenal cortex, infections, hemorrhage, metastases, or
genetic defects (Table 6.1).
Glucocorticoid deficiency due to autoimmune disease accounts for up to 70% of the cases of primary
adrenal failure. Antibodies targeting the 21-hydroxylase enzyme lead to the destruction of the adrenal
cortex. Adrenal insufficiency can occur in combination with other autoimmune conditions such as thy-
roid disease, type 1 diabetes, premature ovarian insufficiency, hypoparathyroidism, autoimmune gastritis,
celiac disease, vitiligo, alopecia, hepatitis, or pneumonitis (autoimmune polyglandular syndrome 1 and
2). Adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) are two phenotypes of an X-linked
recessive disorder caused by peroxisomal abnormalities and affect 1 in 20,000 males. The diagnosis may
be evaluated by measurement of very long-chain fatty acids and then confirmed by genetic testing. This
disorder accounts for up to 10% of all cases of primary adrenal insufficiency.
Secondary Adrenal Insufficiency

Secondary adrenal insufficiency is reported in about 14–28 individuals per 100,000, although the true
prevalence is likely underestimated. It presents in two major forms: either as a deficiency of ACTH and
other pituitary hormones (pituitary tumors, surgery, or radiation therapy), or less commonly as an isolated
ACTH insufficiency (hypophysitis, or hereditary disorders). Hypophysitis is often related to pregnancy
or as an adverse event of immune checkpoint inhibitors. Hypopituitarism secondary to trauma, pituitary
apoplexy in an adenoma, or pituitary infarction, are less common.
Nearly 1% of the general population is treated with long-term regimens of glucocorticoids for inflam-
matory diseases. Adrenal insufficiency secondary to exogenous glucocorticoid may occur using 5 mg
or more of prednisone for longer than 3 weeks. Concomitant use of drugs that inhibit glucocorticoid
metabolism, such as itraconazole and ritonavir, can lead to adrenal suppression, even with local and topi-
cal glucocorticoids. In addition, opiates can suppress ACTH release and lead to the impairment of the
hypothalamic–pituitary–adrenal (HPA) axis. Adrenal insufficiency should be suspected in any individual
taking more than 20 mg morphine-equivalent dose. It occurs in 10%–20% of individuals using daily
morphine-equivalent doses of 100 mg or more.
Hallmark clinical features of primary AI are unintentional weight loss, anorexia, and profound fatigue.
The patients may also complain of postural hypotension, muscle/abdominal pain, and hyponatremia (Table
6.2). Primary adrenal insufficiency may be associated with skin hyperpigmentation (Figures 6.3–6.7),
orthostatic hypotension, and salt craving due to both glucocorticoid and mineralocorticoid deficiency.
TABLE 6.2 Manifestations of Primary Adrenal Insufficiency

SYMPTOM FREQUENCY (%) SIGNS FREQUENCY (%)
Weakness, fatigue 100 Weight loss 100
Anorexia 100 Hyperpigmentation 95
Nausea and/or vomiting 90 Hypotension (systolic BP <100) mmHg) 85–90
Constipation 20–30 Vitiligo 10–15
Diarrhea 15–20 Laboratory Abnormalities
Abdominal pain 30–35 Hyponatremia 80–90
Salt craving 15–20 Hyperkalemia 60–65
Dizziness and/or syncope 12–15 Hypercalcemia 10–20
Azotemia 50–60
Anemia and eosinophilia 20–40
FIGURE 6.3 Vitiligo of the face. (Courtesy of Dr. Leann Olansky.)

FIGURE 6.4 Vitiligo of the body. (Courtesy of Dr. Leann Olansky.)
Secondary adrenal insufficiency is usually milder than primary adrenal insufficiency because miner-
alocorticoid production is intact and adrenal insufficiency is more likely to be partial in nature. All patients
with unexplained hyponatremia should undergo evaluation for adrenal insufficiency. Hypoglycemia is
more common in patients with secondary adrenal insufficiency, which is due to the more chronic nature
of secondary adrenal insufficiency.
Diagnosis
Confirmation of the clinical diagnosis of adrenal insufficiency involves the following three steps (Figure
6.8):
• Establishing the presence of adrenal insufficiency

• Measuring the ACTH level to differentiate between primary and secondary causes
• Investigating the underlying etiology
Establishing the Presence of Adrenal Insufficiency

Morning Serum Cortisol
In normal subjects, serum cortisol concentrations are highest about 1 hour before awakening and range
from 275 to 550 nmol/L (10–20 μg/dL). An early morning cortisol level <80 nmol/l (3 μg/dL) is usually
FIGURE 6.5 Hyperpigmentation of palmar creases. (Courtesy of Dr. Charles Faiman.)
FIGURE 6.6 Hyperpigmentation of tongue. (Courtesy of Dr. Charles Faiman.)
FIGURE 6.7 Hyperpigmentation of gingival mucosa. (Courtesy of Dr. Charles Faiman.)
consistent with adrenal insufficiency, while a value >276 nmol/L (10 μg/dL) makes the diagnosis highly
unlikely. Patients with cortisol levels between 80 and 276 nmol/L (3–10 μg/dL) should be further evalu-
ated by the cosyntropin stimulation test (CST). Due to the diurnal variation of cortisol, random serum
cortisol levels are only of value during stress.
6.8
Clinical Suspicion for Adrenal Insufficiency
8 am cortisol
> 10 μg/dL 3–10 μg/dL < 3 μg/dL
The Cosyntropin Stimulation Test
AI ruled out ≥ 15–18 μg/dLφ < 15–18 μg/dLφ
AI confirmed,
Measure ACTH
Low/normal Elevated
Secondary or tertiary AI Primary AI
φ Normal response ≥15 μg/dL at 30 min & ≥18 μg/dL at 60 min post Cosyntropin Stimulation Test
FIGURE 6.8 Algorithm for the diagnosis of adrenal insufficiency (AI). The standard cosyntropin stimulation
test (CST) may be used as the first-line test for evaluation of adrenal function, especially in patients who are
seen in the clinic later during the day.
The Cosyntropin Stimulation Test

During the standard or high-dose CST (250 μg cosyntropin), plasma cortisol is measured before and at 30
and 60 minutes after intramuscular injection of 250 μg cosyntropin (ACTH analogue). Using the cortisol
II assay, a normal response is a serum cortisol concentration >400–414 nmol/L (14.5–15 μg/dL) at 30
minutes and 485 nmol/L (18 μg/dL) at 60 minutes.
The standard dose CST is an excellent test to exclude primary adrenal insufficiency. However, patients
with recent-onset pituitary ACTH deficiency (e.g., within 2–4 weeks after pituitary surgery) may have a
normal response since the adrenal glands have not undergone sufficient atrophy and still respond to high
concentrations of cosyntropin.
Another pitfall is pregnancy and oral estrogen, increasing corticosteroid-binding globulin (CBG)
concentrations leading to elevated total cortisol levels. Conversely, critically ill patients and those with
cirrhosis can have low levels of CBG and albumin leading to low total cortisol levels.
Differentiation between Primary and Secondary Adrenal Insufficiency

In a patient with a low serum cortisol level, an elevated ACTH level (usually double the upper limit of
normal) is consistent with primary AI. Furthermore, low aldosterone and high renin concentrations may
be additional clues to the diagnosis of primary adrenal insufficiency. A low or normal range ACTH level
in the same setting confirms the diagnosis of secondary AI.
Investigating the Underlying Etiology

The diagnosis of autoimmune adrenal insufficiency is supported by the presence of other autoimmune
disorders and adrenal autoantibodies, which may be present in up to 80%–90% of patients. Patients should
be screened for other autoimmune conditions, such as autoimmune thyroid disease, type 1 diabetes, celiac
disease, and autoimmune gastritis. In patients younger than 20 years old with primary adrenal insuffi-
ciency, autoimmune polyendocrine syndrome type 1 should always be considered. The presence of steroid
side-chain cleavage enzyme autoantibodies indicates a potential risk of developing ovarian insufficiency.
All male patients with negative autoantibodies against 21-hydroxylase should have their serum very
long-chain fatty acid tested to avoid missing an underlying adrenoleukodystrophy (ALD) or adrenomyelo-
neuropathy. Primary AI can be the initial manifestation in 30%-40% of these patients. Early diagnosis of
ALD may improve outcomes of hematopoietic cell transplantation before the development of irreversible
cerebral injury.
Patients with primary adrenal insufficiency should undergo an abdominal computed tomography
(CT) scan if they have negative adrenal antibodies and normal very long-chain fatty acids (Figure 6.9).
Abdominal CT may detect enlarged adrenal glands or adrenal calcification, suggesting an infectious,
hemorrhagic, or metastatic cause. In patients with secondary AI, a thorough evaluation of other pituitary
hormones and an MRI of the pituitary gland is indicated.
Adrenal Insufficiency in the Critically Ill Patient

More than 90% of measured total cortisol is bound to CBG and albumin. The remaining is free cortisol,
which is responsible for its action. Since there is decreased CBG and albumin level in critically ill patients,
the total serum cortisol may be a poor indicator of glucocorticoid activity and can be misleading. In criti-
cally ill patients without sepsis or septic shock, hypoalbuminemia (<25 μ/L) is usually an indirect marker
of low CBG. In such patients, measurement of serum free cortisol may provide a better assessment of
adrenal function. However, there is a need for establishing the reference range of serum free cortisol in
critically ill patients.
A random cortisol level of <15 and <10 μg/dL may be used as evidence of AI in patients with near-
normal (albumin >2.5 g/dL) or hypoalbuminemia, respectively. In patients with equivocal biochemical
results or those with volume-resistant hypotension on vasopressors, a trial of glucocorticoids is appropri-
ate. The benefit of a short course of glucocorticoids in patients with sepsis or septic shock may be related
to the underlying inflammatory condition and not an underlying adrenal insufficiency. Relative adrenal
insufficiency or critical illness-related corticosteroid insufficiency defined by the CST has multiple poten-
tial flaws. Therefore, it should not be used as a guide for glucocorticoid therapy in critically ill patients.
FIGURE 6.9 Plain X-ray of the abdomen demonstrating adrenal calcification on the right side (arrow) in a
patient with a history of adrenal insufficiency secondary to tuberculosis. (Courtesy of Dr. Charles Faiman.)
Treatment of Adrenal Insufficiency
Patients with primary AI require lifelong replacement with both glucocorticoids and mineralocorti-
coids. The minimum dose to treat symptoms should be used, starting with hydrocortisone 10–15 mg in
the morning as soon as the patient wakes and 5 mg in midafternoon to avoid sleep disturbances. Some
patients may have improved energy by taking hydrocortisone three times per day. Treatment of adrenal
insufficiency with steroids with long half-lives, such as prednisolone and dexamethasone, might result
in increased adverse events including hyperlipidemia and reduced bone mineral density, and is usually
avoided. Plasma ACTH and serum cortisol are not useful parameters to assess the adequacy of glucocor-
ticoid replacement.
Patients require fludrocortisone 0.05–0.2 mg for mineralocorticoid replacement. Physically active
people frequently need higher doses than sedentary older people and should be advised to increase their
salt intake as needed. The adequacy of treatment is assessed clinically. However, the measurement of
plasma renin activity may provide additional information about the adequacy of mineralocorticoid intake.
Patients with secondary adrenal insufficiency do not need mineralocorticoid replacement.
During minor illnesses (e.g., flu or fever greater than 38°C), the hydrocortisone dose should be dou-
bled for 2–3 days. Patients must be educated to self-administer hydrocortisone 100 mg intramuscularly if
they cannot keep down their oral glucocorticoids. All patients should carry some form of medical alert.
Hydrocortisone 50–75 mg/day orally (or parenterally if the patient is nil by mouth) provides adequate
glucocorticoid coverage for outpatient surgeries. Parenteral hydrocortisone 100–150 mg/day (in three to
four divided doses) is usually sufficient for moderate to major surgeries with a taper to normal replace-
ment dose during the recovery period.
Adrenal Crisis
Adrenal crisis is a life-threatening condition and refers to the vasomotor collapse associated with infec-
tion, stress, or trauma in a patient with adrenal insufficiency. The clinical features include worsening of
the initial symptoms of fatigue, anorexia, nausea, vomiting, and abdominal pain, followed by sudden dete-
rioration characterized by refractory hypotension leading to death in untreated patients. Glucocorticoid
deficiency should be treated by intravenous administration of 100 mg hydrocortisone. In patients without
a history of AI, a random serum cortisol level should ideally be drawn before the administration of hydro-
cortisone. Large volumes (2–3 L) of 0.9% saline solution with dextrose are initially needed to support
blood pressure and hypoglycemia. Hydrocortisone 50 mg every 6–8 hours should be continued until the
patient is hemodynamically stable and then gradually tapered to physiologic replacement doses. Possible
precipitating causes should be actively searched for and treated. Mineralocorticoid replacement is not
needed in patients receiving 100 mg or more of hydrocortisone per day.
PRIMARY ALDOSTERONISM
Definition
Primary aldosteronism (PA), also known as Conn’s syndrome, is characterized by hypertension, inap-
propriately elevated levels of plasma aldosterone, and low levels of plasma renin. PA is the most common
curable cause of secondary hypertension. The prevalence of PA is about 20% in patients with resistant
hypertension and 6% with uncomplicated hypertension. PA is associated with higher cardiovascular and
cerebrovascular morbidity and mortality compared to patients with essential hypertension. Early diagno-
sis may cure hypertension or provide targeted therapy to prevent irreversible cardiovascular damage and
renal disease. However, the screening rate remains extremely low because screening entails follow-up
(confirmation, imaging, adrenal venous sampling, and surgery when indicated), and these procedures are
time-consuming and costly.
Aldosterone Secretion: Physiology and Pathophysiology

Aldosterone, a mineralocorticoid hormone produced in the zona glomerulosa of the adrenal cortex, binds
to mineralocorticoid receptors and regulates the final stages of sodium reabsorption in the distal renal
tubules and collecting ducts. Mineralocorticoid receptors are also expressed in cardiomyocytes and neu-
rons in the hippocampus, hypothalamus, and brainstem. The secretion of aldosterone is stimulated by
high serum potassium concentration and the renin–angiotensin system and to a much lesser degree by the
ACTH stimulation.
In primary aldosteronism, the aldosterone level is inappropriately high and autonomous of the major
regulators of its secretion. Aldosterone-producing adenoma (APA) and bilateral idiopathic hyperaldo-
steronism (IHA) are the two most common subtypes of PA (Table 6.3). IHA may be associated with
bilateral micronodular or macronodular adrenal hyperplasia. APAs are generally small (<2 cm in diam-
eter), benign tumors and have a golden yellow color on their cut surface (Figures 6.10–6.12). Unilateral
TABLE 6.3 Causes of Primary Aldosteronism

• Bilateral idiopathic hyperplasia (60-70%)
• Aldosterone-producing adenoma (30-40%)
• Unilateral (primary) adrenal hyperplasia (2%)
• Adrenal carcinoma (<1%)
• Ectopic aldosterone-producing tumors (<1%)
• Familial hyperaldosteronism (FH, types I–IV) (1–5%)
⚬ FH type I (glucocorticoid-remediable aldosteronism)
⚬ FH type II (APA or IHA)
⚬ FH type III (germline KCNJ5 mutations)
⚬ FH type IV (germline CACNA mutations)
FIGURE 6.10 Noncontrast CT scan of adrenal glands in a patient with primary aldosteronism showing a 2 cm
nodule in the left adrenal gland with Hounsfield units <10, suggesting a benign adenoma (arrow).
FIGURE 6.11 The cut surface of a resected aldosterone-producing adenoma showing a 1.8 cm discrete
golden nodule within the cortex of a bivalve adrenal gland. (Courtesy of Dr. Howard Levin.)
FIGURE 6.12 Microscopic appearance of an aldosterone-producing adenoma showing uniform cells with
round nuclei and abundant cytoplasm. A spironolactone body is present in the center (arrow). (Courtesy of Dr.
Howard Levin.)
hyperplasia is uncommon and caused by micronodular or macronodular hyperplasia of the zona glo-
merulosa of one adrenal gland. Familial hyperaldosteronism (FH) is a rare cause of PA (see the section
‘Familial Hyperaldosteronism’).
PA usually occurs between 20 and 60 years of age. Patients may experience symptoms related to hyper-
tension (headaches), hypokalemia (polyuria and nocturia related to the hypokalemia-induced renal con-
centrating defect, paresthesia, or muscle cramps), or both. Hypertension is usually moderate to severe and
may be resistant to usual pharmacologic treatment. Hypokalemia is encountered in less than half of the
cases. Compared to those with essential hypertension, patients with PA experience a fourfold increased
risk of strokes, sixfold increase of myocardial infarction, and twelvefold increase of atrial fibrillation.
Diagnosis
Screening Tests
According to the Endocrine Society 2016 guidelines, patients should be screened for PA if they have:
1. Sustained BP above 150/100 mmHg on three occasions measured on different days

2. BP above 140/90 mmHg despite taking three antihypertensive drugs (including a diuretic) at
optimal doses
3. Controlled BP (< 140/90 mm Hg) on at least four antihypertensive drugs, including a diuretic
4. Hypertension and unprovoked or diuretic-induced hypokalemia
5. Hypertension or hypokalemia with adrenal incidentalomas
6. Hypertension and sleep apnea
7. Hypertension and a family history of early-onset (before 40 years) hypertension or cerebrovas-
cular accident
8. Hypertension and a first-degree relative with PA
Screening requires the measurement of paired plasma aldosterone concentration (PAC), plasma renin
activity (PRA; or direct renin concentration), and a basic metabolic panel (Figure 6.13). These measure-
ments can be conducted while patients are on their antihypertensive medications such as beta-blockers,
diuretics, ACE inhibitors, angiotensin receptor blockers, and calcium channel blockers except for miner-
alocorticoid antagonists, which should be stopped for at least 4 weeks before testing. However, patients
with hypokalemia, an aldosterone level >20 ng/dL, and a suppressed plasma renin activity can be assumed
to have primary aldosterone without a need for confirmatory tests. In such patients, discontinuing miner-
alocorticoid antagonists may not be safe. Potassium should be corrected, as hypokalemia may suppress
aldosterone secretion in primary aldosteronism.
6.13 Work up for Primary

Aldosteronism
Plasma renin activity (PRA) Hypokalemia is absent in 50–

Plasma aldosterone concentartion (PAC) 80% of patient with PA
Screening tests Correct hypokalemia before
testing
PAC/PRA > 30 with concomitant serum
aldosterone > 5–15 ng/dI
No need or confirmatory
1. Saline Suppression Test (SST)
testing if K , suppressed
Confirmatory tests 2. 4-day Salt Loading Test PRA and PAC >20 ng/dL
3. Captopril Challenge Test SST to be done in sitting position
Establishing the No need or stopping

source of excess MA if PRA is low
CT scan of adrenal glands
aldosterone Adrenal venous sampling
FIGURE 6.13 Algorithm for the workup of patients with suspected primary hyperaldosteronism.
The aldosterone-to-renin ratio (ARR) >20–30 (PAC in ng/dL and PRA in ng/mL per h) may be
used for further confirmatory testing. Sensitivity improves when samples are collected in the morning
after patients have been out of bed for at least 2 hours, and after they have been seated for 5–15 minutes.
A major pitfall of ARR is that some laboratories report PRA values to a lower limit of 0.1 ng mL –1 h–1.
In such cases, an ARR of 20 can be achieved even when aldosterone is as low as 2 ng dL –1, leading to
false-positive results. Therefore, caution should be used in interpreting ARR when PRA is less than 0.6
ng mL –1 h–1. There is no consensus on an aldosterone level below which a diagnosis of PA should not be
pursued. In the absence of hypokalemia, the authors use an aldosterone cutoff value of 7 ng/dL as the
threshold for further testing. Aldosterone levels between 5 and 15 ng/dL have been suggested by experts
in the literature.
Confirmatory Tests
Patients with an ARR >20 who have a PRA <1 ng mL –1 h–1 and PAC >7 ng dL –1 should undergo one or
more confirmatory tests. Patients should be on pharmacological agents with no effects on the renin–angio-
tensin–aldosterone system during confirmatory testing, including nondihydropyridine calcium channel
blockers, alpha-1 blockers, and hydralazine.
In most centers, one of the following three tests is used for confirmatory testing:
1. Oral salt loading test (4 days)

2. Saline suppression test
3. Captopril challenge test
During the oral sodium loading test, a urinary sodium level of more than 200 mmol/24 h confirms an
adequate salt load. An aldosterone excretion of >12 mcg/24 h is consistent with autonomous aldosterone
secretion.
In the saline infusion test, serum aldosterone is collected after a saline infusion of 2 L over 4 hours.
PAC >7 ng dL –1, measured by mass spectrometry, is consistent with PA. In the captopril challenge test,
blood samples are drawn for measurement of PRA, plasma aldosterone, and cortisol at time 0 and at 1 or
2 hours after 25–50 mg captopril intake. Normal suppression is defined as a PAC less than 11 ng/dL and
a PAC:PRA ratio less than 50 ng/dl per ng/ml per hour. This test is recommended when salt loading is
contraindicated (for patients with heart failure or uncontrolled hypertension).
Lateralizing Studies
Lateralization of the source of the excessive aldosterone secretion is critical to guide the management of
PA. Unilateral adrenalectomy of aldosterone-producing adenoma or unilateral adrenal hyperplasia results
in the normalization of hypokalemia, improvement of hypertension in all patients, and cure of hyperten-
sion in about half of affected patients.
The adrenals in IHA may be normal on CT or show thickening or nodular changes. Adrenal CT is
inferior to adrenal venous sampling in distinguishing between APA and IHA. When the adrenal venous
sampling is performed by an experienced radiologist, it has 95% sensitivity and nearly 100% specificity
for detecting unilateral aldosterone excess (Figure 6.14). Adequate training and experience are essential,
especially in terms of successfully cannulating the smaller right adrenal vein. In most centers, the adrenal
venous sampling is performed under cosyntropin infusion. An aldosterone lateralization ratio (ratio of
PAC/cortisol from the dominant side to that of the nondominant side) >4 indicates unilateral aldosterone
excess. A ratio of <2 suggests bilateral aldosterone hypersecretion. A ratio between 2 and 4 is indeter-
minate. In young patients (<35 years of age) with a discrete adrenal nodule, and a normal contralateral
adrenal gland, unilateral adrenalectomy may be considered without a need for adrenal venous sampling.
FIGURE 6.14 Abdominal radiographs that show adrenal venous sampling for identifying the source of hyper-
aldosteronism. A catheter is placed in the (A) right adrenal (arrow) and (B) left adrenal (arrowhead).
Familial Hyperaldosteronism
FH accounts for 1%–5% of PA cases (Table 6.3). Genetic testing for FH is indicated in patients with PA
diagnosed at <20 years, particularly if they have a family history of PA and/or stroke at an early age (<40
years). To date, there are four forms of FH characterized by their germline mutations.
FH type I (also known as glucocorticoid-remediable aldosteronism) is autosomal dominant and
results from the expression of a chimeric gene, which fuses the promoter region of the 11β-hydroxylase
gene (CYP11B1) with the aldosterone synthase gene (CYP11B2). The enzyme encoded by this hybrid gene
produces aldosterone under the regulation of adrenocorticotropic hormone (ACTH) in the zona fascicu-
lata, where cortisol is normally made. Most patients have a normal potassium level.
FH type II is clinically indistinguishable from sporadic PA except for the early-onset hypertension
and familial occurrence. The underlying mutation is in the voltage-gated chloride channel in adrenal
glomerulosa cells.
FH type III results from a mutation in the gene encoding the potassium channel leading to changes
in sodium conductance, zona glomerulosa cell depolarization, calcium entry, and aldosterone production.
Although the clinical features are variable, FHA type III patients often present with an early onset of
severe hyperaldosteronism that is resistant to pharmacological therapy, associated with hypokalemia and
diabetes insipidus-like symptoms. Bilateral adrenalectomy is often required.
FH type IV is caused by a mutation in a gene encoding L-type voltage-gated calcium channels.
Patients may have mild mental retardation and social skill alterations.
The optimal treatment of APA or unilateral hyperplasia is curative surgery. Medical management with
mineralocorticoid receptor antagonists (MRAs) is the treatment of choice for IHA and glucocorticoid-
remediable aldosteronism. Spironolactone treatment in men may result in gynecomastia. Therefore, treat-
ment with eplerenone in men who require long-term MRAs is preferred.
In patients with FH type I (glucocorticoid-remediable aldosteronism), hypertension is usually con-
trolled by treatment with glucocorticoids in low doses. Spironolactone and amiloride are alternative treat-
ments. Genetic counseling is advisable for patients with this autosomal dominant disorder.
PHEOCHROMOCYTOMA
Definition
Pheochromocytomas and paraganglioma are rare neuroendocrine tumors of catecholamines hypersecre-
tion (norepinephrine, epinephrine, and dopamine) that arise from chromaffin cells of the adrenal medulla
(pheochromocytomas) or ganglia of the autonomic nervous system (paragangliomas). Paragangliomas
can occur in any region from the base of the skull to the pelvic floor. Their incidence is about 0.6 cases
per 100,000 person-years. Functional pheochromocytomas and paragangliomas can be lethal if untreated
(Figures 6.15–6.17).
Clinical Features
Catecholamine-secreting tumors affect men and women equally and occur primarily in the third to fifth
decades. They are rare in children, and when discovered, are associated with hereditary syndromes.
Presenting symptoms are nonspecific and may include the classic triad of headaches, palpitations, and
profuse sweating, often triggered by stressful situations, which occur in less than half of the patients.
Patients may present with resistant hypertension or hypertensive spells. Blood pressure lability is attrib-
uted to the episodic release of catecholamines, volume depletion, and altered sympathetic vascular tone
regulation.
Head and neck paragangliomas are rarely hypersecreting and manifest as painless, slowly growing
masses (carotid-body tumors and vagal paragangliomas), conductive hearing loss, or pulsatile tinnitus
(jugulotympanic paragangliomas).
FIGURE 6.15 Gross appearance of pheochromocytoma. A 6 cm predominantly gray-tan mass with some
areas of hemorrhage is seen within the substance of the adrenal gland. A small remnant of the normal adrenal
cortex is visible (arrow). (Courtesy of Dr. Howard Levin.)
FIGURE 6.16 Microscopic appearance of pheochromocytoma. Cell balls (‘zellballen’; arrows) are demarcated
by connective tissue containing capillaries. Nuclei are round to oval. The cytoplasm is pink, somewhat granular,
and focally vacuolated. (Courtesy of Dr. Howard Levin.)
FIGURE 6.17 In pheochromocytoma, the tumor cells are characteristically arranged in tightly packed nests
separated by a delicate branching vasculature. Tumor cells have strikingly purple cytoplasm due to their dense
complement of cytoplasmic chromaffin granules containing catecholamines. Scattered markedly enlarged cells
(arrow) are not uncommon. These are regarded as degenerative in nature and have no prognostic significance.
H&E, 400×.
Asymptomatic cases of pheochromocytoma and paraganglioma are increasingly being discovered

with the widespread use of imaging and germline-mutation testing of family members of affected indi-
viduals or those with the associated syndrome. The indications for screening patients with suspected
pheochromocytoma are listed in Table 6.4.
Diagnosis
Metanephrine is the metabolite of epinephrine, and normetanephrine is the metabolite of norepineph-
rine. Elevated plasma-fractionated metanephrines (metanephrine and normetanephrine) have a 97% sen-
sitivity and 93% specificity for diagnosing pheochromocytoma and paraganglioma. Plasma-fractionated
TABLE 6.4 Indications for Screening of Patients Suspected of Having Pheochromocytoma

• Episodic symptoms of headaches, tachycardia, and diaphoresis (with or without hypertension)
• Family history of pheochromocytoma or predisposing familial syndromes pheochromocytoma
• Lipid-poor adrenal incidentaloma
• Unexplained paroxysms of tachy-bradyarrhythmia or hypertension during anesthesia, surgery, parturition
or prolonged and unexplained postoperative hypotension
• Adverse cardiovascular reactions to certain drugs including anesthetic agents, beta-blockers, glucagon,
glucocorticoids, tricyclic antidepressants, metoclopramide, phenothiazine, and tyramine-containing foods
• Spells or attacks during exertion, movements of torso, straining, coitus, or micturition
• Refractory or labile hypertension
metanephrines have a similar specificity and more sensitivity than urinary metanephrines when compared
to the same control groups (normotensive versus hypertensive). Fractionated catecholamines (epineph-
rine, norepinephrine, and dopamine) are less sensitive, and their measurement is not routinely indicated.
Although sympathetic paragangliomas can secrete norepinephrine, they do not synthesize epinephrine
since they lack the enzyme for converting norepinephrine to epinephrine, which requires a high level of
cortisol for its expression. Head and neck paragangliomas may only display increased excretion of the
dopamine metabolite 3-methoxytyramine.
Typically, pheochromocytomas and paragangliomas that induce clinical symptoms are associated
with metanephrine or normetanephrine levels that are >4 times above the upper limit of the reference
range. Less than two times the elevated plasma and urine normetanephrine are commonly attributed to
enhanced sympathoadrenergic tone (e.g., stress, illness), the use of catecholamine reuptake inhibitors (e.g.,
tricyclic antidepressants, antipsychotic agents, serotonin-reuptake or norepinephrine-reuptake inhibitors),
and renal insufficiency, causing false-positive test results. Medications that may interfere with biochemi-
cal testing should be discontinued (Table 6.5). Patients with plasma normetanephrine levels about two- to
fourfold above the upper limit of normal may undergo the clonidine suppression test for further evaluation
(Figure 6.18). Any degree of elevated plasma or urinary fractionated metanephrines should be further
evaluated by repeating the level and, if still elevated, pursued with adrenal imaging (Figures 6.19–6.21).
Preoperative Management
Surgical resection of pheochromocytoma or paraganglioma is the mainstay of therapy. To control blood
pressure and prevent hypertensive crises intraoperatively, combined α- and β-adrenergic blockade is usu-
ally started at least two weeks before surgery.
The adrenergic blockade is accomplished with either a nonselective (phenoxybenzamine) or a selec-
tive α-adrenergic receptor antagonist (doxazosin) with a blood pressure goal of <140/90 mmHg and toler-
able adverse events. β-adrenergic antagonists (e.g., extended-release metoprolol for a heart rate goal of
80 beats per minute) should be administered to control tachycardia only after α-adrenergic blockade has
been initiated since β-adrenergic blockade alone can cause a hypertensive crisis because of unopposed
α-adrenergic stimulation. Postoperative sustained hypotension can be a complication of the preoperative
adrenergic blockade and the downregulation of the alpha receptors; therefore, close monitoring is needed.
When blood pressure control is inadequate with combined α- and β-adrenergic blockade or when patients
develop intolerable side effects, calcium channel blockers (nicardipine and amlodipine) may be used with
adequate efficacy.
TABLE 6.5 Medications and Stimulants to Avoid before Measuring Plasma and Urinary Catecholamines and
Metanephrines
Tricyclic antidepressants
Beta-blockers: labetalol and sotalol
Acetaminophen
Phenoxybenzamine
Monoamine oxidase inhibitors
Antipsychotics
Sympathomimetics: ephedrine, pseudoephedrine, amphetamines, albuterol
Stimulants: caffeine, nicotine, theophylline
Miscellaneous: levodopa, carbidopa, alcohol, cocaine
Imaging studies
The imaging modality of choice to assess those neuroendocrine tumors depends on three clinical scenarios.
1. Patients with typical symptoms and significantly elevated metanephrines: In this group, contrast-
enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen and pelvis
is recommended since nearly 95% of the pheochromocytomas and paragangliomas are in the
abdomen and pelvis (Figures 6.18–6.20). Those tumors demonstrate high contrast avidity (often with
heterogeneous enhancement) on CT imaging with intravenous contrast. The CT washout characteristics
of pheochromocytomas are not reliable to confirm or exclude the diagnosis. On MRI,
pheochromocytomas usually display hyperintensity on T2-weighted imaging and have features
suggestive of low lipid content (no loss of signal intensity on out-of-phase T1 images).
2. Patients with incidental adrenal mass: CT without contrast is recommended in this second group,
because low attenuation on unenhanced CT imaging (<10 Hounsfield units) of a lipid-rich mass rules
out the diagnosis of pheochromocytoma and biochemical testing is not necessary.
3. Carriers of asymptomatic germline mutation of a susceptible gene: The specific gene guides the
tailoring of imaging studies as the anatomical locations of pheochromocytomas and paragangliomas
differ among the syndromes.
Once a pheochromocytoma or paraganglioma has been identified, additional testing including functional
imaging (123I-labeled metaiodobenzylguanidine [MIBG] or Gallium Dotatate scan) may be performed to
assess the extent of the disease or further evaluation of patients with positive biochemical testing and
negative CT or MR imaging studies (Figure 6.21).
Surgical Management and Follow-Up

Endoscopic resection of pheochromocytomas with transabdominal or retroperitoneal access is the stan-
dard practice. This procedure has a shorter operative time and hospital stay as well as fewer intraopera-
tive and postoperative complications compared to open laparotomy. For bilateral pheochromocytomas,
cortical sparing adrenalectomy may be considered to avoid lifelong glucocorticoid and mineralocorticoid
replacement.
For patients with a head and neck paraganglioma, treatment options include surgery, stereotactic
radiosurgery, external radiation therapy, and a watchful waiting strategy depending on the location, pres-
ence of tumor extension, symptoms, and staging. With advanced cervical and jugular paragangliomas,
deficits of the lower cranial nerves are frequently seen after surgery and therefore nonsurgical treatment
options including radiotherapy may be considered. Long-term follow-up is necessary for all patients.
Pheochromocytoma-Associated Syndromes
About 40%–50 % of patients have an identifiable mutation, and this number is expected to grow. A brief
description of paraganglioma-associated familial syndromes is discussed here. A more detailed descrip-
tion of them may be found in Chapter 9. Genetic screening is recommended for almost all patients with
pheochromocytoma.
FIGURE 6.18 Algorithm for the biochemical evaluation of patients suspected of having pheochromocytoma.
FIGURE 6.19 Pheochromocytoma. CT scan of adrenal glands showing an 8 cm right adrenal mass, with
central necrosis (arrow). The mass deforms the contour of the liver without evidence of invasion.
• Multiple endocrine neoplasia, type 2 (MEN-2) is caused by germline mutations of the RET
protooncogene. Pheochromocytomas occur in about 50% of individuals with MEN-2. MEN-2
is subclassified into two distinct syndromes: type 2A (MEN-2A) and type 2B (MEN-2B). The
classic MEN-2A is composed of medullary thyroid cancer, pheochromocytoma, and primary
hyperparathyroidism. The latter is not part of the MEN-2B syndrome. They are diagnosed at an
earlier age and are more likely to be bilateral than sporadic tumors. Malignant transformation
occurs in only about 4% of cases.
FIGURE 6.20 Coronal MRI image showing a heterogeneous 6 cm right adrenal mass exhibiting a bright T2
signal intensity suggestive of pheochromocytoma (arrow).
Von Hippel–Lindau disease is caused by mutations in the VHL tumor-suppressor gene. Pheochromocytomas
associated with VHL predominantly make norepinephrine due to a lack of expression of phenylethanol-
amine N-methyltransferase enzyme. They are often benign but may metastasize if left untreated. About
40% are bilateral. Other features of the disease include renal cell carcinoma, retinal and central nervous
system (CNS) hemangioblastomas, and pancreatic neuroendocrine tumors.
Neurofibromatosis type 1 is caused by mutations in the NF1 tumor-suppressor gene.
Pheochromocytomas and paragangliomas are present in only 1% to 3%. The risk of malignancy is higher
than MEN-2 and is about 10%–12%. It is characterized by neurofibromas, café-au-lait spots, axillary
freckling, iris hamartomas, bony abnormalities, CNS gliomas, macrocephaly, and cognitive deficits.
Paraganglioma syndromes 1 through 5 are caused by mutations of the succinate dehydrogenase
genes. They are all characterized by an autosomal dominant inheritance pattern with varying penetrance.
Tumor risk and malignancy rates vary by mutation type.
SDHB carries a greater risk for malignancy and metastatic pheochromocytoma (10%–40%).
Metastatic Pheochromocytoma
The diagnosis of malignant pheochromocytoma and paraganglioma is problematic. It remains difficult to
predict the clinical behavior of individual tumors based on clinical, biochemical, and histologic features,
and accordingly, only metastases are proof of underlying malignancy. The most frequent locations for
metastasis include bones, lymph nodes, liver, lung, and brain. The extent of the disease may be best docu-
mented on nuclear imaging. Most patients with metastatic disease have sporadic tumors, whereas, among
patients with heritable pheochromocytoma in whom metastatic disease develops, tumors caused by SDHB
mutations account for most cases. Treatment options include surgical resection, targeted radiolabeled
therapies (e.g., 131I-MIBG, 90Y-DOTATATE, and 177Lu-DOTATATE), thermal ablation, chemotherapy,
and external irradiation.
FIGURE 6.21 123I-metaiodobenzylguanidine (MIBG) scan of patients with (A) bilateral pheochromocytoma
and (B) metastatic pheochromocytoma. In panel A, arrows indicate abnormal uptake in the region of adrenals.
(Courtesy of Dr. Donald Neumann.)
CUSHING SYNDROME
Definition
Cushing syndrome (CS) comprises signs and symptoms associated with prolonged exposure to inap-
propriately elevated levels of plasma glucocorticoids. Untreated, it has significant morbidity and mortal-
ity. Despite the progress in biochemical evaluation and imaging, diagnosing and managing CS in some
patients continues to be a challenge.
Etiology/Pathophysiology
The most common cause of CS is the use of supraphysiologic amounts of exogenous glucocorticoids.
Here, we will discuss endogenous CS.
Approximately one-third of the US population is obese, and the chance that a person with obesity,
hypertension, hirsutism, type 2 diabetes, and dyslipidemia has endogenous CS is about 1 in 500. In those
with poorly controlled diabetes and hypertension, the reported prevalence of CS is ~2%–5%, although
there may be some referral bias in such estimates. In addition, some of these rates are based on biochemi-
cal evaluation and not the final pathology.
The etiology of CS can be classified into ACTH-dependent and ACTH-independent. Excluding
patients with mild autonomous excess cortisol secondary to an adrenal nodule or hyperplasia, the ACTH-
dependent CS is responsible for 80%–85% of endogenous CS. Pituitary adenomas make about 80% of
ACTH-dependent CS, and the rest are secondary to ectopic ACTH syndrome (EAS). Up to half of ectopic
ACTH syndrome cases are due to small-cell lung carcinoma. Other etiologies may include bronchial car-
cinoids, pheochromocytoma, pancreatic neuroendocrine tumors, and gut carcinoids.
ACTH-independent CS accounts for the remaining 15%–20% of cases. About half of those patients
have a benign adrenal adenoma. The remaining are secondary to unilateral adrenal hyperplasia, adrenal
carcinoma, primary pigmented nodular adrenal disease, bilateral macronodular, and micronodular adre-
nal hyperplasia (Table 6.6 and Figures 6.22–6.25).
Primary Pigmented Nodular Adrenocortical Disease and Carney Complex

Primary pigmented nodular adrenal disease (PPNAD) is usually associated with adrenal nodules that may
be too small to be visualized on imaging (Figure 6.26). In addition, clinical features might be mild and
cyclical, making the diagnosis challenging. The disease can be sporadic or part of the Carney complex
(an autosomal dominant multiple neoplasia syndrome), which may present with blue nevi; atrial myxo-
mas; spotty skin pigmentation; peripheral nerve tumors; and various tumors including breast, testicular,
and growth hormone-secreting pituitary adenomas. Most cases present in late childhood or young adults.
The Carney complex is the most common form of familial CS and requires lifelong surveillance for
cardiac myxomas and other potentially fatal tumors. Germline mutations of the regulatory subunit R1A
of protein kinase A (PRKAR1A) are present in about half of the patients with Carney complex and in
sporadic primary pigmented nodular adrenal disease. Dexamethasone stimulates cortisol release through
a glucocorticoid receptor-mediated effect on protein kinase A catalytic subunits. Therefore, these patients
usually show a paradoxical rise in cortisol secretion in response to dexamethasone, which sometimes may
be mistaken for misplaced blood samples.
McCune–Albright Syndrome
McCune–Albright syndrome is a rare disorder defined as the triad of peripheral precocious puberty,
irregular café-au-lait skin pigmentation, and fibrous dysplasia of bone. It is due to activating mutations of
the Gsa receptor in adrenal cells. This mutation leads to constitutive activation of the cyclic AMP pathway
and continued stimulation of endocrine function, leading to precocious puberty, thyrotoxicosis, growth
hormone excess, CS, and renal phosphate wasting (rickets) in several combinations.
TABLE 6.6 Causes of Adrenal Cushing Syndrome

UNILATERAL BILATERAL
Benign adrenal adenoma Primary pigmented nodular adrenocortical disease
Adrenocortical carcinoma Bilateral macronodular hyperplasia
Unilateral adrenocortical hyperplasia Bilateral micronodular adrenal hyperplasia
FIGURE 6.22 Adrenal cortical adenoma associated with Cushing syndrome: a well-encapsulated 3.6 cm yel-
low-tan intra-adrenal mass with focal hemorrhage. Normal adrenal tissue is seen to the right (arrow). (Courtesy
of Dr. Howard Levin.)
FIGURE 6.23 Nodular hyperplasia associated with Cushing syndrome. Coalescing large nodules are seen,
which are comprised of cells with clear cytoplasm (arrow) and eosinophilic cytoplasm (arrowhead). (Courtesy
of Dr. Howard Levin.)
FIGURE 6.24 Diffuse cortical hyperplasia in a patient with pituitary Cushing syndrome. There is a marked
expansion of the zona fasciculata and reticularis. The zona glomerulosa is not visible. The normal capsule is
seen to the left (arrow). (Courtesy of Dr. Howard Levin.)
FIGURE 6.25 CT scan of the abdomen in a patient with pituitary Cushing syndrome showing bilateral hyper-
plastic (thickened) adrenal glands (arrows). The adrenals tend to maintain their shape.
FIGURE 6.26 Primary pigmented nodular adrenocortical disease. (A) In low power magnification, four dis-
crete intracortical eosinophilic nodules are seen (arrows). A larger nodule extends into periadrenal fat (arrow-
head). A strip of normal medullary tissue is present in the lower center-right (large arrow). (B) High-power
magnification of an eosinophilic nodule present within periadrenal fat. There is a mild variation in nuclear size.
Many adrenal cortical cells contain abundant fine brown lipochrome pigment (arrows), accounting for the
black color of nodules in the gross specimen. (Courtesy of Dr. Howard Levin.)
Bilateral Macronodular Adrenal Hyperplasia (BMAH)

Recent evidence shows that cortisol production by some adrenal tumors is triggered by aberrant expression
and pathologic activation of several G-protein-coupled receptors, such as vasopressin, gastric inhibitory
peptide (GIP), vasoactive intestinal polypeptide (VIP), LH/hCG, and catecholamines. Different stimuli,
such as posture, food, and pregnancy, may result in the excessive release of cortisol from the adrenal
tumor, resulting in clinical manifestations of CS. Patients with GIP-dependent CS have a ‘food-depen-
dent’ pattern of cortisol hypersecretion. The diagnosis is made in patients with bilaterally enlarged nodu-
lar adrenals (Figure 6.27). Hypercortisolemia may range from mild disease to overt CS with suppressed
ACTH and DHEAS levels. Bilateral adrenalectomy is offered for severe CS; unilateral adrenalectomy to
remove the larger adrenal gland may be considered when there is a significant asymmetry in adrenal sizes.
FIGURE 6.27 Noncontrast CT scan of the abdomen in a patient with bilateral macronodular adrenal hyper-
plasia showing bilateral nodules in the adrenals (arrows).
Some of the clinical features of CS are listed in Table 6.7. Among these, skin manifestations and serial
photographs warrant special attention (Figure 6.28). The pathological striae in CS are red-purple and usu-
ally greater than 1 cm in width (Figure 6.29). They are uncommon in older patients. Skin is thinned and
wrinkled (Liddle’s sign – ‘cigarette paper’ – on the dorsum of the hands), and minimal trauma results in
easy bruising. The patients usually have a round face (moon facies) and plethoric appearance, and acne
may be present. Patients may have myopathy involving the proximal muscles of the lower limb and the
shoulder girdle. Supraclavicular and dorsocervical fat pads (buffalo hump) are less specific findings and
may be seen in most patients presenting to obesity clinics. Both sexes complain of decreased libido, and
women may present with irregular menstruation and hirsutism.
Hypertension and hypokalemia may be seen in patients with CS and are mainly due to the binding
of excess cortisol to the nonspecific type 1 aldosterone receptors. The onset of clinical features is usu-
ally gradual in patients with adrenal adenomas but rapid in adrenocortical carcinomas and ectopic CS.
Virilization and feminization may be part of the clinical picture in patients with adrenocortical carcinoma
cosecreting androgens and estrogen, respectively.
Diagnosis
Once CS due to exogenous administration of glucocorticoids is excluded, the evaluation of a patient with
suspected CS should take place in two stages (Figure 6.30):
1. Establishing hypercortisolemia (confirm presence of CS)

2. Establishing the etiology of CS
TABLE 6.7 Clinical Features Suggestive of Cushing Syndrome

• Central obesity • Wide purplish striae (>1 cm)
• Proximal myopathy • Changes in serial photographs
• Spontaneous bruising • Hypokalemia
• Facial plethora • Osteoporosis
FIGURE 6.28 Serial photographs of a patient with Cushing syndrome demonstrating gradual development
of moon face, acne, and facial plethora. The patient underwent surgery in 2003. Note the dramatic improve-
ment in facial appearance 9 months after surgery. (A) 1995; (B) 1996; (C) 1998; (D) 1999; (E) 2000; (F) 2001;
(G) 2002; (H) 2003; (I) 2004. (Not taken as clinical pictures.)
The diagnosis of ACTH-dependent CS has been discussed in detail in the section on hypothalamic–pitu-
itary disorders. Plasma ACTH levels should be measured once hypercortisolemia is established. ACTH
concentrations below 3.3 pmol/L (15 μg/mL) are consistent with an ACTH-independent CS secondary
to an adrenal etiology. ACTH levels >25 pg/mL point toward an underlying ACTH-dependent CS. In
patients with ACTH levels between 15 and 25 pg/mL, repeating ACTH levels in the morning or perform-
ing additional dynamic testing such as the corticotropin-releasing hormone (CRH), desmopressin stimula-
tion, and high-dose dexamethasone suppression tests would be indicated.
Once the diagnosis of ACTH-independent CS has been established, the adrenals need to be imaged
by a noncontrast CT scan. In patients with unilateral hyperfunctioning adrenal tumors, the contralateral
adrenal gland may appear atrophic (Figure 6.31).
In patients with adrenocortical carcinoma, an MRI may provide additional information about the
vascular invasion, particularly of the inferior vena cava, and the adrenal and renal veins. In BMAH, the
FIGURE 6.29 (A) Abdominal and (B) axillary striae in a patient with Cushing syndrome. The striae are purple
and broad (>1 cm in width). (Courtesy of Dr. Charles Faiman.)
adrenal glands can be replaced by the presence of multiple nodules up to 4 cm in diameter (Figure 6.27);
in other cases, the adrenal appears diffusely enlarged without macroscopic nodules. In PPNAD, imaging
of the adrenal glands may reveal slightly enlarged glands with or without nodules.
Pseudo-Cushing State
A pseudo-Cushing state can be defined as some or all of the clinical features of CS that may be associ-
ated with some degrees of hypercortisolism but lack an identifiable etiology for CS. Several causes have
been described including alcoholism, sleep apnea, depression, obesity, uncontrolled type 2 diabetes, and
anorexia nervosa. Resolution of the underlying cause results in the disappearance of the cushingoid state.
The 24-hour urine free cortisol (UFC) in patients with pseudo-Cushing is usually less than four times the
upper limit of normal, although this may vary based on the assay used. It may be necessary to treat the
underlying condition and then repeat the biochemical evaluation for CS.
FIGURE 6.30 Algorithm for evaluation of patients suspected of having Cushing syndrome. ACTH, adreno-
corticotrophic hormone; CRH, corticotropin-releasing hormone; CS, Cushing syndrome; CT, computed tomog-
raphy; DST, dexamethasone suppression test; HDDST, high-dose dexamethasone suppression test; LDDST,
low-dose dexamethasone suppression test; UFC, urine free cortisol.
FIGURE 6.31 Patient with left adrenal gland atrophy due to Cushing syndrome from the contralateral adre-
nal nodule.
The treatment goals of CS include normalization of cortisol levels, eradicating the tumor, and avoid-
ing permanent hormonal deficiency, when possible. Hormone-secreting adrenal adenomas should be sur-
gically removed. Compared to the open adrenalectomy, the laparoscopic approach is associated with
decreased postoperative pain, reduced time to return of bowel function, and decreased length of hospital
stay. Surgical resection of adrenocortical carcinoma at an early stage is the only therapy that may offer a
potential cure. Bilateral adrenalectomy is recommended for patients with PPNAD and BMAH with CS.
Medical therapy may be used in patients who are not surgical candidates, have bilateral disease,
do not wish to undergo bilateral adrenalectomy, and cannot have a complete tumor resection. Patients
with adrenal CS may be treated with steroidogenesis enzyme inhibitors such as osilodrostat, metyrapone,
ketoconazole, levoketoconazole, mitotane, or a cortisol receptor blocker (mifepristone). Etomidate, an
11β-hydroxylase inhibitor, is the only parenteral agent used in severe hypercortisolism to achieve normal
cortisol levels in a short time. This may be a great option before bilateral adrenalectomy. Chemotherapeutic
agents and immune check inhibitors are used for advanced adrenocortical carcinomas.
CONGENITAL ADRENAL HYPERPLASIA
Definition
Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder of adrenal steroid biosynthesis
that can be life-threatening in its classic (severe) form and cause hyperandrogenism and infertility in
women in its nonclassic (mild) form. While testicular adrenal rest tumors and infertility are common in
men, men with nonclassic CAH are usually asymptomatic. The severity of the disease relates to the degree
to which the mutations compromise enzyme activity.
21-Hydroxylase deficiency is the most common cause of CAH, which accounts for >95% of all diagnosed
cases. Classic CAH occurs in 1 in 10,000 to 1 in 20,000 live births. Nonclassic CAH occurs in 1 in 200
to 1 in 1,000 persons. 11β-Hydroxylase deficiency is the second most common cause of CAH, with an
incidence of 1 in 100,000 live births. Other enzyme deficiencies like 3β-hydroxysteroid dehydrogenase
deficiency, 17α-hydroxylase deficiency, and steroidogenic acute regulatory protein deficiency are very
rare. This section will focus on the CAH due to 21-hydroxylase deficiency.
Pathogenesis
Deficient cortisol production is the key aberration in all forms of CAH. CYP21A2 is the gene that encodes
for 21-hydroxylase, a cytochrome P-450 enzyme required to produce cortisol and aldosterone in the adre-
nal cortex (Figure 6.32). Reduced cortisol biosynthesis results in the overproduction of corticotropin
(ACTH), which stimulates the accumulation of cortisol precursors and their subsequent diversion through
the steroid pathways that produce adrenal androgens (Figure 6.33). The classic form is the most common
cause of atypical genitalia in 46,XX newborns and primary adrenal insufficiency during childhood.
Clinical Presentation and Diagnosis

The clinical presentation of CAH is classified as classic versus nonclassic. The terms ‘salt-wasting’ and
‘simple virilizing’ have fallen out of favor because all patients lose salt to some degree.
FIGURE 6.32 Pathways of steroid biosynthesis. The pathways for synthesis of mineralocorticoids (aldoste-
rone), glucocorticoids (cortisol), and androgens (testosterone and dihydrotestosterone) are arranged from left
to right. The enzymes coded by a single gene catalyzing each bioconversion are shown in boxes.
Infancy
Most cases of CAH are first detected by newborn screening, which has reduced morbidity and mortality.
Detection is based on the presence of elevated 17-hydroxyprogesterone levels. 17-Hydroxyprogesterone
levels can be elevated in healthy neonates during the first 1 to 2 days of life and in premature or ill newborns.
Adjusting for age and weight, using second-tier screening by liquid chromatography and tandem mass
spectrometry, measurement of 21-deoxycortisol, or genetic testing improves accuracy. 21-Deoxycortisol
is a more specific biomarker of 21-hydroxylase deficiency because this cortisol precursor is not produced
in the gonads and is uniquely adrenal-derived.
Elevation of 17-hydroxyprogesterone levels may also occur with 11β-hydroxylase and 3β-hydroxysteroid
dehydrogenase (3βHSD) deficiency. They are distinguished by measuring several steroids with ACTH
stimulation testing. In 3βHSD, the elevated 17-hydroxyprogesterone level in the face of defective steroido-
genesis from 17-hydroxypregnenolone is related to the intact activity of the type-1 3βHSD in peripheral
tissues and liver rather than the type-2 3βHSD enzyme that is expressed in adrenal glands.
The clinical presentation differs according to sex. In classic CAH, high levels of androgens affect the
development of external genitalia in 46,XX fetuses, beginning in the first trimester. Clitoral enlargement
(Figure 6.34), partially fused labia majora, and a urogenital sinus in place of separate urethral and vaginal
openings are common. The uterus, fallopian tubes, and ovaries are formed normally. Correctional surgery
for ambiguous genitalia is often performed between 2 and 6 months of age. Excess adrenal androgens do
not affect 46,XY sexual differentiation.
About 75% of infants with classic CAH have a salt-wasting adrenal crisis within the first 3 weeks after
birth if not treated. The diagnosis of classic CAH should be suspected in infants with poor weight gain or
feeding, and dehydration with hyponatremia and hyperkalemia.
FIGURE 6.33 Pathogenesis of CAH. In a patient with normal adrenal function, the adrenals produce both
cortisol and androgens, and the HPA axis is controlled by negative feedback. In the untreated patient with
CAH, the block in cortisol synthesis leads to a lack of negative feedback and increased secretion of CRH and
ACTH, leading to adrenal hyperplasia and oversecretion of androgens. In the patient with treated CAH, the
exogenous corticosteroid replacement leads to suppression of excess androgen secretion.
FIGURE 6.34 Female infant with classic 21-hydroxylase deficiency presenting with ambiguous genitalia as a
result of in utero exposure to excess androgens. (Courtesy of Dr. Charles Faiman.)
Childhood
In approximately 25% of classic CAH, aldosterone production is sufficient to maintain sodium balance
in early childhood. Without newborn screening, affected children present with signs of androgen excess
(pubic hair) typically before the age of 4 years, and girls may have clitoromegaly or a urogenital sinus. The
diagnostic criterion for classic CAH in childhood is the same as that in infancy. Patients who are inade-
quately treated show rapid somatic growth leading to premature epiphyseal fusion and subsequent short stat-
ure. Children with nonclassic CAH may have hyperandrogenism and often are diagnosed during adulthood.
Adolescence and Adulthood

Women with Classic CAH
Women may present with clinical manifestations secondary to excess androgen (irregular menses, acne,
hirsutism, deep voice) due to inadequate treatment or noncompliance. In contrast, women treated with
excess glucocorticoids may present with clinical manifestations of hypercortisolism, such as excess
weight gain, easy bruising, and myopathy. During the transition of care from childhood into adulthood,
women should be assessed for vaginal stenosis. Women with CAH are at increased risk for infertility.
Men with Classic CAH

Men with classic CAH might develop testicular adrenal rest tumors (TARTs), which can masquerade as
testicular tumors. TARTs develop in 30% to 50% of adolescent boys and men with classic CAH, particu-
larly after periods of poor control. TARTs are usually bilateral and arise from the rete testis. The tumors
are identified with ultrasonography, which should be performed on completion of puberty in boys with
classic CAH. The pathogenesis of TARTs is unknown but thought to be related to ectopic adrenal cortex
remnants in the testis or from reprogrammed Leydig stem cells that grow under the influence of chroni-
cally elevated ACTH. The mass effect impairs blood flow to the testis and hinders the outflow of semen
leading to irreversible damage. The presence of a TART and elevated follicle-stimulating hormone levels
are poor prognostic factors for male fertility.
Nonclassic CAH
Mild hyperandrogenism (hirsutism, acne, menstrual dysfunction, and subfertility) associated with non-
classic CAH can affect females, but postpubertal males are often asymptomatic. Those clinical features
may be difficult to differentiate from the more common polycystic ovary syndrome (Figure 6.35), and
FIGURE 6.35 Adult female with nonclassic congenital adrenal hyperplasia presenting with (A) facial acne
and hirsutism and (B) body hirsutism. (Courtesy of Dr. Charles Faiman.)
measurement of corticotropin-stimulated 17-hydroxyprogesterone levels by liquid chromatography-tan-

dem mass spectrometry helps establish the diagnosis.
A level greater than 1500 ng/dL, when measured before 8 a.m. and during the early follicular phase,
is usually diagnostic. Levels between 200 and 1500 ng/dL are suggestive and can be confirmed with a
CST. An increase in 17-hydroxyprogesterone to greater than 1500 ng/dL is confirmatory. A level less than
200 ng/dL rules out CAH in almost all patients. Genetic testing may be done for family planning and in
patients with inconclusive biochemical testing.
Genetics
The diagnosis of CAH can be confirmed by genotyping and is part of newborn screening programs
in some countries. Mutations in the CYP21A2 gene located on chromosome 6p21.3 is responsible for
causing 21-hydroxylase deficiency. 11β-Hydroxylase deficiency is caused by mutations of the CYP11B1
gene located on chromosome 8q21-q22, whereas 17α-hydroxylase deficiency is caused by mutations in
the CYP17 gene, which is located on chromosome 10. 3-β-Hydroxysteroid dehydrogenase deficiency is
related to mutations in the HSD3B2 gene that impairs both adrenal and gonadal steroid production.
Nonclassic CAH is the cause of hirsutism in about 4% of cases worldwide, and it is commonly misdiag-
nosed as polycystic ovary syndrome. Therefore, screening for nonclassic CAH is appropriate in the evalu-
ation of hirsutism or polycystic ovary syndrome. Other differential diagnoses include virilizing adrenal
and ovarian tumors.
The treatment goals for CAH include:
1. Treatment of adrenal insufficiency by replacing cortisol deficiency without causing cushingoid

features and aldosterone deficiency with fludrocortisone (if there is a lack of adequate miner-
alocorticoid activity)
2. Addressing excess ACTH secretion that leads to hyperandrogenism in females and increased
risk for TARTs in males
Classic CAH
Management of adrenal insufficiency was addressed in the section ‘Adrenal Insufficiency’.
In children with CAH, an additional major goal of therapy is to sufficiently suppress adrenal-derived
androgen production to allow for the achievement of normal adult height. Hydrocortisone is preferred in
doses of 10–20 mg/m2 of body surface area per day in three divided doses. During the transition to care
in adulthood, after linear growth has stopped, control of adrenal-derived androgen excess is often relaxed
to limit exposure to prolonged glucocorticoid excess. Androstenedione and 17-hydroxyprogesterone levels
are usually used to guide the intensity of glucocorticoid treatment. Nocturnal glucocorticoids are espe-
cially effective at lowering morning rises in ACTH and adrenal androgen production but impart a greater
risk for CS and mood disorders.
In women who desire pregnancy, the goal is to suppress adrenal-derived progesterone to less than
0.6 ng/mL during the follicular phase. Dexamethasone is not inactivated by placental 11β-hydroxysteroid
dehydrogenase type 2 and will expose the fetus. Accordingly, hydrocortisone, prednisone, or prednisolone
are preferred for women who desire fertility. Preconception genetic counseling is advised for all patients
with classic or nonclassic CAH to assess the risk of fetuses for CAH.
In pregnancies where the fetus is at risk for classic CAH, maternal dexamethasone treatment insti-
tuted early in the first trimester can successfully suppress the fetal HPA axis and prevent the genital ambi-
guity of affected female infants. Chorionic villus sampling or amniocentesis should be performed for the
determination of fetal sex and genotyping for the CYP21A2 gene. The treatment with dexamethasone can
be safely discontinued if the fetus is male or the female is unaffected.
Men with TARTs require glucocorticoid intensification to achieve corticotropin suppression and
tumor shrinkage; however, TARTs develop fibrotic elements over time, which do not regress in response
to glucocorticoids. Large TARTs can be surgically removed, but testicular testosterone and sperm produc-
tion rarely return to normal levels.
Nonclassic CAH
In symptomatic patients with nonclassic CAH, the combined oral contraceptive pill is the most effective
treatment for hyperandrogenism and oligomenorrhea. It would normalize estrogen and menses, increase
SHBG, and decrease free androgen bioavailability. Spironolactone can be added to the oral contracep-
tive pill if there is insufficient improvement of hyperandrogenism. If undesired clinical signs of hyper-
androgenism persist after 6 to 12 months of treatment with an oral contraceptive and spironolactone, a
discussion regarding a low-dosage glucocorticoid can be considered. To improve fertility, a low-dosage
glucocorticoid therapy could also be considered.
ADRENOCORTICAL CARCINOMA
Incidence/Epidemiology
Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy, with an annual incidence of 1 to 2
cases per million. Although ACC can occur at any age, there is a bimodal age distribution, with disease
peaks before 5 and between 40 and 50 years. The incidence is almost tenfold higher in children in south-
ern Brazil, due to the high prevalence of a TP53 germline mutation. In an adrenal incidentaloma, the risk
of ACC is less than 2% with tumors smaller than 4 cm, 6% with tumors between 4 to 6 cm, and >25%
with tumors measuring at least 6 cm.
Molecular Pathogenesis
Most cases of ACC appear to be sporadic, and some present as a component of hereditary cancer syn-
dromes, such as Li–Fraumeni syndrome, Beckwith–Wiedemann syndrome, Lynch syndrome, and
MEN-1. Li–Fraumeni syndrome is an autosomal dominant disorder associated with inactivating muta-
tions of the TP53 tumor-suppressor gene at the 17p13 locus. Beckwith–Wiedemann syndrome is associ-
ated with abnormalities in 11p15 leading to IGF-2 overexpression. MEN-1 is associated with inactivating
mutations of the MEN-1 gene on chromosome 11q. Lynch syndrome is an autosomal dominant disease
and is associated with mutations in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes.
There are three main clinical scenarios in which ACC patients present. Approximately half of the patients
have signs and symptoms of hormone excess (commonly hypercortisolism and/or hyperandrogenism). A
third presents with nonspecific symptoms from local tumor growth (abdominal/flank pain or fullness,
early satiety) since the tumors are generally large, measuring on average 10 to 13 cm. The remaining cases
are incidental.
Hypercortisolism presents with plethora, muscle weakness, hypertension, diabetes mellitus, hypoka-
lemia, and osteoporosis. Hyperandrogenism presents with rapid-onset male pattern baldness, hirsutism,
virilization, and irregular periods (Figure 6.36). Concurrent androgen and cortisol production is evident
in about half of all ACC patients with hormone excess. Isolated hyperandrogenism in men is often chal-
lenging to recognize; however, some patients present with gynecomastia and testicular atrophy related to
estrogen excess. Autonomous aldosterone secretion is rare in ACC. Paraneoplastic syndromes are uncom-
mon and include IGF-2–mediated hypoglycemia, hyperreninemic hyperaldosteronism, and erythropoie-
tin-associated polycythemia.
Diagnosis
Imaging
Available imaging techniques for suspected ACC include CT, MRI, and 18FDG-PET. The initial evalu-
ation is usually an unenhanced CT of the abdomen (Figure 6.37). Large tumors commonly demonstrate
necrosis or hemorrhage and may contain calcifications. Masses with a density of 10 HU or more should be
evaluated with a dedicated adrenal contrast-enhanced CT scan. Almost all ACCs have a noncontrast CT
density >20 HU. Lesions with >60% absolute contrast washout at 15 minutes are likely benign.
If initial CT imaging is highly suspicious for malignancy, additional chest and pelvic CT is needed
to determine the extent of the disease. Although CT imaging is the study of choice, MRI (Figure 6.38)
may provide better resolution on venous tumor thrombus, venous invasion, and small hepatic metasta-
sis. 18F-Fluorodeoxyglucose (FDG)–positron emission tomography (PET)/CT may help to assess disease
extent.
FIGURE 6.36 Clitoromegaly in a woman with adrenocortical carcinoma secondary to excess androgen secre-
tion. (Courtesy of Dr. Charles Faiman.)
FIGURE 6.37 CT scan of the abdomen with intravenous contrast in a patient with adrenocortical carcinoma
showing a 12.6 cm heterogeneous lobulated mass occupying the left renal fossa (arrow). An area of necrosis
is seen in the center (arrowhead).
FIGURE 6.38 Coronal view of T1-weighted gadolinium-enhanced abdominal MRI of the same patient in
Figure 6.37 showing a large lobulated mass in the left upper quadrant of the abdomen (large arrow) displacing
the left kidney inferiorly (arrowhead) and the stomach superiorly (arrow). There is heterogeneous enhance-
ment after giving contrast.
Hormonal Workup
The biochemical workup of an adrenal mass suspicious for ACC should include basal cortisol, ACTH,
DHEAS, and testosterone levels; a 1 mg dexamethasone suppression test; and/or 24-hour urine free cor-
tisol, aldosterone, and plasma renin activity, as well as plasma metanephrines to rule out an underlying
pheochromocytoma. It is important to note that imaging studies cannot reliably distinguish ACC from
pheochromocytoma, which is lipid poor (noncontrast CT density >10) and may appear heterogeneous.
The measurement of other adrenal steroidogenesis intermediary hormones such as 17-hydroxyprogester-
one, androstenedione, and 11-deoxycortisol may serve as a tumor marker and is recommended by some
experts. In addition, urine steroid profiling may reveal increased steroid precursors and metabolites even
in clinically nonfunctioning ACC. Hormonal evaluation is essential in guiding the postoperative need for
hormone replacement and may be a potential tumor marker for surveillance.
Pathology and Staging

Patients with ACC without evidence of extensive multiorgan involvement or widespread distant metasta-
ses should undergo open surgical resection (Figure 6.39), providing a potential cure.
The pathology is used to confirm the diagnosis and determine the grade and stage of the cancer. The
Weiss scoring system relies on microscopic features to make the pathologic diagnosis (Figure 6.40). The
scoring includes the nuclear grade, mitotic rate, presence of atypical mitosis, necrosis, clear cells, venous
invasion, sinusoidal invasion, and capsular invasion. A Weiss score of 3 or more confirms ACC diagnosis.
Adrenal cortical tumors with a Weiss score of 2 are considered to have uncertain malignant potential. It
is worth noting that the Weiss score may overestimate the malignant potential of adrenal cortical tumors
in pediatric patients and in tumors with predominantly oncocytic morphology. In such cases, the Wieneke
and Lin–Weiss–Bisceglia criteria, which have modified criteria for malignancy tailored to these subsets
of tumors, are recommended.
The histologic appearance of adrenal cortical carcinoma is often nonspecific and can overlap with
carcinomas from other sites, such as the liver, kidney, and thyroid, in addition to a variety of mesenchy-
mal tumors. Correlation with clinical history, hormone levels, and imaging studies, as well as confirming
adrenal cortical origin with immunohistochemistry are critical (Figure 6.41). SF1 is the most reliable
immunohistochemical marker to confirm the adrenocortical origin and is useful to exclude metastasis and
pheochromocytoma. Inhibin, Melan-A, chromogranin, and GATA3 are other markers of adrenal corti-
cal origin, although less sensitive and specific than SF1. Synaptophysin expression can be seen in both
adrenal cortical tumors and pheochromocytoma; therefore, it cannot differentiate these entities. After the
diagnosis of ACC is made, the grade of the tumor is determined by the Ki67 proliferation index, where
greater than 10% is considered high-grade. High-grade tumors have a poor prognosis.
The most effective therapy is surgical resection. Surgery often needs to be extensive with en bloc resec-
tion of involved organs. The presence of a tumor thrombus in the inferior vena cava or the renal vein does
FIGURE 6.39 Gross appearance of adrenocortical carcinoma: 15 cm gray-tan and hemorrhagic, variegated
tumor totally replacing the adrenal gland (arrow). The normal kidney is seen inferior to the mass (arrowhead).
(Courtesy of Dr. Howard Levin.)
FIGURE 6.40 Microscopic appearance of an adrenal cortical carcinoma. (A) Marked hypercellularity with
loss of sinusoidal architecture and marked nuclear pleomorphism (arrows). (B) Vascular invasion. Arrows show
the presence of carcinomatous cells within three blood vessels. (C) Nests and sheets of pink cells, with readily
identifiable mitotic activity (arrows). (D) Extensive necrosis (arrow) and focal residual viable adrenal cortical
carcinoma cells (arrowhead). (Courtesy of Dr. Howard Levin.)
FIGURE 6.41 Metastatic melanoma to the adrenal. Malignant neoplasm is composed of pink cells with
prominent nucleoli (arrow), which could be mistaken for an adrenal cortical neoplasm out of context. This case
illustrates the critical importance of correlation with clinical history and imaging studies in diagnosing adrenal
tumors. If metastasis is suspected, the diagnosis can readily be confirmed with immunohistochemistry. Lack of
expression of adrenal cortical markers such as SF1 along with expression of melanocyte-specific markers was
confirmatory in this case. H&E, 400×.
not preclude complete tumor resection but occasionally necessitates cardiac bypass technique. An open
adrenalectomy is advised, since the laparoscopic technique may be associated with a higher risk for local
recurrence. Tumor debulking does not improve survival but may help control the symptoms of hormonal
excess. Surgery for local recurrences or metastatic disease may be associated with improved survival.
Mitotane is the only adrenal-specific agent available for the treatment of ACC. It has adrenolytic and
adrenostatic properties, and it can control symptoms of hormone excess in most patients.
Adjuvant mitotane therapy is recommended for high-grade stage I and II disease, all stages III and IV,
and in those with incomplete surgical resection. Progression of the disease while on mitotane should trig-
ger an escalation of therapy, including chemotherapy (etoposide, doxorubicin, cisplatin), immunotherapy,
repeated surgery, radiotherapy, and radiofrequency ablation of metastases.
Patients on mitotane should be treated with glucocorticoids with or without mineralocorticoids, as
all patients will eventually develop adrenal insufficiency. Patients often need supraphysiologic dosages
of glucocorticoids because mitotane increases cortisol-binding globulin and accelerates glucocorticoid
metabolism by activating P450 CYP3A4. Patients on mitotane commonly develop central hypothyroid-
ism and should have their free T4 levels monitored. Men may also develop hypogonadism, which is often
challenging to treat due to very high levels of sex hormone-binding globulin.
Follow-Up and Prognosis

Hormonal markers and imaging studies are monitored after surgery for early detection of tumor recur-
rence. CT scan of the abdomen, chest, and pelvis is the preferred imaging modality. 18F-FDG PET may be
helpful in selected cases for detecting local recurrence or distant metastasis.
After radical surgery, more than 50% of patients with ACC will develop a recurrence within 5 years.
The 5-year survival rate for patients with metastatic disease is less than 15%. The introduction of new thera-
pies, including immune check inhibitors, has provided additional tools to combat this aggressive cancer.
ADRENAL INCIDENTALOMA
Definition
Adrenal incidentaloma is defined as an adrenal lesion measuring 1 cm or more that is detected on imag-
ing in the absence of symptoms or clinical findings suggestive of adrenal disease. This definition excludes
patients who are undergoing screening and surveillance because of hereditary syndromes or as part of the
staging of an underlying malignancy.
Prevalence/Etiology
The prevalence of adrenal incidentaloma is about 4%–6%. The prevalence increases with age: adrenal
incidentaloma occurs less than 1% in patients younger than 30 years old and about 7% in those over 70
years old.
When faced with a patient with an adrenal incidentaloma, the clinician must answer two important
questions:
1. Is the lesion functioning?

2. Is there any possibility of a primary or secondary (metastasis) malignant tumor?
These determinations are guided by clinical and radiographic features and biochemical assessments.
Evaluation/Management
Ruling Out an Underlying Malignancy
An adrenal incidentaloma may be a primary malignant tumor of the adrenal cortex (adrenocortical carci-
noma) or medulla (pheochromocytoma), or metastases from another primary site such as lung, gastroin-
testinal tumors, melanoma, and renal cell carcinoma (Table 6.8). Tumor size and imaging characteristics
help determine the likelihood of cancer and guide treatment. Since benign incidentalomas are uncommon
in patients younger than 40 years of age, close monitoring is important in this age group, even for masses
smaller than 4 cm. Suspicious imaging features include irregular tumor margins, heterogeneity, necrosis,
increased vascularity, and calcification. A low noncontrast CT attenuation <10 Hounsfield units excludes
malignant lesions (Figures 6.42–6.45). Attenuations of more than 10 Hounsfield units require follow-up
imaging with contrast-enhanced CT to calculate washout characteristics. An absolute washout of more
than 60% and a relative washout of more than 40% are suggestive of an adenoma, but the sensitivities
and specificities of these cutoff values vary across studies owing to variations in technique and timing of
measurement of the washout.
In patients with borderline imaging characteristics, monitoring the tumor size would be a reasonable
approach. A change in tumor size of 0.5–1 cm has been used as a threshold for surgical intervention.
While a change in adrenal mass is a significant predictor of a malignant tumor, it should be used in con-
junction with other imaging and clinical characteristics when surgical resection is considered.
MRI with chemical-shift analysis may also help differentiate between benign and malignant adrenal
masses. On T1-weighted images, a drop in signal intensity during the opposed phase (out-of-phase) com-
pared to in-phase images is consistent with the high fat content seen in benign adrenal masses (Figure
6.46). It has 94% sensitivity and 95% specificity for identifying adenomas.
During the 18F-FDG PET-CT adrenal imaging, using the ratio of maximum standardized uptake in
the adrenal tumor compared with the spleen or liver may be used to distinguish benign from malignant
tumors with inconclusive CT or MR images (sensitivities and specificities of 85% to 91% and 89% to 91%,
respectively).
TABLE 6.8 Causes and Prevalence of Adrenal Incidentalomas

ETIOLOGY PREVALENCE (%)
Adrenal cortical tumors
Adenoma 80–90
Nodular hyperplasia 7–17
Carcinoma 0.1–2
Adrenal medullary tumors
Pheochromocytoma 1.5–5
Other adrenal tumors
Myelolipoma 7–15
Lipoma 0–11
Cysts and pseudocysts 4–22
Hematoma and hemorrhage 0–4
Infections and granulomas Rare
Metastases 0–21
FIGURE 6.42 A left adrenal mass with noncontrast CT scan HU of –5, which is consistent with a benign
adenoma (arrow).
FIGURE 6.43 Adrenal myelolipoma. Noncontrast CT scan image of a left adrenal myelolipoma. The lesion
appears heterogeneous, with areas of very low Hounsfield units (<–30) due to the high fat content (arrow). A
right adrenal adenoma is also seen (arrowhead).
Adrenal Biopsy
Biopsy of an adrenal mass may not distinguish between benign adenoma and ACC and may lead to
tumor seeding of an underlying adrenocortical carcinoma. It should only be considered if an adrenal
metastasis is highly suspected, and confirmation of such a diagnosis would change the management.
Pheochromocytoma must be excluded before a biopsy or any adrenal surgery to avoid a hyperadrenergic
crisis.
Assessment of Bilateral Adrenal Masses

About 15% of adrenal incidentaloma are bilateral. The differential diagnosis of bilateral adrenal masses
includes primary macronodular adrenal hyperplasia and adenomas, pheochromocytomas, congenital
FIGURE 6.44 Gross specimen of an adrenal myelolipoma; 7.5 cm bivalved yellow mass is shown. Normal
adrenal cortex is splayed over the surface (arrow). (Courtesy of Dr. Howard Levin.)
FIGURE 6.45 Microscopic appearance of adrenal myelolipoma. It consists of admixed mature fat and bone
marrow elements, including maturing erythroid and myeloid cells and megakaryocytes (arrow).
adrenal hyperplasia, adrenal hyperplasia due to Cushing disease or ectopic ACTH syndrome, metastases
or primary cancers, myelolipomas (Figures 6.44 and 6.46), infections, hemorrhage, and partial glucocor-
ticoid resistance. Hormonal assessments should also include measurement of the serum 17-hydroxypro-
gesterone level to rule out congenital adrenal hyperplasia. Testing for adrenal insufficiency is indicated if
the lesions appear hemorrhagic or infiltrative, or if there is suspicion of bilateral metastasis. Management
depends on the underlying etiology.
Hormonal Evaluation
Initial hormonal evaluation in patients with adrenal incidentalomas includes 1 mg DST; in all patients,
plasma or urinary metanephrines in lipid-poor lesions and aldosterone; and PRA levels in those with HTN
or a history of hypokalemia. The measurement of plasma ACTH and serum DHEAS levels may provide
additional information about chronic mild autonomous cortisol excess secretion.
FIGURE 6.46 (A) In-phase and (B) out-of-phase coronal MRI image in a patient with left adrenal mass
(arrows). There is a decrease in signal intensity of the mass in the out-of-phase image due to high fat content,
which is consistent with adenoma/hyperplasia.
Mild Autonomous Cortisol Excess (MACE)

About 5% to 30% of patients with incidentally detected adrenal masses (adrenal incidentalomas) have
mild cortisol hypersecretion in the absence of the typical clinical features of CS such as facial plethora,
muscle wasting, or wide purplish striae. The MACE has also been referred to as subclinical CS.
MACE is associated with a higher incidence of coexisting hypertension, obesity, hyperglycemia,
dyslipidemia, and low bone density as compared with nonfunctioning adrenal tumors.
The initial workup includes overnight 1 mg DST. A cortisol level <1.8 mcg/dL after overnight DST
suggests normal cortisol secretion. In the absence of recent glucocorticoid therapy, low plasma ACTH and
serum DHEAS levels support autonomous cortisol secretion. False positives may occur in patients receiv-
ing medications such as phenytoin, rifampin, and phenobarbital that accelerate the hepatic metabolism
of dexamethasone or in those taking estrogen. Following an abnormal overnight 1 mg DST, a 24-hour
urinary free cortisol or late-night salivary cortisol level is reasonable to assess the magnitude of cortisol
excess.
Adrenalectomy may improve diabetes mellitus, hypertension, low bone density, and hyperlipidemia
compared to patients undergoing active surveillance. Patients with MACE may develop temporary adre-
nal insufficiency following removal of the adrenal tumor due to chronic suppression of the contralateral
adrenal gland.
Evaluation/Management/Follow-Up
An approach to incidentally discovered adrenal masses is shown in Figure 6.47. Homogeneous adrenal
masses <4 cm in size with a maximum noncontrast CT <10 HU do not require routine follow-up imag-
ing study. Patients with a normal 1 mg DST do not require continued workup unless they develop new or
worsening comorbidities suggestive of autonomous excess cortisol secretion. Adrenal masses >2.4 cm are
more likely to develop MACE and a closer follow-up is needed.
Patients with a noncontrast CT ≥10 HU and tumor size >4 cm should be referred for surgery. Those
with a noncontrast CT density ≥10 HU and tumor size <4 cm should have their absolute CT washout per-
centage calculated and referred for surgery if the mass has a poor washout (<60%). In patients with a high
washout percentage, a follow-up imaging study in 6–12 months is reasonable. There is no good evidence
FIGURE 6.47 Algorithm for management of patients with adrenal incidentaloma. HU, Hounsfield unit.
supporting continued radiological surveillance in lipid-poor adrenal masses with no significant change in
tumor size beyond 2–3 years.
BIBLIOGRAPHY
Bovio et al., J Endocrinol Invest (2006). PMID: 16699294
Young et al., Endocrinol Metab Clin North Am (2000). PMID: 10732270
Morelli et al., JCEM (2014). PMID: 24423350
Bornstein. NEJM (2009). PMID: 19474430
Husebye et al., Lancet (2021). PMID: 33484633
Li et al., JCEM (2020). PMCID: PMC7470471
Boonen et al., NEJM (2013). PMID: 23506003
Hamrahian et al., Endocr Pract (2017). PMID: 28332876
Hamrahian et al., NEJM (2004). PMID: 15084695
Javorsky et al., J Endocr Soc (2021). PMID: 33768189
Funder et al., JCEM (2016). PMID: 26934393
Byrd et al., Circulation (2018). PMID: 30359120
Rossi. J Am Coll Cardiol (2019). PMID: 31779795
Young. J Intern Med (2019). PMID: 30255616
Milliez et al., J Am Coll Cardiol (2005). PMID: 15837256
Neumann et al., NEJM (2019). PMID: 31693823
Kannan et al., Clin Endocrinol (2014). PMID: 24494743
Geroula et al., Eur J Endocrinol (2019). PMID: 31370000
Newell-Price et al., Lancet (2006). PMID: 16698415
Feelders et al., Lancet Diabetes Endocrinol (2019). PMID: 30033041

Loriaux. NEJM (2017). PMID: 28402781
Yogi-Morren et al., Endocr Pract (2015). PMID: 26121435
Merke et al., NEJM (2020). PMID: 32966723
Speiser et al., JCEM (2018). PMID: 30272171
Fassnacht et al., JCEM (2013). PMID: 24081734
Kiseljak-Vassiliades et al., Endocr Pract (2020). PMID: 33875173
Else et al., Endocr Rev (2014). PMID: 24423978
Male and Female
Reproductive
Disorders
7
Rhoda H. Cobin, MD
ABSTRACT
Reproductive disorders in males and females include those which are congenital or aquired, structural
or functional and range from the very common to the very rare. Understanding normal development and
function as well as basic pathophysiology allows appropriate evaluation and management. This chapter
will provide this information and current evidence based treatment recommendations for these disorders.
AMENORRHEA
Normal women experience regular ovulatory menses from an average age of onset (menarche) of 12.4
years (range 10–16 years) until their cessation (menopause) at an average age of 51.5 years (range 45–55
years). ‘Normal’ menses can be viewed as a sign of normal anatomy, pubertal development, hypotha-
lamic–pituitary–ovarian axis function, and general good health. Although irregular menses can be a
sign of failure to ovulate, menses can be regular but anovulatory in anywhere between 4% and 20% of
otherwise normal women. In the first 2–3 years after menarche and several years before total cessation of
menses (perimenopause; vide infra), anovulatory cycles, which may be regular or irregular, are extremely
common. In conditions such as polycystic ovary syndrome (PCOS; vide infra), up to 20% of regular cycles
may be anovulatory (1).
Normal
The development of normal female anatomy is dependent on the absence of a functional Y chromo-
some (codes for the development of testes, male internal genitalia, androgen production, and regression of
Müllerian duct structures). In the female, Müllerian duct structures (uterus, fallopian tubes, upper vagina)
develop, external genitalia remain female in the absence of androgen, while ovaries secrete estrogen,
resulting in female external genitalia and secondary sex characteristics, and ultimately ovulation during
‘reproductive years’.
192 DOI: 10.1201/9781003100669-7

7 • Male and Female Reproductive Disorders 193
Menses result from cyclic estrogen (and progesterone after ovulation) stimulation of endometrial tis-
sue. Ovarian hormone secretion and ovulation are stimulated by appropriate pulsatile release of pituitary
gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) of variable frequency
and amplitude during the menstrual cycle, which in turn are controlled by pulsatile hypothalamic kiss-
peptin–stimulated gonadotropin-releasing hormone (GnRH). Kisspeptin release by hypothalamic KNDy
neurons is intricately coordinated by integrating signals via neurokinin and kappa opioid peptide recep-
tors from sex steroid feedback as well as metabolic signals including leptin, ghrelin, adiponectin, insulin,
melanocortin, GLP-1, inflammatory signals, and opioids, and neuronal input from POMC/CART and
AgRP/NPY hypothalamic neurons. In both the hypothalamus and pituitary, sex steroids and gonadotropin
inhibitory protein reduce LH, while inhibin from ovarian granulosa cells inhibits FSH release. Ovarian
estrogen production initially causes feedback inhibition in the early phase of the menstrual cycle, which
then becomes positive resulting in the LH surge, which causes ovulation. After ovulation, the ovarian
corpus luteum secretes progesterone, which inhibits gonadotropin and hence estrogen production, begin-
ning the next cycle. As noted, menses can occur without ovulation, with uterine bleeding being caused
by estrogenic stimulation of the endometrium and with subsequent estrogen withdrawal. (Unopposed
estrogen can cause endometrial hyperplasia, which can in turn result in endometrial carcinoma; this will
be important in evaluation and management to be discussed later.)
For a more detailed description of normal development and reproductive function, see Cobin et al. (2).
Females are born with a full complement of ovarian follicles numbering approximately 2 million,
which normally decline over one’s lifetime to about 300,000 at puberty and to 100,000 at age 30 with
eventual further decline thereafter. In addition to gonadotropin stimulation, intraovarian signaling,
including anti-Mullerian hormone (AMH), growth factors, transcription factors, and complex signaling
cascades with endocrine, paracrine, and autocrine regulation result in the development of a dominant fol-
licle and ovulation each cycle, with graduation atresia and loss of oocytes during a woman’s lifetime (3, 4).
Amenorrhea is the inappropriate absence of menses in women of reproductive age. Oligomenorrhea
is a reduced frequency/longer interval between menses, often but not always associated with absent or
less frequent ovulation. Pathologic amenorrhea is considered primary if a woman has never menstruated
by the average age of 15 (age 14 without signs of puberal development [breast tissue development, axil-
lary/pubic hair] or by age 16 with breast development). Secondary amenorrhea is the absence of menses
in a woman who previously had established menstrual function, with the definition being the absence of
menses for 3–12 months, according to various authorities. (It should always be remembered that the most
common cause of secondary amenorrhea is not pathologic but pregnancy!)
The etiology, impact, and therapy of amenorrhea and oligomenorrhea are influenced by this distinc-
tion. Since normal menstrual function requires normal structural development and normal function of the
hypothalamic–pituitary–ovarian axis as well as a normal outflow tract (uterus, vagina, hymen), in women
with primary amenorrhea, there may be defect(s) at any of these levels, whereas, by definition, women
with secondary amenorrhea must have had normal anatomy as well as function.
Table 7.1 summarizes the most common etiology of amenorrhea at each of these levels in both the
primary (congenital) and secondary (acquired) settings.
Hormone replacement treatment (HRT) for all forms of amenorrhea in women in the ‘reproduc-
tive age group’ is indicated. Treatment goals include restoration of normal menses, preservation of bone
mass, reduced psychological concern, and, when appropriate, treatment for infertility. Therapy should
be individualized based on age, goals, expectations, and possible risks. Estrogen is available in multiple
formulations, doses, and routes of administration. Progesterone is required with estrogen therapy in the
presence of a uterus to avoid endometrial hyperplasia and possible endometrial cancer. Contraindications
to estrogen therapy in young women include thrombogenic mutations or a history of venous thromboem-
bolic disease (VTE), pulmonary embolism, and a strong risk of hereditary breast cancer. But it should be
emphasized that the potential risks of HRT commonly cited for menopause, especially cardiovascular and
brain risk (see ‘Menopause’ section) do not apply to this group of young women in which benefit almost
always outweighs risk.
TABLE 7.1 Etiology of Amenorrhea

LEVEL OF AXIS CONGENITAL ACQUIRED*
Hypothalamus Syndromic† Craniopharyngioma
Isolated GnRH deficiency Meningioma
Other tumors
Pituitary Agenesis Hyperprolactinemia
Tumor or other cause
Acromegaly
Cushing’s
Nonsecretory tumors
Ovary Chromosomal ovarian dysgenesis PCOS‡
Androgen-secreting tumors
Premature ovarian failure
Uterus Mullerian duct defects Pregnancy
Outflow tracts Mullerian duct defects
Adrenal Congenital adrenal hyperplasia Cushing's, androgen- secreting tumors
Thyroid Hyper-/hypothyroidism
Miscellaneous Androgen insensitivity syndrome Constitutional delay of puberty
5α-reductase deficiency
Source: Cobin RH, Goodman NF, Jain S, Reproductive disorders, Chapter 5, in Evidence-Based Endocrinology, Camacho, P.
et al. ed., 4th edition, pp. 166–265, Wolters Kluwer, Philadelphia, 2020.
*Congenital disorders always present as ‘primary amenorrhea’, while acquired disorders may present as primary amenorrhea
if their onset is before puberty/menarche or as secondary amenorrhea if they develop afterward.

†Multiple complex genetic syndromes associated with congenital hypogonadotropic hypogonadism have been described with
known genetic mutations. A variety of associated nonreproductive anomalies may be present. For more complete
details, see https://www.ncbi.nlm.nih.gov/books/NBK1334/table/kms.T.syndromes_associated_with_hypogona/.
‡While PCOS is thought to be genetically determined, it does not typically present clinically until puberty. Women with this
disorder undergo normal development of internal and external genitalia and secondary sexual characteristics.
Primary Amenorrhea
Constitutional Retardation of Puberty
When a young female fails to develop at an expected age, there is often concern for pathology, however,
many young women simply have delayed or ‘constitutional delay of puberty’, a normal variant. Although
this is more common in males than females, it does occur. Lab studies are indistinguishable from primary
hypothalamic hypogonadism, but there are no associated anosmia or somatic abnormalities. There may be
a family history of late menarche and often slight breast development may have started. Both adrenarche
and gonadarche are concomitantly delayed, and bone age is appropriate for height age rather than chrono-
logic age. Once puberty eventually starts, it progresses to normal menses, normal body proportions, and
family-appropriate height (5).
Imperforate Hymen
The first step in evaluating a woman with normal growth and pubertal development and primary amenor-
rhea is to determine the patency of the vaginal introitus. Imperforate hymen is readily apparent on thor-
ough examination of the external genitalia. The critical need for full physical examination in any woman
presenting with primary amenorrhea cannot be emphasized strongly enough.
This congenital anomaly is present in only about 0.5% of females. It consists of a persistent band of
tissue without the usual small aperture of the hymen, thus obstructing the flow of menstrual blood from
the vaginal outflow tract. It can sometimes be apparent in newborn females but is often unnoticed until
FIGURE 7.1 Imperforate hymen. (From Stone SM, Alexander JL. Images in clinical medicine. Imperforate
hymen with hematocolpometra. N Engl J Med 2004;351(7):e6.)
the time of menarche when, after fully normal female pubertal development and otherwise normal anat-
omy and hormone secretion, amenorrhea is reported (or sometimes scant infrequent blood flow). Many
girls present with lower abdominal pain and/or distention and sometimes lower back pain. Occasionally,
women have urinary tract symptoms. Laboratory studies are completely normal. Sonography will show
hematocolpos (distended vaginal and uterus filled with blood). Correction is by a simple hymenotomy or
hymenectomy, resulting in a complete, durable cure with normal menses and reproductive function (6).
Mullerian Agenesis (Mayer-Rokitansky-Kuster-Huaser)

Primary amenorrhea results from absent or rudimentary Müllerian-derived structures in a woman with
otherwise normal growth, development, hormone secretion, and secondary sexual characteristics. A rudi-
mentary vaginal canal may be present but with an absent uterus and fallopian tubes. Other congenital
anomalies may be present including scoliosis, unilateral renal agenesis, and, rarely, cardiac defects. Most
cases are sporadic, but autosomal dominant inheritance has been reported in some families. The disorder
has been associated with genetic mutations of various transcription factors involved in embryonic devel-
opment of the reproductive tract including the SHOX, WNT, LHX1, and TBX genes. The diagnosis is
made with sonography. Levels of estrogen and gonadotropins are normal. Treatment may include vaginal
reconstructive procedures (8, 9).
Turner Syndrome
Turner syndrome is a relatively common cause of primary amenorrhea with failure of normal pubertal
development. It results from mitotic error leading to XO or mosaic XX genotypes. Deletion of the short
arm of the X chromosome leads to degeneration of ovarian follicles and typical streak gonads. Variable
somatic abnormalities are associated. Deletion in the SHOX gene on the short arm of the X chromo-
some leads to short stature and other abnormalities, while other X chromosome genes may contribute to
anomalies that may include micrognathia, a high-arched palate, short fourth metacarpals, genu valgum,
Madelung wrist deformities, short limbs, wide-spaced nipples, webbed neck, and low-set hairline. There
may be associated hearing loss, renal developmental abnormalities (30%), and autoimmune disease, espe-
cially Hashimoto thyroiditis (30%) (10).
Liver disease, type 2 diabetes mellitus (T2DM), and metabolic syndrome (MBS) are also more com-
mon in these women.
The presence of Turner syndrome may be diagnosed with prenatal amniotic fluid genetic testing, it
may be apparent because of associated somatic abnormalities before puberty; may be found with evalu-
ation of growth retardation, failure of development of secondary sexual characteristics, or may only be
diagnosed because of primary amenorrhea.
Laboratory studies in addition to karyotype will show low estrogen. FSH is elevated due to lack of
ovarian inhibin in early childhood, falling during prepuberty (as GnRH production normally falls during
this time, occasionally causing diagnostic confusion), then rising to high levels at the time of puberty and
remaining elevated thereafter (12).
Of great importance, congenital heart disease is present in about 50% of women with Turner’s
syndrome, with mortality being three times higher than in the general population, with cardiovascular
disease the most common cause of death. The most common anomalies are a bicuspid aortic valve,
coarctation of the aorta, and thoracic aortic aneurysm. Hypertension, coronary artery disease, myocar-
dial infarction, and stroke risk are exacerbated by the underlying predisposition to MBS and diabetes
mellitus. Thus, it is strongly advised to regularly screen all women with Turner syndrome with initial and
regularly followed noninvasive imaging combining echocardiography, cardiovascular MRI, and some-
times cardiac computed tomography, because of the high incidence of serious lesions that often remain
subclinical. A recent statement on cardiovascular health in Turner syndrome from the American Heart
Association outlines the details of these lesions and suggests guidelines for appropriate screening and
management (13).
Some mosaic genotypes include all or portions of a Y chromosome, increasing the risk of gonado-
blastomas and therefore requiring a gonadectomy at the time of diagnosis (14).
Growth hormone treatment may significantly improve final adult height and should be considered
early in childhood if growth velocity (determined with Turner-specific growth curves) predicts final
height less than the fifth percentile. Estrogen is added at the time of predicted puberty. Because it will
cause epiphyseal fusion and limit further growth, the timing of growth hormone and estrogen administra-
tion is important (15).
Progesterone in estrogen-treated women is necessary because of the presence of a uterus to prevent
endometrial hyperplasia.
Bone density testing should be performed in adulthood and periodically thereafter. HRT in these
women has been shown to significantly improve bone density and reduce fractures, compared with no
treatment (16, 17).
It should be noted that in this and other conditions with amenorrhea in young women, the possible
concerns of menopausal HRT are not relevant.
Occasional spontaneous ovulation and pregnancy have been reported in women with mosaic Turner
syndrome, but outcomes are usually poor. The presence of a uterus, however, allows assisted reproduction
with donor ova, resulting in better outcomes (18).
FIGURE 7.2 Turner syndrome with neck webbing and shield chest (11). (Courtesy of Dr. Donald Gordon.)
FIGURE 7.3 Turner syndrome. (A) Short stature, (B) increased carrying angle in the upper extremities, (C) low
set ears. (Courtesy of Dr. Rhoda Cobin.)
Pure Ovarian Dysgenesis

Women presenting with female phenotype, failure of pubertal development, and primary amenorrhea
may have a normal XX karyotype (and occasionally XY). Although ovarian dysgenesis with low estro-
gen and elevated FSH is present, unlike Turner syndrome, there are no somatic anomalies. Müllerian
duct–derived organs (uterus, vagina) are normal. The condition is inherited as an autosomal recessive
trait. Some women with familial ovarian dysgenesis have been found to have mutations in the nucleoporin
and/or BRCA2 genes, both of which have been associated with ovarian dysgenesis in drosophila (19–21).
Androgen Insensitivity Syndrome (Testicular

Feminization Syndrome; Complete Variant)
Phenotypic females with primary amenorrhea may be found to have XY karyotype and normal testes
that secrete bioactive testosterone and AMH but have mutations in the androgen receptor gene causing
structural abnormalities in the receptor that result in abnormal binding. Occasionally no gene mutation
is found, but there is epigenetic repression of androgen receptor transcription. Male range circulating
FIGURE 7.4 Axial T2-weighted images revealing the testes (green arrows) with adjoining cysts on both sides
(red arrows). 3T Magnetic Resonance Imaging. Axial 4 mm fast T2-weighted image, TR/TE 5030/119. (From
Nezzo M, De Visschere P, T’Sjoen G, Weyers S, Villeirs G. Role of imaging in the diagnosis and management of
complete androgen insensitivity syndrome in adults. Case Rep Radiol 2013:Article ID 158484, 6 pages, 2013.)
FIGURE 7.5 Coronal T2-weighted images revealing the testes (green arrows) with adjoining cysts on both
sides (red arrows). (From Nezzo M, De Visschere P, T’Sjoen G, Weyers S, Villeirs G. Role of imaging in the diag-
nosis and management of complete androgen insensitivity syndrome in adults. Case Rep Radiol 2013:Article
ID 158484, 6 pages, 2013.)
testosterone and dihydrotestosterone (DHT) are found, with the former being aromatized to estrogen.
Clinically normal growth and development of breast tissue occur with minimal to modest axillary and
pubic hair and absent Müllerian duct structures. The testes may be intra-abdominal or inguinal and may
be visualized on sonography or MRI. Because of the presence of a Y chromosome, there is a risk of
gonadoblastoma; therefore, a gonadectomy must be performed but can be deferred until around the time
of puberty, as these tumors do not occur earlier. After removal, estrogen replacement is required to main-
tain breast development and bone density. Since no uterus is present, progesterone is not required and
menses do not occur (22–24). (Note: Incomplete androgen insensitivity results in male phenotype with
incomplete virilization; see ‘Male Hypogonadism’ section.)
FIGURE 7.6 Sagittal image showing the absence of the Müllerian structures and the presence of the lower
vagina (yellow arrowheads). 3T Magnetic Resonance Imaging. Sagittal 5 mm HASTE-sequence, TR/TE 6500/89.
(From Nezzo M, De Visschere P, T’Sjoen G, Weyers S, Villeirs G. Role of imaging in the diagnosis and manage-
ment of complete androgen insensitivity syndrome in adults. Case Rep Radiol 2013:Article ID 158484, 6 pages,
2013.)
5-Alpha Reductase Deficiency

This autosomal recessive trait, clinically expressed in XY males, is caused by mutation of the SRD5A2
gene, which codes for the 5-alpha reductase enzyme, whose function is to catalyze the conversion of
testosterone to DHT, thus reducing the active hormone that binds to the androgen receptor in androgen-
sensitive tissues. Male internal genitalia, adult male muscle mass, voice, and other signs of virilization are
responsive to testosterone, while intrauterine development of external genitalia, adult prostate tissue, and
male pattern baldness require DHT. XY males are not virilized in utero or in prepuberal life even though
normal testes are present and produce AMH, which causes regression of Müllerian structures. Wolffian
duct male internal genitalia develop normally.
Thus in the newborn, external genitalia may appear to be female with mild clitoromegaly, may show
ambiguous genitalia, or may appear male with a micropenis or hypospadias (26, 27).
At the time of puberty, however, the testosterone level becomes high enough to cause virilization
(and/or to result in overcoming a partial defect and cause some DHT production) to cause enlargement of
the phallus and normal virilization. Because the prostate and hair follicles are dependent upon relatively
high DHT concentrations, in the adult male, prostate enlargement and male pattern baldness do not occur
and there is a variable beard and male pattern body hair (28).
Mature men may be fertile but often have abnormal spermatogenesis with low sperm counts and thick
ejaculate, requiring assisted fertilization (29).
In areas where this mutation is common, it is often recognized by the family and people are raised as
males, awaiting ‘penis at 13’ development (30).
XX females with this mutation may be completely normal or may have delayed menarche, minimal
acne, and minimal body hair, with normal fertility.
If XY subjects are raised as girls, when puberty and masculinization occur, gonadectomy and estro-
gen replacement are performed. Since no uterus is present, pregnancy is not possible (31).
Autoimmune Oophoritis
Although this usually presents as secondary amenorrhea, occasionally ovarian destruction occurs before
the onset of first menses and would prevent normal pubertal development as well as amenorrhea. Elevated
LH and FSH and low estrogen similar to other ovarian failure disorders are present; antiovarian antibod-
ies would distinguish this condition from the others.
Primary Hypogonadotropic Hypogonadism

Although this condition is more common in males than females, it may present with failure of pubertal
development and primary amenorrhea in females. Very rarely, spontaneous thelarche and menarche that
fail to progress may occur. Normal female phenotype, normal ovaries, and normal internal and external
genitalia are present. Anosmia is present in 50% of cases, which are labeled Kallmann syndrome. Other
variants may present with midline facial defects, cleft lip/palate, hearing loss, or syndactyly. The diagno-
sis may be suggested because of the presence of these features and/or family history.
Laboratory studies show low estrogen, inappropriately low gonadotropins, normal androgens, and
normal prolactin.
Multiple hereditary patterns have been associated with this condition. Some cases are part of complex
genetic syndromes, including Prader–Willi syndrome and Laurence–Moon–Bardet Biedl syndrome (32).
In classic Kallmann syndrome, various mutations of the KAL gene, inherited in an X-linked recessive
manner, have been shown to cause failure of normal migration of GnRH-producing cells from the olfac-
tory area to the hypothalamus. Other gene mutations presenting as hypogonadotropic hypogonadism with
anosmia and many associated nonreproductive developmental anomalies include autosomal dominant
inherited SOX10, SEM3A, and IL17RD, and autosomal recessive inherited FEZF1. Hypogonadotropic
hypogonadism without anosmia has been linked to various mutations of either kisspeptin or the kisspeptin
receptor, which play important roles in the regulation of GnRH and subsequent gonadotropin release.
Additional mutations in the GNRH1 (prepro-GnRH production), GNRHR (receptor), and TAC3 and
TAC3R genes encoding neurokinin B and its receptor in KNDy neurons have been described. Oligogenic
complex inheritance has also been described. Some of these disorders are associated with nonreproduc-
tive abnormalities (2).
Treatment of hypogonadotropic hypogonadism in females with estrogen and progesterone should be
initiated after full height is attained, to stimulate and maintain secondary sex characteristics and bone
health. In appropriate clinical settings, pulsatile GnRH therapy delivered by pump has restored sex steroid
production and fertility, though this is cumbersome and rarely used.
Pituitary and Hypothalamic Tumors

Most pituitary adenomas present as secondary amenorrhea but can occasionally present earlier.
Craniopharyngiomas and other pituitary–hypothalamic tumors (gliomas, meningiomas, etc.) may present
prepuberally. Infiltrative diseases of the pituitary–hypothalamic area rarely begin in childhood and more
commonly cause secondary amenorrhea.
Hypothalamic Amenorrhea
This disorder is described in greater detail later. Although it generally presents with secondary amenor-
rhea, if the underlying predisposing factors are present early enough in life, primary amenorrhea may be
the presenting feature, usually in young girls who may have had otherwise normal growth and develop-
ment but fail to menstruate. In this situation, it must be differentiated from hypothalamic hypogonadism
and constitutional retardation of puberty, and thus requires full investigation being a diagnosis of exclu-
sion, with all other causes of primary amenorrhea fully ruled out.
Secondary Amenorrhea
Uterine Dysfunction (Asherman’s Syndrome)
Destruction of the endometrium is most commonly caused by overly aggressive D&C performed for ter-
mination of pregnancy or incomplete or missed abortion, retaining the placenta after delivery, for removal
of uterine polyps, testing for endometrial cancer, or surgery to remove uterine polyps. These women have
no other symptoms or physical findings, and laboratory studies are normal, with normal estrogen, gonado-
tropins, prolactin, androgens, and otherwise general good health. The diagnosis is suggested by the failure
to bleed after a progesterone challenge (a positive test would indicate adequate estrogen) but also after
priming with estrogen, indicating an inadequate endometrium. Saline sonography or hysterosalpingog-
raphy may be suggestive, but a definitive diagnosis may require a hysteroscopy. Since these women are
hormonally normal, no treatment is indicated, but pregnancy cannot be achieved (33).
Premature Ovarian Failure

Women with previously normal menses that end before the expected age of menopause (usually <40 years
old) are said to have premature ovarian failure. They may present with amenorrhea and may experience
hot flashes, vaginal dryness, and other typical menopausal symptoms. Since estrogen levels are low, a pro-
gesterone challenge will fail to produce bleeding, but estrogen priming will result in a positive progester-
one challenge since the uterus is normal. Because of primary ovarian failure with loss of follicles, serum
AMH, estrogen, and inhibin are low, and LH and FSH are elevated. Some genetic causes of premature
ovarian failure have been identified (34).
There is a strong association with other autoimmune disorders, including Hashimoto’s disease, auto-
immune adrenal insufficiency, autoimmune polyglandular syndrome, and vitiligo. Circulating antiovarian
antibodies are found in up to 67% of women with this disorder. A candidate antigen (MATER) has been
identified. Antibodies to adrenocortical and thyroid may sometimes be found.
Often an alerting, easily detected physical finding suggestive of autoimmune disease is the presence
of vitiligo.
Treatment with estrogen and progesterone is indicated to preserve bone density, treat menopausal
vasomotor symptoms, and possibly have cardioprotective effects (see ‘Menopause’ section) unless there
are specific contraindications to HRT. Fertility with assisted reproductive technology with donor ova has
been achieved (35).
FIGURE 7.7 Vitiligo of the (A) arm and (B) abdomen in a patient with premature ovarian failure and
Hashimoto’s thyroiditis. (Courtesy of Dr. Rhoda Cobin.)
Fragile X Syndrome
All women with premature ovarian failure should be screened for fragile X syndrome, an X-linked domi-
nant disorder in which 20% of female carriers have premature ovarian failure. They are at risk of tremor/
ataxia syndrome, neuropathy, dizygotic twinning, and musculoskeletal problems. Their offspring suffer
cognitive impairment, worse in males than females. Genetic studies can identify the condition to avoid its
transmission. Preimplantation genetic testing is available (36).
PCOS
This disorder is extensively discussed in its own section. Although it is congenital and may present with
primary amenorrhea, it usually presents as oligomenorrhea first noticed at the time of puberty.
Hyperprolactinemia
This disorder is discussed in its own section.
Pituitary and Hypothalamic Tumors and Infiltrative Disease

Any space-occupying lesion, infiltrative disease, or destruction of the hypothalamic/pituitary region may
produce amenorrhea, either by destroying the production of normal regulatory peptides or by producing
hyperprolactinemia by direction secretion or by ‘stalk section’, which causes hyperprolactinemia by lack
of dopaminergic inhibition of pituitary prolactin production. Sheehan’s syndrome, or postpartum pituitary
necrosis, generally occurs in the setting of obstetrical bleeding in a physiologically hypertrophic gland,
often with preexistent anemia. Fortunately, it is increasingly rare in developed countries.
FIGURE 7.8 Neuroendocrine Causes of Amenorrhea and Infertility. (Image from Fourman, LT, Fazeli PK.
Neuroendocrine causes of amenorrhea—An update. J Clin Endocrinol Metab 2015;100(3):812–824.)
Functional Hypothalamic Amenorrhea (HA)

In clinical practice, functional hypothalamic amenorrhea is a diagnosis of exclusion. It is important to
take a full history and perform a full physical examination to exclude all other conditions listed earlier.
HA is often termed ‘diet-stress amenorrhea’, as it is thought to be caused by perturbations that disturb the
complex regulatory mechanisms in the hypothalamus involving the KNDy neuron system. This system
integrates multiple intrinsic and extrinsic signals, as described earlier.
The typical history is one of regular menses that become irregular, anovulatory, and/or cease alto-
gether. A physical exam reveals normal growth and development, normal secondary sex characteris-
tics, lack of galactorrhea, and lack of hyperandrogenism. There may be evidence of weight loss and or
anorexia/bulimia, but this is not always present. Excessive exercise, nutritional deficiency, and emotional
stress may play a role, but this is not always apparent or forthcoming in an initial history.
Laboratory studies include normal to low estrogen, inappropriately low/‘normal’ gonadotropins, nor-
mal thyroid, adrenal hormones, normal prolactin, and normal androgens. Because of the inappropriate
low gonadotropin levels, it is critical to exclude structural pathology in the hypothalamic–pituitary area
with imaging (38).
Treatment goals include restoring menses (and fertility when indicated) and, importantly, restoring
normal nutrition, body weight, and fat mass. Bone loss is a serious issue in these women, and often when
bone accretion in adolescence is inadequate, it is very difficult to restore and may result in fracture risk
even later in life.
Sometimes, counseling to address underlying psychosocial issues and to advise appropriately benefi-
cial but not excessive exercise will result in restoration of menses, normal body weight, better nutrition,
improved bone mass, and improved psychological status. If not adequate, HRT is indicated.
Although estrogen/progesterone therapy will restore normal menses (and often psychological reas-
surance), it is not always successful in restoring bone mass. Lack of IGF-1 may also contribute to bone loss
caused by undernutrition. Treatment with antiresorptive and/or bone anabolic agents, although helpful in
adults, has not been as useful in adolescents. Novel treatments, including IGF and DHEA, have been tried
(39, 40).
FIGURE 7.9 Clinical algorithm for amenorrhea evolution. (Algorithm from Cobin RH, Goodman NF, Jain S,
Reproductive disorders. Chapter 5, in Evidence-Based Endocrinology, Camacho, P. et al. ed., 4th edition, pp.
166–265, Wolters Kluwer, Philadelphia, 2020.)
Algorithm for Evaluation of Amenorrhea
Polycystic Ovarian Syndrome (PCOS)

PCOS is the most common endocrine disorder of women in the reproductive age group, affecting as many
as 8% of women. It is the most common cause of anovulatory infertility and hyperandrogenism. Its meta-
bolic consequences have profound medical consequences that persist beyond menopause (41, 42).
Confusion regarding the diagnosis, incidence, and consequences of PCOS occurs because of different
sets of criteria. Specifically, under the original Rotterdam classification, women may have only menstrual/
ovulatory irregularity along with polycystic ovarian morphology (PCOM) (which in itself is a major
issue, both because of the need for precise dedicated sonography equipment and experienced readers, and
because of the clinical overlap with hypothalamic amenorrhea, especially in adolescents, who may have
polycystic ovarian morphology without having the syndrome).
Authorities emphasize the need for caution in interpreting sonography in adolescence, often deferring
this to 8 years after menarche. The International PCOS Network guidelines published in 2018 (see later)
recently endorsed modified Rotterdam criteria in adolescence to require both hyperandrogenism and
menstrual/ovulatory dysfunction without considering PCOM, i.e., making them the same as the National
Institutes of Health (NIH) criteria, reducing prevalence in the group from 29% to 16% of women in one
study, reducing overdiagnosis. One study found that women with the updated criteria had a higher body
mass index (BMI) and greater risk of long-term weight gain. This fits with a long series of observations of
the strong connection between insulin resistance and androgen levels (see later) (43).
Since acne and insulin resistance may be part of normal adolescence, and rising testosterone and fall-
ing sex steroid-binding globulin (SSBG) (within range) are typical in this age group, a diagnosis of PCOS
by these criteria in adolescence should be made with caution; excessive hirsutism and age-inappropriate
chemical hyperandrogenism, however, may allow an earlier diagnosis
Women may have regular menses yet be anovulatory. It is estimated that about 90% of diagnosed
PCOS adult women have PCOM, suggesting that 10% do not.
Conversely, many normal adult ovulatory women may have PCOM on sonography, rarely progressing
to PCOS and frequently normalizing over time (44).
TABLE 7.2 Definitions of PCOS

All sets of criteria, other causes of hyperandrogenism and menstrual irregularities including congenital
adrenal....(content in notes)
• NIH (need all)
• Clinical and/or biochemical hyperandrogenism
• Menstrual dysfunction
• Rotterdam (ES) (2 of following)
• Oligoovulation or anovulation
• Polycystic ovaries
• AES-PCOSA (AACE) (need all)
• Ovarian dysfunction and/or polycystic ovaries
• Consequence of which criteria used:
• Rotterdam may include women with amenorrhea/PCOM only; not PCOS
• Requirement of hyperandrogenism increases likelihood of MBS, etc
• Influences diagnosis and management
FIGURE 7.10 Gross pathology, cut section polycystic ovary. (From Kurman RJ, Ellenson LH, Ronnett BM,
Blaustein’s Pathology of the Female Genital Tract, Springer. doi: 10.1007/978-3-319-46334-6.)
FIGURE 7.11 Ultrasound appearance of polycystic ovary. (From Giménez-Peralta I, Lilue M, Mendoza N,
Tesarik J, Mazheika M. Application of a new ultrasound criterion for the diagnosis of polycystic ovary syn-
drome. Front Endocrinol 2 September 2022, Sec. Developmental Endocrinology.)
Pathophysiology
Insulin resistance is present in the majority of patients with PCOS and provides a plausible explanation for
many of the abnormalities seen. Impaired insulin-mediated glucose uptake in fibroblasts of PCOS women,
compared with controls, independent of but exacerbated by obesity and greater than that seen in T2DM,
led to the hypothesis that downstream pathways of insulin action are affected, with excess phosphoryla-
tion of serine over tyrosine leading to resistance in insulin’s metabolic effects and to increased ovarian
17,20-lyase, resulting in excess ovarian androgen production. This action is exacerbated by a direct effect
of compensatory hyperinsulinism in multiple sites: in the ovary, causing stimulation of androgen produc-
tion, in the hypothalamus where persistent rapid GnRH release with increased frequency and amplitude
of LH pulses increased LH secretory burst mass, disorderly LH release, and elevated in vitro LH bioactiv-
ity all are affected, indirectly leading to greater stimulation ovarian androgen production and in the liver
where SSBG production is decreased, leading to higher levels of circulating free testosterone.
Genetic variants in DDEN1A, which is involved with regulating androgen production have been
found in a significant number of families with PCOS (45).
Increased production of AMH, found in the majority of PCOS patients, is produced by ovarian granu-
losa cells, reflects a larger pool of preantral and small antral follicles, and not only affects follicular
development but decreases aromatase activity in the ovary increasing relative androgen/estrogen levels in
a paracrine manner.
Hypothalamic dysfunction may be intrinsic to the disorder and also affected by hyperinsulinism and
hyperandrogenism, as suggested by improvement with insulin sensitizers and anti-androgens.
Genetic variants in AMH or its receptor have been found to affect AMH signaling in 7% of Caucasian
women with PCOS (46).
AMH and its receptor have been found in hypothalamic neurons, GnRH neurons, and the pituitary. It
is unclear whether AMH can act in neurons that control the GnRH pulse generator in the arcuate nucleus,
in kisspeptin neurons, and in other neuronal afferents that control GnRH/LH secretion. In animal stud-
ies, complex interactions between AMH, either produced locally in neural tissue or derived from ovarian
sources in the circulation, may play a role in both the normal development and functioning of this system,
There is a positive correlation between AMH and LH, with AMH likely stimulating the GnRH pulse
generator, and LH increasing AMH production in the ovary (47–49).
SHBG (sex hormone-binding globulin), which binds testosterone and estradiol, a product of the liver,
is reduced in insulin resistance, metabolic syndrome (MBS), nonalcoholic fatty liver disease (NAFLD),
and PCOS. Androgens and insulin reduce SSBG production, and lower SHBG results in higher levels of
bioavailable testosterone. Studies now suggest a possible etiologic role of SHBG in the pathogenesis of
PCOS, as in vitro studies suggest that it may be a signal transduction factor itself. Using cellular models
of human insulin resistance, decreased expression of SHBG protein and mRNA may downregulate the
PI3K/AKT pathway, leading to insulin resistance and hence to hyperandrogenism (50).
Although discrepant results have previously been reported, a recent meta-analysis has revealed
the presence of eight or more SHBG-specific polymorphisms associated with low SHBG levels and an
increased risk of PCOS (51).
Familial Clustering
A complex genetic etiology is clear from strong familial clustering with mothers of PCOS women hav-
ing a greater likelihood of the syndrome, and both male and female first-degree relatives having a higher
incidence of MBS, HBP (high blood pressure), and DM. Despite this, no specific genotype/phenotype
correlation has yet been found.
Prenatal exposure to androgens may also play a role in hypothalamic dysfunction in adult offspring.
In animal models, prenatal exposure to high levels of AMH results in hyperandrogenism in female
fetuses, in part due to the effect of AMH in reducing placental aromatase of androgens to estrogen. In a
small portion of PCOS patients, genetic alterations leading to altered AMH function have been found.
Epigenetic alterations may also explain transgenerational effects on AMH regulation in both male and
female offspring (52–55).
Recent advances in the genetics of various subtypes of PCOS may eventually clarify more fundamen-
tal genomic physiologic explanations for the heterogeneity seen within the broader definition of PCOS,
possibly revealing separate genotypes producing distinct or overlapping phenotypes.
Genome-wide association studies (GWAS) of PCOS have suggested genetic association with gonado-
tropin secretion and action, androgen biosynthesis, metabolic regulation, and ovarian aging. Only 1 of 14
PCOS susceptibility loci identified seemed to differentiate between the various clinical phenotypes, being
significantly more strongly associated with the NIH phenotype compared to non-NIH Rotterdam pheno-
types or to self-reported PCOS. Therefore, the current phenotypic diagnostic criteria do not correlate with
genetically distinct disease subtypes.
Using an unsupervised clustering approach of reproductive and metabolic quantitative traits from a
large cohort of women with PCOS, a new study characterized phenotypic subtypes of PCOS. Subjects
were 13–45 years old and fulfilled the NIH criteria of hyperandrogenism and chronic anovulation, after
FIGURE 7.12 Subtypes of PCOS by genetic analysis. (From Dapas M, et al. Distinct subtypes of polycystic
ovary syndrome with novel genetic associations: An unsupervised, phenotypic clustering analysis. PLOS Med
2020;17(6):e1003132.)
excluding other etiologies. Clustering was performed in PCOS cases on eight adjusted quantitative traits:
BMI, T, dehydroepiandrosterone sulfate (DHEAS), insulin, glucose, SHBG, LH, and FSH. There were
893 genotyped cases from the GWAS samples with complete quantitative trait data available for cluster-
ing. Clustering analysis revealed two distinct phenotypic subtypes: (1) a group (23%) characterized by
higher LH and SHBG levels with relatively low BMI and insulin levels, which were designated ‘reproduc-
tive’; and (2) a group (37%) characterized by higher BMI and glucose and insulin levels with relatively low
SHBG and LH levels, which were designated ‘metabolic’. The key traits distinguishing the reproductive
and metabolic subtypes were BMI, insulin, SHBG, glucose, LH, and FSH, in order of importance, while
the remaining cases (40%) were designated ‘indeterminate’. The reproductive and metabolic subtypes
clustered along opposite ends of the SHBG versus the insulin/BMI axis.
The clustering procedure was then repeated in an independent, nongenotyped cohort of 263 NIH
PCOS cases diagnosed according to the same criteria as the genotyped clustering cohort. The clustering
yielded similar results, with a comparable distribution of reproductive (26%), metabolic (39%), and inde-
terminate clusters (35%).
This important study will allow further work to help determine the genetic basis for the pathophysiol-
ogy of what we now label PCOS, but which may represent several different genetic entities with similar
phenotypes.
The clinical presentation of PCOS, as well as its treatment, depends upon the time in a woman’s life when
it becomes an issue. Precocious pubarche may be an early clue in some women. The most common pre-
sentation is oligomenorrhea/amenorrhea beginning at the time of puberty with slowly progressive signs
of hyperandrogenism (hirsutism, acne, alopecia) and insulin resistance (acanthosis nigricans, skin tags).
Often, infertility may bring the woman to seek medical attention. Although obesity is often present and
may exacerbate the metabolic consequences of PCOS, it is not considered a necessary part of the defini-
tion of the syndrome. Because of the effect of ‘unopposed estrogen’ (i.e., anovulation resulting in loss of
progesterone secretion), endometrial hyperplasia and ultimately endometrial carcinoma may occur but
can be prevented by regular exogenous progesterone.
FIGURE 7.13 Acne and hirsutism in a PCOS female. (From Cobin RH, Fenichel R, Chapter 6, in Clinical
Endocrinology and Metabolism, Camacho, P. ed., p. 151, Manson Publishing Ltd, London, 2011.)
FIGURE 7.14 Acanthosis at nape of neck. (Courtesy Dr. Rhoda H. Cobin.)
Diagnosis
A full history should be taken, including growth, development, menarche, menstrual frequency, presence
of molimina, and family history including reproductive, and cardiometabolic factors.
Physical examination should include height, weight, BMI, blood pressure, waist circumference, skin
evaluation for acanthosis, careful evaluation of the type, quantity (vellus or terminal) and distribution of
facial and body hair, voice, muscle development, presence and severity of acne and alopecia, as well as a
complete physical examination, including external genitalia. Gynecologists usually are the providers who
perform full pelvic examinations.
Laboratory studies should be done both to rule out other causes of menstrual disturbances and/or
hyperandrogenism (cortisol, prolactin, 17 OH progesterone, TFT). In very young women, androgen levels
may not be especially elevated but progress with age. LH, FSH, testosterone, SSBG, free testosterone,
DHEAS, and androstenedione should be measured. It is important to use accurate testosterone mea-
surements by LC/MS and free testosterone preferably by equilibrium dialysis, or if not available, by
correcting total testosterone by SSBG. Testing should be done in the follicular phase of women who are
menstruating. In women who are having either regular or irregular menses, evidence of ovulation may be
sought (progesterone level, cervical mucus) for those who are seeking fertility and to exclude the need for
supplemental progesterone.
Very high levels (usually T >150–200), rapid progression of symptoms, and severe hyperandrogenic
signs (virilization: increased musculature, deepening of the voice, clitoromegaly, and severe male pattern
baldness) should lead to suspicion of etiology other than PCOS. Although DHEAS is commonly thought
of as a purely adrenal precursor, it is often mildly elevated in PCOS. Likewise, mild elevations of prolactin
may be noted.
The level of AMH is higher in PCOS women than in normal controls or women with other forms of
amenorrhea. AMH levels correlate with the number of large preantral and early antral follicles. It has been
suggested as a surrogate marker for PCOS, especially when sonography is not possible. AMH levels in
relation to the diagnostic criteria for PCOS have been examined. The highest AMH levels were found in
cases where all three main diagnostic criteria existed. AMH has been shown to play a role in intraovarian
signaling in the recruitment and survival of follicular cells. New evidence (see earlier) has suggested that
it also plays a role in the neuroendocrine regulation of menses and may have a role in the pathogenesis of
PCOS. As yet, however, there is not enough evidence to allow AMH levels to become part of the diagnos-
tic criteria for PCOS (60).
If the diagnosis is suspected or confirmed, FBS, lipids, and Hb1ac should be done (guidelines differ
on screening for MBS and frequency of follow-up; see later).
Management
Treatment of PCOS depends upon the time of diagnosis, the goal of therapy, and patient preference.
In young women, acne and hirsutism are often the most significant issue. Androgen suppression using
oral contraceptive pills (OCPs) may be the most effective therapy, often combined with androgen recep-
tor blockers including spironolactone in the USA, while in other countries, finasteride and glutamine are
often added to estrogen. Progestational agents with antiandrogenic properties in OCPs may be helpful. Of
note, drospirenone has been linked to a higher risk of VTE. Cyproterone, used outside the USA, is effec-
tive but is not approved by the US Food and Drug Administration (FDA). A topical ornithine decarbox-
ylase inhibitor of hair growth, eflornithine, is approved but is costly and of variable success. Electrolysis
may be helpful.
Menstrual irregularity may be treated by OCPs, with or without metformin, providing suppression of
androgen production and action, improving menstrual regularity and providing contraception.
If OCPs are not used, cyclic progestins to create a secretory endometrium will eliminate the risk of
endometrial hyperplasia and carcinoma.
Anovulatory infertility may be treated with antiestrogen letrozole, clomiphene, and/or with met-
formin, in descending order of effectiveness. If these measures fail, gonadotropin stimulation may be
required, with special attention to the risk of hyperstimulation syndrome.
There is a greater risk of gestational diabetes, hypertension, preeclampsia, early miscarriage, and
preterm delivery. Prepregnancy counseling, early and regular screening, and treatment are advised. There
is conflicting data regarding the efficacy of metformin prior to or during pregnancy.
Weight loss, exercise, and bariatric surgery, when necessary, result in improvement in ovulatory
function, menses, and metabolic consequences by reducing insulin resistance. Lifestyle interventions to
promote healthy eating and adequate exercise are always the cornerstone of therapy.
Treatment of individual cardiometabolic risk factors (i.e., DM, HBP, hyperlipidemia, obesity) should
be treated ‘to target’.
Metformin reduces hepatic glucose output and has other less well-understood actions that lead
to a reduction in insulin resistance/hyperinsulinism. It is often the first therapy tried. It is moderately
successful in ovulation induction, helpful in regularizing menses, and in preventing or improving dysgly-
cemia and its complications (61).
Thiazolidinediones (PPAR gamma agonists) may improve ovulation but are not approved for PCOS,
are Class C in pregnancy, and may cause weight gain and fluid retention, as well as potentially reducing
bone density, thus limiting their use in PCOS.
Newer drugs, including SGLT 2 inhibitors and GLP1 agonists, already approved for DM, although
not specifically approved for PCOS per se, are quite effective in producing weight loss, improving gly-
cemic control, and reducing the risk of cardiovascular disease (CVD) and kidney disease, while GLP1,
especially semaglutide, already approved for weight loss in very obese patients, has significant benefit
in NAFLD. Thus some patients may already meet the criteria for their use, while many practitioners are
already using them off-label. Formal studies of SGLT2 specifically in PCOS are ongoing (https://clinical-
trials.gov/ct2/show/ NCT04700839 (62).
Both exenatide and liraglutide in obese/overweight women resulted in improvements in reproductive
function, body weight, insulin action, and psychological health; increases in the remission rate of predia-
betes; decreases in free testosterone and free androgen index; amelioration of dyslipidemia and ectopic
fat accumulation leading to improved glucoregulation, inflammatory markers, and cardiovascular param-
eters; and reduced body weight, total fat, HOMA-IR, menstrual frequency, and rate of natural pregnancy.
Studies with semaglutide in this population are ongoing (63).
Cardiometabolic Consequences
PCOS, especially but not exclusively, using the NIH/AES criteria is strongly associated with insulin resis-
tance, often appearing at an early age, with metabolic syndrome (glycemic dysregulation, hypertension,
dyslipidemia [high Tg/low HDL], large waist circumference, and elevated inflammatory markers). There
is a strong association with T2DM, often beginning at a younger age, independent of BMI but exacerbated
by obesity. Several studies confirm this risk. In a meta-analysis of 40 studies, impaired glucose tolerance
(IGT) was 3.26 and for T2DM was 2.87 for PCOS women compared with controls. Ethnicity and location
contributed significantly to IGT risk: fivefold greater for Asians, fourfold for Americans, and threefold
for Europeans. Obesity increased the risk further, but the difference among groups persisted when BMI
was adjusted (64).
However, in nonobese Nordic PCOS women aged 14 to 57, only 3% had T2DM and 23% had IGT.
The prevalence of BMI over 25 was 66% in this population. Although dysglycemia was related to BMI
and waist circumference, no diabetes was detected in women with a BMI less than 25, and 91% of subjects
with T2DM had a BMI of over 30. In contrast to other studies, neither the PCOS phenotype nor testoster-
one level was related to the presence of dysglycemia (65).
Additional consequences of insulin resistance, including NAFLD and obstructive sleep apnea (OSA),
exacerbated by obesity, are more prevalent in PCOS, as is depression, the latter both as a consequence of
poor body image and perhaps more intrinsic dysregulation. Even after menopause, these disorders persist.
Thus there is theoretically a high risk of coronary artery disease and stroke.
The clinical impact of the metabolic derangements seen in PCOS has been shown to include a greater
frequency of abnormal surrogate markers of cardiovascular disease. Carotid intima-media thickness
(CIMT), a well-validated surrogate for coronary artery disease, is higher in PCOS lean women than in
age- and BMI-matched controls as early as in the third decade of life, especially in those women with the
highest androgen levels. CIMT was also correlated with subcutaneous and visceral fat mass and insulin
resistance.
Obese, sedentary PCOS teenagers have also been shown to have high CIMT, increased arterial wall
stiffness, and more atherogenic lipids than obese, sedentary non-PCOS girls despite normal blood pres-
sure and lipids.
Coronary artery calcification, likewise, is nearly twice as high (40% vs. 20%) in young women
with mean age 38 as compared with age- and BMI-matched controls. In a 10-year prospective study in
middle-aged women with PCOS, coronary artery calcification was greater than in controls, related to
MBS, insulin resistance, and HDL cholesterol, and worsened by obesity.
Despite the high prevalence of CVD risk factors, the demonstration of early-onset dysglycemia, and
worse surrogate markers for CVD, an excess of clinical major adverse cardiovascular events (MACE) is
not universally reported, because of a lack of high-quality studies using strict criteria, but this is strongly
suspected (see later). Some of the disparities in clinical studies and resulting guideline recommendations
are due to the actual ascertainment of disease; the age of patients studied; the nature, methodology, dura-
tion, and statistical power of the study; and the differences in geography and ethnicity of subjects (2).
Indirect but compelling evidence of this association comes from longitudinal cohort studies As PCOS
is the most common cause of oligomenorrhea in reproductive-age women, irregular menses have been
thought to likely be a surrogate marker of PCOS.
In a community-based longitudinal cohort study of women born between 1946 and 1951 (N = 13,714)
over a 20-year follow-up period, women with irregular menstrual cycles had a 20% higher risk of develop-
ing heart disease and a 17% higher risk of diabetes than women who had regular menstrual cycles (66).
This study confirms similar data described 2 decades ago in the landmark Nurses’ Health Study,
where a 14-year cohort prospective questionnaire-based study of 82,439 female nurses who provided
information on prior menstrual regularity at ages 20–35 years, followed for incident reports of nonfatal
myocardial infarction, fatal coronary heart disease (CHD), and nonfatal and fatal stroke were made.
Medical records were reviewed for confirmation. Compared with women reporting a history of very regu-
lar menstrual cycles, women reporting usually irregular or very irregular cycles had an increased risk for
nonfatal or fatal CHD (age-adjusted relative risks [RR], 1.25 and 1.67, respectively), remaining significant
after adjustment for BMI but slightly attenuated when adjusted for hypertension, diabetes, and hyperlip-
idemia, as these markers of CVD risk themselves were more frequent in women with less regular cycles.
Adjustments for confounding variables, including smoking, physical activity, alcohol, and menopausal
status, did not change outcomes (67).
Clinical Cardiovascular Disease Events

A systematic review and meta-analysis of controlled observational showed a twofold risk of macrovascular
disease for patients with PCOS, including all major definitions of the condition, relative to women without
PCOS. This result was unaffected by controlling for BMI. The study concluded that PCOS doubles the
risk of CHD and stroke independent of obesity. Another meta-analysis showed that in five studies where
the average age was more than 45 years old, the risk of nonfatal stroke was significantly increased, while
in six studies, the risk of CHD was insignificantly increased in PCOS compared with controls. In three
studies with BMI-matched subjects over age 45, both stroke and CHD risks were greater in PCOS women,
though not reaching statistical significance. An additional meta-analysis of five case–control studies and
five cohort studies was performed involving a total of 104,392 subjects. PCOS was significantly associ-
ated with the increased risk of CVD in both case–control and prospective cohort studies. In this analysis,
PCOS was significantly associated with CHD but not with myocardial infarction. A recent study demon-
strated a clear-cut increase in stroke risk in PCOS women. A meta-analysis of nine cohort studies found
a statistically increased risk of stroke in PCOS patients not entirely explained by higher BMI. There was
no increase in all-cause mortality (68–71).
In contrast, an extensive review of studies published from 1990 to 2021, including participants with
or without PCOS diagnosed according to the 2003 Rotterdam (without specifying phenotype) or the 1990
NIH criteria, with data on cardiometabolic outcomes, consisted of 31 longitudinal studies with 28,316
participants from four continents. Women were 19 to 49 years old at onset with a follow-up period ranging
from 2 to 32 years. Changes in BMI and the risk of coronary heart disease were similar in adult women
with and without PCOS. Women with PCOS had a higher risk of type 2 diabetes than their non-PCOS
counterparts. It was noted, however, that “evidence for the majority of all other outcomes was conflicting
and with inadequate data”.
Commenting on the current state of knowledge, the authors note the inadequate information on cardio-
vascular morbidity and mortality and focus on women of reproductive age (with the oldest being 69 years), a
cohort in whom the absolute rates of CVD events are low regardless of risk factor profiles. Therefore, event
rates are low and longer follow‐up periods are necessary to determine if there is a true increase in actual
CVD risk. CVD risk may be higher if women are menopausal or have had premature menopause.
The heterogeneity of the studies precluded meta‐analyses. A substantial number of included studies
had no control group. Further, given the role played by phenotypic differences such as the hyperandro-
genemic phenotype in cardiometabolic outcomes, longitudinal findings that are PCOS phenotype‐specific
will clarify true cardiometabolic risk. Homogeneous long-term longitudinal cohort studies reporting key
metabolic features of PCOS over time are lacking in the current literature and suggest the need for further
investigation (72).
Guidelines for PCOS Diagnosis and Management have

been Published by a Number of Organizations
• Androgen Excess/PCOS Society (AES) (73, 74)
• Endocrine Society (ES) (75)
• American Association of Clinical Endocrinologists, American College of Endocrinology,
Androgen Excess and PCOS Society (41, 42)
• American College of Obstetrics and Gynecology (ACOG) (76)
• Pediatric Endocrine Society (77)
• American Association of Family Physicians (AAFP) (78)
• International PCOS Network (79, 80)
Given the heterogeneity of presentation and frequency of DM and MBS in background populations, it is
not surprising that guidelines and recommendations from different bodies may be somewhat different,
depending on their perspective.
The AES, which considers hyperandrogenism a sine qua non for the diagnosis, emphasizes the criti-
cal link between it and lipid and glycemic risk and the importance of screening for these risk factors.
The ACOG, not surprisingly, focuses its guidelines on reproductive consequences and their manage-
ment, most recently endorsing letrozole as a first-line treatment.
AACE/PCOSA guidelines are comprehensive, emphasizing pathophysiology as a determinant of
clinical and therapeutic issues.
AAFP guidelines outline findings in other guidelines and provide practical advice for clinicians. The
international guidelines of the International PCOS Network, authored by a consortium of 3,000 people
from 37 countries, including experts in various fields, multiple societies as well as consumers, are some-
what more flexible in accommodating differences in regional or ethnic likelihood of various components,
e.g., hirsutism, hyperglycemia, and hypertension. These comprehensive guidelines are divided into sec-
tions regarding all aspects of the syndrome and transparency in evidence used to support the recommen-
dations, which are very specific.
Unlike the AES, ES, and AACE/PCOSA guidelines, the international guidelines recommend screening
for metabolic syndrome and dysglycemia in young women only if obese, with follow-up determined by risk.
They also state assessment of biochemical hyperandrogenism is recommended only when signs of clinical
hyperandrogenism are missing or unclear. They emphasize the need for more accurate standardized labora-
tory testing of androgen levels in women. They do not recommend routine testing of 17-OHP to rule out CAH.
Despite these differences, there is now consensus regarding diagnostic criteria, recognizing the
pitfalls of sonography, especially in adolescents, and recommending against its use in that age group
for diagnosis. The link between PCOS and insulin resistance and its consequences is recognized by all
groups, with the understanding that not all women fit in this category and that further genomic informa-
tion as well as more accurate measurements will be helpful in the future in determining recommendations
for screening, diagnosis, and treatment.
Evaluation of Guidelines
A review of the recommended PCOS assessment criteria from the 2018 international evidence-based
guidelines highlights the need to optimize the diagnosis of PCOS. In particular, it notes the need to stan-
dardize terms including the definition of oligomenorrhea, the clinical evaluation of hirsutism (as opposed
to hypertrichosis), and its variation by ethnicity, variability in measurement of androgen level by age and
laboratory methods, and sonographic features (especially during the first 8 postmenarchal years (81).
Two semiquantitative analyses of guidelines have been published.
The guidelines were evaluated by mapping clinical recommendations in each guideline and assigning
them to prespecified domains: diagnosis in adolescents and adults; lifestyle interventions; management of
menstrual irregularity, hirsutism, acne, and infertility; and risk assessment for metabolic disease, cardio-
vascular disease, mental health, and cancer.
The methodological quality of 23 guidelines organized into six domains (scope and purpose, stake-
holder involvement, rigor of development, clarity and presentation, applicability, and editorial indepen-
dence) were scored according to set formulas.
Guidelines were mostly focused on screening for and managing metabolic disease (12/13, 92%),
followed by cardiovascular risk assessment (10/13, 77%). Mental health (8/13, 62%) and diagnosis in ado-
lescents (7/13, 54%) were the least reported domains. Most clinical practice guidelines (CPGs) had a high
quality for scope and purpose description (12/13, 92%), while stakeholder involvement and applicability
of recommendations to clinical practice were appropriate in only two CPGs (2/13, 15%). Inconsistency
was found in recommendations on PCOS diagnosis in adolescents, optimal lifestyle interventions, hir-
sutism and acne treatments, interventions to reduce the risk of ovarian hyperstimulation syndrome, the
frequency and screening criteria for metabolic and cardiovascular disease, and optimal screening tools for
mental health illness in women with PCOS (82).
Another analysis from China used an assessment tool, the RIGHT checklist, which contains 22
requirements organized into 7 sections with a total of 35 items: basic information (6 items), background
(8 items), evidence (5 items), recommendations (7 items), review and quality assurance (2 items), fund-
ing and declaration and management of interest (4 items), and other information (3 items). Two authors
independently assessed the adherence of each PCOS clinical guideline with the RIGHT checklist, and
a yes indicated full reporting of necessary information, whereas a no indicated partial or no reporting.
High quality was determined if the yes responses were >70%, medium quality if they were 40% to 70%,
and low quality if they were <40%. Assessment by this method revealed that the reporting quality varied
among guidelines. Low-quality items were the processes of evidence decision and the declaration of fund-
ing in most included CPGs (83). This novel guideline evaluation approach highlights the overall lack of
high-quality evidence to make specific consistent recommendations, as well as the various issues most
relevant to specific societies.
Future Investigation
Because of the limited data regarding normative cutoffs for the diagnostic features in different subpopu-
lations, leading to inconsistent study populations affecting diagnostic features and ultimately clinical
outcomes, a systematic review is proposed. In an attempt to further quantify and characterize participants
in studies to better distinguish PCOS from non-POS patients, by the creation of an international database
of de-identified subjects with variables to include directly assessed modified Ferriman–Gallwey scores;
menstrual cycle lengths; follicle number per ovary, ovarian volume, and AMH; and circulating androgens,
including total testosterone (TT), free testosterone, bioavailable testosterone, free androgen index (FAI),
androstenedione (A4), and DHEAS. Normative ranges and cutoffs will be defined using cluster analysis.
It is hoped that this will provide much-needed differentiation among subjects and lead to further clarity
in subsequent studies (84).
MENOPAUSE
Menopause is defined as a period of amenorrhea lasting 12 months or longer in women with previous men-
ses. Laboratory studies show FSH and low AMH, reflecting a lack of ovarian inhibin and low follicular
reserve, respectively. The average age of natural or spontaneous menopause is 51 years (range 45–55). If
menses cease at an appropriate time, with no other extenuating signs or symptoms, no further investiga-
tion is required.
Premature menopause is defined as ovarian failure before the age of 40. This may be caused by hys-
terectomy, although without oophorectomy, menses are absent but ovarian function may remain normal
for years afterward. (The distinction may be made by measuring estrogen, FSH, AMH, and inhibin.)
There may be a family history of early menopause and early menarche. In addition to surgical menopause,
premature ovarian failure commonly is produced by chemotherapy and/or radiation for cancer. Conditions
such as chromosomal abnormalities, fragile X syndrome, autoimmune oophoritis, mumps, thyroid, or
chronic inflammatory disorders may contribute to early menopause.
Spontaneous menopause is preceded by a transition period – perimenopause – in which estrogen
production is declining and erratic, ovulation is less regular or absent, menses may become irregular, and
bleeding may be heavier or lighter. This period may last for 2 to as long as 14 years in some women, and
‘menopausal symptoms’ may be present for many years before final menses. Some women experience few
or no symptoms, while in others, the symptoms may be so severe as to be life-altering. The timing and
duration of perimenopause may be influenced by lifestyle factors such as smoking, age of onset, race, and
ethnicity.
Menopausal vasomotor symptoms include hot flashes, flushing, night sweats, and insomnia. These
vasomotor symptoms are caused by cutaneous vasodilation, a result of the lack of negative inhibition
of estrogen on hypothalamic infundibular thermoregulatory neurons that are innervated by the KNDy
system. Within the KNDy complex, neurokinin binds to the NK3R receptor, dynorphin to kappa opioid
receptors, and kisspeptin to its receptors, integrating multiple signals to regulate menstrual function.
Estrogen is inhibitory at NK3 receptors and with its decline at menopause, KNDy neurons exhibit hyper-
trophy and there is dysregulation of the thermoregulatory neurons, leading to increased heat dissipation.
Understanding this system has led to the development of novel NK3 receptor antagonists, which may be
useful in treatment.
Modifiable risk factors for hot flashes include smoking, a BMI greater than 30, and sedentary behav-
ior. Nonmodifiable risks include maternal history; menopause earlier than age 32; and abrupt menopause
from surgery, radiation, or chemotherapy.
Estrogen deprivation causes urogenital atrophy with resulting dyspareunia, dysuria, and more fre-
quent urinary tract infections.
Estrogen deprivation is a well-known cause of bone loss, osteoporosis, and fragility fractures.
Sexual dysfunction, mood disorders, and cognitive issues are often considered menopausal symptoms,
though they may be multifactorial in origin and secondary to previously mentioned primary symptoms.
Other asymptomatic pathology in menopause may not be a direct effect of estrogen loss alone but
rather that of aging or other disorders, perhaps compounded by estrogen deprivation; this includes cardio-
vascular disease and cognitive impairment.
It has also been noted that the age of menopause or duration of reproductive years may be related to
the risk of T2DM, CVD, all-cause mortality, and cognitive dysfunction, with longer reproductive years
having a beneficial effect. This data comes from cross-sectional epidemiologic studies that may suggest
association rather than causation (85–88).
Treatment of menopausal symptoms may include estrogen (with progesterone in the presence of a
uterus), in various chemical formulations, doses, and routes of administration. Estrogen is nearly always
effective in treating estrogen-deficiency symptoms. It has salutary effects on bone. Its benefit in other
aspects of menopause (i.e., less clearly estrogen withdrawal symptoms) is more controversial.
The FDA has approved the use of menopausal hormone therapy for the following applications:
1. Treatment of moderate to severe vasomotor such as hot flashes and night sweats associated with
menopause.
2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy such as dryness,
itching, and burning associated with menopause. Topical estrogen may be effective for this
purpose.
3. Prevention of postmenopausal osteoporosis.
The FDA notes:
(When menopausal hormone therapy is being prescribed solely for the prevention of postmenopausal
osteoporosis, approved non-estrogen treatments should be carefully considered. Estrogens and combined
estrogen/progestin products should be considered only in women with a substantial risk of osteoporosis
that outweighs the potential drug-related risks.)
The FDA has recommended that menopausal hormone therapy should generally not be prescribed to
women with the following conditions (89):
1. Current, past, or suspected breast cancer

2. Known or suspected estrogen-sensitive malignant conditions
3. Undiagnosed genital bleeding
4. Untreated endometrial hyperplasia
5. Previous idiopathic or current venous thromboembolism (deep vein thrombosis, pulmonary
embolism)
6. Active or recent arterial thromboembolic disease (angina, myocardial infarction)
7. Untreated hypertension
8. Active liver disease
9. Known hypersensitivity to the active substances of menopausal hormone therapy or any of the
excipients
10. Porphyria cutanea tarda (absolute contraindication)
Hormone replacement therapy may be administered orally, transdermally, intravaginally, or, less com-
monly, parenterally. Therapy may consist of estrogen only, either as conjugated equine estrogen (CEE),
estradiol, or various synthetic estrogens. Progesterone, either separately or in combination with estrogen,
may be synthetic (medroxyprogesterone acetate [MPA]), various steroid congeners, or micronized proges-
terone. Evidence suggests that transdermal estrogen may produce less risk of thromboembolic disease by
bypassing the liver where it can induce thrombogenic proteins. Likewise, intravaginal progesterone might
be considered when women have a risk of breast cancer (see later) but still have a uterus and need to have
protection from ‘unopposed estrogen’ to avoid endometrial hyperplasia. Available formulations are listed
in reference (90).
Consumers have been told by some sources that compounded ‘bioidentical hormones’ are superior to
pharmaceutical hormone products, despite the lack of any scientific evidence.
The FDA has warned consumers regarding these claims (91):
The FDA is also not aware of sound evidence showing the superiority of compounded BHRT [bioidenti-
cal hormone replacement therapy] products over FDA-approved drugs. Likewise, FDA has no informa-
tion indicating that the side effects and risks of compounded BHRT products are dissimilar to those of
FDA-approved drugs. Thus, claims regarding the safety, efficacy, and superiority of compounded BHRT
products have not been substantiated by FDA and may mislead patients and practitioners … The absence
of warnings and risk information may be viewed by patients as implicit evidence that compounded BHRT
products are safer than FDA-approved drugs, when there is no data to support this conclusion.
The FDA approved a formulation of a pharmaceutically produced estradiol/micronized progesterone oral

capsule, which is being termed a bioidentical product. But, unlike compounded products, it must meet
FDA standards and oversight (92).
Risks and Benefits of HRT

In addition to being the most effective treatment for vasomotor symptoms and urogenital atrophy,
HRT is associated with a lesser risk of colon cancer, although it is not recommended for its prevention.
HRT improves bone density and quality, but other non-hormonal therapies are as or more effective and
are first line treatment.
HRT benefit in improving libido and sexual performance is controversial, as other factors, including
improving dyspareunia and a significant placebo effect may play a role.
In line with current evidence, the US Preventive Services Task Force does not recommend HRT for the
prevention of chronic disorders including CVD, colon cancer, cognitive impairment, and osteoporosis (93).
Known risks of HRT include venous thromboembolic disease, gallbladder disease, and endometrial
hyperplasia/carcinoma (the latter when estrogen is used without progesterone).
The relative risk of stroke is higher in women taking HRT compared with nonusers, particularly in older age
groups, where the absolute risk of stroke is greatest. Multiple studies of various designs suggest that later ini-
tiation of HRT, older age, and use of oral as compared with transdermal estrogen increase the risk (94–97).
Breast Cancer
In the Women’s Health Initiative (WHI), the most robust long-term prospective randomized controlled
trial (RCT), the use of estrogen alone (CEE 0.625 mg) in the 7.2-year intervention phase was associated
with a lower risk of breast cancer and breast cancer death (hazard ratio [HR] 0.55 compared with placebo),
even in the long-term 18-year follow-up period. Although the number of users was smaller in this study,
using different doses of CEE or using oral estradiol or transdermal estradiol there was no difference in
this comparative risk.
The addition of progestin (MPA 2.5 mg) to (CEE) estrogen increases the risk of breast cancer, even
in the prolonged 18-year follow-up after the 5.6-year intervention phase, with an HR 1.44 for death from
breast cancer compared with placebo (98).
The use of progestins other than MPA (used in WHI) has been associated with a lesser risk of breast
cancer in some observational studies of lower power than the WHI. The use of combined estrogen–pro-
gestin conferred a greater risk than sequential regimens. Some studies have noted an amplification of risk
related to older age and duration of therapy (99–102).
For a more detailed description of these studies, see Cobin et al. (2).
Cognitive Function
The use of HRT in the development of cognitive decline has shown conflicting results. Cumulative knowl-
edge from multiple studies of various design suggest that HRT is likely not deleterious to cognitive func-
tion in younger recently postmenopausal women with low inherent cardiovascular risk. However, for older
women, those with diabetes, or those with inherent cardiovascular risk, long-term use of HRT or those
already developing early dementia may be more adversely affected (103).
A recent study confirmed earlier findings that early menopause itself is associated with greater
dementia risk, with greater tau deposits on PET scans, but only if elevated beta-amyloid deposits were
already present. Younger initiation of HRT use did not affect tau levels, while delayed initiation was asso-
ciated with greater risk (104).
A promising strategy was reported in 2023. A longitudinal study featured 1,906 healthy persons in 10
European countries with no demonstrable dementia, categorized by APOE4 and non-E4 genotypes and
HRT use, type, and duration. The study measured brain volumes in areas significant for cognition, as well
as the performance of standardized cognitive testing. The study found that HRT introduction is associated
with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 homozygotes
only (who are at higher risk of dementia at baseline), especially when introduced early. The authors postu-
lated that some of the discrepant findings of HRT effect on cognition in previous studies may be ascribed
to different APOE genotypes and the age of HRT initiation, and suggested that APOE genotype testing
may present an opportunity for more selective personalized targeted therapy (105).
Since these recent studies require further investigation, prudent guidance would suggest against HRT
use in at-risk individuals, but reassurance in younger, low-risk individuals who require HRT for symptom
relief in early menopausal years.
Diabetes
Estrogen deficiency itself is not associated with an increased risk of diabetes. As women age, however,
insulin resistance, metabolic syndrome, and diabetes become more prevalent. The use of HRT, by any
route and any formulation, has yielded overall neutral results with respect to glucose intolerance in many
trials, despite a small increase or decrease in risk in some subpopulations, which did not persist with lon-
ger follow-up (106, 107).
Cardiovascular Disease
Although HRT has been shown to lower LDL, raise HDL, and raise triglycerides, the overall effect on
CVD and mortality has now been explored in multiple significant clinical trials, the most robust of which
has been the ongoing WHI.
In the WHI, a series of prospective double-blind placebo-controlled trials, the effect of HRT on car-
diovascular health is beneficial or at least neutral if given to women within 10 years of menopause onset or
less than 60 years old, while in older women further removed from menopause onset, there is an increased
risk, at least in the intervention phase of the trial. Over a longer observation period, however, the risk of
CVD equalized between HRT-treated and placebo groups, likely the result of aging.
Over an 18-year follow-up of women, in the WHI trial, age 50–79 treated with CEE/MPA or CEE
alone for a median of 5.6 and 7.2 years, respectively, there was no increase in CVD, cancer, or all-cause
mortality (108–110).
The use of HRT in women with MBS is associated with greater CVD risk than in treated women
without MBS (111).
Subsequent and ongoing studies examining differences in CVD surrogate outcomes, including car-
diovascular disease itself, breast cancer, and other outcomes with the use of formulations of estrogen and
progestins other than CEE/MPA, have been smaller non-RCT, epidemiologic, observational, and unlikely
to ever be as statistically robust as the large WHI RCT, leading to inconclusive outcomes regarding risk/
benefit profiles. Nonetheless, the trend to use pure estradiol and micronized progesterone transdermally
has significant advocates among experts (112–114).
Alternatives to HRT
When hormonal therapy to treat menopausal symptoms is medically contraindicated or unacceptable to
patients, several nonhormonal treatments are available. Some, such as SSRIs, gabapentin, clonidine, and
SERM–estrogen combination, have been formally studied.
In a double-blind RCT with the strategy to minimize the placebo effect, the SSRIs escitalopram and
venlafaxine were compared with estradiol and were found to have equal benefit in reducing hot flashes,
with all conferring modestly improved sleep. Other SSRIs and SNRIs have also been effective (115).
In breast cancer patients using tamoxifen, fluoxetine and paroxetine should not be used, as they
inhibit the effect of tamoxifen (116).
Both gabapentin and pregabalin in relatively high doses have shown benefit in reducing hot flashes,
compared with placebo. Their side effect of causing drowsiness may make bedtime administration useful
(117).
Clonidine has modest effects in reducing hot flashes compared with placebo in 39 studies reviewed by
a literature search, although a significant placebo effect was noted in these studies (118).
Adverse effects of nonhormonal therapy included somnolence, dizziness, hypotension, and dry mouth
for clonidine; weight gain, reduced appetite, nausea, sleepiness, and sweating with SSRIs; and constipa-
tion, headache, and somnolence with gabapentin (119).
A combination of bazedoxifene, a selective estrogen receptor modulator, and CEE is effective in
treating hot flashes and reducing fracture risk. Vaginal dryness is improved. No progestin is necessary, as
endometrial hyperplasia does not develop. There is a risk of venous thromboembolic disease and stroke
(120).
A new drug, fezolinetant, a nonhormonal selective neurokinin 3 receptor (NK3R) antagonist blocks
binding of neurokinin B to the KNDy neurons to restore normal sensitivity of the thermoregulatory center
in the hypothalamus. It has been shown to have significant efficacy in reducing moderate to severe vaso-
motor symptoms in a phase 3, double-blind placebo-controlled RCT including a diverse population of 527
otherwise healthy women in 97 international settings. In the treated population, symptoms abated in as
little as one week and were significantly different from placebo at 4 and 12 weeks with efficacy persisting
for the full 52 weeks of the trial. Side effects were rare, including headache and mildly elevated liver func-
tion tests, which reversed with discontinuation. Recent approval by the FDA has now made this treatment
option available for the management of vasomotor symptoms (121–123).
Nonprescription ‘Herbal’ Remedies

Phytoestrogens are sterol molecules with weak estrogenic activity, which include isoflavones derived from
plants including soy and red clover. They are available over the counter in concentrated nutraceuticals.
They are not FDA regulated and may vary in their estrogen receptor agonist/antagonist properties. They
are moderately effective in controlling vasomotor symptoms in some women. In vitro and animal studies
have shown growth promotion in breast tissue and breast cancer tissue, but there has been no evidence of
initiation or growth promotion in human breast cancer. Because of this potential, however, isoflavones are
not recommended for women with or at high risk for breast cancer.
Isoflavones may impact thyroid function, reducing thyroid hormone synthesis, secretion, and bind-
ing to transport proteins, especially in the iodine-deficient state. In patients taking exogenous thyroid
hormone, isoflavones and especially soy may interfere with its absorption. Neonates and people with
subclinical hypothyroidism may be at greater risk of these effects (124).
Black cohosh is an unregulated herbal supplement available without a prescription, which has vari-
able efficacy in treating vasomotor symptoms. Its mechanism of action may or may not be via estrogenic
effects. A review and meta-analysis of human studies, which included 14 RCTs, 7 uncontrolled trials, and
5 observational studies, reported conflicting efficacy data. Overall, black cohosh showed a response when
compared with baseline but not when compared with placebo (125). A Cochrane review found insufficient
evidence to recommend its use (126). Its use is strongly contraindicated in women with breast cancer or at
high risk for it. Liver toxicity has been reported, placing it in a ‘do not use’ category overall (127).
Other agents including Chinese herbs and primrose oil are available, but no high-quality studies sup-
port their efficacy.
Nonmedical interventions such as yoga, acupuncture exercise, and mindfulness are of uncertain ben-
efit, while cognitive behavioral therapy may be of benefit.
Guidelines
With the accumulation of robust data from multiple trials, particularly the WHI but including other obser-
vational and epidemiologic studies, there is wide concordance among experts represented by multiple
specialty societies. These conclusions inform recommendations for the use of HRT to alleviate vasomotor
and genitourinary symptoms, with demonstrated safety in women under the age of 60 and/or less than 10
years from menopause with no inherent risk factors. Guidelines warn about contraindications to HRT as
set forth by the FDA and inform about possible risks of HRT. HRT may carry a greater risk of CVD and
stroke in older women. Risks of HRT including VTE and breast cancer (with combination therapy) are
noted. Each guideline mentions the possible differences in outcomes with various formulations, doses,
and routes of administration, as well as notes where strong evidence is lacking. HRT is not recommended
for the prevention of chronic disease. Menopausal symptoms may be managed by alternative therapies
rigorously studied and approved by the FDA, while unregulated and/or ineffective interventions are not
recommended. All guidelines stress the importance of individualization of therapy and communication
among women and their physicians.
Please see the specific guidelines from the following specialty societies:
American Association of Clinical Endocrinologists and American College of Endocrinology (89)

American College of Obstetrics and Gynecology (128)
North American Menopause Society (129)
The Endocrine Society (130)
French College of Gynecologists and Obstetricians (131).
MALE HYPOGONADISM
Masculinization is mediated by testosterone production in the testes and its action via androgen receptors
in susceptible tissues. These effects include anabolic actions on bone, cartilage, and muscle; facilitation
of pubertal growth spurt; maturation of external genitalia; and normal sperm production. Testosterone
affects prostate growth and growth of beard and body hair, and permits scalp hair loss in genetically
susceptible males.
Differentiation of the primordial gonad into a testis requires the presence of testis differentiating
factors (SRY gene present on the Y chromosome), allowing differentiation of primordial cells into Sertoli
cells, which, via multiple transcriptional regulators, cause differentiation of testosterone-producing
Leydig cells. Regulation of testosterone is stimulated by pituitary LH, while sperm production in the
seminiferous tubules is stimulated by FSH. Sertoli cells produce inhibin, which reduces hypothalamic
GnRH and selectively reduces FSH. The KNDy neuron system in the hypothalamus regulates gonadotro-
pin secretion, responding to input from other brain centers as well as feedback from testosterone, DHT,
estradiol, and inhibin.
In peripheral tissues, testosterone is converted to estrogen by aromatization or to dihydrotestosterone,
the active hormone in most target tissues, by 5-alpha reductase.
Primary hypogonadism, or testicular failure, may be the result of the lack of testicular tissue, enzy-
matic defects in testosterone synthesis, or its action. These may be congenital as a result of genetic abnor-
malities or acquired as a result of physical, radiation, or chemical damage, disease, or aging.
Secondary hypogonadism is the result of inadequate stimulation of the testis by pituitary gonadotro-
pins and may be due to congenital or acquired disorders of the hypothalamic–pituitary system.
Androgen receptor defects may cause either a complete failure of masculinization of the male fetus
(which then appears female) or partial failure resulting in ambiguous genitalia.
The clinical manifestations of hypogonadism depend upon the timing of its onset as well as its sever-
ity, individual susceptibility, and personal clinical concerns.
Problems occurring in the first trimester of intrauterine life result in ambiguous genitalia, while those
beginning during the third trimester may cause cryptorchidism and microphallus. Male hypogonadism in
the postnatal prepubertal period results in failure of development of the phallus and scrotal rogation, as
well as failure of development of secondary sexual characteristics (male voice, muscle mass, beard, and
body hair), eunuchoidal proportions (due to failure of epiphyseal closure), and reduced bone mass, as well
as gynecomastia.
Postpubertal hypogonadism results in diminished libido, erectile dysfunction, and variable degrees
of reduction in male hair distribution. Low testicular volume and abnormal texture may be noted.
Gynecomastia may be present. Bone density and muscle mass may be reduced. Low ‘energy’ and mea-
surements of physical stamina have been reported. Hypogonadism in the male has been linked to cardio-
vascular disease via poorly understood mechanisms.
Primary Hypogonadism: Congenital

In Klinefelter’s syndrome, a chromosomal nondisjunction results in the XXY genotype, resulting in small
firm testes with reduced seminiferous tubules, low sperm count, reduced testosterone production with
failure of normal pubertal male secondary sexual characteristics, and infertility. Body habitus is eunuch-
oidal with long extremities due to failure of epiphyseal fusion during growth.
At birth, the syndrome may be suspected with a micropenis, hypospadias, or cryptorchidism.
However, delayed diagnosis may occur:
(1) Teenage boys may present with delayed puberty, failure of secondary sexual characteristics,
disproportionate growth of limbs, and gynecomastia.
(2) Learning disabilities and personality disorders may be present.
(3) Adult men often present with infertility and are noted to have small, fibrotic testes with azo-
ospermia and androgen deficiency. The latter may result in osteoporosis.
(4) Comorbidities including dental abnormalities, facial abnormalities, increased CVD risk, MVP,
varicose veins, COPD, Parkinson’s disease, male breast cancer, and autoimmune disorders all
have been linked to Klinefelter’s syndrome. Although the relative risk is greater, absolute risks
are still small.
Klinefelter’s syndrome is diagnosed by physical examination, including small firm testes, eunuchoidal
body habitus, and gynecomastia. Testosterone and free testosterone are low, LH and FSH are high, and
the karyotype shows XXY. Some men have mosaicism, usually with milder clinical features. In this
case, constitutional retardation of puberty, a benign self-limited condition with normal gonadotropins and
karyotype should also be considered.
Other chromosomal abnormalities may cause inadequate testicular development, including a variety
of nondisjunction abnormalities, mixed gonadal dysgenesis with the Y chromosome, or chimerism (2).
Incomplete Androgen Insensitivity Syndrome

This condition is caused by several different X-linked recessive mutations coding for the androgen recep-
tor, resulting in abnormal androgen receptor structure and function. XY individuals present at birth with
incomplete masculinization and ambiguous genitalia of variable severity, including hypospadias, micro-
penis, and bifid scrotum. Testes may be descended, inguinal, or intra-abdominal. Wolffian duct structures
are variably developed. Müllerian duct–derived structures are absent or rudimentary, since testes produce
FIGURE 7.15 Klinefelter’s syndrome patients: eunuchoid body habitus, decreased pubic hair, gynecomastia,
karyotype (2). (Courtesy of Dr. Donald Gordon.)
AMH. Testosterone and LH levels are normal or high. Defective androgen-binding activity of genital skin
fibroblasts may be demonstrated.
At puberty, gynecomastia and impaired spermatogenesis occur.
Most individuals with partial androgen insensitivity are raised as males. Treatment consists of geni-
toplasty, the success of which is dependent upon the amount of tissue available. Breast reduction surgery
may be required.
If cryptorchid testes are present, gonadectomy is advised because of the 50% risk of gonadoblastoma
development (132, 133).
(Complete androgen insensitivity results in female phenotype; see ‘Amenorrhea’ section.)
5-Alpha Reductase Deficiency

Deficiency of this enzyme, which converts testosterone to dihydrotestosterone, the active hormone that
binds to androgen receptors, is inherited as an autosomal recessive trait with mutations in the SRD5A2
gene. During fetal life and childhood, this results in female or ambiguous external genitalia or a micro-
penis and hypospadias, despite the XY genotype and high levels of testosterone. Since AMH is present,
there is regression of Müllerian ducts (uterus, vagina), while testosterone-dependent Wolffian duct struc-
tures are present.
During puberty, when the testicular output of testosterone increases dramatically, the enzyme defi-
ciency is overcome, male external genitalia mature, and virilization occurs. However, male pattern baldness
and prostate enlargement, both of which require DHT rather than testosterone, may fail to develop (134).
For individuals raised as girls, am orchidectomy may be advised to prevent virilization and testicular
malignancy, while those raised as boys may anticipate virilization at puberty but may require surgical
procedures to correct ambiguous genitalia. (See ‘Amenorrhea’ section, and References 26–31.)
Other causes of congenital primary hypogonadism include cryptorchidism, myotonic dystrophy, and
gonadotropin receptor defect.
Acquired Primary Hypogonadism

Acquired primary hypogonadism may result from any damage to the testis, including:
Infections, especially mumps in adulthood

Radiation
Chemicals: suramin, ketoconazole, glucocorticoids, alkylating agents
Environmental toxins
Trauma
Testicular torsion
Autoimmune damage
Chronic systemic illnesses (which may cause secondary hypogonadism)
Hepatic cirrhosis
Chronic renal failure
HIV
Idiopathic
Secondary Hypogonadism
Congenital Secondary Hypogonadism
The most common form of congenital secondary hypogonadism is Kallmann syndrome, caused by vari-
ous mutations of the KAL gene (Xp22.3) leading to failure of migration of GnRH neurons from the olfac-
tory area to the hypothalamus resulting in hypothalamic hypogonadism and variable degrees of anosmia.
Additional genetically diverse mutations have been described in multiple genes involved in the develop-
ment and/or function of the hypothalamic gonadotropin regulatory pathway, including kisspeptin and its
receptor, and GnRH and its receptor, some associated with nonreproductive developmental anomalies.
There is variable inheritance, most commonly X-linked recessive.
Prader–Willi syndrome, caused by deletions of paternally derived critical genes on chromosome 15,
is characterized by hypogonadotropic hypogonadism, neonatal hypotonia, and somatic features including
narrow forehead, small hands and feet, short height, and light skin and hair. Uncontrollable hyperphagia
and obesity ensue, often resulting in T2DM. Until now, management has been supportive only. Ongoing
research into the specific genetic alterations and their consequences may offer more specifically targeted
therapy, as much as a newly FDA-approved gene replacement treatment for other rare forms of genetic
obesity has been reported (135–137).
Bardet–Biedermeier syndrome (BBS) is a rare multisystem genetic disease. In addition to hypogonad-
ism, rod–cone dystrophy, obesity, polydactyly, hypogonadism, cognitive impairment, renal abnormalities,
FIGURE 7.16 Young male with Prader–Willi syndrome. (From Butler MG, Angulo MA, Cataletto ME. Prader–
Willi syndrome: A review of clinical, genetic, and endocrine findings. J Endocrinol Invest 1998;12(38):1249–
1263. doi: 10.1007/s40618-015-0312-9.)
and defects in other organs have been described. Multiple genetic abnormalities and wide variability in
phenotype have been reported (139).
Recently, the FDA has granted priority review of setmelanotide, a melanocortin-4 receptor agonist for
patients with BBS as well as Alström syndrome, another extremely rare genetic disorder associated with
hyperphagia and hypogonadotropic hypogonadism. It has already been approved for other rare genetic
causes of obesity including POMC, PCSK1, or LEPRECHAUN deficiency (140).
Acquired Secondary Hypogonadism

Acquired secondary hypogonadism is caused by:
PATHOLOGIC: Hypothalamic/ pituitary disease,including tumors, infiltrative disease, and

hyperprolactinemia (either by prolactin secreting adenomas, stalk compression or dopamine
antagonists.
ACUTE ILLNESS: Since acute illness may cause transient secondary hypogonadism, men
should not be investigated for hypogonadism until the inter-current illness has resolved. Low
measurements of total testosterone concentrations are required on at least two separate occa-
sions to confirm hypogonadism.
EXOGENOUS CHEMICALS: Opioid induced secondary hypogonadism and withdrawal from
inappropriate use of exogenous androgens have become more common in clinical practice.
OBESITY IN YOUTH: Interestingly, given the rising incidence of obesity in children and ado-
lescents, its impact on genital development may be noted early in life, just as gonadal func-
tion has been shown to be affected by obesity in older adults, perhaps as a result of insulin
resistance.In a cross sectional study of 1130 ( 833 normal-weight and 297 obese) boys tested
for testosterone level and a validated measure of penile length from birth to age 20, at general
periodic examination,.. Age, height, weight, BMI, penile length and Tanner stage, gonadotro-
pins and testosterone were recorded. Boys with genetic or endocrine pathology were excluded.
Puberty in obese young children started later and evolved more rapidly at more advanced
Tanner stages. Testes volume was slightly smaller across pubertal stages in obese boys.
Testosterone levels were approximately 50% lower in obese compared to normal-weight boys at
all puberal stages. Penis length and testosterone are strongly related in children during puberty.
Penile growth is significantly decreased (by about 10%) in obese boys, another among the
many reasons to emphasize healthy nutrition and exercise early in life (141).
HIV: Hypogonadism commonly affects HIV-positive men, especially those with advanced immu-
nosuppression and sarcopenia. The introduction of antiretroviral therapy has lowered the
incidence of hypogonadism among HIV-infected men. Free testosterone should be measured
because it may be artifactually affected, as SSBG may be elevated in HIV men, beyond the
effect of aging, while insulin resistance, obesity, and uncontrolled diabetes lower it.
Many common symptoms of hypogonadism in adult men are nonspecific, including fatigue,
low mood, reduced libido, erectile dysfunction, reduced muscle mass, loss of body hair, weight
loss, poor sleep, reduced concentration, memory difficulties, and increased risk of osteopenia,
though conditions more common in HIV men or their treatment should be excluded.
Primary hypogonadism in HIV infection may be caused by upregulated tumor necrosis fac-
tor and interleukin-1, which impair testicular steroidogenesis and cause inflammation resulting
in autoimmune testicular damage and the development of antisperm antibodies.
Secondary hypogonadism in HIV patients may be caused by cirrhosis, end-stage renal
disease, lymphoma or syphilis of the pituitary, meningeal or pituitary infection with
Mycobacterium tuberculosis, or toxoplasmosis (with or without evidence of deficiency of other
pituitary hormones).
Current Endocrine Society clinical practice guidelines suggest at least short-term testoster-
one therapy as adjunctive therapy in HIV-infected men with weight loss and low testosterone
levels to promote gain in muscle strength and lean body mass. Bone density, fracture risk,
strength, and quality of life may be improved (142).
Diagnostic Studies in Hypogonadism

Measurement of gonadotropins (LH and FSH) will distinguish between primary and secondary hypo-
gonadism in the face of low testosterone. SSBG and/or free testosterone by equilibrium dialysis should
be measured to exclude binding protein abnormalities yielding falsely high or low testosterone values.
Prolactin should be measured to rule out hypogonadism caused by hyperprolactinemia. Karyotype analy-
sis will assess genotype. When fertility issues are at stake, semen analysis is required.
An accurate testosterone assay by LC/MS/MS must be used. Reference ranges cross-calibrated by the
Centers for Disease Control (CDC) are available.
Management of true hypogonadism should begin at the time of expected puberty in congenital cases
and upon diagnosis in acquired cases. In prepubertal boys with proven hypogonadism of any etiology,
once a diagnosis is established (and constitutional retardation of puberty excluded) testosterone ther-
apy will result in normal virilization, appropriate growth, and establishment of healthy bone mass and
musculature.
Treatment of low testosterone in adult men who have true ‘organic’ hypogonadism results in improved
libido and potency, male body hair distribution, bone density, and lean body (muscle mass). It should be
offered to all, excluding those with serious contraindications including prostate or breast cancer.
Testosterone levels should be kept at an age-appropriate normal range. Testosterone may be adminis-
tered via intramuscular injection, by implantable pellets, and subcutaneously by patch or topical creams.
Newly approved oral testosterone undecanoate is safe, unlike previous oral formulations.
Side effects of excess exogenous replacement include polycythemia, lower HDL cholesterol, and
exacerbation of benign prostatic hyperplasia. Testosterone replacement does not appear to increase the
risk of developing prostate cancer and may be safe in men with previously treated localized low-grade
prostate cancer, but there is limited data concerning more aggressive disease. Thus individualization and
caution are recommended for treatment in hypogonadal men in that situation. The prostate-specific anti-
gen (PSA) will likely rise from low to normal levels in hypogonadal men treated with testosterone. This
is of no concern if it remains in the normal range (143, 144).
Hypogonadism in the Aging Male

It has been reported that in the aging male, testosterone levels fall, while SSBG and gonadotropin levels
rise, suggesting testicular failure or compensated testicular failure. Because of the rise of SSBG, the mea-
surement of total testosterone may overestimate free bioactive testosterone (145).
A 2015 cross-sectional study of 1,093 Chinese men divided into 5-year age groups, from ages 20
to 87, however, showed slight increases in SSBG and LH, while total testosterone and calculated free
testosterone fell slightly up to age 60, then rose so that levels were equivalent to the youngest men (146).
However, using data from four large epidemiologic studies of nonobese, nondiabetic men, and harmo-
nized free testosterone levels performed by LC/MS/MS confirmed by CDC reference labs, the difference
between the lowest and highest testosterone levels differed little by age. This fact suggests that many of
the studies performed in aging males may be suspect simply based on assay use alone.
Because of previous conflicting or inconclusive studies, in 2003, an Institute of Medicine panel rec-
ommended a coordinated set of clinical trials to determine whether testosterone would benefit older men
who had age-related low testosterone levels, including those with clinical conditions to which low testos-
terone might contribute or which conversely might cause low testosterone.
The T Trials were a series of placebo-controlled, RCTs of 790 men over age 65, with a serum total
testosterone concentration of less than 275 ng/dL and symptoms suggesting hypoandrogenism, random-
ized to receive either testosterone gel or placebo gel for 1 year. To achieve relevance to real-world condi-
tions, possibly contributing ‘nongonadal’ factors were not a basis for exclusion: 62.9% were obese, many
were diabetic, 71.6% had hypertension, and 14.7% had a history of myocardial infarction. The two study
groups had similar baseline characteristics, including those comorbidities. Of the testosterone-treated
group, total testosterone rose to and was maintained at the normal range for men aged 19–40. Free tes-
tosterone, dihydrotestosterone, and estradiol also increased to midnormal for young men. (Critics of these
studies have questioned whether young, normal-range testosterone levels are appropriate for older men
or represent overtreatment, while others suggest that negative studies may have resulted from inadequate
testosterone doses. See later.)
Testosterone compared with placebo resulted in significant effects on all measures of sexual function
and some measures of physical function, mood, and depressive symptoms: all small to moderate degrees,
consistent with the degree of testosterone deficiency; moderate benefit with respect to sexual function;
some benefit with respect to mood and depressive symptoms; and no benefit with respect to vitality or
FIGURE 7.17 Box-and-whisker plots showing the distribution of total testosterone levels by decades of age
in the four cohorts without harmonization (upper panel) and after harmonization (lower panel). The lower
and upper boundaries of the box represent the 25th and 75th percentile values; the line inside the box rep-
resents the median. Independent adjustment of each study’s measurements to the CDC (as shown in the
lower panel) reduces the interstudy variation substantially over that observed in unstandardized measurements
(shown in the upper panel). (From Travison, TG. et al. Harmonized reference ranges for circulating testoster-
one levels in men of four cohort studies in the United States and Europe. J Clin Endocrinol Metab 2017 April
1;102(4):1161–1173.)
walking distance. The number of participants was too few to draw conclusions about long-term risks
including prostate cancer and cardiovascular outcomes (148).
In a subtrial trial, 211 participants (mean age 71, BMI 31, 86% Caucasian) were treated with the same
aforementioned protocol. Spine and hip bone mineral density (BMD) were determined by quantitative
computed tomography at baseline and 12 months. Bone strength was estimated by finite element analysis
of quantitative computed tomography data. Areal BMD was assessed by dual-energy X-ray absorptiom-
etry at baseline and 12 months. Testosterone treatment was associated with significantly greater increases
than placebo in mean spine trabecular volumetric BMD (vBMD), spine peripheral vBMD, and hip tra-
becular and peripheral vBMD; and mean estimated strength of spine trabecular bone, spine peripheral
bone, and hip trabecular and peripheral bone. The estimated strength increases were greater in trabecular
than peripheral bone and greater in the spine than the hip. Testosterone treatment increased spine areal
BMD but less than vBMD. No fracture data were reported. A larger, longer trial could determine whether
this treatment also reduces fracture risk (149).
The T Trial investigators commented, “Unlike in previous studies where there T level was too low
or there were not enough subjects, the T Trial trials yielded more statistically and clinically significant
results. As expected, hemoglobin levels rose in treated patients. Sexual activity but not erectile function
were improved by T in doses which were kept stable.” (Although they did not comment on the use of a
young normal range.) Testosterone compared with placebo did not improve cognitive function, physical
function, or vitality, although using different assessment tools there was a modest improvement in vitality,
mood, and depressive symptoms.
In this group of men with a high incidence of CVD and comorbidities, testosterone increased the
noncalcified coronary plaque volume, compared with placebo, and was adjusted for the pretreatment
scores in each group.
These findings, thought to be more methodologically sound in large RCTs than previous studies, have
been used as the basis of many but not all new guidelines (150).
Metabolic Consequences of Hypogonadism and Its Treatment

Conflicting data have reported that low endogenous testosterone levels are associated with higher CVD,
atrial fibrillation, and all-cause morbidity and mortality, perhaps in a bidirectional manner. Obesity and
metabolic syndrome are strongly associated with low endogenous testosterone and may be responsible for
changes in testosterone attributed to aging.
Androgen deprivation in men with prostate cancer has been associated with increased insulin resis-
tance, worse glycemic control, and greater risk of diabetes. Low serum testosterone is associated with the
development of metabolic syndrome and type 2 diabetes. SSBG has been inversely correlated with type
2 diabetes.
There is conflicting data on the risks and benefits of testosterone therapy with regard to morbidity
(DM, MBS, MACE) and mortality.
Improvement in insulin sensitivity with testosterone treatment has been reported in healthy and dia-
betic adult men. In studies conducted in men with central adiposity, testosterone therapy has been shown
to inhibit lipoprotein lipase activity in abdominal adipose tissue leading to decreased triglycerides (151).
Previously, lifestyle intervention alone had shown no benefit in improving body composition and
function and created a concern for weight loss–induced exacerbation of age-related loss of muscle and
bone. A 26-week RCT of testosterone versus placebo was conducted in men >65 years old with BMD
>30, testosterone <300 ng/ml. A supervised diet providing an energy deficit of 500–750 kCal/day and 1
g/kg body weight, and nutritional counseling were instituted in both groups, plus supervised aerobic and
resistance training resulting in 9% body weight loss. The treated group received transdermal testosterone
to maintain healthy young (age 19–40) male levels. Testosterone increased aerobic capacity and mini-
mized or prevented muscle and BMD loss that occurs with lifestyle therapy as well as improved sexual
function, but did not further improve overall physical function or reduce frailty compared with lifestyle
alone. There were no differences in adverse effects between the two groups (152).
In contrast, possibly because of the effect of weight loss, and with a longer follow-up period, a testos-
terone plus lifestyle program reduced the risk of T2DM in overweight and obese men (12.4% vs. 21% with
placebo), with a small improvement in sexual function, but with a greatly increased risk of erythrocytosis
and more adverse ischemic heart disease, cardiac arrhythmia syndrome, and benign prostatic hyperplasia,
with similar mortality rates (153).
Meta-Analyses
A 2018 review of meta-analyses of placebo-controlled RCT risks and benefits of testosterone replacement
found only four studies (of 2,807 reviewed) that met standards for inclusion. These studies included only
men who met the ES guidelines for replacement (T <300, at least one definitive hypogonadal symptom).
Treatment in all four studies consisted of transdermal testosterone to reach a normal level for age, for at
least 12 weeks (12,16,52,12 weeks); one study included only men >65 years old. Only total, not free, tes-
tosterone was used and most studies used only one measurement. Within the appropriately treated group,
meta-analyses revealed that testosterone treatment was associated with moderate improvement in sexual
function. High-quality evidence shows that compared with placebo, testosterone therapy was associated
with a small but substantial improvement in sexual desire (libido), erectile function, sexual activity, and
sexual satisfaction in hypogonadal men. Treated men had more erythrocytosis but no effect on lower uri-
nary tract symptoms and no statistically significant effect on energy.
None of the trials was long enough or large enough to have sufficient statistical power to determine
the effects of testosterone replacement therapy on the incidence of prostate cancer, major adverse cardio-
vascular events, or bone fractures. The data on performance-based measures of physical function were
available only in one trial, precluding a meta-analysis (154).
GUIDELINES
Based on a review of all studies in the aforementioned references, including the meta-analysis reviews, the
Endocrine Society published its most current guidelines, still leaving room for physician–patient discus-
sion of symptoms, levels, and individual risks and benefits.
By contrast, other societies’ guidelines, while largely in agreement, differ in recommendations
regarding indications for screening; testosterone measurement and cut points; classification and therapy
in older men with obesity, T2DM, and MBS; and the use of a therapeutic trial of testosterone replacement
in equivocal cases. A detailed granular review and comparison can be found in
Al-Sharefi and Quinton (155), which compares several guidelines from 2015 to 2018:
2015 International Society for Sexual Medicine (ISSM)

2017 British Society for Sexual Medicine (BSSM)
2015 Canadian Medical Association Journal (CMAJ)
2018 American Urological Association (AUA)
2018 European Association of Urology (EAU)
2018 Endocrine Society (ES)
2016 Endocrine Society of Australia (AUS)
Topics covered in this review of guidelines are:
Screening criteria – Criteria vary from those that advise testing only for men with specific clinical
features of hypogonadism (AUS, ES), to those (CMAJ, AUA, ISSM and BSSM) that suggest
screening in situations where the risk of male hypogonadism (MH) is high, even without symp-
toms. Some take account of the coexistence of aging, obesity, metabolic syndrome, and other
comorbidities with MH, without the recognition that the latter may be a result of the former
and thus possibly amenable to treatment of the underlying condition, while others recommend
therapy with testosterone. Exposure to drugs, radiation, and HIV, along with other conditions,
may be criteria for screening. While impaired spermatogenesis may be multifactorial, it is only
part of the diagnostic criteria for MH in the ES and AUS, noting normal semen virtually rules
out testosterone deficiency. Treatment of these men with normal testosterone but, abnormal
semen with exogenous testosterone may exacerbate infertility by suppressing gonadotropins
and intratesticular testosterone concentrations necessary for spermatogenesis.
Testosterone cut points – These vary by the guideline for MH. All agree that testosterone should
be measured in the morning, but there is disagreement regarding whether the local laboratory
normal range should be used rather than a universal cutoff lower limit of normal (see earlier)
and what that should be, and whether it should be modified by age or other comorbidities. Even
the requirements of fasting or confirming with a second sample are conflicting.
Measurement of bioavailable testosterone – Free testosterone calculation by mass action for-

mula was recommended by the BSSM, ISSM, EAU, and ES. The EAU recommends cal-
culating free testosterone in case of a discrepancy between serum (total) testosterone and
symptoms, while the ES recommends the use of calculated free testosterone in the presence
of conditions that alter SHBG levels or when serum testosterone levels are in the borderline
range. The AUS is opposed to using calculated free testosterone because of its poor correla-
tion to the measurement of free testosterone by equilibrium dialysis. The more recent ES
guidelines recommend measuring total testosterone by LC/MS/MS with direct measurement
of free testosterone by equilibrium dialysis, using calculated free testosterone only if the
former is unavailable (156).
Approach to Low-Borderline Serum Testosterone Level – The ISSM and BSSM suggest that
in symptomatic men with repeat serum testosterone in the 8 to 12 nmol/L (230–346 ng/dL)
range, measurement of LH, SHBG, and prolactin should be undertaken, with either high lev-
els of LH (indicating Leydig cell impairment) or SHBG affecting total, but not bioactive,
testosterone. A therapeutic trial of testosterone (ISSM, 6 to 12 months; BSSM, 6 months) to
determine whether this alleviates symptoms is recommended. The CMAJ likewise suggests
considering a trial of testosterone replacement therapy for 3 months in the presence of a con-
vincing clinical picture.
Apart from recommending prolactin measurement, neither the ISSM, BSSM, nor CMAJ address in any
great depth the importance of identifying and treating potential causes of nongonadal illness (NGI) in
men with sexual symptoms, low-normal testosterone and normal LH. Nor is a possible placebo effect from
the testosterone trial considered.
The AUA suggests measuring prolactin levels in those with repeat low testosterone and low-normal
LH levels (without measurement of free testosterone).
The AUA does not recommend measurement of free testosterone until later in their algorithm, e.g.,
after prolactin is measured and found to be normal in men with HH (hypothalamic hypogonadism). Since
SSBG is affected in so many individuals with aging, obesity, liver disease, etc., it would seem more rea-
sonable to first confirm that bioactive testosterone is indeed abnormal before proceeding with other inves-
tigations. They then suggest proceeding to treat with testosterone for MH if prolactin levels are normal,
and only recommending further endocrine workup and pituitary magnetic resonance imaging if prolactin
is elevated or testosterone <150 ng/dL, to rule out a structural pituitary lesion. (These arbitrary levels may
miss cases of HH where prolactin is not elevated, is only minimally elevated, and not considering free
testosterone, such as with nonsecretory pituitary adenomas, stalk compression, panhypopituitarism, and
less severe impairment of testosterone.)
In addition to structural pituitary disease, investigating other potential causes of HH is recommended
by some, but not all guidelines. For example, for hereditary hemochromatosis, a genetic disease causing
pituitary iron overload, the ISSM, BSSM, AUA, EAU, and CMAJ provide no guidance on how best to
approach men with hypogonadism secondary to opiate or exogenous androgens. The ES recommends
only considering testosterone treatment of opiate-induced hypogonadism in men with distressing symp-
toms and in whom opiate withdrawal is not an option. The AUS stresses that opiates or androgens cause
functional and reversible hypothalamic hypogonadism and that cessation of the offending drug should
always be attempted first.
Aging, Obesity, and Other Comorbidities – All clinical practice guidelines acknowledge that the
prevalence of subnormal serum testosterone levels increases with advancing age (despite the
aforementioned recent data), either from age- or comorbidity-related decline in Leydig cell
function, or from hypothalamic hypogonadism or nongonadal illness). The implications of this
fact and the impact on recommendations for testosterone therapy vary widely and are a source
of confusion to both physicians and patients. The ES considers advanced age to be a cause of
primary but not secondary organic hypogonadism, whereas the AUS does not consider age
to cause any form of hypogonadism and does not necessarily consider a raised LH level in
an older man as indicating pathological MH requiring testosterone treatment. The ISSM and
BSSM both defined low testosterone associated with comorbidity as a form of age-related MH,
requiring treatment the same as those with classical organic hypogonadism.
The CMAJ, ISSM, and BSSM state that obesity, T2DM, and metabolic syndrome are all strongly associ-
ated with MH in a bidirectional manner, i.e., while they contribute to low testosterone, administration of
testosterone may improve metabolic function, promoting muscle anabolism, lipolysis, and weight loss.
Therefore, they recommend screening for hypogonadism in all men with these metabolic derangement
syndromes and testosterone treatment for low testosterone associated with obesity, especially in people
who are not likely to adhere to lifestyle modification. The AUA recommends screening for all men with
diabetes and treatment of low testosterone if found, even if no hypogonadal signs or symptoms are pres-
ent. (Note: This recommendation would result in a great deal more screening and likely more ambiguous
conclusions regarding therapy. None of the guidelines give specific recommendations for the management
of hypothalamic hypogonadism or nongonadal illness and MBS.)
The EUA, ES, and AUS all recommend lifestyle modification and addressing the underlying comor-
bid illness as a first-line intervention, with the EUA also recommending the use of PDE5 inhibitors as a
first-line therapy ahead of testosterone for erectile dysfunction in symptomatic men with low serum tes-
tosterone. The ES and AUS concur that functional HH/NGI due to obesity can be reversed by addressing
excess weight through diet and exercise. The AUS also noted only limited data from high-quality RCTs of
testosterone, achieving clinically significant outcomes in older men – usually with chronic disease (such
as obesity) – having low testosterone levels but no evidence of pathological MH. The AUS considers low
testosterone in this context to be the marker of underlying poor health and does not support prescribing
of testosterone in such settings. The T Trials, published after the AUS, were carefully performed placebo-
controlled trials in hypogonadal older men with many comorbidities including diabetes, high blood pres-
sure, obesity, and MBS. Their conclusions are reviewed earlier. More recent RCTs (152) have found no
benefit in adding testosterone to lifestyle modification.
Testosterone and Cardiovascular Disease

Current guidelines state that there is no credible evidence that testosterone increases the risk of cardio-
vascular (CV) events, provided that it is prescribed appropriately to men with a well-founded diagnosis of
male hypogonadism.
There have been no consistent results evaluating the relative risk of CVD in untreated older hypogo-
nadal men because of differences in study populations, difference in assays, baseline testosterone levels, and
study methodology, More importantly, results of morbidity and mortality in older men treated with testos-
terone have varied widely for similar reasons, as well as treatment dose, levels achieved, comorbidities, and
trial length. Despite a multitude of studies, conclusions regarding CVD safety and efficacy in this group of
men are therefore difficult to draw and likewise are difficult to form strong evidence for guidelines.
(An excellent detailed tabulation of epidemiological and observational studies, as well as basic sci-
ence and preclinical animal studies, can be found in Gagliano-Juca and Basaria (157).)
Clinical trials raised CV safety concerns when testosterone was prescribed to older men having a
primary diagnosis of age-related frailty or hypothalamic hypogonadism or nongonadal illness associated
with obesity, T2DM, or metabolic syndrome. A 50% increased risk of CV thrombosis among men in the
top 5% for hematocrit (0.48%), compared with the 25th to 50th centiles has been reported. Testosterone
may shorten the cardiac QT interval as a potential contributing factor to CV risk, however, a possible role
for testosterone to treat men predisposed to short QT–arrhythmias is currently being investigated.
Current recommendations from various guidelines therefore differ because of the lack of strong con-
sistent evidence.
The ISSM recommends that hypogonadism in men with CVD be assessed and monitored in the same
way as in other men, whereas BSSM recommends addressing CV risk factors and secondary prevention
in men with established disease before starting testosterone therapy. The EAU suggests a greater need for
caution in men with preexisting CVD and, potentially, considering echocardiography before initiation of
testosterone.
The AUA recommends counseling patients before starting testosterone, explaining that the evidence
is patchy and that it is unknown whether testosterone can increase or decrease the risk of any major
adverse CV event. The CMAJ guideline makes a weak recommendation, based on low-quality evidence,
that testosterone treatment in men with CVD be restricted to those with stable disease and only after a dis-
cussion of the potential risks and benefits. The AUA and ES caution against initiating testosterone since a
recent CV or stroke event (3 to 6 months for the AUA and 6 months for the ES), while the AUS suggests
the need for caution when using T in older men with known CVD.
The UK Society for Endocrinology has produced a brief position statement on testosterone in older
men, discussing the uncertainty and potential risks of testosterone therapy in obese and/or older men with
low testosterone. It notes, however, that the majority of older men retain Leydig cell function into old
age and that, consequently, withholding testosterone treatment in symptomatic older men with a verified
diagnosis of organic or syndromic MH is not warranted.
In the future, more reliable results should be available from the TRAVERSE study, the first random-
ized, controlled trial that was adequately able to evaluate the incidence of CV events with testosterone
replacement therapy. A study sample of 6,000 men at high risk of CVD and with total testosterone of
<300 was randomized to receive either testosterone gel or placebo for 5 years, beginning in 2018. The
primary endpoint will be time to MACE (nonfatal myocardial infarction, nonfatal stroke, or death from
cardiovascular causes). Secondary outcomes include time to occurrence of the composite cardiovascular
end point (nonfatal myocardial infarction, nonfatal stroke, death from cardiovascular causes, or cardiac
revascularization procedures including percutaneous coronary intervention and coronary artery bypass
graft surgery). The findings of this trial will provide more definitive evidence about the cardiovascular
safety of testosterone replacement therapy (157).
Indications for Testosterone Treatment

All guidelines affirm that testosterone replacement is indicated with a verified diagnosis of MH, i.e., the
presence of characteristic symptoms combined with the unequivocal biochemical finding of low testoster-
one. According to the ES and AUS, hypogonadal men with a known organic pathologic hypogonadism,
either primary or secondary, should be treated, absent contraindications. Some guidelines (particularly
the ISSM, BSSM, and CMAJ) apply significantly lower thresholds for treatment and endorse trials of
testosterone treatment with symptoms conceivably due to male hypogonadism, even when biochemistry
is not entirely supportive, or potentially due to nongonadal illness.
None of the guidelines consider a high LH level, indicating a defect of Leydig cell function and physi-
ological nongonadal illness or inappropriate sample collection time as a cause of lower serum testosterone.
The AUS emphasizes the importance of searching for organic pathologic causes of low testosterone.
Testosterone treatment is not generally recommended by the ES or AUS for men who have an intrinsi-
cally intact hypothalamic–pituitary–thyroid axis, but suppressed function due to other functional causes
(e.g., obesity or other comorbidity). The ES defines these men as having functional MH, whereas the AUS
does not consider them as having true hypogonadism at all.
In contrast, other guidelines do not differentiate between organic/classical/pathological MH and
functional HH/NGI in terms of indications for treatment.
Aging, obesity, metabolic syndrome, and other comorbidities are acknowledged by all societies as a
cause of low testosterone. But their approach to the significance of this, its pathophysiology, and the need
for therapy is very divergent. The ES states that elevated LH denotes an age-related decline in Leydig cell
function, while the AUS does not consider age to be a cause of any form of hypogonadism and does not
indicate that elevated LH is not pathologic or requires testosterone replacement. The ISSM and BSSM
regard low testosterone as age-related hypogonadism, even while recognizing that it may be due to comor-
bid conditions, and recommend treatment the same as organic/classical male hypogonadism.
The ES allows clinicians to individualize the decision to treat or not to treat with T based on careful
consideration of the severity of symptoms, the degree of T deficiency, the confounding influence of the
comorbid illness, patient preferences, and the uncertainty of the risks and benefits of testosterone therapy.
The authors of this cited guideline (157) stated that this recommendation “leaves open the possibility
for prescribing T based solely upon patient expectations”.
A careful reading of the ES recommendation, however, considers patient preference only in the set-
ting of meeting other criteria, i.e., some older men with low testosterone counseled carefully may decide
that the potential risks of therapy outweigh the benefits, especially in light of the unresolved issue of car-
diovascular risk, while other men, particularly those with very low testosterone and distressing symptoms
may decide that current benefit might outweigh the long-term risk.
The AUA offers the criticism that the ES does not recommend treatment for men over 65 years old.
To this author, however, this criticism seems an oversimplification because the ES recommendation for
older men is modified by clinical evaluation of hypogonadal symptoms and the degree of low testosterone
as well as suggesting individualization and a possible therapeutic trial. This more nuanced recommenda-
tion takes into account the frequency of abnormal SSBG, the higher prevalence of obesity morbidities
associated with low testosterone, and the unsettled question of CVD risk of treatment in older men, while
allowing a discussion of therapy in men who have low free testosterone and low testosterone symptoms.
https://doi.org/10.1038/s41443-021-0047
Testosterone Treatment and Androgen-Sensitive Cancers

All guidelines emphasize precautionary baseline PSA measurement and digital rectal examination (DRE),
with periodic repeats during treatment. The ES advises against testosterone in men with prostate cancer,
palpable prostate nodule, or induration; PSA level ≥4 ng/mL (or ≥3 ng/mL if combined with a high risk of
prostate cancer such as African American origin and those with first-degree relatives with having prostate
cancer); and without urological evaluation. In relatively younger men (age 55 to 69) with a life expectancy
of ≥10 years or men aged 40 to 69 who have high risk, the ES suggests shared decision-making after
discussing risks and benefits, and potential prostate monitoring. The ES advises that all men receiving
testosterone treatment should have an urological evaluation upon the detection of a prostate nodule or
induration, or a ≥40% rise in PSA level over the first year of treatment.
Most guidelines counsel against testosterone in patients with metastatic or locally advanced prostate
cancer (PCa), any form of male breast cancer, and in patients at high risk for recurrent prostate cancer.
The ISSM and AUA recommend a mutual decision to be made between the patient and the physician
taking into account benefits versus the potential risks. The BSSM, EAU, and CMAJ recommend offer-
ing testosterone to symptomatic men with a history of treated localized low-risk PCa (Gleason score <8,
stages 1–2, preoperative PSA levels <10 ng/mL, and not within 1 year of treatment with curative intent)
and without evidence of active disease (based on measurable PSA level, DRE result, and imaging evi-
dence of metastatic disease). The EAU advises that testosterone can be cautiously offered to patients who
underwent brachytherapy or external beam radiation for low-risk prostate cancer.
Monitoring Testosterone Therapy

Testosterone levels, PSA, hematocrit, DRE, and symptoms should all be monitored while patients are being
treated. The AUA in particular recommends a DRE, while others do not, suggesting that non-urologists
may not be comfortable with the examination and/or that PSA will yield adequate information. To avoid
testosterone-induced erythrocytosis, many guidelines counsel against initiating testosterone in patients
with baseline elevated hematocrit, but advise it should be monitored during treatment even with a normal
baseline (155).
For the sake of simplicity, recommendations from the Endocrine Society guidelines, most commonly
used in the USA, are quoted (158), while recognizing that questions can be reasonably asked when com-
paring the other guidelines reviewed earlier.
Endocrine Society Guidelines

This guideline, which is the most commonly utilized in the United States, combines a practical approach
to ensure that testosterone therapy is prescribed only in appropriate patients, by limiting its prescription
to only those men who are hypogonadal by symptomatology and definitively low serum testosterone con-
centrations in accurate assays. Testosterone should be measured fasting in the morning and repeated for
confirmation. Free testosterone by equilibrium dialysis and/or correction with a formula accounting for
SSBG concentrations should be used. Most importantly, this guideline strongly recommends TESTING
TO DETERMINE THE ETIOLOGY OF THE HYPOGONADISM, a feature not included in some of
the other guidelines. The therapeutic goal is a testosterone in the mid-normal range. As in all guidelines,
contraindications to testosterone therapy include breast or prostate cancer, or a high risk of the same,
elevated PSA which has not been investigated, elevated hematocrit, untreated severe obstructive sleep
apnea, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke
within the last 6 months, or thrombophilia. The importance of patient counseling and regular follow-up to
measure testosterone, hematocrit, PSA and symptoms is highlighted.
GYNECOMASTIA
Enlargement of the male breast is due to an elevated estradiol/testosterone ratio causing stimulation of
normal breast tissue proliferation. This may be due to various alterations in production and/or clearance
of both hormones, or changes in SSBG, as testosterone and DHT have a greater affinity for SSBG than
does estradiol. Therefore, as SSBG rises with aging, free testosterone falls more significantly relative to
free estradiol (159).
Though gynecomastia is usually bilateral, it can be asymmetric or unilateral, raising the differen-
tial diagnosis of male breast cancer (which is rare). True gynecomastia should be differentiated from
breast enlargement caused by obesity. Usually, palpation can differentiate between the two. Gynecomastia
occurs physiologically in pubertal boys in as many as 50% with careful examination. It is usually mild
and self-limited. In older men, gynecomastia may be a manifestation of low testosterone levels caused
by aging and or metabolic syndrome (see earlier). Pathologically elevated estrogen levels may be seen in
liver disease, renal failure (because of decreased clearance), and excess estrogen production in tumors of
the adrenal or testis.
Medication-induced gynecomastia is very common.
Management of gynecomastia depends upon the timing, severity, and associated signs and symp-
toms. In adolescents with mild gynecomastia and otherwise normal pubertal development, reassurance is
all that is required. In aging men, evaluation of testosterone/estradiol and prolactin should be performed
TABLE 7.3 Mechanisms of Drug-Induced Gynecomastia

MECHANISM DRUGS
Increases estrogenic activity or increases Anabolic steroids, conjugated and synthetic estrogens, hCG,
estrogen production digoxin, clomiphene, phenytoin, diazepam
Decreases androgen activity or decreases Ketoconazole, metronidazole, cimetidine, ranitidine,
androgen production omeprazole, spironolactone, flutamide, methotrexate,
isoniazid, penicillamine
Increases androgen clearance Alcohol
Causes hyperprolactinemia Metoclopramide, phenothiazine, haloperidol
Increases SHBG Phenytoin, diazepam
Source: Adapted from Ismail A, Barth J, Review: Endocrinology of gynaecomastia. Ann Clin Biochem,
2001;38(66):596–607.
FIGURE 7.18 (A–C) Bilateral gynecomastia. (Courtesy of gynecomastia.org.) (D) Unilateral gynecomastia (2).
(Courtesy of Dr. Donald Gordon.)
to exclude true pathology. If this is not found, counseling and reassurance are adequate. In men of all
ages, the presence of significant hypogonadism, hyperprolactinemia, or other syndromic features should
prompt further investigation and treatment as necessary. In those men whose gynecomastia is severe,
uncomfortable, or psychologically stressful, surgical breast reduction may be performed.
HYPERPROLACTINEMIA
Prolactin, a peptide hormone secreted by lactotroph cells in the anterior pituitary gland, is predominantly
regulated by tonic inhibition via hypothalamic dopamine release. Normal stimuli for secretion include
TRH, GnRH, and vasoactive intestinal peptide, and nipple stimulation via reflex neurogenic input to the
hypothalamus. Estrogen amplifies stimulation. Clinically, the most important function of prolactin is
development of the mammary gland and milk secretion, although many other functions have been found
that are outside the scope of this section.
Physiologically prolactin levels rise during pregnancy and lactation. Pharmacologic estrogenic stimu-
lation, e.g., OCPs, causes appropriately elevated prolactin.
Etiology
Inappropriate excess production of prolactin may be caused by tumors of the lactotrophs or mixed pitu-
itary tumors (cosecreting ACTH or GH) that cause autonomous secretion, or by disruption of the normal
inhibitory action of dopamine, either by structural interruption of the pituitary stalk by non-prolactin-
secreting pituitary adenomas, non-pituitary tumors, or infiltrative disease. Impaired clearance of prolactin
in renal failure may cause elevated levels. Excess stimulation by TRH may be present in primary hypo-
thyroidism. Prolactin elevation may be seen in PCOS and empty sella syndrome, while transient increases
may be caused by nipple stimulation, stress, and exercise.
Medication-Induced Hyperprolactinemia
Hyperprolactinemia may be caused by the chemical suppression of dopamine or its action. Agents include
dopamine receptor blockers, catecholamine or dopamine depleters, phenothiazine and other neuroleptics,
antidepressants, antihypertensives (methyldopa, verapamil), metoclopramide, cimetidine, opiates, and
exogenous estrogen.
In females, hyperprolactinemia may present clinically with galactorrhea (inappropriate milk secretion)
and/or oligomenorrhea or anovulation, with infertility. Low estrogen levels may lead to osteoporosis.
Galactorrhea may be spontaneous and noticeable by the patient or may only be detected with breast
expression. Since there are several types of breast secretion, if there is doubt whether the fluid is milk, an
oil red stain may be done to demonstrate fat globules that only occur in milk.
In males, hyperprolactinemia may cause hypogonadism (both primary and secondary), impaired
libido (possibly by a central mechanism), infertility, and low bone density as a result of low testosterone.
In either gender, large pituitary tumors may cause headaches or visual changes from compression of
the optic chiasm.
FIGURE 7.19 Human milk fat globules stained with Nile red. (From Post A, De Heijninga B, Actona D et
al. A novel infant milk formula concept: Mimicking the human milk fat globule structure. Colloids Surf B
Biointerfaces 2015;136(1):329–339.)
Measurement of prolactin is therefore mandatory in any of the aforementioned conditions. It is impor-

tant to beware of pitfalls in measurement (see later) to properly assess clinical importance.
It has been stated that prolactin levels over 150–200 are nearly always a result of secretion from pro-
lactinomas; however, 5% of those with drug-induced hyperprolactinemia had levels over 250, especially
with haloperidol, phenothiazines, domperidone, and metoclopramide.
Laboratory Measurement
Immunometric assays are used to measure prolactin. Pitfalls in measurement may be caused by either
overestimation because of the presence of big prolactin or underestimation due to the ‘hook effect’.
Prolactin circulates in a monomeric chemically active form that binds to the prolactin receptor, caus-
ing its clinical effects. Inactive prolactin (including dimeric big prolactin), prolactin aggregates, and pro-
lactin bound to antibodies may also be detected in immunoassays used to measure prolactin. This results
in falsely elevated prolactin levels in patients with normal levels of monomeric prolactin, typically in
patients with normal physiologic function. PEG (polyethylene glycol) precipitation will remove these
large inactive forms. Assays report the percentage of macroprolactin (162).
The hook effect may return falsely low prolactin levels in double antibody ‘sandwich’ immunoassays.
This occurs as a result of excess antigen concentration saturating available binding sites on the bivalent
capture and detector monoclonal antibodies preventing the formation of a sandwich complex leading to a
paradoxical loss of antigen signal intensity. If the sample is diluted, lowering the concentration of antigen,
the hook effect may be resolved. This is particularly important in the case of known pituitary macroad-
enomas, as prolactinomas are treated differently from other tumors (163).
In well-differentiated pure prolactin-producing adenomas, the level of prolactin generally correlates
well with the size of the tumor. Microprolactinomas are usually visible on dedicated high-resolution
MRIs, and produce modest prolactin elevations; however, prolactin levels resulting from stalk compres-
sion from non-prolactin-secreting pituitary tumors, cystic prolactinomas, or nonpituitary masses (e.g.,
craniopharyngiomas, gliomas, meningiomas) of considerable size, and infiltration disease may also cause
only modest elevations. Recognition of this fact is extremely important, as the decision to image the pitu-
itary–hypothalamic area will depend at least in part upon this information. It should not be assumed that
minimal elevations in prolactin indicate a microprolactinoma. Most authorities suggest imaging in nearly
all cases of hyperprolactinemia in order not to miss a critical diagnosis.
FIGURE 7.20 (From Saleem M, Martin H, Coates P. Prolactin biology and laboratory measurement: An
update on physiology and current analytical issues. Clin Biochem Rev 2018;39(1):3–16.)
Imaging
Imaging is performed by MRI dedicated to the hypothalamic–pituitary area. It should be noted that
occasionally very small microadenomas or lactotroph hyperplasia may not be apparent in even the most
high-resolution studies.
Treatment
Not all patients with hyperprolactinemia require treatment. In patients with microadenomas or ‘idiopathic
hyperprolactinemia’ without bothersome galactorrhea with adequate estrogen production and no desire
for fertility, or in postmenopausal women, treatment may be withheld. Hypogonadal women or men may
be treated with dopamine agonists to lower prolactin and prevent osteoporosis, or if this is not tolerated
and/or fertility is not desired, estrogen in women or testosterone in men may be used instead to prevent
osteoporosis. No RCTs have compared the efficacy of these treatments on bone. Microadenomas rarely
grow and there is no evidence that growth is stimulated by exogenous estrogen or pregnancy. When preg-
nancy is confirmed in a patient with a microadenoma, dopamine agonists may be discontinued.
FIGURE 7.21 MRI of the sella showing a prolactinoma. (From Schlechte JA. Clinical practice: Prolactinoma.
N Engl J Med 2003;349(21):2035–2041.)
Medical Therapy
Cabergoline, a second-generation dopamine agonist, is considered a first-line treatment, with better effi-
cacy and tolerability and longer half-life than bromocriptine. It is taken once or twice a week and lowers
prolactin levels to normal in 90% of those treated, usually within several weeks, while shrinkage of pitu-
itary adenomas may take several weeks or months, particularly in large tumors. Visual field defects from
macroadenomas may resolve promptly. The clinical consequences of hyperprolactinemia in both males
and females resolve. In responsive patients with normal prolactin and no evidence of tumor on MRI, treat-
ment may be continued for 2 years, before a trial of medication discontinuation may be instituted. About
20% will remain normoprolactinemic, while the rest will relapse and require reinstitution of therapy.
Side effects may include nausea and orthostatic hypotension, generally occurring just at the initiation
of treatment. Although much higher doses used for the treatment of Parkinson’s disease have been asso-
ciated with valvular heart disease, there is only a questionable increase in mild asymptomatic tricuspid
regurgitation in doses used in patients treated for hyperprolactinemia compared with the general popula-
tion, leading to different guidelines for echocardiogram evaluation in the USA and Europe.
Treatment should be considered for all prolactin-secreting macroadenomas, because of mass effects,
especially optic chiasm pressure, loss of other anterior pituitary hormones, and potential for further
growth, including during pregnancy. Cabergoline is theoretically safe during pregnancy but has not been
approved, so many authorities advise switching to bromocriptine for large tumors where medication is
indicated throughout pregnancy. Prolactin levels will normally rise during pregnancy, thus there is no
need to measure them. Tumor growth is assessed by clinical exam including visual fields. Routine MRIs
are not recommended during pregnancy, but if headache or visual impairment occurs, may be required.
Occasionally, pituitary surgery during pregnancy is required. There is controversy regarding the benefit
of prepregnancy surgery for macroadenomas (165).
Previous concerns regarding the risk of cardiac valvular disease have been addressed by long-
term studies with active echocardiogram surveillance, which has found no evidence of risk, unlike in
Parkinson’s disease treated with 3 mg/day cabergoline versus 0.5 mg one to two times a week for prolac-
tinomas. In some dopamine agonist-resistant tumors, very large doses, e.g., up to 24 mg/week, have been
tried with some success; here echocardiogram surveillance is advised.
After 2 years of successful treatment with normal prolactin and tumor shrinkage, a trial of medica-
tion withdrawal may be undertaken. Recurrence rates of 26% to 69% have been reported. If recurrence
occurs, it is generally within 1 year, in larger tumors with higher pretreatment prolactin levels. Often
there is no increase in tumor size but an elevation of prolactin and hypogonadism requiring resumption
of therapy (166, 167).
Dopamine-Resistant Tumors
Dopamine-resistant tumors are defined as a failure to normalize prolactin with maximally tolerated
doses, a failure to decrease macroprolactinoma tumor size by 50% (with other guidelines suggesting
30%), while others emphasize a reduction in the height of the tumor (i.e., the risk of chiasmatic pressure),
and failure to achieve fertility, absent other causes. Failures occur in 10% of patients with microadenomas
and 18% of macroprolactinomas that do not achieve normal prolactin with conventional doses of caber-
goline. Resistant tumors are more common in men. The expression of estrogen receptor α is lower in men
than in women, and is closely correlated to aggressiveness, in larger and or invasive tumors, and in pro-
lactinomas associated with MEN 1 and AIRP syndromes. Bromocriptine has a failure rate of about 25%,
while cabergoline fails in only about 10%. Some particularly aggressive tumors continue to grow and
invade surrounding structures, with particular concern for the optic chiasm and cavernous sinuses. Even
though these aggressive tumors may cause significant local effects, the definition of pituitary carcinoma
is reserved for those with cerebrospinal fluid/systemic metastases and amounts to fewer than 100 cases in
the world literature (168).
Histologic features that may be associated with more aggressive behavior include tumor invasiveness
presence of more mitoses, Ki-67 index, p53 expression and apoptosis, and the density of somatostatin
receptors (169).
The mechanism(s) of drug resistance are incompletely understood. Some tumors have a reduced num-
ber of D2 receptors, although apparently with normal binding affinity. No mutations in dopamine recep-
tors have been found. It is postulated that defects downstream affect the regulation of tumor growth and
secretion and thus may determine the response to dopamine agonists. Other factors, such as the expres-
sion of growth factors (vascular endothelial growth factor [VEGF] and epidermal growth factor [EGF]);
the genes regulating invasion, differentiation, and proliferation; adhesion molecules (E-cadherin); matrix
metalloproteinase 9; and chromosome abnormalities (chromosomes 11, 19, and 1) have also been corre-
lated with aggressiveness (170).
Epigenetic studies have revealed high levels of methylation in invasive and large pituitary tumors.
DNA methyltransferase overexpression has been detected in pituitary tumors, especially in macroadeno-
mas. Methylation differences at CpG sites in promoter regions may distinguish several types of tumors
from normal pituitary tissue. Histone modifications have been linked to increased p53 expression and
longer progression-free survival in pituitary tumors. Upregulation in citrullinating enzymes may be an
early pathogenic marker of prolactinomas. Numerous genes involved with cell growth and signaling show
altered methylation status for pituitary tumors, including cell cycle regulators, components of signal trans-
duction pathways, apoptotic regulators, and pituitary developmental signals (171).
After initial surgery and radiotherapy, watchful waiting on maximum-tolerated cabergoline may be
reasonable as long as there is no threat to vision or other symptoms. Some authorities use up to 24 mg/
week, while being mindful of cardiac valvular risk. If vital structures are jeopardized, repeat surgery is
often attempted, with the surgical approach determined by the location and anatomy of the tumors.
Surgery
Surgical treatment is reserved for symptomatic patients; resistant to or intolerant of cabergoline; have
macroadenomas but desire subsequent pregnancy; or, rarely, have a cerebrospinal fluid leak or apoplexy.
Although microadenomas rarely grow during pregnancy, up to 35% of macroadenomas grow with ana-
tomically, clinically significant effects. Tumor growth during pregnancy may be less likely with medical
pretreatment for more than 1 year.
Various transsphenoidal approaches have been used for either initial or repeat surgery. A transcranial
approach may be necessary in some cases with threatening superior extension. Success rates are measured
by normalization of prolactin, tumor elimination (or debunking), and, in some guidelines, restoration of
fertility. Adverse effects of surgery include diabetes insipidus, loss of other anterior pituitary hormones
(especially with extensive surgery required for macroadenomas), and, less likely, damage to surrounding
tissue, especially the cavernous sinus.
Successful surgery is best predicted by the experience of the neurosurgeon, moderately increased
serum prolactin levels (<200 ng/mL), tumor size, and invasiveness. In a literature review involving more
than 50 series, initial surgical remission, defined as the normalization of prolactin levels, occurred on
average in 74.7% and 34% of patients with microprolactinomas and macroprolactinomas with a recur-
rence rate of 18% and 23%, respectively. Another report of surgical results from 13 published series,
including at least 100 patients, has shown the control of prolactin levels to be achieved in approximately
73% of 1,211 microprolactinomas and 38% of 1,480 macroprolactinomas (165, 167)
Radiation
Radiation as the primary therapy is effective in reducing prolactin in only 30% of patients, with a very
long lag period often decades. As an adjunct to medical and surgical therapy, radiation may be added to
dopamine-resistant tumors and malignant prolactinomas. Radiation modalities may include conventional
external beam radiation, stereotactic methods, and gamma knife, with the latter being preferred because
of its more focused beam. Risks of radiotherapy include hypopituitarism: More than 50% of patients
receiving pituitary radiotherapy will develop at least one anterior pituitary hormone deficiency within the
following decade. Although very rare, cerebrovascular accidents, second brain tumors, and optic nerve
injuries have been reported with conventional radiotherapy, the frequency of all increasing over time.
Very rarely, encephalomalacia of surrounding tissues has been reported. Because of the narrower focus of
gamma knife, the incidence of cerebrovascular accidents and encephalomalacia seems to be less, but the
slow onset of action and eventual hypopituitarism are likely the same (172).
Alternative/Investigational Drugs
In patients who have failed conventional medical, surgical, and radiation therapy, alternative medical ther-
apy may be added. Somatostatin analogues have been used. All somatostatin receptor (SSTR) types are
present in prolactinomas; SSTR5 was particularly frequent. Trials using octreotide along with cabergoline
have not normalized prolactin, but in a few cases have resulted in an 80% reduction and 90% reduction
in tumor volume. Pasireotide, a second-generation somatostatin receptor antagonist, has a greater affinity
for SSTR5 and shows promise in vitro. Very few patients have been reported, but with normalization of
prolactin and either tumor shrinkage or stabilization (173, 174).
Temozolomide has been used with moderate success in 23 prolactinomas and 19 carcinomas resistant
to all other therapy. Shrinkage was reported in 76% of patients. Reduced prolactin levels were observed
in 75% of patients, while normalization of prolactin was reported in 8%. Temozolomide failure occurred
in 20.6% of cases. Most patients exhibited no serious adverse effects (175).
Oral lapatinib, an ErbB1-epidermal growth factor receptor (EGFR)/ErbB2 or human EGFR2 (HER2)
tyrosine kinase inhibitor, was tested for 6 months in four aggressive prolactinomas. None achieved the
primary endpoint of a 40% reduction in any tumor dimension and normalization of prolactin. Three had
stable disease. EGFR/HER2 expression did not correlate with treatment response. Lapatinib was well
tolerated and might be an option for otherwise resistant tumors, but more study is necessary (176).
Guidelines
Endocrine guidelines for prolactinoma were published in 2006, 2011, and 2015. Their recommendations
are incorporated in the preceding text. The most recently published guideline in 2020 of the European
Society of Endocrinology emphasizes the need for histopathologic analysis, including evaluation of Ki-67
for proliferative activity and p53 and mitotic count if Ki-67 is greater than 3% (178). This guideline
FIGURE 7.22 Invasive pituitary adenoma. (From Chuang CC, et al. Different volumetric measurement
methods for pituitary adenomas and their crucial clinical significance. Sci Rep 2017;7:40792. doi: 10.1038/
srep40792.)
focuses on aggressive tumors and recommends radiotherapy if tumors grow despite surgery and as adju-
vant therapy in tumor postsurgical remnants with ominous markers. Temozolomide is recommended as
chemotherapy for aggressive tumors and pituitary carcinomas with documented growth, often in combi-
nation with radiotherapy.
REFERENCES
1. Lynch KE, et al. Assessment of anovulation in eumenorrheic women: Comparison of ovulation detection algo-
rithms. Fertil Steril 2014;102(2):511–518.
2. Cobin RH, Goodman NF, Jain S, Chapter 5, in Reproductive disorders in evidence based endocrinology,
Camacho, P. et al. ed., 4th edition, pp. 166–265, Wolters Kluwer, Philadelphia, 2020, by permission of author.
3. Dunlop C, Anderson R. The regulation and assessment of follicular growth. Scand J Clin Lab Investig
2014;74(suppl 244):13–17.
4. Russell D, Robker R. Molecular mechanisms of ovulation: Co-ordination through the cumulus complex. Hum
Reprod Update 2007;13(3):289–312.
5. Harrington J, Palmert M. Clinical review: Distinguishing constitutional delay of growth and puberty from
isolated hypogonadotropic hypogonadism: Critical appraisal of available diagnostic tests. J Clin Endocrinol
Metab 2012;97(9):3056–3067.
6. Lee KH, et al. Imperforate hymen: A comprehensive systematic review. J Clin Med 2019;8(1):56. Published
2019 Jan 7. doi:10.3390/jcm8010056.
7. Stone SM, Alexander JL. Images in clinical medicine. Imperforate hymen with hematocolpometra. N Engl J
Med 2004;351(7):e6.
8. Robbins J, Broadwell C, Chow LC, Parry JP, Sadowski EA. Müllerian duct anomalies: Embryological develop-
ment, classification, and MRI assessment. J Magn Reson Imaging 2014;41(1):1–12.
9. Biason-Lauber A, Konrad D, Navratil F, Schoenle EJ. A WNT4 mutation associated with Müllerian-duct
regression and virilization in a 46,XX woman. N Engl J Med 2004;351(8):792–798.
10. Goldacre M, Seminog O. Turner syndrome and autoimmune diseases: Record-linkage study. Arch Dis Child
2013;99(1):71–73.
11. Turner’s syndrome with neck webbing and shield chest. (Courtesy of Dr. Donald Gordon.) from ref 2.
12. Levitsky L, Luria AH, Hayes FJ, Lin AE. Turner syndrome: Update on biology and management across the life
span. Curr Opin Endocrinol Diabetes Obes 2015;22(1):65–72.
13. Silberbach M, et al. Cardiovascular health in turner syndrome: A scientific statement from the American Heart
Association. Circ Genom Precis Med 2018;11(10):e000048.
14. Dabrowski E, et al. Turner syndrome with Y chromosome: Spontaneous thelarche, menarche, and risk of
malignancy. J Pediatr Adolesc Gynecol 2020 February;33(1):10–14. doi: 10.1016/j.jpag.2019.08.011. Epub 2019
Aug 26. PMID: 31465855; PMCID.
15. Reiter E, Blethen SL, Baptista J, Price L. Early initiation of growth hormone treatment allows age-appropria-
teestrogen use in Turner’s syndrome. J Clin Endocrinol Metab 2001;86(5):1936–1941.
16. Hogler, et al. Importance of estrogen on bone health in Turner syndrome: A cross-sectional and longitudinal
stud using dual-energy Xray absorptiometry. J Clin Endocrinol Metab 2004;89(1):193–199.
17. Bakalov V, et al. Bone mineral density and fractures in Turner syndrome. Am J Med 2003;115(4):259–264.
18. Cabanes L, et al. Turner syndrome and pregnancy: Clinical practice. Recommendations for the manage-
ment of patients with Turner syndrome before and during pregnancy. Eur J Obstet Gynecol Reprod Biol
2010;152(1):18–24.
19. Marrakchi A, Belhaj L, Boussouf H, Chraibi A, Kadiri A. Pure gonadal dysgenesis XX and XY: Observations
in fifteen patients. Ann Endocrinol (Paris) 2005;66(6):553–556.
20. Weinberg-Shukron A, et al. A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesis. J Clin
Invest 2015;125(11):4295–4304.
21. Weinberg-Shukron A, et al. Essential role of BRCA2 in ovarian development and function. N Engl J Med
2018;379(11):1042–1049.
22. Gulía C, et al. Androgen insensitivity syndrome. Eur Rev Med Pharmacol Sci 2018;22(12):3873–3388.
23. Chauhan P, Rani A, Singh SK, Rai AK. Complete androgen insensitivity syndrome due to mutations in the
DNA-binding domain of the human androgen receptor gene. Sex Dev 2018;12(6):269–274.
24. Hornig N, et al. Epigenetic repression of androgen receptor transcription in mutation-negative androgen insen-
sitivity syndrome (AIS Type II). J Clin Endocrinol Metab 2018;103(12):4617–4627.
25. Nezzo M, De Visschere P, T'Sjoen G, Weyers S, Villeirs G. Role of imaging in the diagnosis and management
of complete androgen insensitivity syndrome in adults. Case Rep Radiol 2013:Article ID 158484, 6 pages,
2013. doi: 10.1155/2013/158484.
26. Isfort A. 5 alpha reductase deficiency, 2021. Medscape https://emedicine.medscape.com /article/924291
-overview.
27. UPtoDate: https://www-uptodate-com.eresources.mssm.edu/contents/steroid-5-alpha-reductase-2-deficiency
?search=5%20alpha%20reductase%20deficiency&source = search _ result&selectedTitle =1~12&usage_type
=default&display_ rank=1#H693108660.
28. Kumar G, Barboza-Meca JJ. 5 alpha reductase deficiency. [Updated 2022 October 17]. In: StatPearls [Internet],
Treasure Island (FL): StatPearls Publishing; 2023 Jan. https://www.ncbi.nlm.nih.gov/ books/ NBK539904/.
29. Kang HJ et al. The first successful paternity through in vitro fertilization-intracytoplasmic sperm injection
with a man homozygous for the 5a-reductase-2 gene mutation. Fertil Steril 2011 May;95(6):2125:e5–e8.
30. Imperato-McGinley J, Gautier T, Peterson RE, Shackleton C. The prevalence of 5 alpha reductase deficiency
in children with ambiguous genitalia in the Dominican republic. J Urol 1986;136(4):867–873.
31. Cheng J, et al. Phenotype and molecular characteristics in 45 Chinese children with 5α-reductase type 2 defi-
ciency from South China. Clin Endocrinol (Oxf) 2015;83(4):518–526.
32. https://www.ncbi.nlm.nih.gov/ books/ NBK1334/table/kms.T.syndromes_associated_with_ hypogona/.
33. Smikle C, Yarrarapu SNS, Khetarpal S, Stat Pearls, Internet, 2023 https://www.ncbi.nlm.nih.gov/ books/
NBK448088/.
34. Chon JC, Umair Z, Yoon MS. Premature ovarian insufficiency: Past, present, and future. Front Cell Dev Biol
10 May 2021, Sec. Molecular and Cellular Reproduction , Volume 9 - 2021.
35. Silva C, et al. Autoimmune primary ovarian insufficiency. Autoimmun Rev 2014;13(4–5):427–430.
36. Hoyos L, Thakur M. Fragile X premutation in women: Recognizing the health challenges beyond primary
ovarian insufficiency. J Assist Reprod Genet 2016;34(3):315–323.
37. Fourman, LT, Fazeli PK. Neuroendocrine causes of amenorrhea—An update. J Clin Endocrinol Metab
2015;100(3):812–824.
38. Shufelt CL, Torbati T, Dutra E. Hypothalamic amenorrhea and the long-term health consequences. Semin
Reprod Med 2017 May;35(3):256–262.
39. Misra M, et al. Physiologic estrogen replacement increases bone density in adolescent girls with anorexia ner-
vosa. J Bone Miner Res 2011;26(10):2430–2438.
40. Fazeli P, Klibanski A. Effects of anorexia nervosa on bone metabolism. Endocr Rev 2018;39(6):895–910.
41. Goodman N, et al. Futterweit, W, American Association of Clinical Endocrinologists (AACE); American
College of Endocrinology (ACE); androgen Excess and PCOS Society (AES): Disease state Clinical Review:
Guide to the Best Practices in the Evaluation and Treatment of polycystic ovary syndrome, Part 1. Endocr
Pract 2015 November;21(11):1291–1300.
42. Goodman N, et al. Futterweit, W, American Association of Clinical Endocrinologists (AACE); American
College of Endocrinology (ACE); androgen Excess and PCOS Society (AES): Disease state Clinical Review:
Guide to the Best Practices in the Evaluation and Treatment of polycystic ovary syndrome, Part 2. Endocr
Pract 2015 December;21(12):1415–1426.
43. Tay C, et al. Updated adolescent diagnostic criteria forpolycystic ovary syndrome: Impact onprevalence and
longitudinal body mass index trajectories from birth to adulthood. BMC Med 2020;18(1):389.
44. Murphy M, Hall E, Adams M. Polycystic ovarian morphology in normal women does not predict the develop-
ment of polycystic ovary syndrome. J Clin Endocirnol Metab 2006;91(10):3878–3884.
45. Dapas M. et al. Family-based quantitative trait meta-analysis implicates rare noncoding variants in DENND1A
in polycystic ovary syndrome. J Clin Endocrinol Metab 2019;104(9):3835.
46. Gorsic l, Dapas M, Legro R, Hayes MG, Urbanek M. Functional genetic variation in the anti-Müllerian hor-
mone pathway in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2019;104(7):2855.
47. Cimino I, et al. Novel role for anti-Müllerian hormone in the regulation of GnRH neuron excitability and hor-
mone secretion. Nat Commun 2016;7:10055.
48. Barbotin AL, Peigné M, Malone SA, Giacobini P. Emerging roles of anti-Müllerian hormone in hypothalamic-
pituitary function. Neuroendocrinology 2019;109(3):218–229.
49. Silva MSB, Giacobini P. New insights into anti-Müllerian hormone role in the hypothalamic-pituitary-gonadal
axis and neuroendocrine development. Cell Mol Life Sci 2021 January;78(1):1–16.
50. Qu X, Donnelly R. Sex hormone-binding globulin (SHBG) as an early biomarker and therapeutic target in
polycystic ovary syndrome. Int J Mol Sci 2020 November 1;21(21):8191.
51. Li Y, et al. Association between human SHBG gene polymorphisms and risk of PCOS: A meta-analysis.
Reprod Biomed Online 2021 January;42(1):227–236.
52. Yilmaz B, Vellanki P, Ata B, Yildiz BO. Metabolic syndrome, hypertension, and hyperlipidemia in mothers,
fathers, sisters, and brothers of women with polycystic ovary syndrome: A systematic review and meta-analy-
sis. Fertil Steril 2018;109(2):356.e32–364.e32.
53. Yilmaz B, Vellanki P, Ata B, Yildiz BO. Diabetes mellitus and insulin resistance in mothers, fathers, sisters,
and brothers of women with polycystic ovary syndrome: A systematic review and meta-analysis. Fertil Steril
2018;110(3):523.e14–533.e14.
54. Torchen L, et al. Increased antiMüllerian hormone levels and other reproductive endocrine changes in adult
male relatives of women with polycystic ovary syndrome. Fertil Steril 2016;106(1):50–55.
55. Liu D, et al. Evidence for gonadotrophin secretory and steroidogenic abnormalities in brothers of women with
polycystic ovary syndrome. Hum Reprod 2014;29(12):2764–2772.
56. Dapas M, et al. Distinct subtypes of polycystic ovary syndrome with novel genetic associations: An unsuper-
vised, phenotypic clustering analysis. PLOS Med 2020;17(6):e1003132.
57. Kurman RJ, Ellenson LH, Ronnett BM, Blaustein's Pathology of the Female Genital Tract, Springer. doi:
10.1007/978-3-319-46334-6.
58. Giménez-Peralta I, Lilue M, Mendoza N, Tesarik J, Mazheika M. Application of a new ultrasound criterion
for the diagnosis of polycystic ovary syndrome. Front Endocrinol 02 September 2022, Sec. Developmental
Endocrinology.
59. Cobin RH, Fenichel R, Chapter 6, in A Color Handbook, Clinical Endocrinology and Metabolism, Canacho,
P. ed., p. 151, Manson Publishing Ltd, London, 2011.
60. Gorsic L, et al. Pathogenic anti-Müllerian hormone variants in polycystic ovary syndrome. J Clin Endocrinol
Metab 2017;102(8):2862–2872.
61. Graham R, Grahame H, Ewan R, Pearson E, The mechanisms of action of metformin. Diabetologia
2017;60(9):1577–1585.
62. Marinkovic-Radosevic J, Berkovic, Cigrovski,Kruez ME, Mrzljak A. Exploring new treatment options for
polycystic ovary syndrome: Review of a novel antidiabetic agent SGLT2 inhibitor. World J Diabetes 2021 July
15;12(7):932–938.
63. Siamashvili M , Davis S. Update on the effects of GLP-1 receptor agonists for the treatment of polycystic ovary
syndrome. Expert Rev Clin Pharmacol 2021;14(9):1081–1089.
64. Kakoly N, et al. Ethnicity, obesity and the prevalence of impaired glucose tolerance and type 2 diabetes in
PCOS: A systematic review and meta-regression. Hum Reprod Update 2018;24(4):455–467.
65. Pelanis R, et al. The prevalence of Type 2 diabetes is not increased in normal-weight women with PCOS. Hum
Reprod 2017;32(11):2279–2286.
66. Kiconco S, Teede, Earnest A et al. Menstrual cycle regularity as a predictor for heart disease and diabetes:
Findings from a large population-based longitudinal cohort. Clin Endocrinol (Oxf) 2021, November 24. doi:
10.1111/cen.14640. Online ahead of print.
67. Solomon CG. et al. Menstrual cycle irregularity and risk for future cardiovascular disease. J Clin Endocrinol
Metab 2002 May;87(5):2013–2017.
68. de Groot P, Dekkers OM, Romijn JA, Dieben SW, Helmerhorst FM. PCOS, coronary heart disease, stroke and
the influence of obesity: A systematic review and meta-analysis. Hum Reprod Update 2011;17(4):495–500.
69. Anderson S, Barry JA, Hardiman PJ. Risk of coronary heart disease and risk of stroke in women with polycys-
tic ovary syndrome: A systematic review and meta-analysis. Int J Cardiol 2014;176(2):486–487.
70. Zhao L. et al. Polycystic ovary syndrome (PCOS) and the risk of coronary heart disease (CHD): A meta-
analysis. Oncotarget 2016;7(23):33715–22721.
71. Zhou Y. et al. Association between polycystic ovary syndrome and the risk of stroke and all-cause mortality:
Insights from a meta-analysis. Gynecol Endocrinol 2017;33(12):904–910.
72. Kiconco S, et al. Natural history of polycystic ovary syndrome: A systematic review of cardiometabolic out-
comes from longitudinal cohort studies. Clin Endocrinol (Oxf) 2021 December 11. doi: 10.1111/cen.14647.
Online ahead of print.
73. Azziz R, et al. The androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: The com-
plete task force report. Fertil Steril 2009;91(2):456–488.
74. Dewailly D, et al. Definition and significance of polycystic ovarian morphology: A task force report from the
Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update 2014;20(3):334–352.
75. Dumesic D, et al. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and Molecular
Genetics of polycystic ovary Syndrome. Endocr Rev 2015;36(5):487–525.
76. ACOG Committee on Practice Bulletins, with Richard S, Legro MD, ACOG Practice Bulletin. Obstet Gynecol
2018, 131(6):e157–e171.
PEDIATRIC ENDOCRINE SOCIETY

77. Ibáñez L, et al. An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic
Ovarian Syndrome in Adolescence, lInternational Consortium of Paediatric Endocrinology (ICPE). Horm Res
Paediatr 2017;88(6):1–25.
78. Williams T, Mortada M, Porter S. Diagnosis and treatment of polycystic ovary syndrome. Am Fam Physician
2016;94(2):106–113.
79. Teede H, Misso M, Costello M et al., on behalf of the International PCOS Network. International evidence-
based guideline for the assessment and management of polycystic ovary syndrome, Monash University,
Melbourne Australia, 2018. monash.edu/medicine/sphpm/mchri/pcos.
80. International evidence based guidelines for assessment and management of polyystic ovarian syndrome. Clin
Endocrinol (Oxf) 2018 September;89(3):251–268. doi: 10.1111/cen.13795. Epub 2018 Jul 19.
81. Kiconco S, Teede, HJH, Azziz R, Joham AE. The need to reassess the diagnosis of polycystic ovary syndrome
(PCOS): A review of diagnostic recommendations from the international evidence-based guideline for the
assessment and management of PCOS. Semin Reprod Med 2021 July;39(3–04):71–77.
82. Al Wattar B et al. Clinical practice guidelines on the diagnosis and management of polycystic ovary syndrome:
A systematic review and quality assessment study. J Clin Endocrinol Metab 2021;106(8):2436–2446.
83. Li H, Zhang Y, Lu L, Yi W. Reporting quality of polycystic ovary syndrome practice guidelines based on the
RIGHT checklist. Medicine 2020;99(42):(e22624).
84. Kiconco S, et al. PCOS phenotype in unselected populations study (P-PUP): Protocol for a systematic review
and defining PCOS diagnostic features with pooled individual participant data. Diagnostics (Basel) 2021
October 21;11(11):1953.
85. Muka T, et al. Age at natural menopause and risk of type 2 diabetes: A prospective cohort study. Diabetologia
2017;60(10):1951–1960.
86. Ley S, et al. Duration of reproductive life span, age at menarche, and age at menopause are associated with risk
of cardiovascular disease in women. J Am Heart Assoc 2017;6(11).
87. Kuh D, Cooper R, Moore A, Richards M, Hardy R. Age at menopause and lifetime cognition: Findings from a
British birth cohort study. Neurology 2018;90(19):e1673–e1681.
88. Svejme O, Ahlborg HG, Nilsson JÅ, Karlsson MK. Early menopause and risk of osteoporosis, fracture and
mortality: A 34-year prospective observational study in 390 women. BJOG 2012;119(7):810–818.
89. Cobin R, Goodman N. American Association of Clinical Endocrinologists and American College of
Endocrinology position statement on menopause–2017 update. Endocr Pract 2017;23(7):869–880.
90. https://www.fda.gov/consumers/free-publications-women /menopause-medicines-help-you.
91. Galson S. PharmacyCompounding/CompoundingofBio-identicalHormoneReplacement therapies. Testimony
before the senate special committee on aging, 2017. https://wayback.archive-it.org/7993/20170723044115/
https://www. fda.gov/ NewsEvents/ Testimony/ucm154031.htm.
92. https://www.accessdata.fda.gov/drugsatfda_docs/ label/2021/210132s006lbl.pdf.
93. Preventive Services Task Force recommendation statement: Hormone therapy for the primary prevention of
chronic conditions in postmenopausal persons. JAMA 2022;328(17):1740–1746.
94. Henderson VW, Lobo RA. Hormone therapy and the risk of stroke: Perspectives 10 years after the Women's
Health Initiative trials. Climacteric 2012 June;15(3):229–234.
95. Canonico M, et al. Postmenopausal hormone therapy and risk of stroke: Impact of the Route of Estrogen
Administration and Type of Progestogen. Stroke 2016;47(7):1734–1741.
96. Carrasquilla G, et al. Postmenopausal hormone therapy and risk of stroke: A pooled analysis of data from
population-based cohort studies. PLOS Med 2017;14(11):e1002445.
97. Løkkegaard E, Nielsen LH, Keiding N. Risk of stroke with various types of menopausal hormone therapies: A
national cohort study. Stroke 2017;48(8):2266–2269.
98. Manson J, et al. Menopausal hormone therapy and long-term all-cause and cause- specific mortality. JAMA
2017;318(10):927–938.
99. Asi N, et al. Progesterone vs. synthetic progestins and the risk of breast cancer: A systematic review and meta-
analysis. Syst Rev 2016;5(1):121.
100. Stute P, Wildt L, Neulen J. The impact of micronized progesterone on breast cancer risk: A systematic review.
Climacteric 2018;21(2):111–122.
101. Bakken K et al. Menopausal hormone therapy and breast cancer risk: Impact of different treatments. The
European prospective investigation into cancer and nutrition. Int J Cancer 2010;128(1):144–156.
102. Brusselaers N, et al. Different menopausal hormone regimens and risk of breast can− cer. Ann Oncol
2018;29(8):1771–1776.
103. Savolainen-Peltonen H, et al. Use of postmenopausal hormone therapy and risk of Alzheimer’s disease in
Finland: Nationwide case-control study. BMJ 2019;364:l665.
104. Coughlan GT, et al. Association of age at menopause and hormone therapy use with tau and β-amyloid positron
emission tomography. JAMA Neurol. Published online April 3, 2023. doi: 10.1001/jamaneurol.2023.0455.
105. Saleh R, Hornberger M, Ritchie CW, Minihane AM. Hormone replacement therapy is associated with
improved cognition and larger brain volumes in at-risk APOE4 women: Results from the European Prevention
of Alzheimer’s Disease (EPAD) cohort. Alzheimers Res Ther 2023;15(1):10. doi: 10.1186/s13195-022-01121-.
106. Stuenkel C. Menopause, hormone therapy and diabetes. Climacteric 2017;20(1):11–21.
107. Grossman D, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal
women: US Preventive Services Task Force Recommendation Statement. JAMA 2017;318(22):2224.
108. Grodstein F, et al. Hormone therapy and coronary heart disease: The role of time since menopause and age at
hormone initiation. Obstet Gynecol Surv 2006;61(6):392–394.
109. Manson J, et al. Menopausal hormone therapy and health outcomes during the intervention and extended post-
stopping phases of the women’s health initiative randomized trials. JAMA 2013;310(13):1353–1368.
110. Manson JE, et al. Anderson GL; WHI investigators. Menopausal hormone therapy and long-term all-cause
and cause-specific mortality: The Women's Health Initiative randomized trials. JAMA 2017 September
12;318(10):927–938.
111. Wild R, et al. Coronary heart disease events in the Women’s Health Initiative hormone trials. Menopause
2012;20(3):254–260.
112. Shufelt C, et al. Hormone therapy dose, formulation, route of delivery, and risk of cardiovascular events in
women. Menopause 2014;21(3):260–266.
113. Poornima I, et al. Coronary artery calcification (CAC) and post-trial cardiovascular events and mortality
within the Women’s Health Initiative (WHI) estrogen-alone trial. J Am Heart Assoc 2017;6(11).
114. Miller V, Hodis HN, Lahr BD, Bailey KR, Jayachandran M. Changes in carotid artery intima-media thickness
3 years after cessation of menopausal hormone therapy. Menopause 2019;26(1):24–31.
115. Shams T, et al. SSRIs for hot flashes: A systematic review and meta-analysis of randomized trials. J Gen
Intern Med 2013;29(1):204–213.
116. Binkhorst L, et al. Unjustified prescribing of CYP2D6 inhibiting SSRIs in women treated with tamoxifen.
Breast Cancer Res Treat 2013;139(3):923–929.
117. Pinkerton J, et al. Phase 3 randomized controlled study of gastroretentive gabapentin for the treatment of
moderate-to-severe hot flashes in menopause. Menopause 2014;21(6):567–573.
118. LiL, et al. Comparative efficacy of nonhormonal drugs on menopausal hot flashes. Eur J Clin Pharmacol
2016;72(9):1051–1058.
119. Hervik J, Stub T. Adverse effects of non-hormonal pharmacological interventions in breast cancer survivors, suf-
fering from hot flashes: A systematic review and meta- analysis. Breast Cancer Res Treat 2016;160(2):223–236.
120. Sharifi M, Lewiecki E. Conjugated estrogens combined with Bazedoxifene: The first approved tissue selective
estrogen complex therapy. Exp Rev Clin Pharmacol 2014;7(3):281–291.
121. Lederman S, Ottery F, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated
with menopause (SKYLIGHT 1): A phase 3 randomized controlled study. Lancet 2023;401(10382):1091–1102.
122. Johnson KA, Martin N, Nappi RE, Neal-Perry G, Shapiro M, Stute P, Thurston RC, Wolfman W, English M,
Franklin C, Lee M, Santoro N. Efficacy and safety of fezolinetant in moderate to severe vasomotor symptoms
associated with menopause: A Phase 3 RCT. J Clin Endocrinol Metab 2023;108(8):1981–1997.
123. Johnson KA, Martin N, Nappi RE, Neal-Perry G, Shapiro M, Stute P, Thurston RC, Wolfman W, English M,
Franklin C, Lee M, Santoro N. Efficacy and safety of fezolinetant in moderate to severe vasomotor symptoms
associated with menopause: A phase 3 RCT. J Clin Endocrinol Metab 2023;108(8):1981–1997. doi: 10.1210/
clinem/dgad058. PMID: 36734148; PMCID: PMC10348473. https://www.astellas.com/en/system/files/news
/2023- 02/20230220_en_1.pdf.
124. Hüser S, et al. Effects of isoflavones on breast tissue and the thyroid hormone system in humans: A compre-
hensive safety evaluation. Arch Toxicol 2018;92(9):2703–2748.
125. Fritz H, et al. Black cohosh and breast cancer: A systematic review. Integr Cancer Ther 2013;13(1):12–29.
126. Leach M, Moore V. Black cohosh (Cimicifuga spp.) for menopausal symptoms. Cochrane Database Syst Rev
2012;9(9):CD007244.0004386954.INDD 259 8/27/2019 1:55:16 PM.
127. Brown A. Liver toxicity related to herbs and dietary supplements: Online table of case reports. Part 2 of 5
series. Food Chem Toxicol 2017;107(A):472–501.
128. American College of Obstetrics and Gynecology (ACOG), Practice Bulletin No. 141. Obstet Gynecol
2014;123(1):202–216.
129. North American Menopause Society (NAMS), The 2022 hormone therapy position statement of the North
American menopause society Advisory Panel. The 2022 hormone therapy position statement of The North
American Menopause Society. Menopause 2022 July 1;29(7):767–794.
130. The Endocrine Society (TES), et al. Treatment of symptoms of the menopause: An Endocrine Society clinical
practice guideline. J Clin Endocrinol Metab 2015 November;100(11):3975–4011.
131. French College of Gynecologists and Obstetricians. Trémollieres FA, et al. Management of postmenopausal
women: Collège National des Gynécologues et Obstétriciens Français (CNGOF) and Groupe d'Etude sur la
Ménopause et le Vieillissement (GEMVi) Clinical Practice Guidelines 2022 September;163:62–81.
132. Mohan S, Garima Kapoor G, Raman DK. Partial androgen insensitivity syndrome: A diagnostic and therapeu-
tic dilemma. Armed Forces India Med J 2011;67(4):382–384.
133. Hannema SE, Hughes I. A: Regulation of Wolffian duct development. Horm Res 2007;67(3):142–151.
134. https://rarediseases.info.nih.gov/diseases/5680/5-alpha-reductase-deficiency.
135. Mendiola AJP, LaSalle JM. Epigenetics in Prader-Willi syndrome. Front Genet 2021 February 15;12:624581.
136. Bochukova EG. Transcriptomics of the Prader-Willi syndrome hypothalamus. Handb Clin Neurol
2021;181:369–379.
137. https://www.ncbi.nlm.nih.gov/ books/ NBK367946/#dup15q.Genetically_Related_Disordersis.
138. Butler MG, Angulo MA, Cataletto ME. Prader-Willi syndrome: A review of clinical, genetic, and endocrine
findings. J Endocrinol Invest 1998;12(38):1249–1263. doi: 10.1007/s40618-015-0312-9.
139. Castro-Sánchez S, Álvarez-Satta M. Laurence-Moon-Biedel syndrome, generalized congenital hypothalamic
deficiency which presents with microphallus and neonatal hypoglycemia, and midline craniofacial develop-
mental defects. J Pediatr Genet 2013.
140. https://ir.rhythmtx.com /news-releases/news-release- details/rhythm-pharmaceuticals-announces-fda-accep-
tance-filing-and.
141. Mancini M, et al. Obesity is strongly associated with low testosterone and reduced penis growth during devel-
opment. J Clin Endocrinol Metab 2021;106(11):3151–3159.
142. Wong M, Levy M, Stephenson M. Hypogonadism in the HIV-infected man. Curr Treat Options Infect Dis
2017;9(1):104–116.
143. Kaplan A, Hu C, Morgentaler A. Testosterone therapy in men with prostate cancer. Eur Urol 2016
May;69(5):894–903.
144. Lenfant L et al. Testosterone replacement therapy (TRT) and prostate cancer: An updated systematic review
with a focus on previous or active localized prostate cancer. Urol Oncol 2020 August;38(8):661–670.
145. Araujo A, Wittert G. Endocrinology of the aging male. Best Pract Res Clin Endocrinol. Metab.
2011;25(2):303–319.
146. Liu Z et al. Dynamic alteration of serum testosterone with aging: A cross-sectional study from Shanghai,
China. Reprod Biol Endocrinol 2015;13:111. doi: 10.1186/s12958-015-0107-z.
147. Travison, TG. et al. Harmonized reference ranges for circulating testosterone levels in men of four cohort stud-
ies in the United States and Europe. J Clin Endocrinol Metab 2017 April 1;102(4):1161–1173.
148. Snyder P, et al. Effects of testosterone treatment in older men. N Engl J Med 2016;374(7):611–624.
149. Snyder PJ, et al. Effect of testosterone treatment on volumetric bone density and strength in older men with low
testosterone: A controlled clinical trial. JAMA Intern Med 2017;177(4):471–479.
150. Snyder PJ, et al. Lessons from the testosterone trials. Endocr Rev 2018;39(3):369–386.
151. Araujo AB, Wittert GA. Endocrinology of the aging male. Best Pract Res Clin Endocrinol Metab
2011;25(2):303–319.
152. Barnouin Y. Testosterone replacement added to intensive lifestyle intervention in older men with obesity and
Hypogonadis. Jclinendometab 2021 March;106(3):e1096–e1110.
153. Practice Update. ADA, 2020: Testosterone plus lifestyle program reduced risk of type 2 diabetes in overweight
and obese men (Internet]. Amsterdam: Elsevier; c2020 [cited 2020 August 4]. https://www.practiceupdate.
Com/Content /ada-2020-testosterone-plus-lifestyle-program- Reduced -Risk-of-type-2-diabetes-in-overwei
ght-and-obese- Men/102636)}}.
154. Ponce O et al. The efficacy and adverse events of testosterone replacement therapy in hypogonadal men: A
systematic review and meta-analysis of randomized, placebo-controlled TrialsJ. J Clin Endocrinol Metab 2018
May;103(5):1745–1754.
155. Al-Sharefi, A, Quinton, R. Current national and international guidelines for the management of male hypo-
gonadism: Helping clinicians to navigate variation in diagnostic criteria and treatment recommendations.
Endocrinol Metab (Seoul) 2020 September;35(3):526–540.
156. Zucker IJ, Masterson TA. Comparison of American Urological Association and Endocrine Society guidelines
on testosterone replacement. Int J Impot Res 2021. doi: 10.1038/s41443-021-0047.
157. Gagliana-Jura, B. Testosterone Replacement therapy and cardiovascular Risk. Nat Rev Cardiol 2019
September;16:555.
158. Bhasin S et al. Testosterone therapy in men with hypogonadism: An Endocrine Society* clinical practice
guideline. J Clin Endocrinol Metab 2018;103(5):1715–1744.
159. Laurent MR et al. Sex hormone-binding globulin regulation of androgen bioactivity in vivo: Validation of the
free hormone hypothesis. Sci Rep 2016;6:35539. doi: 10.1038/srep35539.
160. Ismail A, Barth J, Review: Endocrinology of gynaecomastia. Ann Clin Biochem, 2001;38(6):596–607.
161. Post A, De Heijninga B , Actona D et al. A novel infant milk formula concept: Mimicking the human milk fat
globule structure. Colloids Surf B Biointerfaces 2015;136(1):329–339.
162. Saleem M, Martin H, Coates P. Prolactin biology and laboratory measurement: An update on physiology and
current analytical issues. Clin Biochem Rev 2018;39(1):3–16.
163. Ross, GMS, Filippini, D, Nielen, MWF, Gert IJ. Salentijn, unraveling the hook effect: A comprehen-
sive study of high antigen concentration effects in sandwich lateral flow immunoassays, Anal Chem
2020;92(23):15587–15595.
164. Schlechte JA. Clinical practice: Prolactinoma. N Engl J Med 2003;349(21):2035–2041.
165. Vilar L. et al. Controversial issues in the management of hyperprolactinemia and prolactinomas – An overview
by the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism. Arch
Endocrinol Metab 2018;62(2):236–263.
166. Casanueva F. et al. Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas.
Clin Endocrinol (Oxf) 2006;65(2):265–273.
167. Melmed S. et al. Diagnosis & treatment of hyperprolactinemia: An endocrine society clinical practice guide-
line. J Clin Endocrinol Metab 2011;96(2):273–288.
168. Maiter D. Management of dopamine agonist resistant prolactinomas. Neuroendocrinology 2019;109(1):42–50.
169. Kontogeorgos G. Predictive markers of pituitary adenoma behavior. Neuroendocrinology 2006;83(3–4):179–188.
170. Trouillas J, et al. Clinical, pathological, and molecular factors of aggressiveness in lactotroph tumours.
Neuroendocrinology 2019;109(1):70–76.
171. Hauser B, Lau A, Sacksham S, Bi WL, Dunn IF. The epigenomics of pituitary adenoma. Front Endocrinol
(Lausanne) 2019 May 14;10:290.
172. Frederic Castinetti F, et al. Long-term results of stereotactic radiosurgery in secretory pituitary adenomas. J
Clin Endocrinol Metab 2009;94(9):3400–3407.
173. Souteiro P, Karavitaki N. Dopamine agonist resistant prolactinomas: Any alternative medical treatment?
Pituitary 2020;23(1):27–37.
174. Raverot G, Vasiljevic A, Jouanneau E, Lasolle H. Confirmation of a new therapeutic option for aggres-
sive or dopamine agonist-resistant prolactin pituitary neuroendocrine tumors. Eur J Endocrinol 2019
August;181(2):C1–C3.
175. Almalki M et al. Temozolomide therapy for resistant prolactin-secreting pituitary adenomas and carcinomas:
A systematic review. Hormones (Athens) 2017;16(2):139–149.
176. Cooper O, et al. EGFR/ErbB2-targeting lapatinib therapy for aggressive prolactinoma. J Clin Endocrinol
Metab 2021;106(2):e917–e925.
177. Chuang CC. et al. Different volumetric measurement methods for pituitary adenomas and their crucial clinical
significance. Sci Rep 2017;7:40792. doi: 10.1038/srep40792.
178. Raverot G et al. The European Society of Endocrinology, European Society of Endocrinology Clinical
Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. Eur J Endocrinol
2018;178(1):G1–G24.
Lipid Disorders
Fatima Kazi and Francis Q. Almeda

8
LIPID DISORDERS
Definition/Overview
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality in industrialized
nations, and cardiac event rates remain significant despite major advances in cardiovascular care.
Abnormalities in lipid metabolism increase the risk for the development and progression of coronary
heart disease (CHD) and the diagnosis and treatment of patients with lipid disorders has been shown
to significantly reduce the risk of future adverse cardiac events. In general, the intensity of risk reduc-
tion therapy should approximate the individual’s absolute risk, and thus the accurate assessment of
the patient’s overall cardiovascular risk status is the central component for the optimal treatment of
individuals with dyslipidemia.
Dyslipidemia comprises a range of conditions, primarily defined by elevations in lipoprotein cho-
lesterol, including high-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cho-
lesterol (HDL-C), as well as elevated triglycerides. All of these conditions independently increase the
risk of ASCVD. The American Association of Endocrinology and American College of Endocrinology
(AACE/ACE) released a consensus statement in 2020 outlining risk categories and treatment goals
(Table 8.1).
The Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP)
Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment
Panel III [ATP III]) provides evidence-based recommendations for the diagnosis and management of
high cholesterol and related disorders in high-risk populations and primary prevention in patients with
multiple risk factors. Table 8.2 summarizes the definitions for elevated total cholesterol (TC), LDL, HDL,
and triglycerides (TAGs).
Etiology
Lipid disorders can be classified into primary (genetic or inherited) (see Tables 8.3 and 8.4) or sec-
ondary (due to disease or environmental factors). Severe hypercholesterolemia has been associated
with genetic abnormalities such as familial hypercholesterolemia with mutations in the LDL receptors,
DOI: 10.1201/9781003100669-8 249

TABLE 8.1 ASCVD Risk Categories and Treatment Goals

TREATMENT GOALS (Mg/dL)
RISK
CATEGORY RISK FACTORS AND 10-YEAR RISK LDL-C NON-HDL-C APOB TG
Extreme risk – Progressive ASCVD including <55 <80 <70 <150
unstable angina
– Established clinical ASCVD plus
diabetes or CKD ≥3 or
heterozygous familial
hypercholesterolemia
– History of premature ASCVD
(<55 years, male; <65 years,
female)
Very high – Established clinical ASCVD or <70 <100 <80 <150
risk recent hospitalization for ACS,
carotid or peripheral vascular
disease, or 10-year risk >20%
– Diabetes with ≥1 risk factor(s)
– CKD ≥3 with albuminuria
– Heterozygous familial
hypercholesterolemia
High risk – ≥2 risk factor and 10-year risk <100 <130 <90 <150
10%–20%
– Diabetes or CKD ≥3 with no
other risk factors
Moderate – <2 risk factors and 10-year <100 <130 <90 <150
risk risk<10 %
Low risk No risk factors <130 <160 Not recommended <150
TABLE 8.2 ATP III Lipid and Lipoprotein Classification

I. Total Cholesterol Mg/dL (Mmol/L) III. HDL Cholesterol mg/dL (mmol/L)
<200 (5.2) Desirable <40 (1.0) (males) Low
<50 (1.3) (females)
200–239 (5.2–6.2) Borderline high ≥60 (1.5) High
≥240 (6.2) High
II. LDL Cholesterol Mg/dL (Mmol/L) IV. Triglycerides (mg/dL)
<100 (2.6) Optimal <150 (1.6) Normal
100–129 (2.6–3.3) Near optimal/above 150–199 (1.6–2.1) Borderline high
optimal
130–159 (3.4–4.1) Borderline high 200–499 (2.2–5.4) High
160−189 (4.2–4.9) High ≥500 (5.5) Very high
≥190 (5.0) Very high
TABLE 8.3 Clinical History, Physical Examination, and Laboratory Evaluation of Hyperlipoproteinemias
HYPERLIPOPROTEIN MOLECULAR MAJOR DENSITY PHYSICAL

EMIA DEFECT LIPOPROTEINS CLASS CLINICAL HISTORY EXAMINATION EVALUATION
Familial LPL (lipoprotein ApoC-II deficiency Chylomicrons Occurs in approximately 1 Eruptive xanthoma Very high TAG >1500
chylomicronemia lipase) elevated in a 1,000,000 Lipemic plasma mg/dL (15 mmol/L)
syndrome deficiency TGLs, VLDL/IDL Pancreatitis Lipemia retinalis
elevated Dry eyes and mouth Hepatosplenomegaly
Numbness or tingling of the
extremities
Neuropsychiatric symptoms
(depression and memory
loss)
Familial Structural defect Elevated plasma apoB LDL elevated Occurs in 1 in 500 Tendon xanthomas (in Heterozygous FH; LDL
hypercholesterolemia or absence of Premature CAD the dorsum of the range (325–450 mg/dL
(FH) LDL receptor hands and Achilles [8.5–12 mmol/L])
tendons) Homozygous FH with
Xanthomas very high LDL
Xanthelasmas and (500–1000 mg/dL
xanthomas of the [13–26 mmol/L]);
eyes normal TAG
Arcus juvenilis
Dysbetalipoproteinemia Delayed clearance ApoE deficiency TGLs/cholesterol Premature CAD Palmar xanthomas Elevated TC
(type III of remnants of elevated Peripheral vascular disease (pathognomonic) and TAG
hyperlipoproteinemia) TAG-rich VLDL/IDL Relatively common (up to Tuberous xanthomas
lipoproteins elevated 2% of Xanthelasma
population) Premature CAD
Familial combined To be established Increased apoB-100 LDL/VLDL Premature CAD No tendon xanthomas Varying patterns of high
hyperlipidemia (FCH) elevated Common comorbidity Xanthelasma LDL with moderate
Often HDL includes diabetes, Arcus juvenilis elevations of TAG and
reduced hypertension, and obesity Eruptive xanthomas low HDL
Familial defective ApoB-100 Defective apoB-100 (the LDL elevated Premature CAD Arcus juvenilis Elevated TC
apoB-100 (FDB) mutation mutation affects the receptor- Tendon xanthomas Elevated LDL
binding domain of the protein Xanthelasma
decreasing the affinity of the
mutant apoB-100 for its
receptor to 3%–5% of normal;
the result is decreased
receptor- mediated clearance of
LDL from
the circulation)
8 • Lipid Disorders 251
resulting in impaired clearance of LDL and elevated LDL-C levels. Important secondary factors that
result in altered lipid metabolism include hypothyroidism, diabetes mellitus, renal disease, obstruc-
tive liver disease, and alcohol intake. In addition, several medications, including estrogens/progestins,
glucocorticoids, thiazides, isotretinoin, and cyclosporine, have been associated with mild to moderate
hypercholesterolemia.
Pathophysiology
The central concept of lipid transport is that plasma lipids circulate in lipoprotein particles. Lipoproteins
are large complexes that transport lipids (mainly cholesterol esters, TAGs, and fat-soluble vitamins)
between the vasculature and various body tissues. The plasma lipoproteins are divided into major classes
based on their relative densities: chylomicrons, very low-density lipoproteins (VLDLs), intermediate-
density lipoproteins (IDLs), LDLs, HDLs, and lipoprotein (a) (Lp(a)). There are ten major human plasma
apolipoproteins (Table 8.5).
Lipoprotein metabolism occurs through two basic mechanisms: the transport of dietary lipids to the
liver and peripheral tissues (exogenous pathway), and the production and delivery of hepatic lipids into the
circulation and peripheral tissues (endogenous pathway). In the exogenous pathway, dietary cholesterol
is acted upon by the intestinal cells to form cholesterol esters through the addition of fatty acids (Figure
8.1). TAGs from the diet are hydrolyzed by pancreatic lipases within the intestine and emulsified with bile
acids to form micelles. Longer-chain fatty acids are incorporated into TAGs and complexed with other
particles such as cholesterol esters and phospholipids to form chylomicrons (which have a high concentra-
tion of TAG). These particles are acted upon by lipoprotein lipase along the capillary endothelium, and
the TAGs are hydrolyzed releasing free fatty acids, most of which are taken up by adjacent adipocytes or
myocytes, and the remaining particles (chylomicron remnants) are transported to the liver.
In the endogenous pathway, VLDL is transformed into IDL and then into LDL through hepatic
metabolism (Figure 8.2). VLDL particles are similar to chylomicrons but have a higher ratio of cholesterol
to TAG and contain apolipoprotein B-100. The TAG of VLDL is hydrolyzed by lipoprotein lipase and the
particles continue to become smaller and denser and transform into IDL, which is composed of similar
amounts of cholesterol and TAG. The hepatic cells remove approximately half of VLDL remnants and
IDL. The remainder of IDL is modified by hepatic lipase to form LDL. LDL is composed of a core of pri-
marily cholesterol esters, surrounded by a surface of phospholipids, free cholesterol, and apolipoprotein
B. The majority of circulating LDL is cleared through LDL-mediated endocytosis in the liver. Modified
(oxidized) plasma LDL accumulates in the intima and is acted upon by activated macrophages (foam
cells) and through complex mechanisms involving cytokines, growth factors, smooth cell proliferation,
and inflammation, and results in atheroma formation (Figure 8.3). The process of transferring cholesterol
from peripheral cells to the liver for removal from the body by biliary secretion is called reverse choles-
terol transport. The role of HDL in enhancing reverse cholesterol transport is one of the mechanisms by
which HDL protects against the process of atherosclerosis (Figure 8.4). The major protein of HDL is apo
A-1.
TABLE 8.4 Clinical History, Physical Examination, and Laboratory Evaluation of Hypolipoproteinemias
MOLECULAR MAJOR DENSITY PHYSICAL LABORATORY

HYPOLIPOPROTEINEMIA DEFECT LIPOPROTEINS CLASS CLINICAL HISTORY EXAMINATION EVALUATION
Tangier disease ABCA1 Decreased apoA-I HDL <5 mg/dL Modest increased Orange-yellow tonsils TC1 <120 mg/dL (3.1
transporter 0.1 mmol/L) risk of premature (pathognomonic) mmol/L)
mutation CAD Corneal opacities Normal or elevated
Peripheral neuropathy TAG
Low HDL
Abetalipoproteinemia Defect in ApoB-100 deficiency Absence of cardiac Neurologic dysfunction TC <50 mg/dL (13
(autosomal recessive) assembly and ApoB-48 deficiency ALDL/IDL, LDL arrhythmias Nystagmus mmol/L)
secretion of Retinitis pigmentosa Low TAG
apoB- Progressive blindness Vitamin A and E
containing deficiency
lipoproteins Hemolytic anemia
(acanthocytes)
Familial ApoB gene ApoB-48 and Deficiency of Mild Absence of neurologic Mild deficiency of
hypobetalipoproteinemia mutation apoB-100 chylomicrons malabsorption dysfunction fat-soluble vitamins
deficiency and VLDL Progressive
degeneration
Sitosterolemia ABCG5 or Defective transporter Elevated plant Premature CAD Tendon xanthomas Elevated TC
ABCG8 (ABCG5 or ABCG8); and fish sterols Arthralgia Tuberous xanthomas Elevated plant and
mutation this transporter Arthritis at a Hypersplenism fish sterols
preferentially young age (500–600 mg/dL
transports plant and [13–15.6 mmol/L])
shellfish sterols from Hemolytic anemia
the intestine or liver
into the
gastrointestinal tract
thus preventing
absorption of the
plant and shellfish
sterols
TABLE 8.5 Major Human Plasma Apolipoproteins

APOLIPOPROTEIN MAJOR DENSITY CLASS
A-I HDL
A-II HDL
A-IV Chylomicrons, HDL
B-100 VLDL, IDL, LDL
B-48 Chylomicrons, VLDL, IDL
C-I Chylomicrons, VLDL, IDL, HDL
C-II Chylomicrons, VLDL, IDL, HDL
C-III Chylomicrons, VLDL, IDL, HDL
E Chylomicrons, VLDL,
Apo(a) Lp(a)-density LDL to HDL
FIGURE 8.1 Exogenous pathway of lipid metabolism. Free fatty acids are absorbed in the gastrointestinal
tract and combine with glycerol in the intestinal cell to form triglycerides. These triglycerides combine with a
variety of apolipoproteins including apoA, apoB-48, apoC-II, apoC-III, and apoE, the main one being apoB-48.
This combination forms a very large particle called a chylomicron to carry the dietary lipid. The enzyme lipopro-
tein lipase hydrolyzes the core and releases fatty acids. The remnant is then taken up and cleared by the liver.
FIGURE 8.2 Endogenous pathway of lipid metabolism. Nascent VLDL is synthesized by the liver. It becomes
mature VLDL after the addition of cholesterol esters and several apolipoproteins (the main ones as shown in
the diagram). At this point, lipoprotein lipase breaks down the VLDL into smaller remnants. The smaller VLDL
remnants can then proceed down one of two paths: they can be taken up and cleared by the liver, or hydro-
lyzed and released as LDL.
FIGURE 8.3 Magnified view (10×) of atheroma seen in atherosclerosis. At this level, intima, media, and
adventitia are evident. Blue areas in the media represent calcification. (Courtesy of Drs. J.H. Lim and C. Oyer.)
FIGURE 8.4 HDL metabolism. The liver produces lipid-poor apolipoprotein A-I, which removes excess cel-
lular cholesterol by interacting with ABCAI. LCAT then esterifies this more lipid-rich particle into cholesterol
esters, which can either return to the liver directly to be taken up by SRB-I (1) or they can transfer the choles-
terol to VLDL and LDL (2). LDL can then be taken up by the liver via its receptor. ABCI, ATP-binding cassette
transporter; CEPT, cholesterol ester transfer protein; HDL, high-density lipoprotein; LCAT, lecithin cholesterol
acyltransferase; LDL, low-density lipoprotein; SRB-I, scavenger receptor class B, type I; VLDL, very low-density
lipoprotein.
There are two kinds of genetic dyslipoproteinemia, which result in abnormal plasma levels of several
classes of plasma lipoproteins: hyperlipoproteinemias and hypolipoproteinemias. The clinical presenta-
tion, physical exam, differential diagnosis, and laboratory evaluation of lipoproteinemias are summarized
in Tables 8.3 and 8.4. Important clinical findings in patients with significant hypercholesterolemia include
xanthomas (Figures 8.5 and 8.6), xanthelasma (Figure 8.7), arcus juvenilis (Figure 8.8), and lipid kera-
topathy (Figure 8.9). The chylomicronemia syndrome results in very high triglyceride levels of >1500 mg/
dL (15 mmol/L) and is associated with eruptive xanthoma (Figures 8.10 and 8.11), a creamy layer on top of
plasma left overnight in a refrigerator (Figure 8.12), and lipemia retinalis (Figure 8.13). Palmar xanthomas
(Figure 8.14) are often demonstrated in patients with dysbetalipoproteinemia.
Elevated LDL, low HDL, and elevated TAG are associated with progressive atherosclerosis in the
coronary, carotid, cerebral, and peripheral vasculature (Figure 8.15). Acute myocardial infarction (MI)
often occurs in coronary plaques with ‘mild’ stenosis (<50%), and factors associated with plaque rupture
include a large lipid core, a thin fibrous cap, and activated macrophages and inflammatory cytokines.
Rupture often occurs at the lateral edge or ‘shoulder’ at the interface of plaque and normal intima. Acute
MI usually occurs when a ‘vulnerable’ atherosclerotic plaque ruptures with subsequent thrombosis and
FIGURE 8.5 A 7 × 4 mm firm nodule representing a xanthomatous nodule of the flexor pollicis brevis in a
patient with hypercholesterolemia. (Courtesy of foto@ finlay- online.org.)
FIGURE 8.6 Cutaneous xanthomas in homozygous familial hypercholesterolemia. (From Teruel JL, Lasunción
MA. Images in clinical medicine. Cutaneous xanthoma in homozygous familial hypercholesterolemia. N Engl J
Med 1995:332(17):1137. Copyright 1995 Massachusetts Medical Society. All rights reserved.)
FIGURE 8.7 Xanthelasma in the periorbital region of a patient with hypercholesterolemia. (Reprinted from
Dorland’s Dictionary, 30th ed. Copyright 2004, with permission from Elsevier.)
FIGURE 8.8 Arcus juvenilis is an opaque circle around the cornea, identical to arcus senilis but occurring in
young people. Deposits of lipids cause a white ring around the periphery of the cornea and when seen in a
young person it can be associated with hypercholesterolemia. (Courtesy of www.argy-bargey.blogspot.com.)
FIGURE 8.9 Lipid degeneration of the cornea, also known as lipid keratopathy, appears as a dense yellow-
cream-colored opacification or cholesterol crystals on the corneal stroma surrounding blood vessels as a result
of cholesterol or free fatty acid infiltration. The primary form is often bilateral and can occur in conditions such
as Tangier disease. (Courtesy of www.eyeatlas.com.)
FIGURE 8.10 Close-up of an eruptive xanthoma in a patient with hypercholesterolemia. (Reprinted from
Dorland’s Dictionary, 30th ed. Copyright 2004, with permission from Elsevier.)
FIGURE 8.11 Eruptive xanthomas on the (A) arm and (B) upper torso in a patient with severe hypertriglyceri-
demia. (From Nayak KR, Daly RG. Images in clinical medicine. Eruptive xanthomas associated with hypertriglyc-
eridemia and new-onset diabetes mellitus. N Engl J Med 2004:350(12):1235. Copyright 2004 Massachusetts
Medical Society.)
occlusion of coronary flow (Figure 8.16), and is treated with either thrombolytic therapy or percutaneous
coronary intervention. Cholesterol emboli syndrome may occur after any invasive arterial procedure and
may also occur spontaneously. The clinical syndrome may involve worsening renal function, hyperten-
sion, and distal ischemia, and may be associated with characteristic dermatologic and ophthalmologic
findings (Figures 8.17 and 8.19). The pathophysiology of this syndrome may involve cholesterol crystals
showering the distal vascular beds with the associated local vasospastic mediators, or larger cholesterol
plaques breaking off and occluding the peripheral vessels resulting in tissue and organ ischemia.
FIGURE 8.12 Creamy layer on top of plasma left overnight in a refrigerator, usually occurs when triglycerides
are over 1500 mg/dL. (From Fred HL, Accad M. Images in clinical medicine. Lipemia retinalis. N Engl J Med
1999:340(25):1969. Copyright I999 Massachusetts Medical Society.)
FIGURE 8.13 Lipemia retinalis, characterized by the creamy white appearance of retinal vessels, is a fun-
doscopic finding occurring with very high triglyceride levels that can be seen in chylomicronemia syndrome.
(From Fred HL, Accad M. Images in clinical medicine. Lipemia retinalis. N Engl J Med 1999:340(25):1969.
Copyright 1999 Massachusetts Medical Society.)
FIGURE 8.14 Palmar xanthomas are pathognomonic for dysbetalipoproteinemia type III. (Courtesy of Dr.
Pham Thi Thu Thuy.)
FIGURE 8.15 Aortogram demonstrating a large infrarenal abdominal aortic aneurysm measuring approxi-
mately 6.0 cm (arrow) with an associated severe stenosis of the proximal left renal artery.
FIGURE 8.16 Coronary angiogram in a patient who presented with chest pain and an acute ST segment ele-
vation myocardial infarction, demonstrating a large thrombus totally occluding the mid-left anterior descend-
ing artery (arrow).
FIGURE 8.17 Characteristic needle-shaped clefts (arrow) resulting from atheroembolism. (From Bradley M.
Images in clinical medicine. Spontaneous atheroembolism. N Engl J Med 1995:332(15):998. Copyright 1995
Massachusetts Medical Society.)
FIGURE 8.18 Cholesterol emboli demonstrated by livedo reticularis on the legs and a bluish discoloration of
the toes in a patient 12 hours after cardiac catheterization. (From Rana O, McCrea W. Cholesterol emboli after
coronary angioplasty. N Engl J Med 2006;354(12):1294. Copyright 2006 Massachusetts Medical Society. All
rights reserved.)
The diagnosis of elevated lipoproteins can be established with the appropriate laboratory tests. If an
underlying genetic abnormality is present, the diagnosis is suggested by the severity and pattern of the
lipoprotein abnormalities, the family history, and the presence of premature atherosclerotic vascular dis-
ease. The history, physical examination, and laboratory evaluation remain crucial for the proper diagnosis
as well as the appropriate treatment (Tables 8.3 and 8.4). Certain clinical features, such as tendon xan-
thomas, help distinguish familial hypercholesterolemia (present) from familial combined hypercholester-
olemia (absent) (Figures 8.20 and 8.21). Some of the rare entities have pathognomonic or characteristic
clinical findings, such as orange-yellow tonsils. Tangier disease (Figures 8.22 and 8.23). It is essential
to rule out secondary factors that result in altered lipid metabolism, including hypothyroidism, diabetes
mellitus, renal disease, obstructive liver disease, and alcohol intake, and medications such as estrogens/
progestins, glucocorticoids, thiazides, and cyclosporine.
FIGURE 8.19 Fundoscopic examination showing a cholesterol emboli (arrow) at the bifurcation of a reti-
nal and vascular sheathing distal to the occlusion (arrowheads). (From Bradley M. Images in clinical medi-
cine. Spontaneous atheroembolism. N Engl J Med 1995;332(15):998. Copyright 1995 Massachusetts Medical
Society.)
FIGURE 8.20 Sagittal proton-weighted magnetic resonance imaging showing a homogeneously enlarged
Achilles tendon with increased signal intensity (arrow, A) and axial T-2 weighted magnetic resonance imaging
revealing diffuse stippled pattern (arrow, B). Both are characteristic of xanthomas in this patient with hyper-
cholesterolemia. (From van den Bosch HC, Vos LD. Images in clinical medicine. Achilles’ tendon xanthoma in
familial hypercholesterolemia. N Engl J Med 1998;338:1591. Copyright 1998 Massachusetts Medical Society.)
Diagnosis
The diagnosis of dyslipidemia is established by laboratory data and supported by comprehensive history
and physical exam.
Significant dyslipidemia often results in progressive cardiovascular disease, and various imaging
modalities for measuring clinical and subclinical atherosclerotic vascular disease include exercise and
FIGURE 8.21 Tendon xanthomas in a patient with hypercholesterolemia. (From JIACM 2003;4(1):69. With
permission.)
FIGURE 8.22 Enlarged tonsils seen in Tangier disease. (Courtesy of the National Institutes of Health.)
chemical stress testing, arterial Doppler evaluation, MRI, and conventional coronary and peripheral angi-
ography. The availability of cardiac CT/coronary calcium scan provides an excellent noninvasive tool for
the evaluation of the degree and extent of coronary plaque and imparts incremental value for risk strati-
fication (Figure 8.24).
The largest body of evidence exists for improved outcomes with LDL lowering, and thus LDL remains the
major therapeutic target for intervention. Large epidemiologic studies have confirmed the continuous and
graded association between total serum cholesterol and coronary heart disease. Large, placebo-controlled,
randomized trials have confirmed the benefit of LDL lowering in reducing long-term cardiac event rates
in both primary and secondary prevention. Although LDL remains the primary lipid lowering priority,
a low HDL and high TAG have been associated with increased cardiac risk and are potential targets for
therapeutic intervention. Pooled data from several studies estimate a 2%–3% reduction in cardiovascular
risk for every 1 mg/dL increase in HDL. If the TAG level is ≥500 mg/dL (5.6 mmol/L), then treatment of
TAG takes priority over LDL reduction due to the desire to lower the risk of acute pancreatitis.
FIGURE 8.23 Enlarged orange-yellow tonsils in a patient with Tangier disease.
FIGURE 8.24 Coronary angiogram using a 64-slice computed tomography, demonstrating severe athero-
sclerosis with multiple mixed calcified and soft plaque in the left anterior descending artery and circumflex
artery.
The central principle of management of the patient with dyslipidemia is that the intensity of risk
reduction should be commensurate with the individual’s absolute cardiovascular risk (Table 8.6). The
major risk factors (exclusive of LDL cholesterol) include age ≥45 years in men and >55 years in women,
cigarette smoking, hypertension (defined as >140/90 mmHg or on antihypertensive medication), low HDL
cholesterol (<40 mg/dL [1 mmol/L] in males, <50 mg/dL in females [1.3 mmol/L]), family history of
premature coronary heart disease in a first-degree relative (≥55 years in male relative, and <65 years in
female relative). The 10-year risk of a cardiac event is assessed by using Framingham scoring, which takes
into account these factors and may be calculated using tables or handheld and internet-based online cal-
culators (www.cvriskcalculator.com or www.nhlbi.nih.gov/guidelines/cholesterol). The highest risk group
includes those patients with established cardiovascular disease or a ‘CHD risk equivalent’. This group is
comprised of patients with known coronary artery disease; other clinical forms of atherosclerotic vascular
disease including peripheral vascular disease, carotid artery disease, abdominal aortic aneurysm, and dia-
betes mellitus; and patients with multiple risk factors that confer a risk for a major cardiac event of >20%
over 10 years. The identification of subclinical atherosclerotic disease such as high coronary calcification,
significant carotid intimal medial thickness, or significant atherosclerotic burden on CT angiography
likewise warrants aggressive and intensive lipid lowering.
Recent trials have demonstrated incremental reductions in risk for adverse cardiac events with LDL
levels lowered to below 100 mg/dL (2.6 mmol/L). Overall, these data suggest that there is no clear-cut
TABLE 8.6 Major Atherosclerotic Cardiovascular Disease Risk Factors

NONTRADITIONAL RISK
MAJOR RISK FACTORS ADDITIONAL RISK FACTORS FACTORS
• Advancing age • Obesity, abdominal obesity • Elevated Lp(a)
• Elevated total serum cholesterol • Family history of hyperlipidemia • Elevated clotting factors
• Elevated non-HDL-C • Elevated small dense LDL-C • High inflammatory markers
• Elevated LDL-C • Elevated apoB • Elevated homocysteine
• Low HDL-C • Elevated LDL particle levels
• Diabetes mellitus concentration • Apo E4 isoform
• Hypertension • Hypertriglyceridemia • Elevated uric acid
• Chronic kidney disease stages 3, 4 • PCOS • Elevated TG-rich remnants
• Cigarette smoking • Dyslipidemia triad
• Family history of ASCVD
identifiable threshold for LDL level for risk reduction and that ‘lower is better’. Based on these new trials
demonstrating reduced cardiovascular event rates with lower LDL levels, the current recommendation for
optimal LDL is <70 mg/dL (1.8 mmol/L) and ideally <55 mg/dL (1.4 mmol/L) in patients with the highest
risk, including those with established ASCVD and CHD equivalents, and multiple major risk factors. No
major safety issues have been identified thus far with lowering LDL in the range of 50–70 mg/dL (1.3–1.8
mmol/L) and even extremely low levels of about 20 mg/dL (0.5 mmol/L) are well tolerated and appear to
be free of adverse effects.
Therapeutic Modalities for Dyslipidemia

A summary of the available agents for hypercholesterolemia is provided in Table 8.7.
Dietary Modification
Lifestyle and dietary modification remain the cornerstone of therapy, and reduced intake of saturated fat
and cholesterol, increased physical activity, and weight control for all patients are strongly recommended.
All patients should be advised to adopt therapeutic lifestyle changes including reduced intake of saturated
fats (<7% of total calories) and cholesterol (<200 mg/d), increased intake of soluble fiber (10–25 g/day),
weight reduction, and increased physical activity. However, although dietary modification should be a
mainstay of any LDL-lowering strategy, the average LDL reduction from diet alone is in the range of 5%
to 10%. HDL levels have been shown to increase with weight reduction, regular aerobic exercise, modest
alcohol consumption, and smoking cessation. Typically, one may expect a 1 mg/dL increase in HDL for
every 3 kg weight loss. Regular aerobic exercise may increase HDL by 10%–20% in sedentary adults.
Statins (3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors)

Statins lower serum LDL levels through intracellular inhibition of the rate-limiting step in cholesterol
production, which reduces cholesterol biosynthesis in the liver and upregulates LDL receptors to increase
clearance of LDL from the blood. The statins lower the LDL by 18%–55%, increase HDL by 5%–15%,
and lower TAG by 7%–30% (Table 8.2). At the currently available doses, rosuvastatin and atorvastatin
are the most potent statins followed in order of LDL-lowering potency by simvastatin, lovastatin, pravas-
tatin, and fluvastatin. Each doubling of a statin dose achieves an approximately 6% additional reduction
in serum LDL (the ‘rule of 6s’). A large meta-analysis involving 14 randomized, placebo-controlled trials
with 90,056 patients showed that lowering LDL cholesterol levels by 39 mg/dL (1 mmol/L) with statin
therapy significantly reduces the 5-year risk of major coronary events, coronary revascularization, and
stroke by 21%. Although treatment with statins has resulted in major reductions in cardiac event rates,
the amount of plaque regression demonstrated has been modest at most, raising the possibility that the
TABLE 8.7 Effects of LDL-C Lowering Agents

LDL-C
AGENT REDUCTION SIDE EFFECTS/DRUG INTERACTIONS
Moderate Intensity Statins
Atorvastatin 10–20 mg –29% to –52% Increased risk of myopathy with itraconazole,
Pravastatin 40–80 mg –34% to –37% ketoconazole, erythromycin, clarithromycin, HIV
Simvastatin 20–40 mg –29% to –41% protease inhibitors, nefazodone, amiodarone,
verapamil, or large quantities of grapefruit juice
Rosuvastatin 5–10 mg –45% to 52 %
(>1 quart [<1L] daily); may raise hepatic levels
High Intensity Statins
Atorvastatin 40–80 mg 50% to 60%
Rosuvastatin 20–40 mg –55% to 63%
Cholesterol Absorption –12% to –17% Side effects include headache and diarrhea;
Inhibitor (Ezetimibe 10 mg myopathy and hepatitis rare
daily)
Fibric Acids
Gemfibrozil 600 mg twice per –5% to –20% Side effects include rash and dyspepsia; potentiates
day the action of warfarin; contraindicated in patients
Fenofibrate (48–145 mg or with gallstones, or severe renal insufficiency/
43–130 mg daily) hemodialysis; variable effects on serum LDL and
may increase LDL
PCSK9 Inhibitors
Evolocumab 140 mg q2w or 420 –63% to –71% Nasopharyngitis, headache, hypertension, skin rash,
q4w diabetes mellitus
Alirocumab 75–150 mg q2w –48% to –58%
Bile Acid Sequestrants
Colesevelam (3750–4375 mg –8% to 16% Common side effects include nausea, constipation
daily) and bloating; associated with increased TAG levels
Bempedoic Acid –17 to –18% Rise in serum uric acid, tendon rupture (rare)
Small Interfering RNA Therapy
Inclisiran 248 mg Subq 6 months –52% Local injection site reaction, antibody development,
arthralgia, bronchitis
beneficial effects extend over and beyond LDL lowering, including anti-inflammatory, antithrombotic,
immunomodulatory, and vascular effects.
Statins are generally well tolerated; however, common minor side effects include muscle and joint
aches (up to 5%), fatigue, dyspepsia, and headaches. More serious side effects, such as severe myositis
with generalized muscle pain and weakness and elevated creatine kinase (rarely leading to rhabdomyoly-
sis and acute renal failure) or severe hepatitis, may occur infrequently. Adverse drug interactions should
be carefully monitored, particularly at higher doses and in elderly patients with low body weight, and in
patients with impaired renal function or on combination therapy with fibrates and/or nicotinic acid.
Ezetimibe (Cholesterol Absorption Inhibitor)

Ezetimibe acts through inhibition of intestinal cholesterol absorption in the small intestine leading to
a reduction in hepatic cholesterol stores, increasing clearance of cholesterol from the blood. As mono-
therapy, ezetimibe effectively decreases LDL by 12%–17%. The combination of ezetimibe and a statin
provides a dual effect by inhibiting cholesterol intestinal absorption and cholesterol production in the
liver, respectively. This combination lowers the LDL by as much as an additional 25%, with potentially
fewer side effects. Large randomized clinical trials evaluating the effect of the combination of ezetimibe
and simvastatin compared with simvastatin alone on ‘hard’ clinical end points such as mortality and MI
are currently underway.
Bile Acid Sequestrants (Resins)

Bile acid sequestrants act through binding bile acids in the intestine resulting in increased excretion in
the stool, stimulating greater intrahepatic cholesterol utilization for bile acid synthesis. This results in
upregulation of the LDL receptor, which enhances the clearance of LDL in the bloodstream. In general,
resins lower LDL by 15%–30%. The available bile acid sequestrants include cholestyramine, colesevelam,
and colestipol. Treatment with cholestyramine has been associated with a reduction in the progression
of atherosclerosis compared to control. Since resins are not systemically absorbed, they are extremely
safe; however, they are associated with side effects including nausea, constipation, and bloating. Other
medications should be taken either 1 hour before or 4 hours after the resins due to binding and decreased
absorption (i.e., warfarin, digoxin). Resins may significantly raise the TAG level and should be avoided in
patients with hypertriglyceridemia.
PCSK9 Inhibitors
The development of monoclonal antibody inhibitors of PCSK9, a protein that regulates the recycling
of LDL receptors, has revolutionized the treatment of hyperlipidemia with profound LDL lowering in
the range of 60%. Inhibiting PCSK9 results in more LDL receptors being recycled to the surface of the
hepatocyte leading to increased clearance of LDL cholesterol from the circulation. Alirocumab and evo-
licumab are the two subcutaneous injections available, and have been shown to reduce cardiovascular
outcomes and all-cause deaths by 15% in high-risk patients (ODYSSEY OUTCOMES trial NEJM 2018
and FOURNIER trial NEJM 2017). PCSK9 inhibitors should be considered for use in conjunction with
statin therapy for LDL-C lowering in individuals with clinical cardiovascular disease who are unable
to reach goal LDL-C/non-HDL-C levels with maximally tolerated statin, for individuals with familial
hypercholesterolemia, or as monotherapy in statin-intolerant individuals. These drugs have a favorable
safety profile and tolerability. Nasopharyngitis is the most reported side effect of both formulations.
Bempedoic Acid
Bempedoic acid is an oral inhibitor of adenosine triphosphate citrate lyase, an enzyme in the cholesterol
biosynthesis pathway. Bempedoic acid alone or in combination with statin or ezetimibe lowers LDL-C by
approximately 20% by upregulating LDL receptors. Side effects noted from the use of bempedoic acid
include a rise in serum uric acid. Therefore, patients with active gout should be stabilized before starting
bempedoic acid. Tendon rupture has also been rarely reported, and this risk may be increased in patients
over 60 years of age, patients taking corticosteroids or fluoroquinolones, or with prior tendon disorders
(CLEAR Harmony trial NEJM 2019).
Small Interfering RNA (siRNA) Therapy/Inclisiran

Inclisiran is a first-in-class small interfering RNA (siRNA) therapy that is administered subcutaneously
and is selectively taken up by hepatocytes. The drug is slowly released into the cytoplasm and loads onto
the RNA-induced silencing complex (RISC) and works with RISC to sequentially cleave multiple copies
of PCSK9 protein mRNA, thus preventing PCSK9 protein production. As a result, there is upregulation
of the LDL receptor on the surface of the hepatocyte, which leads to increased clearance of circulat-
ing LDL in the bloodstream. In patients with atherosclerotic cardiovascular disease with elevated LDL
despite statin therapy, subcutaneous administration of inclisiran every 6 months has been shown to result
in sustained and effective reduction of LDL cholesterol in the range of 52% (ORION-10 and ORION-11
trials NEJM 2020). Inclisiran was well tolerated for over 18 months and the most common side effect was
injection site reaction (8.2%).
Nicotinic Acid
Nicotinic acid, or niacin, is a B-complex vitamin that raises HDL by 15%–35%, decreases TAG by 20%–
50%, and modestly lowers LDL (approximately 5%–20%). Niacin raises HDL through metabolic path-
ways that increase the pre-β, apoA-I–rich HDL particles, which are the cardioprotective subfraction of
HDL. Treatment with niacin reduced the risk of nonfatal MI even after 15 years of follow-up. The most
common side effect is cutaneous flushing, and the major adverse side effect is hepatotoxicity.
Fibric Acids
Fibrates are agonists of PPARa, which is a nuclear receptor involved in the modulation of lipid and car-
bohydrate metabolism. Fibrates increase the hydrolysis of TAG by enhancing lipoprotein lipase activity,
increasing clearance of TAG-rich lipoproteins from the plasma, and decreasing the rate of release of free
fatty acids from adipocytes. Fibrates are the most effective agents for reducing TAG (20%–55%) and
effectively raising HDL (10%–20%). These agents have variable effects on the serum LDL, and treated
patients with hypertriglyceridemia may have an increase in their LDL. Fibrates are the drug of choice in
patients with severe hypertriglyceridemia (>1000 mg/dL [11 mmol/L]). These drugs are beneficial in both
primary prevention and in patients with established coronary artery disease.
Omega-3 Fatty Acids

Fish oils contain a high concentration of polyunsaturated fatty acids and have been shown to significantly
reduce plasma triglycerides, by up to 45%. Omega-3-acid ethyl esters are available as an adjunct to the diet
for the reduction of very high TG levels (≥500 mg/dL [5.5 mmol/L]) in adults. The mechanism of action is
poorly defined but may involve the inhibition of acyl Coa:1,2- diacylglycerol acyltransferase and increased
peroxisomal β-oxidation in the liver. Icosapent ethyl (Vascepa) has gained much attention in the last few
years since this pure form of eicosapentaenoic acid at 2 grams twice a day was superior to placebo in low-
ering triglycerides, cardiovascular events, and cardiovascular death (31% relative risk reduction) among
patients with high triglycerides and either known cardiovascular disease or those at high risk of develop-
ing it, and who were already on statin therapy with relatively well-controlled LDL levels (REDUCE-IT
trial NEJM 2019). Conversely, adding a carboxylic acid formulation of omega 3-3 fatty acids (eicosapen-
taenoic acid and docosahexaenoic acid) in statin-treated patients with high cardiovascular risk resulted in
no significant difference in the composite outcome of major cardiovascular events compared with placebo
(STRENGTH trial JAMA 2020).
Nonpharmacologic Strategies for Lowering LDL Cholesterol

LDL apheresis involves the direct removal of LDL from the plasma and may be the preferred option in
severe drug-resistant or refractory hyperlipidemia. Partial ileal bypass surgically depletes the entero-
hepatic supply of bile acids resulting in upregulation of the LDL receptor in the liver increasing LDL
clearance, and may be an option for patients with severely elevated LDL and normal TAG refractory to
maximal medical management who are not candidates for LDL apheresis.
New Treatment Options for Raising HDL

Cholesterol ester transfer protein (CETP) is a plasma glycoprotein produced in the liver that circulates
in the bloodstream bound to HDL that facilitates the transfer of cholesterol esters between lipoproteins.
CETP inhibition is a potential new therapy. CETP activity is potentially atherogenic and results in the net
transfer of cholesterol esters from HDL to VLDL and LDL, thereby decreasing the concentration of HDL
and increasing the concentration of LDL. Pharmacologically inhibiting CETP has been shown to increase
the reverse cholesterol transport to the liver by increasing HDL and enhancing the hepatic uptake of cho-
lesterol via scavenger receptor B-1 (SRB-1). However, CETP inhibition with torcetrapib was associated
with increased mortality in a phase III clinical trial diminishing the enthusiasm for this class of drugs.
Other novel therapies under investigation for raising HDL include direct infusions of plasma-derived
or synthetic apolipoprotein A-1 and agents that augment the expression of scavenger receptors.
LIPOPROTEIN (A)
Lipoprotein (a) (Lp(a)) is a lipoprotein similar to LDL in lipid and protein concentration but is composed
of two protein particles – apolipoprotein (Apo) B-100 and apolipoprotein (a). The precise role of Lp(a)
in the pathogenesis and progression of atherosclerosis remains controversial, but potential mechanisms
of Lp(a) include binding to proinflammatory oxidized phospholipids, decreased nitric oxide synthesis,
increased leukocyte adhesion and smooth muscle proliferation, and inhibition of the fibrinolytic system.
However, there remains substantial uncertainty regarding the role of Lp(a) in clinical practice, although
an elevated level might warrant more aggressive treatment in patients who have high-risk family histories
but few other risk factors. Treatment options for patients with elevated Lp (a) include aspirin, statins, and
PCSK9-I. Niacin is no longer recommended by National Lipid Association guidelines.
Studies evaluating the use of antisense oligonucleotide (ASO) administered subcutaneously (where a
single DNA strand binds to messenger RNA), as well as siRNA therapy, which results in marked reduc-
tions in lipoprotein (a) levels are currently underway (APOLLO trial NEJM 2020).
Monoclonal Antibodies against ANGPTL3

Angiopoietin-like proteins (ANGPTLs) are regulators of lipoprotein metabolism. ANGPTL3 is a hor-
mone produced by the liver that inhibits lipoprotein lipase. Evinacumab is a fully human monoclonal
antibody against ANGPTL3 approved by the US Food and Drug Administration in 2021 for the treatment
of familial hypercholesterolemia. It causes about a 50% reduction in LDL-C. The approved dose is 15 mg/
kg IV infusion every 4 weeks. Nasal congestion, upper respiratory infection, and fatigue were the most
common side effects of evinacumab reported.
FUTURE DIRECTIONS
The optimal diagnostic and therapeutic approach to lipid disorders remains a crucial component of con-
temporary clinical practice. The increasing prevalence of obesity, metabolic syndrome, and diabetes mel-
litus continues to fuel the need for comprehensive treatment strategies for dealing with multiple lipid and
metabolic disorders. LDL cholesterol will remain the primary target for intervention, and new therapies
targeting specific genetic pathways will continue to evolve. The proper identification and assessment of
the patients at increased risk for the development and progression of atherosclerotic cardiovascular dis-
ease and the selection of the appropriate goals for therapy will continue to be the focus of basic science
research and clinical trials in the future.
Neuroendocrine
Tumors and Genetic
Endocrine Disorders
9
Multiple Endocrine
Neoplasia Type 1
Norma Lopez, Ikram Haque, and Shanika Samarasinghe
DEFINITION/OVERVIEW
Multiple endocrine neoplasia type 1 (MEN1), or Wermer’s syndrome, is a complex autosomal dominant
tumor syndrome with >95% penetrance by the fifth decade. It predisposes patients to more than 20 endo-
crine and non-endocrine tumors (Table 9.1); however, the primary manifestations are the occurrence of
parathyroid, enteropancreatic, and anterior pituitary tumors. Duodenopancreatic neuroendocrine tumors,
particularly nonfunctional neuroendocrine tumors, with their malignant potential represent the leading
cause of death in patients with MEN1 followed by thymic neuroendocrine tumors.
PATHOPHYSIOLOGY
A germline inactivating mutation in the MEN1 gene located on chromosome 11q13.1 encodes a 610 amino
acid protein called menin. More than 700 different germline and somatic mutations in the MEN1 gene
270 DOI: 10.1201/9781003100669-9

9 • Neuroendocrine Tumors and Genetic Endocrine Disorders 271
TABLE 9.1 Tumors Associated with MEN1

TUMOR ESTIMATED PENETRANCE
Endocrine
Parathyroid 90%
Enteropancreatic Tumors
• Gastrinoma 40%
• Insulinoma 10%
• Nonfunctional, PPoma 20%–50%
• Glucagonoma <1%
• VIPoma <1%
Pituitary Adenomas
• Prolactinoma 20%
• Somatotropinoma 10%
• Corticotropinoma <5%
• Nonfunctioning <5%
Adrenal
• Adrenal cortical tumor 25%
• Pheochromocytoma <1%
Foregut Carcinoid
• Gastric enterochromaffin NET 10%
• Thymic NET 4%
• Bronchopulmonary NET 2%
Non-Endocrine
Angiofibromas 85%
Collagenomas 70%
Lipomas 30%
Meningiomas 8%
Leiomyomas of uterus or esophagus 30%
Ependymoma 1%
Predisposition to breast cancer*
Source: Adapted from Thakker RV et al., JCEM (2012), The Endocrine Society, with
permission. * From Dreijerink, KMA, NEJM, 371, 2014.
have been reported since its cloning in 1997. Menin is primarily a nuclear protein involved in essential cell
functions such as transcription, regulation, proliferation, DNA repair, cell division, and cell cycle control.
Germline MEN1 mutations are not sufficient per se to develop clinical MEN1, and loss of the unaffected
MEN1 allele is necessary for tumorigenesis. There is no clear genotype–phenotype correlation to date and
approximately 10% of patients have a de novo mutation.
DIAGNOSIS
The clinical diagnosis of MEN1 is based upon the occurrence of two or more primary MEN1 tumor types
(parathyroid gland, anterior pituitary, or enteropancreatic) or at least one MEN1-related tumor and a first-
degree relative with a confirmed MEN1 gene mutation. It can also be diagnosed by identifying a germline
MEN1 mutation in an individual or asymptomatic family member in whom the clinical diagnosis is not
yet clearly established.
The optimal role of mutational analysis in MEN1 is not well defined. Guidelines suggest testing in
any index patient with clinical MEN1, all first-degree relatives of known MEN1 carriers to identify those
who require tumor screening, and individuals with suspicious MEN1 such as manifestations in young
patients (<30 years) or those with multiple lesions in the same gland (multigland parathyroid disease or
multiple pancreatic neuroendocrine tumors [pNETs]). All patients with gastrinoma should have MEN1
mutational analysis given that 25%–35% of patients will have MEN1 and its malignant potential.
PROGNOSIS AND SCREENING

Despite advances in diagnosis and management, this syndrome has a decreased life expectancy with a
mean age of death of 55–60 years. The most common cause of death has shifted from complications of
hormone excess states mainly due to gastrinomas to malignant neuroendocrine tumors (NETs). A moni-
toring program has been developed for patients and asymptomatic carriers with testing suggested as early
as age 5, to detect and prevent significant morbidity and mortality (Table 9.2).
TABLE 9.2 Suggested Surveillance for MEN1-Associated Tumors

AGE TO BEGIN BIOCHEMICAL TESTING
TUMOR (YEARS) ANNUALLY IMAGING
Parathyroid 8 Calcium, PTH None
Gastrinoma 20 Gastrin (±pH) None
Insulinoma 5 Fasting glucose, insulin None
Other enteropancreatic <10 CgA, PPP, glucagon, VIP MRI, CT or EUS (annual)
Anterior pituitary 5 Prolactin, IGF-1 MRI (every 3 years)
Adrenal <10 None unless symptoms or MRI or CT (annual with
tumor >1 cm seen on pancreatic imaging)
imaging
Thymic and bronchial 15 None CT or MRI (every 1–2 years)
carcinoid
Source: Adapted from Thakker RV et al., JCEM (2012), The Endocrine Society, with permission.
CLINICAL PRESENTATION AND MANAGEMENT
Parathyroid
Primary hyperparathyroidism (PHPT) is the most common manifestation, occurring in almost all patients
by age 50. Differences in PHPT associated with MEN1 include an earlier age of onset (by 25 years vs.
55 years), greater reduction in bone mineral density, an equal male/female ratio (1:1 vs. 1:3), and mul-
tiple gland involvement. Preoperative localization with Tc99 sestamibi scintigraphy or neck ultrasound
offers limited value since all parathyroid glands may be impacted and bilateral neck exploration is often
required.
The recommended surgical approach is subtotal parathyroidectomy with the removal of 3.5 glands.
Parathyroid tumors can be asynchronous and differ in size, each tumor likely representing a different
clonal adenoma (Figure 9.1). MEN1-associated PHPT has a high recurrence rate that reaches up to 50% at
12 years compared to a 4%–16% recurrence rate in sporadic cases. As such, a less favored option would
be total parathyroidectomy with autotransplantation of a parathyroid graft in the forearm or neck in those
with extensive disease or at repeat surgery, but this is associated with higher rates of hypoparathyroid-
ism (up to 46%). A thymectomy is also recommended in patients with MEN1, as additional glands are
detected in 6%–20% of MEN1 patients with intrathymic parathyroid tissue as a cause as well as due to
the risk of thymic carcinoid.
Enteropancreatic
MEN1 is the most common hereditary syndrome associated with pancreatic NET with a prevalence of
30%–80% depending on the series. These tumors are either nonfunctional or can be associated with
a hormonal syndrome producing gastrin, insulin, vasoactive intestinal polypeptide (VIP), glucagon, or
somatostatin. PNETs have an earlier age of onset in MEN1 (10–50 years vs. 50–80 years in sporadic
cases), tend to be small (<2 cm) and multiple, and can lead to diffuse microadenomatosis (tumors <0.5
cm) (Figure 9.2). Nonfunctional tumors are increasingly recognized as the most frequent pNETs associ-
ated with MEN1 and tend to carry a worse prognosis.
FIGURE 9.1 Parathyroid-SPECT shows synchronous multigland parathyroid adenomas in the two inferior
glands. Faint uptake is also seen in the right superior gland. (Courtesy of the Nuclear Medicine Team, Loyola
University.)
FIGURE 9.2 Multiple pancreatic islet cell tumors (arrows).
Diagnosis of NET depends on systematic imaging studies and hormonal measurements (Table 9.2).
Endoscopic ultrasound (EUS) is the most sensitive method but is invasive and operator dependent (Figure
9.3). MRI is more sensitive than CT with less radiation. The role of functional imaging is uncertain, but
68Ga-DOTATATE PET/CT seems to have increased sensitivity in detecting NETs in MEN1, and FDG
PET/CT may provide risk stratification in determining the malignant potential of pNETs (Figure 9.4).
Insulinomas, glucagonomas, and VIPomas are usually treated surgically once the tumor is local-
ized. Figures 9.5 and 9.6 show CT images and resection of a pancreatic glucagonoma. Pancreatic cystic
islet cell tumors in a MEN1 patient are shown in Figure 9.7. Figures 9.8 and 9.9 show imaging and his-
topathology in a patient with metastatic insulinoma. Gastrinomas are typically treated medically with
proton-pump inhibitors, histamine 2-receptor blockers, and/or somatostatin analogues. Correction of con-
comitant hyperparathyroidism is associated with a decrease in gastrin levels and improvement in symp-
toms. Nonfunctional NETs larger than 2 cm or with rapid growth should be considered for resection given
the concern for metastatic spread, whereas watchful waiting is reasonable for smaller tumors.
FIGURE 9.3 Endoscopic ultrasound depicts a 12 mm × 10 mm hypoechoic round mass in the pancreatic
tail of a patient with MEN1. The endosonographic borders were well-defined. An intact interface was seen
between the mass and the adjacent structures suggesting a lack of invasion. Fine needle aspiration demon-
strated a well-differentiated NET. (Courtesy of Nuclear Medicine Team, Loyola University.)
FIGURE 9.4 68Ga-DOTATATE PET/CT demonstrating a pancreatic neuroendocrine tumor with metastatic
disease to the liver. (Courtesy of Nuclear Medicine Team, Loyola University.)
FIGURE 9.5 Pancreatic glucagonoma. A 6 cm solid mass with peripheral calcification at the tail of the pan-
creas is seen.
Pituitary
Hormonal studies including prolactin, IGF-1, and imaging with MRI of the sella (Figure 9.10) should
be done at regular screening intervals. The management of pituitary adenomas in MEN1 patients is the
same as those with sporadic tumors, although some reports suggest these tumors may be less responsive
to medical management.
Cutaneous Lesions
Angiofibromas and collagenomas may be a strong sign in diagnosing MEN1 and tend to be multiple and
more common in these patients (64% vs. 8% in the general population and 62% vs. 5%, respectively)
(Figure 9.11).
FIGURE 9.6 Tail of resected pancreas glucagonoma (arrow) from a patient with MEN1. Spleen (Sp) is seen
on the left.
FIGURE 9.7 Cystic islet cell tumor in a MEN1 patient. (A) Exceptionally large homogeneous low-attenuation
mass on the scan with thickened irregular wall, arising from the body of the pancreas. (B) Intraoperative pho-
tograph. (C) Gross resected pancreas, with tumor on the left, spleen on the right. (D) Dissected tumor on the
left, spleen on the right.
Other
Adrenal tumors are common in MEN1. These lesions are usually bilateral, nonfunctional hyperplasia,
although hyperaldosteronism, Cushing’s syndrome, pheochromocytoma, and adrenocortical carcinoma
have all been reported in up to 15% of MEN1-associated tumors. Recent studies from the Dutch MEN1
FIGURE 9.8 CT imaging in a patient with metastatic insulinoma with MEN1. (A) CT pancreas with contrast,
showing a pancreatic body lesion measuring 1.4 × 1.2 × 1.5 cm (red arrowhead) with central hypodense
cystic area. (B) A hyperenhancing liver lesion measuring 1.8 × 1.8 cm (red circle). ([A] From Poku C, Amjed H,
Kazi F, Samarasinghe S. Metastatic insulinoma presenting after bariatric surgery in a patient diagnosed with
MEN1. Clinical Case Reports. 2022 Feb;10(2). [B] From Poku C, Amjed H, Kazi F, Samarasinghe S. Metastatic
insulinoma presenting after bariatric surgery in a patient diagnosed with MEN1. Clinical Case Reports. 2022
Feb;10(2).)
FIGURE 9.9 Histopathology in metastatic insulinoma. (A) Well-differentiated pancreatic neuroendocrine

tumor. (B) Separate neuroendocrine microadenoma surrounded by normal pancreas. (C) Metastatic, well-
differentiated neuroendocrine tumor within the liver (left, normal liver; right, metastatic tumor). (From Poku
C, Amjed H, Kazi F, Samarasinghe S. Metastatic insulinoma presenting after bariatric surgery in a patient diag-
nosed with MEN1. Clinical Case Reports. 2022 Feb;10(2).)
database have shown an increased risk of breast cancer in female patients with a risk ratio of 1.96 (95%
CI 1.33–2.88) compared to the general population. MEN1-associated carcinoid tumors include thymic,
bronchial, and gastric enterochromaffin NETs (Table 9.1) and are discussed elsewhere in the chapter.
FIGURE 9.10 A pituitary macroadenoma measuring 1.5 × 1.9 × 1.8 cm, with slight elevation of the optic
chiasm and invasion into the right cavernous sinus seen on MR of sella.
FIGURE 9.11 Cutaneous lesions are common in MEN1. (A) Angiofibromas are benign tumors that consist
of acneiform papules that do not regress. (B) Collagenomas are round and firm and range from a few mm
to several centimeters. (From A. Vashi, N. et al. Dermatology Online Journal, 18(12); B. Simi SM et al. Indian J
Dermatol, 2012: 57:304-7.)
MULTIPLE ENDOCRINE NEOPLASIA TYPE 2
Definition/Overview
Multiple endocrine neoplasia type 2 is an autosomal dominant syndrome that can be classified into
MEN2A, MEN2B, and familial medullary thyroid cancer (FMTC). These are rare genetic cancer syn-
dromes involving multiple endocrine organ systems, more commonly the thyroid, adrenal, and parathy-
roid glands. First-degree relatives of patients with MEN2 have a 50% risk of inheriting the gene mutation
leading to the syndrome. The prevalence of all MEN2 worldwide is 1 in 35,000.
FIGURE 9.12 Representation of RET gene showing codons identified in MEN2 families. (From Jhiang, S.M.
The RET proto-oncogene in human cancers. Oncogene, 2000: 19(49):5590–5597.)
MEN2A is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (Pheo), and

hyperparathyroidism (HPT). Those affected by MEN2B display a more aggressive MTC and present with
Pheo and ganglioneuromas but not with HPT. FMTC only manifests with MTC (characteristic features
can be found in Brandi ML, et al., CONSENSUS: Guidelines for diagnosis and therapy of MEN type 1
and type 2, Journal of Clinical Endocrinology & Metabolism, 2001 Dec;86(12):5658–71.)
Pathophysiology
The pathophysiology for MEN2 involves the RET (rearranged during transfection) protooncogene. The
RET gene is located on chromosome 10. It is expressed in neuroendocrine and neural cells where it
encodes receptor-type tyrosine kinase in extracellular, transmembrane, and intracellular tyrosine kinase
domains. Missense mutations in this gene are the cause of MEN2. A specific RET mutation has been
identified in over 95% of families with MEN2A (Figure 9.12).
Patients with classic MEN2A will almost all develop MTC (90%–100%). A lower number of patients
develop Pheo (up to 50%) and HPT (up to 30%) with risk and penetrance depending on the RET gene
mutation. Most MEN2A RET mutations involve codon 609, 611, or 620 of exon 10 or codon 634 of exon
11 with the latter being the most common mutation. MEN2B is associated with MTC (100%) presenting
at an earlier age, Pheo (up to 50%) depending on gene mutation, and no demonstration of HPT. The most
common mutation in MEN2B is M918T, which is present in over 95% of MEN2B patients. Patients with
MEN2B also manifest extra-adrenal features of intestinal ganglioneuromas, ophthalmologic signs, muco-
sal neuromas, and marfanoid body habitus. Patients with FMTC present with medullary thyroid cancer
and RET germline mutation but without Pheo, HPT, or other somatic abnormalities (Figures 9.13–9.15).
MEN2A includes rare variants with cutaneous lichen amyloidosis (CLA) and MEN2A with
Hirschsprung’s disease. CLA is an intense itchy rash consisting of raised spots that are scaly and brown
on the shins, thighs, feet, and forearms. Hirschsprung’s disease presents at birth due to missing nerve end-
ings in an infant’s colon resulting in gastrointestinal symptoms such as constipation, vomiting, diarrhea,
or the more serious condition of toxic megacolon.
FIGURE 9.13 Mucosal neuromas of the tongue. (From NCI Visuals Online, Edward Cowen, National Cancer
Institute. Available from https://visualsonline.cancer.gov/details.cfm?imageid=12516.)
FIGURE 9.14 Marfanoid body habitus, typical facial features, and colostomy due to megacolon complications.
FIGURE 9.15 Neuromas in MEN2B. (A) Thick, lumpy lips. (B) Mucosa neuromas of the tongue and lips.
MEDULLARY THYROID CANCER

Medullary thyroid carcinoma (MTC) originates from parafollicular C-cells of the thyroid. These cells
secrete calcitonin (Ct). Medullary thyroid cancer represents 3%–5% of all thyroid cancers with most cases
being sporadic (75%) and 25% associated with MEN2. Advances in genetic analysis of tumor cells have
shown that there is a difference in levels of regulators of genetic expression called microRNAs (miRNAs)
in hereditary MTC compared to sporadic disease. Investigators have found higher levels of miRNAs asso-
ciated with worse clinical outcomes, and persistent and metastatic disease.
MTC presents in the first few years of life in MEN2B and presents about 10 years earlier on aver-
age than in MEN2A. MTC in MEN2 is usually multifocal and bilateral, and exhibits c-cell hyperplasia,
known to be a precursor to tumors. This differs from sporadic MTC, which is usually unifocal and uni-
lateral (Figure 9.16).
Diagnosis
Medullary thyroid cancer is suspected on fine needle aspiration specimen and confirmed on thyroid-
ectomy specimen. Guidelines recommend immunohistochemical analysis for the presence of markers
such as calcitonin, chromogranin, and CEA, and the absence of thyroglobulin in surgical specimens
suspected of MTC due to its variance of histologic appearance. More than 14 different histological vari-
ants of MTC have been described; usually, epithelioid cells predominate, however, spindle cells may be
seen (Figure 9.17). Medullary thyroid cancer can often be confused with other types of thyroid tumors
FIGURE 9.16 Gross specimen of MTC in MEN2A. Pathologic specimen from a thyroidectomy. Right MTC (1.5
cm) and multiple small foci of MTC in a patient with MEN2A.
FIGURE 9.17 (A) Spindle-shaped cells can be seen in MTC (H&E ×300). (B) Positive calcitonin immunostain-
ing, consistent with MTC (H&E ×150).
FIGURE 9.18 Strong immunoreactivity with calcitonin in MTC tumor with diffuse reactivity in surrounding
thyroid parenchyma with C-cell hyperplasia. (From Thompson L. Pathology Clinic. Available from https://lester-
thompsonmd.com/pdf/ ENTJ-2010 - 07_ Medullary%20thyroid%20carcinoma.pdf.)
including papillary and follicular thyroid cells. Concurrent serum Ct and CEA should be measured in all
patients with MTC. Levels of Ct and CEA are used for prognosis and surveillance. High CEA in relation
to Ct as well as low levels of Ct and CEA in advanced disease are associated with poorly differentiated
tumors (Figure 9.18).
Management and Treatment

The treatment of MTC is resection of the thyroid tumor and resection of locoregional metastasis in both
sporadic as well as hereditary forms of MTC. Postoperative management and staging depend on the
postoperative Ct and CEA levels. Most guidelines recommend checking tumor markers 2–3 months post-
operatively when levels would expect to nadir. Systematic additional imaging to search for metastasis is
recommended if postoperative Ct remains above 500 pg/ml. Metastatic medullary thyroid cancer can be
found using cross-section imaging modalities such as CT and MRI as well as functional imaging such as
DOPA/PET-CT (Figure 9.19). Systemic therapy with RET-targeted tyrosine kinase inhibitors (TKIs) is
not curative but offers promising results for some patients with progressing or symptomatic disease.
Genetic testing is recommended for early screening of patients at risk for MEN2. The decision to
perform prophylactic thyroidectomy based on RET mutation testing alters the clinical course of MTC and
FIGURE 9.19 PET/CT DOPA MTC with DOPA-positive disease in the right thyroid lobe and central and bilat-
eral lymph node metastasis. (From Rasul S, Hartenbach S, Rebhan K, Göllner A, Karanikas G, Mayerhoefer M,
et al. [18F]DOPA PET/ceCT in diagnosis and staging of primary medullary thyroid carcinoma prior to surgery.
European Journal of Nuclear Medicine and Molecular Imaging. 2018 [cited 2023 Feb 28];45(12):2159–69.
Available from https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC6182401/.)
early thyroidectomy can be curative in MEN2. Prophylactic thyroid surgery is recommended based on
the youngest age at the first diagnosis of MEN2 according to a specific codon. Medullary thyroid cancer,
however, remains the main cause of mortality in patients with both MEN2A and MEN2B due to improved
diagnosis and treatment of other associated conditions involving the syndrome including Pheo.
Prognosis
The RET-specific mutations determine the phenotypic expression of MEN2 and the aggressiveness of
the medullary thyroid cancer component. Specific mutations have been shown to correlate with the age
of onset of MTC as well as the risk of developing Pheo or HPT. Investigators determined that there is a
moderate, high, or highest risk of development and growth of MTC based on the distinct point mutation
of RET in MEN2. This discovery led to an improved ability to predict clinical course and optimize treat-
ment and management based on RET mutation risk. Moderate- and high-risk mutations have similar rates
of overall survival and distant metastatic disease, therefore, experts suggest early-onset versus late-onset
MTC in MEN2 should be considered in predicting clinical course.
PHEOCHROMOCYTOMA IN MEN2
Diagnosis
Pheochromocytoma (Pheo) is the second most common disease in MEN2 and is seen in approximately
50% of patients. The penetrance of Pheo in this syndrome depends on the specific RET mutation and
varies in penetrance from 10% to 80%. It is important to note that in families with known MEN2, early
thyroidectomy greatly decreases the risk of MTC; therefore, Pheo remains the main disease requiring
close surveillance.
Penetrance of Pheo is higher in RET mutations in codons 634, 883, and 918. Due to the progres-
sive nature of Pheo in MEN2, bilateral disease diagnosis may be synchronous or metachronous, thereby
requiring prolonged surveillance.
One-third of patients with MEN2 and Pheo were asymptomatic at the time of diagnosis, there-
fore, most are identified during Pheo screening due to known MEN2. Pheochromocytoma in MEN2
secrete both metanephrines and normetanephrines, therefore, both should be checked every year even in
asymptomatic patients. Adrenal CT can be used to detect Pheo and usually reveals an unenhanced density
of >10 HU (with washout >50%).
Functional imaging may be reserved for consideration of multifocal or rarely metastatic Pheo.

Surgery is the only treatment option for patients with Pheo in MEN2. Experienced centers have reported
data suggesting adrenal-sparing surgery has advantages over bilateral adrenalectomies, sparing patients
from lifelong steroid dependence. Moreover, current application of laparoscopic adrenalectomy has
reduced surgical morbidity (Figures 9.20–9.23).
FIGURE 9.20 Gross specimen of pheochromocytoma. Note the vascular and dusky appearance of the tumor,
a characteristic of Pheo. (Courtesy of Dr. Steven De Jong.)
FIGURE 9.21 CT scan of abdomen in a patient with MEN2B demonstrating a pheochromocytoma. The 2 cm
left adrenal pheochromocytoma (arrow) was subsequently removed by laparoscopic adrenalectomy.
FIGURE 9.22 Left adrenal nodule (arrow) in an asymptomatic patient with MEN2A. Biochemistry was nega-
tive for Pheo. Note surgical clips from previous right adrenalectomy due to Pheo.
FIGURE 9.23 MIBG demonstrating a left Pheo. Increased MIBG uptake in the left upper abdomen corre-
sponding to previously seen mass on MRI and consistent with a left 7 cm pheochromocytoma postoperatively.
(Courtesy of Nuclear Medicine Team, Loyola University.)
PRIMARY HYPERPARATHYROIDISM IN MEN2
Diagnosis and Management

Primary hyperparathyroidism has been reported in as high as 20%–30% of MEN2A syndromes with
some series detailing lower prevalence. All patients with MEN2 syndrome should be screened for HPT.
The peak age of presentation is the third decade, a younger presentation compared to non-syndrome-
related HPT. Parathyroid tumors do not usually occur in MEN2B. The workup and clinical indication
for surgery are similar to sporadic cases of HPT. Most cases are asymptomatic and are diagnosed with
a finding of asymptomatic hypercalcemia. The surgical approach considers the possibility of multigland
disease, both hyperplasia and adenoma presenting in the same patient, and the possibility of only a single
adenoma.
CARCINOID SYNDROME
Definition and Etiology

Carcinoid syndrome is the most frequent of the ectopic hormone syndromes. It describes a constellation of
symptoms including cutaneous flushing, diarrhea, bronchospasms, and skin changes arising from tumoral
secretion of a variety of biogenic amines and peptides such as serotonin, 5-hydroxytryptophan, kallikrein,
histamine prostaglandins, and VIP. Over 40 types of secretary products have been implicated in carcinoid
syndrome.
Not all carcinoid tumors produce carcinoid syndrome; frequency varies from 1.7% to 18.7% in some
series, whereas prior series describe it in 8% of patients. The frequency of carcinoid varies with the loca-
tion of the carcinoid tumor. The most common locations causing the syndrome are found in parts of the
small intestine, pulmonary tract, certain types of gastric carcinoid tumors, and Meckel’s diverticulum.
Midgut carcinoids account for a mean of 72% of carcinoid syndrome cases.
Pathophysiology
The dominant culprit substance produced by a tumor explains the symptoms of carcinoid syndrome.
Serotonin and its precursors affect gut motility and secretion and cause bowel hypermotility and diarrhea.
Tumor vasoactive products stimulate myofibroblast proliferation and deposits of extracellular matrix,
which is thought to be the mechanism of carcinoid heart disease. Histamine, kallikrein, and prostaglan-
din secretion cause peripheral vasodilation leading to spells of flushing and even hypotension. Niacin
deficiency is not uncommon and can cause symptoms in carcinoid syndrome, although severe niacin
deficiency causing pellagra is uncommon. Niacin and serotonin share the precursor tryptophan, therefore,
niacin deficiency can ensue when there is a large amount of serotonin synthesis.
The most common symptoms of carcinoid syndrome are flushing and secretory diarrhea. The frequency
of flushing is up to 90%; and can be long lasting and purple or violaceous in hue with foregut tumors, or
short lasting and pink to red in hue for midgut tumors. Diarrhea is reported in anywhere from 60% to 80%
of cases of carcinoid syndrome and is spontaneous or a result of alcohol or tyramine-containing foods,
and occurs with or without abdominal pain. Bronchospasms occur with 15% frequency and manifest with
wheezing. Pellagra is rare but can manifest as dermatitis, diarrhea, or dementia in carcinoid syndrome
(Figure 9.24). Carcinoid heart disease has been reported in 19%–60% of carcinoid cases and may mani-
fest as dyspnea or a murmur indicating valvular disease (Figure 9.25).
Diagnosis
Initial testing to confirm the diagnosis of suspected carcinoid syndrome most frequently consists of a
24-hour urine assessment for 5-HIAA after avoiding serotonin-rich foods and potentially interfering
drugs. This measurement has a sensitivity of 73%–93% and a specificity of 100%. Plasma and serum
5-HIAA have similar sensitivity and specificity compared to urine and can be used for the diagnosis and
surveillance of carcinoid syndrome as long there is consideration of renal function given that there was an
inverse relationship between serum 5-HIAA levels and eGFR. Echocardiography is required to diagnose
FIGURE 9.24 Pellagra skin findings. Dry skin and scratches in a patient with pellagra. (From Anezka C. Rubin
de Celis Ferrari, João Glasberg, Rachel P Riechelmann, Carcinoid syndrome: Update on the pathophysiology
and treatment, Clinics, 73, Suppl 1, 2018, https://doi.org/10.6061/clinics/ 2018/e490s.)
FIGURE 9.25 Carcinoid valvular disease. Severe tricuspid regurgitation as seen in Doppler resulting from
thickened tricuspid valve (TV).
carcinoid heart disease and experts recommend using echocardiography for screening in patients with
known carcinoid syndrome.

Somatostatin analogues are considered standard treatment in carcinoid syndrome both for controlling
symptoms and for their antigrowth effect on the carcinoid tumor. Octreotide and lanreotide are somatosta-
tin analogues that bind to somatostatin receptors to inhibit the hormones and vasoactive substances that
cause the symptoms in carcinoid syndrome. They have been shown to reduce the frequency of diarrhea
and flushing in 70%–90% of patients with carcinoid symptoms. Octreotide-LAR and Lanreotide Autogel
are longer-acting agents requiring monthly administration. Pasireotide LAR has a different pharmacody-
namic profile than octreotide and lanreotide and has shown similar symptom control.
Promising studies have been undertaken in patients with somatostatin analogue-resistant disease.
Alternative therapies and methods include the mTOR inhibitor everolimus, PRRT (peptide-directed
radiotherapy) using 177Lu-DOTATATE with octreotide-LAR, cytoreductive therapy, liver-directed thera-
pies such as radiofrequency ablation of the tumor, as well as the tryptophan hydroxylase (TPH) inhibitor
telotristat ethyl. These alternative therapies can be considered for refractory disease or to palliate severe
symptoms (Figures 9.26 and 9.27).
FIGURE 9.26 PET/CT DOTATATE of lung carcinoid. Abnormal PET/CT DOTATATE study demonstrating
DOTATATE avid left lower lobe lung nodule, compatible with a lung carcinoid tumor. (Courtesy of Nuclear
Medicine Team, Loyola University.)
FIGURE 9.27 Carcinoid metastasis to the liver.
AUTOIMMUNE POLYENDOCRINE SYNDROMES
Definition/Etiology
Autoimmune polyglandular syndrome (APS) is a hereditary, diverse group of clinical syndromes of endo-
crine deficiencies caused by autoantibody-mediated destruction of endocrine and non-endocrine organs.
APS type I, also called autoimmune polyendocrinopathy–candidiasis– ectodermal dystrophy
(APECED) syndrome, can be inherited in both the autosomal recessive and autosomal dominant fashion.
It is associated with a mutation in the autoimmune regulator gene (AIRE) on chromosome 21q22.3. This
usually presents in early childhood and is noted to have a higher prevalence in certain populations such as
those living in Finland, Sardinia, and Persian Jews in Israel.
APS type II, also called Schmidt’s syndrome, is likely polygenic and is more prevalent than APS type
I. There is a female predominance, and the disease has a later onset than APS type I, usually manifesting
in adulthood.
IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked) is an extremely rare inher-
ited syndrome. IPEX has an earlier onset than APS type I and usually manifests in infancy. It has a high
mortality rate if treatment is not started promptly in the first few years of life.
Pathophysiology
The main abnormalities are loss of immune tolerance due to defects in the AIRE gene leading to lympho-
cytic infiltration of affected organs, along with the generation of autoantibodies to various components
of the affected organs. These include antibodies to adrenocortical enzymes such as 21-hydroxylase or
17-alpha-hydroxylase, glutamic acid decarboxylase (GAD), islet cell antibodies (ICA), thyroid peroxidase
(TPO), and type 1 interferon autoantibodies. The result of the aforementioned dysregulated processes
leads to autoimmune destruction of the glands and endocrine insufficiency.
Also, the use of an immune checkpoint inhibitor for cancer therapy has been identified as a new
trigger for autoimmune polyendocrine syndromes. For example, colitis is common, and autoimmune
thyroiditis has frequently been seen in patients treated with both CTLA-4 and PD-1 immune checkpoint
blockade, with an incidence of more than 10%.
Characterizing APS can be challenging due to the large heterogeneity and overlap of clinical manifesta-
tions and the broad spectrum. Table 9.1 summarizes the broad characteristics and classification of APS.
APS Type I
APS-I is characterized by the development of at least two of three cardinal components during childhood:
chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency (Addison’s
disease). Other manifestations include primary hypogonadism, type 1 diabetes mellitus, autoimmune
gastritis and other gastrointestinal problems, skin conditions such as alopecia and vitiligo, keratocon-
junctivitis, autoimmune hepatitis, and thyroid disease (less common than in APS type II). Ectodermal
dystrophies may manifest as tooth enamel hypoplasia and nail dystrophy (Figure 9.28).
APS Type II
APS-II is far more prevalent than APS-I and IPEX. Patients with APS-II have courses characterized by
at least two of the following three endocrinopathies: type 1 diabetes, autoimmune thyroid disease, and
Addison’s disease. Other autoimmune diseases may also be present such as celiac disease, alopecia, vit-
iligo, primary ovarian insufficiency, and pernicious anemia. Additional manifestations are more frequent
among patients with APS-II who have Addison’s disease. Unlike APS-I, APS-II usually manifests in
adulthood, most commonly in the third and fourth decades of life, and is more common in females.
IPEX
IPEX is an extremely rare inherited syndrome manifesting during infancy characterized by early-onset
type 1 diabetes; autoimmune enteropathy with intractable diarrhea and malabsorption; and dermatitis that
FIGURE 9.28 Secondary oral pseudomembranous candidiasis infection. (From Centers for Disease Control
and Prevention, Sol Silverman Jr., DDS, ID 6053.)
may be eczematiform, ichthyosiform, or psoriasiform. Eosinophilia and elevated IgE levels are seen often
in patients with IPEX. Renal involvement, most often with membranous glomerulonephritis or interstitial
nephritis, is also common.
Diagnosis
There is no universally accepted diagnostic protocol for APS. However, once APS is suspected, testing
for autoantibodies is indicated. Organ-specific autoantibodies predict for preexisting, or a potential for,
insufficiency of that endocrine gland. These include ICA and GAD for type 1 diabetes, TPO for thyroid
disease, 21-hydroxylase for Addison’s disease, and antismooth muscle antibody for autoimmune hepatitis.
Patients with IPEX have autoantibodies against harmonin and villin, proteins that are found in the micro-
villi of the intestinal brush border. Endocrine organ-specific function can be evaluated by measuring
fasting glucose (pancreas), calcium and phosphorus (parathyroid hormone [PTH] if indicated), TSH, early
morning cortisol, gonadotropins with sex steroids, and hemoglobin (pernicious anemia).
The general theme in the management of APS syndromes is hormone replacement as needed and treat-
ment of complications. All patients with the disease and asymptomatic carriers should have endocrine
organ function evaluation at least twice annually. Siblings of all patients with APS-I should be screened
for the disease. Patients with IPEX can be cured with allogenic bone marrow transplantation.
Chronic mucocutaneous candidiasis is treated with oral mycostatin and oral amphotericin B to avoid
drug resistance associated with continuous azole use. In addition, azoles inhibit steroid synthesis, which
increases the risk of precipitating adrenal insufficiency in patients with undiagnosed Addison’s disease.
Immunosuppressants, such as prednisone, azathioprine, and cyclosporine, are used for the treatment
of autoimmune hepatitis, keratitis, pneumonitis, and enteritis.
McCUNE–ALBRIGHT SYNDROME
Definition/Overview
Fibrous dysplasia/McCune–Albright syndrome (FD/MAS) is a rare disease typified by skeletal lesions,
skin hyperpigmentation, and variable hyperfunctioning endocrinopathies. The classic triad includes
fibrous dysplasia of the bone, café-au-lait skin macules, and precocious puberty. It results from an embry-
onic post-zygotic activating mutation in the GNAS gene, which encodes the α-subunit of the Gs signaling
protein. This leads to constitutive Gα s activation, ligand-independent signaling of the Gs-coupled protein
receptor, and inappropriate cAMP production. The clinical presentation is determined by the extent and
site of the mutation-bearing tissue, and there is a high degree of variability between individuals. FD/MAS
is not inherited and there are no known genetic or environmental triggers.
Pathophysiology
Constitutive signaling through LH, FSH, TSH, GnRH, and ACTH receptors results in endocrinopathies.
These include precocious puberty due to activation of ovarian or testicular tissue, thyroid enlargement,
nodules with or without hyperthyroidism, growth hormone (GH) excess, and neonatal hypercortisolism.
In bone, Gα s activation impairs differentiation of skeletal stem cells, leading to replacement of normal
bone with fibrotic stroma and immature woven bone. These FD lesions can also secrete increased fibro-
blastic growth factor 23 (FGF-23), which can lead to renal phosphate wasting. Increased cAMP signaling
in the skin stimulates melanin production, resulting in café-au-lait macules.
Characteristic café-au-lait macules show jagged and irregular borders (‘coast of Maine’) and are often
the first clinical sign. Location respects the midline of the body with distribution reflecting patterns of
embryonic cell migration (Figure 9.29). FD ranges from monostotic disease affecting one bone to poly-
ostotic and can involve any combination of the craniofacial, axial, or appendicular skeleton (Figure 9.30).
Radiographs show a characteristic lesion of thinning cortex and intramedullary ground glass. The proxi-
mal femur is a frequently involved site and may develop a classic ‘shepherd’s crook’ deformity (Figure
9.30A). Lesions of the craniofacial region can present with painless facial asymmetry or, in rare cases,
malocclusion, hearing, or visual impairment.
GNAS activation in ovarian tissue results in recurrent estrogen-producing cysts leading to early
breast development, vaginal bleeding, and growth acceleration. Precious puberty is less common in boys
and presents with macroorchidism and ultrasonographic abnormalities such as focal testicular heteroge-
neity, masses, and microlithiasis. Approximately 10%–15% of such boys show signs of early pubic and
axillary hair, acne, aggressive behavior, and early growth. Thyroid abnormalities occur in approximately
50% of patients with sonographic findings of diffuse thyroid enlargement and mixed cystic and solid
FIGURE 9.29 Characteristic café-au-lait macules show jagged and irregular borders (‘coast of Maine’).
Location respects the midline of the body with distribution reflecting patterns of embryonic cell migration.
(From Javaid MK, Boyce A, Appelman-Dijkstra N, Ong J, Defabianis P, Offiah A, et al. Best practice manage-
ment guidelines for fibrous dysplasia/McCune-Albright syndrome: A consensus statement from the FD/MAS
international consortium. Orphanet Journal of Rare Diseases. 2019 Jun 13;14(1).)
FIGURE 9.30 Fibrous dysplasia. (A) Radiographs show a characteristic lesion of thinning cortex and intramed-
ullary ground glass. (B) The proximal femur is a frequently involved site and may develop a classic ‘shepherd’s
crook’ deformity. (C) FD ranges from monostotic disease affecting one bone to polyostotic, and can involve
any combination of the craniofacial, axial, or appendicular skeleton. (From Javaid MK, Boyce A, Appelman-
Dijkstra N, Ong J, Defabianis P, Offiah A, et al. Best practice management guidelines for fibrous dysplasia/
McCune-Albright syndrome: A consensus statement from the FD/MAS international consortium. Orphanet
Journal of Rare Diseases. 2019 Jun 13;14(1).)
lesions interspersed with areas of normal-appearing tissue. In the pituitary, GNAS activation results in
somatolactotroph cell hyperplasia, leading to excessive growth hormone and prolactin production in 15%
of patients (Figure 9.31). A clinical sign in these patients is the expansion of craniofacial FD, which is
FIGURE 9.31 (A) Pelvic ultrasound in 5-year-old girl with large ovarian cyst and clinical signs of precocious
puberty. (B) Testicular ultrasound in a patient with macroorchidism. (C) Thyroid ultrasound showing multiple
hyper and hypoechoic nodules. (D) A pituitary MRI in a patient with growth hormone excess revealing a
pituitary macroadenoma. (From Javaid MK, Boyce A, Appelman-Dijkstra N, Ong J, Defabianis P, Offiah A, et
al. Best practice management guidelines for fibrous dysplasia/McCune-Albright syndrome: a consensus state-
ment from the FD/MAS international consortium. Orphanet Journal of Rare Diseases. 2019 Jun 13;14(1).)
sensitive to the effects of GH. Hypercortisolism is the rarest complication arising from GNAS activation
in the fetal adrenal gland and presents during the first year of life. There are no medical therapies that can
alter the disease course of FD, however, treatment of underlying endocrinopathies can help lessen skeletal
complications.
CARNEY COMPLEX
Carney complex (CNC) is a rare multiple endocrine neoplasia syndrome that is a constellation of distinc-
tive pigmented lesions of the skin and mucosal surfaces, cardiac and noncardiac myxomatous tumors,
and multiple endocrine tumors. It was previously known as NAME (nevi, atrial myxoma, ephelides) and
LAMB (lentigines, atrial myxoma, blue nevi) syndrome.
CNC is inherited in an autosomal dominant pattern with high penetrance but heterogeneous expres-
sion. It is mostly associated with mutations in the PRKAR1A gene. It can also occur sporadically due to
de novo mutations (approximately 25% of the cases).
Lentiginous skin pigmentation is the hallmark lesion of CNC, found in about 70%–80% of the
patients, with perioral and periocular distribution. About 40% of patients have multiple blue nevi. Café-
au-lait macules, nevus spilus, and, rarely, Spitz nevus can also be seen in patients with CNC (Figure 9.32).
Cutaneous myxomas of the head, neck, and trunk are seen in less than half of patients, but when pres-
ent strongly suggest a diagnosis of CNC (Figure 9.33).
Endocrine tumors such as large-cell calcifying Sertoli cell tumors (LCCSCTs), primary pigmented
nodular adrenocortical disease (PPNAD), and GH-secreting pituitary adenomas, are frequent manifes-
tations of CNC. Almost 75% of male patients with CNC have LCCSCTs, which often leads to prepu-
bertal gynecomastia. Cushing’s syndrome secondary to PPNAD can be seen in 25%–45% of patients.
FIGURE 9.32 Demonstrating the characteristic lentigines associated with Carney syndrome in the facial
region. (From British Journal of Plastic Surgery. With permission.)
FIGURE 9.33 Cutaneous myxomas associated with Carney syndrome. (From British Journal of Plastic Surgery.
With permission.)
GH-secreting pituitary adenomas are the least common, occurring only in 10%–15% of patients.
Approximately 75% of patients with CNC have thyroid nodules, however, the incidence of thyroid cancer
is less than 10%.
Hallmark non-endocrine tumors associated with CNC include cardiac myxomas (most
frequent), psammomatous melanotic schwannomas, breast myxomas and ductal adenomas, and
osteochondromyxomas.
Diagnosis is made on clinical suspicion. Treatment consists of surgical resection of various tumors.
For surveillance, an annual echocardiogram for myxomas and annual ultrasounds of the thyroid and testes
for nodules is recommended. Annual measurement of urinary free cortisol, IGF-1, and prolactin begin-
ning in adolescence is also recommended to screen for cortisol excess and pituitary overactivity (Figure
9.34).
FIGURE 9.34 Histologic examination of the myxoma pictured in Figure 9.33. (From British Journal of Plastic
Surgery. With permission.)
VON HIPPEL–LINDAU DISEASE

Von Hippel–Lindau (VHL) disease is an inherited, autosomal dominant syndrome characterized by a
variety of benign and malignant tumors. The disease can manifest at any point in a patient’s life; the mean
age at initial presentation is about 26.
The spectrum of VHL-associated tumors includes:
• Hemangioblastomas of the brain (cerebellum) and spine

• Retinal capillary hemangioblastomas (retinal angiomas)
• Clear cell renal cell carcinomas
• Pheochromocytomas
• Endolymphatic sac tumors of the middle ear
• Serous cystadenomas and neuroendocrine tumors of the pancreas
• Papillary cystadenomas of the epididymis and broad ligament
VHL disease can be broadly classified into two categories based on the likelihood of developing pheo-
chromocytoma. Patients with type 1 disease have a lower risk of developing pheochromocytoma, whereas
those with type 2 have a higher risk for it.
VHL disease results from a deletion or mutation in the VHL gene located on the short arm of chro-
mosome 3. The normal VHL gene acts as a tumor-suppressor gene, with the function of preventing the
formation of tumors. Incidence is 1 in 36,000 individuals and 20% of cases are due to de novo mutations.
Hemangioblastomas are the most common lesions associated with VHL disease, affecting 60% to
84% of patients, and typically occur in the cerebellum, spinal cord, or retina (Figure 9.35). Renal cell
carcinomas (particularly the clear cell variant) are the second most common tumor, occurring in almost
two-thirds of the patients. Patients with VHL disease also have a 25%–30% chance of developing pheo-
chromocytoma. Pheochromocytomas seen in VHL disease usually present at a younger age, may be
extra-adrenal, and are less likely to present with symptoms or biochemical evidence of catecholamine
production compared with those occurring in patients without VHL.
Diagnosis is made by genetic testing to look for pathogenic variants in the VHL gene. Surveillance for
the development of tumors, especially hemangioblastomas and pheochromocytomas, starts in childhood
(Figures 9.36 and 9.37).
Treatment modalities include different surgical interventions based on tumor size and stage, and radi-
ation therapy. Belzutifan is also used for the management of hemangioblastomas, renal cell carcinomas,
and pancreatic tumors. Belzutifan specifically inhibits hypoxia-inducible factor-2 alpha (HIF-2 alpha), a
key protein regulated by the VHL pathway.
FIGURE 9.35 Retinal hemangioblastoma. (From Toth, Cynthia A., Handbook of Pediatric Retinal OCT and the
Eye–Brain Connection, 2019, Elsevier Books. With permission.)
FIGURE 9.36 Histology of clear cell renal carcinoma. (From Nephron, CC BY-SA 3.0, via Wikimedia Commons.)
FIGURE 9.37 Gross specimen of clear cell renal carcinoma. (From Ed Uthman, MD (1953– ), Public domain,
via Wikimedia Commons.)
BIBLIOGRAPHY
Accardo, G., et al., Genetics of medullary thyroid cancer: An overview. Int J Surg, 2017. 41. suppl 1: p. S2–s6.
Adaway, J.E., et al., Serum and plasma 5-hydroxyindoleacetic acid as an alternative to 24-h urine 5-hydroxyindole-
acetic acid measurement. Ann Clin Biochem, 2016. 53(5): p. 554–560.
Agarwal, S.K., Multiple endocrine neoplasia type 1. Front Horm Res, 2013. 41: p. 1–15.
Al-Salameh, A., C. Baudry, and R. Cohen, Update on multiple endocrine neoplasia Type 1 and 2. Presse Med, 2018.
47(9): p. 722–731.
Al-Salameh, A., et al., Clinical aspects of multiple endocrine neoplasia type 1. Nat Rev Endocrinol, 2021. 17(4): p.
207–224.
Alevizaki, M. and K. Saltiki, Primary hyperparathyroidism in MEN2 syndromes. Recent Results Cancer Res, 2015.
204: p. 179–186.
Amodru, V., et al., MEN2-related pheochromocytoma: Current state of knowledge, specific characteristics in
MEN2B, and perspectives. Endocrine, 2020. 69(3): p. 496–503.
Aufforth, R.D., et al., Pheochromocytoma screening initiation and frequency in von Hippel-Lindau syndrome. J Clin
Endocrinol Metab, 2015. 100(12): p. 4498–4504.
Baghai, M., et al., Pheochromocytomas and paragangliomas in von Hippel–Lindau disease: A role for laparoscopic
and cortical-sparing surgery. Arch Surg, 2002. 137(6): p. 682–688; discussion 688–689.
Barzaghi, F., et al., Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An inter-
national multicenter retrospective study. J Allergy Clin Immunol, 2018. 141(3): p. 1036–1049.e5.
Bouma, G., et al., Niacin (vitamin B3) supplementation in patients with serotonin-producing neuroendocrine tumor.
Neuroendocrinology, 2016. 103(5): p. 489–494.
Boutzios, G. and G. Kaltsas, Clinical syndromes related to gastrointestinal neuroendocrine neoplasms. Front Horm
Res, 2015. 44: p. 40–57.
Boyce, A.M., et al., Fibrous dysplasia/McCune-Albright syndrome. In: GeneReviews®, Eds. M.P. Adam, et al. 1993,
Seattle, WA: University of Washington.
Brandi, M.L., et al., CONSENSUS: Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol
Metab, 2001. 86(12): p. 5658–5671.
Buffet, A., et al., An overview of 20 years of genetic studies in pheochromocytoma and paraganglioma. Best Pract
Res Clin Endocrinol Metab, 2020. 34(2): p. 101416.
Carlomagno, F., et al., The different RET-activating capability of mutations of cysteine 620 or cysteine 634 correlates
with the multiple endocrine neoplasia type 2 disease phenotype. Cancer Res, 1997. 57(3): p. 391–395.
Carney, J.A. and B.C. Toorkey, Ductal adenoma of the breast with tubular features. A probable component of the
complex of myxomas, spotty pigmentation, endocrine overactivity, and schwannomas. Am J Surg Pathol, 1991.
15(8): p. 722–731.
Castinetti, F., et al., A comprehensive review on MEN2B. Endocr Relat Cancer, 2018. 25(2): p. T29–T39.
Castinetti, F., et al., Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associ-
ated with multiple endocrine neoplasia type 2: An international retrospective population-based study. Lancet
Oncol, 2014. 15(6): p. 648–655.
Correa, R., P. Salpea, and C.A. Stratakis, Carney complex: An update. Eur J Endocrinol, 2015. 173(4): p. M85–97.
Coyle, D., F. Friedmacher, and P. Puri, The association between Hirschsprung's disease and multiple endocrine neo-
plasia type 2a: A systematic review. Pediatr Surg Int, 2014. 30(8): p. 751–756.
Dalin, F., et al., Clinical and immunological characteristics of autoimmune Addison disease: A nationwide Swedish
multicenter study. J Clin Endocrinol Metab, 2017. 102(2): p. 379–389.
Donovan, D.T., et al., Familial cutaneous lichen amyloidosis in association with multiple endocrine neoplasia type
2A: A new variant. Henry Ford Hosp Med J, 1989. 37(3–4): p. 147–150.
Dreijerink, K.M., et al., Breast-cancer predisposition in multiple endocrine neoplasia type 1. N Engl J Med, 2014.
371(6): p. 583–584.
Eisenbarth, G.S. and P.A. Gottlieb, Medical progress: Autoimmune polyendocrine Syndromes. N Engl J Med, 2004.
350(20): p. 2068–2079.
Eisenhofer, G., et al., Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type
2 display distinct biochemical and clinical phenotypes. J Clin Endocrinol Metab, 2001. 86(5): p. 1999–2008.
Erichsen, M.M., et al., Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency:
Observations from a Norwegian registry. J Clin Endocrinol Metab, 2009. 94(12): p. 4882–4890.
Feldman, J.M., Carcinoid tumors and the carcinoid syndrome. Curr Probl Surg, 1989. 26(12): p. 835–885.
Fisher, G.A., Jr., et al., Lanreotide therapy in carcinoid syndrome: Prospective analysis of patient-reported symptoms
in patients responsive to prior octreotide therapy and patients naïve to somatostatin analogue therapy in the
elect PHASE 3 study. Endocr Pract, 2018. 24(3): p. 243–255.
Golden, T. and J.A. Siordia, Osteochondromyxoma: Review of a rare carney complex criterion. J Bone Oncol, 2016.
5(4): p. 194–197.
Gomes-Porras, M., J. Cárdenas-Salas, and C. Álvarez-Escolá, Somatostatin analogs in clinical practice: A review.
Int J Mol Sci, 2020. 21(5).
Grey, J. and K. Winter, Patient quality of life and prognosis in multiple endocrine neoplasia type 2. Endocr Relat
Cancer, 2018. 25(2): p. T69–T77.
Guerin, C., et al., Looking beyond the thyroid: Advances in the understanding of pheochromocytoma and hyper-
parathyroidism phenotypes in MEN2 and of non-MEN2 familial forms. Endocr Relat Cancer, 2018. 25(2): p.
T15–T28.
Hassan, S.A., et al., Carcinoid heart disease. Heart, 2017. 103(19): p. 1488–1495.
Husebye, E.S., et al., Clinical manifestations and management of patients with autoimmune polyendocrine syndrome
type I. J Intern Med, 2009. 265(5): p. 514–529.
Ito, T., L. Lee, and R.T. Jensen, Carcinoid-syndrome: Recent advances, current status and controversies. Curr Opin
Endocrinol Diabetes Obes, 2018. 25(1): p. 22–35.
Javaid, M.K., et al., Best practice management guidelines for fibrous dysplasia/McCune-Albright syndrome: A con-
sensus statement from the FD/MAS international consortium. Orphanet J Rare Dis, 2019. 14(1): p. 139.
Jensen, R., J. Norton, and K. Oberg, Neuroendocrine Tumors in Sleisenger and Fordtran’s Gastrointestinal and
Liver Diseases, 10th ed., Eds. M. Feldman, L.S. Friedman, L.J. Brandt. 2016, Philadelphia: Elsevier Saunders.
Jhiang, S.M., The RET proto-oncogene in human cancers. Oncogene, 2000. 19(49): p. 5590–5597.
Kamilaris, C.D.C. and C.A. Stratakis, Multiple endocrine neoplasia Type 1 (MEN1): An update and the significance
of early genetic and clinical diagnosis. Front Endocrinol (Lausanne), 2019. 10: p. 339.
Kloos, R.T., et al., Medullary thyroid cancer: Management guidelines of the American Thyroid Association. Thyroid,
2009. 19(6): p. 565–612.
Kornaczewski Jackson, E.R., et al., Utility of FDG-PET imaging for risk stratification of pancreatic neuroendocrine
tumors in MEN1. J Clin Endocrinol Metab, 2017. 102(6): p. 1926–1933.
Lampasona, V., et al., Autoantibodies to harmonin and villin are diagnostic markers in children with IPEX syn-
drome. PLOS ONE, 2013. 8(11): p. e78664.
Lenders, J.W., et al., Phaeochromocytoma. Lancet, 2005. 366(9486): p. 665–675.
Li, S.R., et al., Clinical and biochemical features of pheochromocytoma characteristic of Von Hippel-Lindau syn-
drome. World J Surg, 2020. 44(2): p. 570–577.
Lonser, R.R., et al., Von Hippel-Lindau disease. Lancet, 2003. 361(9374): p. 2059–2067.
Luis, S.A. and P.A. Pellikka, Carcinoid heart disease: Diagnosis and management. Best Pract Res Clin Endocrinol
Metab, 2016. 30(1): p. 149–158.
Maher, E.R. and W.G. Kaelin, Jr., Von Hippel-Lindau disease. Med (Baltim), 1997. 76(6): p. 381–391.
Maher, E.R., et al., Clinical features and natural history of von Hippel-Lindau disease. Q J Med, 1990. 77(283): p.
1151–1163.
McDonnell, J.E., et al., Multiple endocrine neoplasia: An update. Intern Med J, 2019. 49(8): p. 954–961.
Mendelsohn, G., S.A. Wells, Jr., and S.B. Baylin, Relationship of tissue carcinoembryonic antigen and calcitonin
to tumor virulence in medullary thyroid carcinoma. An immunohistochemical study in early, localized, and
virulent disseminated stages of disease. Cancer, 1984. 54(4): p. 657–662.
Okafor, C., et al., Update on targeted therapy in medullary thyroid cancer. Front Endocrinol (Lausanne), 2021. 12:
p. 708949.
Powell, B.R., N.R.M. Buist, and P. Stenzel, An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infec-
tion in infancy. J Pediatr, 1982. 100(5): p. 731–737.
Raue, F. and K. Frank-Raue, Genotype-phenotype correlation in multiple endocrine neoplasia type 2. Clin (S Paulo),
2012. 67 (Suppl 1): p. 69–75.
Rizzoli, R., J. Green, 3rd, and S.J. Marx, Primary hyperparathyroidism in familial multiple endocrine neoplasia type
I. Long-term follow-up of serum calcium levels after parathyroidectomy. Am J Med, 1985. 78(3): p. 467–474.
Rubin de Celis Ferrari, A.C., J. Glasberg, and R.P. Riechelmann, Carcinoid syndrome: Update on the pathophysiol-
ogy and treatment. Clin (Sao Paulo), 2018. 73. suppl 1: p. e490s.
Russell, T.R. and R. Ho, Conversion of 3T3 fibroblasts into adipose cells: Triggering of differentiation by prostaglan-
din F2alpha and 1-methyl-3-isobutyl xanthine. Proc Natl Acad Sci U S A, 1976. 73(12): p. 4516–4520.
Sadowski, S.M., et al., Results of (68)gallium-DOTATATE PET/CT scanning in patients with multiple endocrine
neoplasia Type 1. J Am Coll Surg, 2015. 221(2): p. 509–517.
Shetty Roy, A.N., et al., Familial recurrent atrial myxoma: Carney's complex. Clin Cardiol, 2011. 34(2): p. 83–86.
Shields, L.B., et al., Malignant psammomatous melanotic schwannoma of the spine: A component of Carney com-
plex. Surg Neurol Int, 2011. 2: p. 136.
Soga, J., Y. Yakuwa, and M. Osaka, Carcinoid syndrome: A statistical evaluation of 748 reported cases. J Exp Clin
Cancer Res, 1999. 18(2): p. 133–141.
Spencer, T., et al., The clinical spectrum of McCune-Albright syndrome and its management. Horm Res Paediatr,
2019. 92(6): p. 347–356.
Stratakis, C.A., Hereditary syndromes predisposing to endocrine tumors and their skin manifestations. Rev Endocr
Metab Disord, 2016. 17(3): p. 381–388.
Stratakis, C.A., Carney complex: A familial lentiginosis predisposing to a variety of tumors. Rev Endocr Metab
Disord, 2016. 17(3): p. 367–371.
Thakker, R.V., et al., Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol
Metab, 2012. 97(9): p. 2990–3011.
Tonelli, F., et al., Surgical approach in hereditary hyperparathyroidism. Endocr J, 2009. 56(7): p. 827–841.
Torino, F., S.M. Corsello, and R. Salvatori, Endocrinological side-effects of immune checkpoint inhibitors. Curr
Opin Oncol, 2016. 28(4): p. 278–287.
Uchino, S. Multiple endocrine neoplasia type 2 in Japan: Large-scale analysis of data from the MEN consortium of
Japan. Nihon Geka Gakkai Zasshi, 2012. 113(4): p. 362–367.
Vinik, A., et al., ELECT: A phase 3 study of efficacy and safety of lanreotide autogel/depot (LAN) treatment for
carcinoid syndrome in patients with neuroendocrine tumors (NETs). J Clin Oncol, 2014. 32(3): p. 268–268.
Voss, R.K., et al., Medullary thyroid carcinoma in MEN2A: ATA moderate- or high-risk RET mutations do not
predict disease aggressiveness. J Clin Endocrinol Metab, 2017. 102(8): p. 2807–2813.
Waguespack, S.G., et al., Management of medullary thyroid carcinoma and MEN2 syndromes in childhood. Nat Rev
Endocrinol, 2011. 7(10): p. 596–607.
Walther, M.M., et al., Clinical and genetic characterization of pheochromocytoma in von Hippel-Lindau families:
Comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma. J
Urol, 1999. 162(3 Pt 1): p. 659–664.
Wei, S., et al., Detection of molecular alterations in medullary thyroid carcinoma using next-generation sequencing:
An institutional experience. Endocr Pathol, 2016. 27(4): p. 359–362.
Wells, S.A., Jr., et al., Revised American Thyroid Association guidelines for the management of medullary thyroid
carcinoma. Thyroid, 2015. 25(6): p. 567–610.
Wildin, R.S., S. Smyk-Pearson, and A.H. Filipovich, Clinical and molecular features of the immunodysregulation,
polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet, 2002. 39(8): p. 537–545.
Wolin, E.M., et al., Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine
tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Des Devel Ther, 2015.
9: p. 5075–5086.
Yip, L., et al., Multiple endocrine neoplasia type 2: Evaluation of the genotype-phenotype relationship. Arch Surg,
2003. 138(4): p. 409–416.
Zbar, B., et al., Germline mutations in the von Hippel-Lindau disease (VHL) gene in families from North America,
Europe, and Japan. Hum Mutat, 1996. 8(4): p. 348–357.
Endocrinologic Care of
Transgender Patients 10
Pranav Gupta, Mark Walsh,
Howa Yeung, and Mary O. Stevenson
ABSTRACT
The importance of providing comprehensive transgender care is increasingly recognized, with grow-
ing societal acceptance, destigmatization, and more transgender persons seeking medical care.
Endocrinologists play an important role in providing gender-affirming hormonal therapy to help align
secondary sex characteristics with the affirmed gender. For transgender adolescents, therapy can begin
with medication to halt the progression of puberty followed by sex hormone therapy. Estradiol is the
main hormone used for transgender females to induce feminizing characteristics in combination with
antiandrogen therapy. For transgender males, testosterone is used to induce masculinizing characteristics.
Fertility-preserving options should be discussed with all patients before initiation of gender-affirming
hormone therapy. Patients on gender-affirming hormone therapy should be closely monitored to minimize
the potential side effects and assess therapy progress. Assorted surgeries and procedures are available for
transgender patients to help align their primary and secondary sex characteristics with their gender, which
will be briefly reviewed.
INTRODUCTION AND TERMINOLOGY

Gender identity is defined as one’s internal sense of being male, female, or something else. Transgender
individuals are persons whose gender identity differs from their sex assigned at birth. Transgender men
identify as male and were sex assigned female a birth. Transgender women identify as female and were
sex assigned male at birth. Transgender individuals have always existed, but the fear of marginalization
and social stigma have led to an underestimation of their numbers in the past. With more societal accep-
tance, the number of individuals publicly identifying as transgender is rising. Approximately 1 in every
250 adults, or almost 1.4 million Americans, identify as transgender (1). One avenue of gender affirmation
that many, but not all, transgender persons will pursue is gender-affirming hormone therapy (GAHT).
Additional methods may include social transition and/or gender-affirming surgeries. Endocrinologists
DOI: 10.1201/9781003100669-10 301

play a pivotal role in providing gender-affirming care by prescribing and managing hormone therapy. This
chapter will not discuss diagnosing or managing gender nonbinary or genderqueer patients.
DIAGNOSIS OF GENDER DYSPHORIA AND

SPECIAL HEALTH CONSIDERATIONS
Gender dysphoria (GD) is the term used to describe the distress or impairment in social, occupational, or
other important areas of functioning that can be caused when a person’s biological sex and their gender
identity are incongruent (2). Not all transgender persons experience gender dysphoria but articulate a
gender identity that differs from their designated sex, known as gender incongruence (3). For adults, the
criteria to start GAHT include persistent and well-documented GD/gender incongruence, full decision-
making capacity and ability to provide informed consent, age of majority, and reasonable control of any
mental health condition(s), if present (3).
Transgender persons are disproportionately affected by human immunodeficiency virus (HIV),
depression, anxiety, substance use disorder, and risk of suicide, exacerbated by experiences of oppression,
discrimination, and violence (4). In adults, GAHT can reduce symptoms of anxiety and depression, lower
perceived and social distress, and improve quality of life and self-esteem (5). Therefore, access to GAHT
is crucial for the well-being of transgender persons.
FERTILITY
For all patients wishing to start GAHT, clinicians should discuss possible permanent effects on fertil-
ity (6). This includes all adolescents seeking to initiate pubertal suppressant medications and patients
of any age initiating sex hormone therapy. Techniques for fertility preservation should be addressed,
which include cryopreservation of spermatozoa, oocytes, or embryos. Because the long-term outcomes of
GAHT on reproductive ability have not been widely studied, it is ideal to offer fertility-preserving treat-
ments prior to initiation of hormone therapy, but treatments may still be possible with or without interrup-
tion for those already on GAHT. Fertility-preserving procedures may be cost-prohibitive and can require
examinations and invasive procedures that may be intolerable to patients.
Fertility potential may not be possible for adolescents that start pubertal suppression in early Tanner
stages with subsequent initiation of hormones for the affirmed gender. This is due to impairment of sper-
matogenesis or oocyte maturation leading to gamete immaturity (3). Pubertal suppression can be delayed
to later stages of puberty to allow for gamete maturation, but this is often not preferred by patients due to
the development of secondary sexual characteristics associated with later stages of puberty.
PEDIATRIC AND ADOLESCENT GENDER CARE

The number of children and adolescents in the United States (U.S.) who identify as transgender contin-
ues to increase, with approximately 150,000 adolescents between the ages of 13 and 17 identifying as
transgender (7). In adolescents, older age and later pubertal stage at the time of presentation for gender-
affirming care are associated with increased rates of depression and anxiety (8). The Endocrine Society
10 • Endocrinologic Care of Transgender Patients 303
recommends a multidisciplinary team for the treatment of transgender children and adolescents, including
a qualified mental health professional experienced in diagnosing GD (3). Parents or guardians need to
consent to treatment as well as provide support throughout the transition process (3). Prepubertal children
are not recommended to start medical treatment (3). Adolescents who meet diagnostic criteria for GD and
express an understanding of the outcomes and side effects of treatment should initially undergo puber-
tal suppression using gonadotropin-releasing hormone (GnRH) analogues starting at Tanner stage 2 of
puberty (3). Tanner stage 2 is discernable by breast budding in natal females (9), and penis and testicular
enlargement in natal males (10). Pubertal suppression in transgender adolescents is associated with favor-
able mental health outcomes (11). Treatment with GnRH analogues is fully reversible with the return of
pubertal progression after discontinuation of therapy.
Sex hormone therapy can be started once a multidisciplinary team has confirmed the persistence of
GD and that an adolescent has sufficient capacity to give informed consent, which most adolescents have
by age 16 (3). The impact of sex hormone initiation at 14 years of age is being studied due to possible
detrimental effects on bone health and isolation from same-aged peers associated with delaying to 16
years of age (12). For adolescents presenting in later stages of puberty, GnRH analogues and sex hormone
therapy may be started simultaneously. Sex hormone is initiated using gradually increasing doses with
adjustments every 6 months. Clinical pubertal development should be monitored every 3–6 months; and
laboratory parameters, including luteinizing hormone (LH), follicle-stimulating hormone (FSH), total
testosterone or estradiol, and 25-hydroxy vitamin D levels, should be measured every 6–12 months (3).
Due to the risk-impaired bone growth from GnRH analogues, bone mineral density (BMD) evaluation
can be considered every 1–2 years (3, 13).
FEMINIZING HORMONE THERAPY, LONG-TERM

MONITORING, AND ADVERSE OUTCOMES
Feminizing hormone therapy for transgender women includes both estradiol and antiandrogen therapy
if testes are present. In the U.S., estradiol is prescribed as 17-beta estradiol in either oral, parenteral,
or transdermal formulations. Oral estradiol is recommended at doses of 2–6 mg per day in twice-daily
divided dosing, transdermal estradiol in 0.025–0.2 mg/day dosing with a new patch placed every 3–5
days, and intramuscular (IM) estradiol ester (either valerate or cypionate) at doses of 5–30 mg every 2
weeks or 2–10 mg every week (3). Weekly injections may cause less variation in hormone levels between
injections. Spironolactone is the primary antiandrogen in the U.S. and acts principally as an androgen
receptor antagonist. It is recommended in doses of 100–300 mg/day divided into twice-daily dosing (3).
An alternative option for antiandrogen therapy is GnRH analogue therapy, recommended at doses of 3.75
mg subcutaneously (SQ) every month or 11.25 mg SQ every 3 months. Indications for GnRH analogue
therapy may include failure to suppress testosterone level to goal at maximum doses, intolerable side
effects, chronic kidney disease, or hyperkalemia limiting titration of doses.
Feminizing effects of therapy generally take 1–6 months to see the onset of changes, but some may
take up to 12 months, and maximum feminizing effects can take up to 3 years (3). Feminizing changes
include a redistribution of body fat from the abdomen to the gynoid (hips/buttocks) region; a decrease in
muscle mass and strength; an increase in scalp hair growth; a decrease in terminal hair growth; decrease
in oiliness and softening of skin; and decrease in testicular volume, sexual desire, and spontaneous erec-
tions (3).
The highest risk of adverse outcome from estradiol therapy is venous thromboembolism (VTE) (3).
Additional risk factors, including tobacco smoking, immobilization, hypertension, hyperlipidemia, and
baseline clotting disorders, likely amplify the possibility of VTE for transgender women on estradiol
therapy (14). Transdermal formulations of estradiol may pose the least risk of VTE (15). The moderate
risks of adverse outcomes include macroprolactinoma, coronary artery disease, cerebrovascular disease,
hypertriglyceridemia, cholelithiasis, and breast cancer (3). There are currently conflicting data regard-
ing breast cancer development risk, with some studies showing no increased signal for hormone-related
cancers up to 10 years (14). However, a Dutch study in 2019 did find an increased risk of breast cancer
in transgender women compared to cisgender men, but the risk was not increased compared to cisgender
women (16). Transgender women may experience several dermatologic conditions, including hirsutism,
pseudofolliculitis barbae, and melasma (17). Feminizing hormone therapy with estradiol has been shown
to preserve or improve bone mineral density across studies (18–20).
Long-term monitoring should include clinical evaluation of patients every 3 months during the first
year, as well as monitoring of laboratory values of estradiol and testosterone levels, and potassium and
kidney function for individuals on spironolactone therapy (3, 21). The Endocrine Society recommends
targeting estradiol levels of 100–200 pg/dL and testosterone <50 ng/dL (3). Estradiol levels should be
measured halfway between injections or at peak/trough levels if patients are on parenteral therapy (3).
Transgender females should have breast exams, mammograms, and prostate cancer screening, according
to national cancer screening guidelines. BMD evaluation should be considered at baseline, as transgen-
der females have been shown to have lower bone mineral density before starting GAHT as compared to
cisgender males (13, 22), as well as for those patients who have been noncompliant with hormone therapy
and have had a gonadectomy (3, 23).
MASCULINIZING HORMONE THERAPY, LONG-

TERM MONITORING, AND ADVERSE OUTCOMES
For transgender men, testosterone is used to induce masculinizing secondary sex characteristics.
Testosterone can be given as an injection in either IM or SQ form, or transdermally as a patch or gel.
Testosterone enanthate or cypionate are recommended in doses of 100–200 mg IM every 2 weeks or
half dose of 50–100 mg SQ every week (3). Subcutaneous injections are associated with less discomfort
due to the smaller needle sizes used for SQ administration. Testosterone undecanoate is recommended
at doses of 1000 mg every 12 weeks. For transdermal preparations, testosterone gel 1.6% is suggested
at 50–100 mg/day and a testosterone patch of 2.5–7.5 mg/day (3). Testosterone gel can be transferred to
intimate partners or children through skin-to-skin contact, and patients should be counseled on thorough
handwashing and coverage of application sites. Testosterone patches may produce local contact dermatitis
in areas of patch placement. Menstrual bleeding is expected to stop within 1–6 months of testosterone
initiation, and progesterone can be initiated in either oral or parenteral formulation (as depot medroxypro-
gesterone) to halt menses before this time (24). Masculinizing changes of testosterone therapy include the
redistribution of body fat from the hips and buttocks to the abdominal region, an increase in muscle mass
and strength, an increase in facial/body hair growth, scalp hair loss, clitoral enlargement, vaginal atrophy,
and deepening of the voice (3). The onset of changes can vary but typically are between 1 and 12 months,
and maximum effects can be seen for up 5 years after initiation of therapy (3).
The highest risk of adverse outcome from testosterone therapy is erythrocytosis, defined as a hema-
tocrit level >50% (3). The risk of erythrocytosis in transgender men on testosterone has been shown
to increase with tobacco use, higher body mass index, underlying chronic obstructive pulmonary dis-
ease (COPD), sleep apnea, asthma (25), and longer-acting preparations of testosterone administration,
particularly testosterone undecanoate (25, 26). Therefore, strategies to mitigate erythrocytosis include
addressing underlying conditions that may be contributing to blood count elevations as well as changes to
shorter-acting formulations of testosterone, including transdermal preparations. Clinicians should ensure
testosterone levels are within the goal range outlined by the Endocrine Society (see later) and reduce dos-
ages for supratherapeutic levels.
The moderate risks of testosterone therapy include liver dysfunction, coronary artery disease, cere-
brovascular disease, hypertension, and breast or uterine cancer (3). The risk of severe liver dysfunction
(transaminases >3-fold the upper limit of normal) was primarily associated with oral 17-alkylated testos-
terone use, which is not recommended due to this concern. To date, studies with approximately 10 years
of follow-up have not shown an increase in cardiovascular outcomes, including myocardial infarction,
ischemic stroke, or venous thromboembolism, in transgender men taking testosterone therapy (14, 27,
28). Similarly, no increased signal for hormone-related cancers has been seen in studies up to 10 years
(14). Lipid profile changes may include increases in triglyceride and low-density lipoprotein levels and
decreases in high-density lipoprotein cholesterol levels (28). Transgender men frequently experience acne
vulgaris (see Figures 10.1 and 10.2) and androgenic alopecia (17). Finally, masculinizing therapy with
testosterone resulted in stable or improved BMD across studies (13, 18, 20, 29).
Monitoring should include clinical evaluation every 3 months during the first year, including evalu-
ation of weight and blood pressure, and laboratory values of testosterone, hemoglobin/hematocrit, liver
function, and lipids (3). Recommended target testosterone levels are 400–700 ng/dL, measuring levels
halfway between injections or peak/trough levels if patients are on parenteral therapy and at least 2 hours
after transdermal administration (3). Annual breast exams, mammograms, and cervical cancer screening
should be done according to national cancer screening guidelines. BMD testing should be considered for
patients who are noncompliant with or discontinue hormone therapy after gonadectomy (3).
FIGURE 10.1 Eighteen-year-old transgender man with moderate inflammatory acne affecting the trunk.
FIGURE 10.2 Eighteen-year-old transgender man with moderate inflammatory acne affecting the face and
trunk.
SURGICAL OPTIONS FOR TRANSGENDER PATIENTS

Surgical procedures can be an important component of gender-affirming care. Some transgender patients
will pursue surgeries to help further align either primary or secondary sexual characteristics with their
gender identity. For both transgender men and women, special consideration should be paid to surgical
procedures that have permanent effects on fertility and are further described later. The Endocrine Society
recommends that for all surgical procedures that affect fertility, patients have persistent, well-documented
GD; be the legal age of majority; have lived full-time in their affirmed gender; taken GAHT (if desired
by the patient and not medically contraindicated) for 12 months; and demonstrate an understanding of
the risks and benefits of surgery (3). Examples of surgical procedures that transgender women may seek
include (but are not limited to) facial feminization, breast augmentation, orchiectomy, penectomy, and
vaginoplasty (30). Surgical procedures that transgender men may undergo include bilateral mastectomy
and reconstruction of the masculine chest (see Figures 10.3 and 10.4), hysterectomy and/or oophorectomy,
phalloplasty, and metaoidioplasty (30).
Finally, for both transgender women and men, therapy with a speech language pathologist may be an
additional resource to help patients align speech patterns with their gender identity.
FIGURE 10.3 Nineteen-year-old transgender male who underwent double incision mastectomy with free
nipple grafts, preoperative frontal view.
FIGURE 10.4 Nineteen-year-old transgender male who underwent double incision mastectomy with free
nipple grafts, 3 months postoperative front view.
CONCLUSION
More individuals are now seeking GAHT. For transgender persons, GD can significantly improve on hor-
mone therapy, and endocrinologists need to be aware of the current treatment guidelines, risks, and limita-
tions of GAHT. Hormonal therapy is deemed safe when given in a clinical setting but should be monitored
due to the risks and side effects. Fertility preferences should always be addressed prior to initiation of
GAHT. Currently, there is limited but growing research on both the short- and long-term effects of GAHT
on adolescents and adults. Most of the studies have been done in Western countries and higher socioeco-
nomic groups, and therefore less is known about underrepresented populations. Transgender individuals
have specific and unique needs during the journey of their transition. Therefore, GAHT should be done in
a way that guidelines are followed but also aligns with patients’ priorities and preferences.
REFERENCES
1. Meerwijk EL, Sevelius JM. Am J Public Health (2017). PMID: 28075632/DOI: 10.2105/ajph.2016.303578
2. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric
Association (APA); 2013.
3. Hembree WC, Cohen-Kettenis PT, Gooren L, Hannema SE, Meyer WJ, Murad MH, et al. Endocr Pract (2017).
PMID: 29320642/DOI: 10.4158/1934-2403-23.12.1437
4. Winter S, Diamond M, Green J, Karasic D, Reed T, Whittle S, et al. Lancet (2016). PMID: 27323925/DOI:
10.1016/s0140-6736(16)00683-8
5. Nguyen HB, Chavez AM, Lipner E, Hantsoo L, Kornfield SL, Davies RD, et al. Curr Psychiatry Rep (2018).
PMID: 30306351/DOI: 10.1007/s11920-018-0973-0
6. Mattawanon N, Spencer JB, Schirmer DA, Tangpricha V. Rev Endocr Metab Disord (2018). PMID: 30219984/
DOI: 10.1007/s11154-018-9462-37
7. Herman JL FA, Brown TN, Wilson BD, Conron KJ. The Williams Institute (2017)
8. Sorbara JC, Chiniara LN, Thompson S, Palmert MR. Pediatrics (2020). PMID: 32958610/DOI: 10.1542/
peds.2019-3600
9. Marshall WA, Tanner JM. Arch Dis Child (1969). PMID: 5785179/DOI: 10.1136/adc.44.235.291
10. Zachmann M, Prader A, Kind HP, Häfliger H, Budliger H. Helv Paediatr Acta (1974). PMID: 4838166
11. Turban JL, King D, Carswell JM, Keuroghlian AS. Pediatrics (2020). PMID: 31974216/DOI: 10.1542/
peds.2019-1725
12. Rosenthal SM. J Clin Endocrinol Metab (2014). PMID: 25140398/DOI: 10.1210/jc.2014-1919
13. Stevenson MO, Tangpricha V. Endocrinol Metab Clin North Am (2019). PMID: 31027549/DOI: 10.1016/j.
ecl.2019.02.006
14. Wierckx K, Elaut E, Declercq E, Heylens G, De Cuypere G, Taes Y, et al. Eur J Endocrinol (2013). PMID:
23904280/DOI: 10.1530/EJE-13-0493
15. Ott J, Kaufmann U, Bentz EK, Huber JC, Tempfer CB. Fertil Steril (2010). PMID:19200981/DOI: 10.1016/j.
fertnstert.2008.12.017
16. de Blok CJM, Wiepjes CM, Nota NM, van Engelen K, Adank MA, Dreijerink KMA, et al. BMJ (2019). PMID:
31088823/DOI: 10.1136/bmj.l1652
17. Yeung H, Kahn B, Ly BC, Tangpricha V. Endocrinol Metab Clin North Am (2019). PMID: 31027550/DOI:
10.1016/j.ecl.2019.01.005
18. Wiepjes CM, de Jongh RT, de Blok CJ, Vlot MC, Lips P, Twisk JW, et al. J Bone Miner Res (2019). PMID:
30537188/DOI: 10.1016/j.ecl.2019.01.005
19. Van Caenegem E, Wierckx K, Taes Y, Schreiner T, Vandewalle S, Toye K, et al. Osteoporos Int (2015).
PMID:25377496/DOI: 10.1530/EJE-14-0586
20. Singh-Ospina N, Maraka S, Rodriguez-Gutierrez R, Davidge-Pitts C, Nippoldt TB, Prokop LJ, et al. J Clin
Endocrinol Metab (2017). PMID: 28945851/DOI: 10.1210/jc.2017-01642
21. Chantrapanichkul P, Stevenson MO, Suppakitjanusant P, Goodman M, Tangpricha V. Endocr Pract (2021).
PMID: 33471729/DOI: 10.4158/ep-2020-0414
22. Van Caenegem E, Taes Y, Wierckx K, Vandewalle S, Toye K, Kaufman JM, et al. Bone (2013). PMID:
23369987/DOI: 10.1016/j.bone.2013.01.039
23. Rosen HN, Hamnvik OR, Jaisamrarn U, Malabanan AO, Safer JD, Tangpricha V, et al. J Clin Densitom (2019).
PMID: 31327665/DOI: 10.1016/j.jocd.2019.07.004
24. T’Sjoen G, Arcelus J, Gooren L, Klink DT, Tangpricha V. Endocr Rev (2019). PMID: 30307546/DOI: 10.1210/
er.2018-00011
25. Madsen MC, van Dijk D, Wiepjes CM, Conemans EB, Thijs A, den Heijer M. J Clin Endocrinol Metab ( 2021).
PMID: 33599731/DOI: 10.210/clinem/dgab089
26. Nolan BJ, Leemaqz SY, Ooi O, Cundill P, Silberstein N, Locke P, et al. Intern Med J (2021). PMID: 32237098/
DOI: 10.1111/imj.14839
27. Getahun D, Nash R, Flanders WD, Baird TC, Becerra-Culqui TA, Cromwell L, et al. Ann Intern Med (2018).
PMID: 29987313/DOI: 10.7326/M17-2785
28. Maraka S, Singh Ospina N, Rodriguez-Gutierrez R, Davidge-Pitts CJ, Nippoldt TB, Prokop LJ, et al. J Clin
Endocrinol Metab (2017). PMID: 28945852/DOI: 10.1210/jc.2017-01643
29. Van Caenegem E, Wierckx K, Taes Y, Schreiner T, Vandewalle S, Toye K, et al. Eur J Endocrinol (2015).
PMID: 25550352/DOI: 10.1530/EJE-14-0586
30. Safer JD, Tangpricha V. N Engl J Med (2019). PMID: 31851801/DOI: 10.1056/NEJMcp1903650
Index
5-Alpha reductase deficiency, 199 MACE, 189
prevalence/etiology, 185–186
Abdominal aortic aneurysm, 260, 264 underlying malignancy, 186–188
Acanthosis nigricans, 54; see also Diabetes mellitus Adrenal insufficiency (AI), 148–155
clinical presentation, 54 adrenal calcification, 154
definition/overview, 53–54 adrenal crisis, 155
diagnosis, 55 clinical presentation, 150–151
differential diagnosis, 54 cosyntropin stimulation test, 152, 153
etiology, 54 in critically ill patient, 154
management/treatment, 55 definition, 148
pathophysiology, 54 diagnosis, 151–154
Acquired immunodeficiency syndrome (AIDS), 18 epidemiology, 149–150
Acromegaly; see also Diabetes mellitus; Hypothalamic- etiology, 149–150, 153–154
pituitary disorders hyperpigmentation, 150
acanthosis nigricans, 134 of gingival mucosa, 152
clinical presentation, 69, 131 of palmar creases, 152
coarse facies, 131 of tongue, 152
definition, 68, 130–135 vitiligo, 150–151
degenerative arthritis, 134 morning serum cortisol, 151–153
diagnosis, 69, 133–135 primary, 149, 150, 153
differential diagnosis, 130 secondary, 149–150, 153
enlarged sinuses in, 132 treatment of, 155
etiology, 68, 130 Adrenocortical carcinoma (ACC), 180–185
GH-secreting tumors, 131 clinical presentation, 181
hands in, 132 clitoromegaly, 182
management/treatment, 135 diagnosis, 181–183
normalization of IGF-1, 135 follow-up and prognosis, 185
overview, 130–135 incidence/epidemiology, 180
pathophysiology, 68 management/treatment, 183–185
radiation therapy, 135 metastatic melanoma, 184
surgical approach, 135 molecular pathogenesis, 180
thick heel pad, 133 pathology and staging, 183, 184
treatment/management, 69 Adrenocorticotrophic hormone (ACTH), 124
Addison’s disease, 8, 140, 291 Adult Treatment Panel III [ATP III], 249
Adrenal cortical adenoma, 169 Albright’s hereditary osteodystrophy (AHO), 104
Adrenal disorders Aldosterone-producing adenoma (APA), 156
adrenal gland, anatomy and physiology of, 147–148 Aldosterone-to-renin ratio (ARR), 159
adrenal incidentaloma, 185–190 Alström syndrome, 223
adrenal insufficiency, 148–155 Amenorrhea, 192–203
adrenocortical carcinoma, 180–185 androgen insensitivity syndrome, 197–200
congenital adrenal hyperplasia, 175–180 etiology of, 194
Cushing syndrome, 167–175 evolution, 203
pheochromocytoma, 161–167 hyperandrogenism and menstrual irregularities, 204
primary aldosteronism, 155–161 neuroendocrine causes of, 202
Adrenal gland, 147–148 PCOS, see Polycystic ovarian syndrome (PCOS)
Adrenal hyperplasia, 174 primary, see Primary amenorrhea
Adrenal incidentaloma, 185–190 secondary, see Secondary amenorrhea
adrenal biopsy, 187 American Association of Clinical Endocrinologists and
adrenal myelolipoma, 187, 188 American College of Endocrinology
assessment of bilateral adrenal masses, 187–188 (AACE/ACE), 90
causes and prevalence of, 186 Anaplastic thyroid cancer, 35
definition, 185 Androgen insensitivity syndrome, 198; see also Amenorrhea
evaluation/management, 186–190 5-alpha reductase deficiency, 199
follow-up, 189–190 autoimmune oophoritis, 199–200
hormonal evaluation, 188–189 hypothalamic amenorrhea, 200
309
310 Index
pituitary and hypothalamic tumors, 200 differential diagnosis, 146

primary hypogonadotropic hypogonadism, 200 etiology, 145
Apathetic thyrotoxicosis, 5 management/treatment, 146
Arcus juvenilis, 257 Charcot foot; see also Diabetic foot
Asherman’s syndrome, see Uterine dysfunction with hammer toes, 61
Atheroembolism, 261 neuropathic ulcer in, 62
Atherosclerotic cardiovascular disease (ASCVD), Cholesterol emboli, 261, 262
249, 250, 265 Clear cell renal carcinoma, 297
Autoimmune oophoritis, 199–200 Cohen syndrome, 76
Autoimmune polyendocr inopathy–candidiasis– ectodermal Cold nodules, 37
dystrophy (APECED) syndrome, 289 Complete variant, see Androgen insensitivity syndrome
Autoimmune polyglandular syndrome (APS), 289–291 Congenital adrenal hyperplasia (CAH), 175–180
APS type I, 290 adolescence and adulthood, 178–179
APS type II, 290 classic CAH, 178
clinical presentation, 290 nonclassic CAH, 178–179
definition/etiology, 289 ambiguous genitalia, 178
diagnosis, 291 childhood, 177–178
IPEX, 290–291 clinical presentation and diagnosis, 175–179
management/treatment, 291 definition, 175
pathophysiology, 289–290 differential diagnosis, 179
Axillary intertrigo, 57 epidemiology/etiology, 175
genetics, 179
Bardet–Biedermeier syndrome (BBS), 76, 222 infancy, 176–177
Beckwith–Wiedemann syndrome, 180 management/treatment, 179–180
Bilateral macronodular adrenal hyperplasia (BMAH), 170, 171 classic CAH, 179–180
Bone mineral density (BMD), 90 nonclassic CAH, 180
Brachydactyly, 105 pathogenesis, 175–177
Bullae, diabetic, 59; see also Diabetes mellitus Conn’s syndrome, see Primary aldosteronism
Coronary heart disease (CHD), 65, 249
Carcinoid syndrome, 286–289 Corticotrophin-releasing hormone (CRH), 124
carcinoid valvular disease, 287 Cosyntropin stimulation test (CST), 152, 153
clinical presentation, 286 COVID-19 and pituitary disease
definition and etiology, 286 definition/overview, 146
diagnosis, 286–288 diagnosis, 146
to liver, 289 management/treatment, 146
management and treatment, 288 Cowden’s syndrome, 24, 28
pathophysiology, 286 Crohn’s disease, 96
pellagra skin findings, 287 Cushing syndrome (CS), 80, 167–175
PET/CT DOTATATE of lung carcinoid, 288 abdominal and axillary striae, 171, 173
Cardiovascular disease in diabetes, 65–68; see also Diabetes adrenal cortical adenoma, 169
mellitus adrenal hyperplasia, 174
atherosclerosis and calcification, 66 causes of adrenal, 168
clinical presentation, 67 clinical features, 171
definition/overview, 65 clinical presentation, 171
diagnosis, 67 definition, 167
etiology, 65 diagnosis, 171–173
management/treatment, 67–68 differential diagnosis, 173–174
pathophysiology, 65 diffuse cortical hyperplasia, 169
postischemic subendocardial fibrosis, 67 disease and ectopic ACTH syndrome, see Ectopic ACTH
ruptured atherosclerotic plaque, 66 syndrome
secondary causes of diabetes, 68 etiology/pathophysiology, 168–171
Carney complex, 168, 294–295 evaluation of patients, 174
Carpal tunnel syndrome, 142 excess cortisol states, see Excess cortisol states (Cushing
CDC’s Division of Nutrition, Physical Activity, and Obesity syndrome)
(DNPAO), 75 management/treatment, 174–175
Celiac sprue, 99 nodular hyperplasia, 169
Centers for Disease Control and Prevention Diabetes pituitary, 170
Surveillance System, 40 skin manifestations, 171, 172
Central diabetes insipidus, 144 Cutaneous infections, 55–56; see also Diabetes mellitus
craniopharyngioma with suprasellar mass, 145 clinical presentation, 55
definition/overview, 145 definition/overview, 55
diagnosis, 145 diagnosis, 56
Index 311
differential diagnosis, 56 fibric acids, 268

management/treatment, 56 nicotinic acid, 268
pathophysiology, 55 nonpharmacologic strategies for lowering LDL C, 268
omega-3 fatty acids, 268
Diabetes mellitus PCSK9 inhibitors, 267
acanthosis nigricans, 53–55 siRNA therapy/inclisiran, 267
acromegaly, 68–69 statins, 265–266
bullae, 59 treatment options for raising HDL, 268
cardiovascular disease, 65–68
common drug reactions, 58–59 Ectopic ACTH syndrome (EAS), 168; see also Cushing
Cushing’s syndrome, 69–72 syndrome (CS); Hypothalamic-pituitary disorders
cutaneous infections, 55–56 ACTH-producing adenoma, 136
diabetic dermopathy, 56–58 clinical presentation, 136
diabetic foot, 60–65 Cushing evaluation, 138
drug reactions definition/overview, 135–136
definition/overview, 58 diagnosis, 138, 139
diagnosis, 59 hypercortisolism state, 136
differential diagnosis, 58 management/treatment, 139–140
etiology, 58 small-cell carcinoma, 137
management/treatment, 59 Empty sella syndrome; see also Pituitary adenomas
pathophysiology, 58 auricular calcification, 141
glucagonoma, 71–72 definition/overview, 140
infections, 57–58 enlarged empty sella, 141
nephropathy, 44–47 etiology, 141
neuropathy, 47–51 management/treatment, 142
retinopathy, 40–44 Endocrine-disrupting chemicals (EDCs), 78
skin manifestations, 51–53 Excess cortisol states (Cushing syndrome), 69–71; see also
type 1 diabetes (T1DM), 40 Cushing syndrome (CS); Diabetes mellitus
type 2 diabetes (T2DM), 40 clinical presentation, 70
Diabetic dermopathy, 56–58; see also Diabetes mellitus definition, 69
axillary intertrigo, 57 diagnosis, 70
definition/overview, 56–58 etiology, 70
differential diagnosis, 56 management/treatment, 71
etiology, 56 pathophysiology, 70
management/treatment, 56
Diabetic foot, 60–65; see also Diabetes mellitus Familial clustering, 206–207
chronic charcot feet with hammer toes, 61 Familial hyperaldosteronism (FH), 157, 160
clinical presentation, 64 Fibrous dysplasia/McCune–Albright syndrome
definition/overview, 60 (FD/MAS), 291
diagnosis, 64 Follicle-stimulating hormone (FSH), 124
distal ischemic ulcer, 63 Follicular adenocarcinoma, 34
etiology, 60 Follicular cell cancer, 33
extensive limb threatening, 62 Fragile X syndrome, 76
management and treatment, 64–65
neuropathic ulcer in charcot foot, 62 Gardner’s syndrome, 24, 28
osteomyelitis, 64 Gender dysphoria (GD), 302
pathophysiology, 60 Gender identity, 301
plantar focal pressure calluses, 62 Genome-wide association studies (GWAS), 206
severe ischemic ulceration, 63 GH-secreting adenoma, 127
ulcer secondary to chronic focal pressure callus, 60 Glucagonoma; see also Diabetes mellitus
ulcer with exposed bone and osteomyelitis, 63 clinical manifestations, 71–72
Diabetic retinopathy (DR), 41 definition, 71
Diet-stress amenorrhea, 203 diagnosis, 72
Diffuse cortical hyperplasia, 169 etiology, 71
DiGeorge syndrome, 103–104 management/treatment, 72
Drug-induced gynecomastia, 234 pathophysiology, 71
Dysbetalipoproteinemia type III, 260 therapeutic options for T2DM, 72
Dyslipidemia, 265–268 Graves’ disease, 8
bempedoic acid, 267 autoimmune disorders, 8
bile acid sequestrants (resins), 267 clinical presentation, 8–11
dietary modification, 265 definition/overview, 7–8
ezetimibe (cholesterol absorption inhibitor), 266–267 diagnosis/investigations, 12
312 Index
differential diagnosis, 12 other pituitary adenomas, 139–142

epidemiology/etiology, 8 pituitary adenomas, 125–127
Hashimoto’s disease, 8 pituitary apoplexy, 143–144
lid retraction with proptosis and conjunctival injection, 10 pituitary gland, anterior and posterior lobe, 124
management/treatment, 12–13 pituitary hormones, 124
marked periorbital edema and chemosis, 9 posterior pituitary, 144–148
measurement of TSHRAbs, 12 prolactinoma, 127–130
ophthalmopathy, 9 Hypothyroidism, 80
ophthalmoplegia, 10 central, 13
orbital CT, 10 clinical presentation, 13–14
skin changes, 11 common signs, 14
thyroid acropachy, 11 definition, 13
thyroid-associated dermopathy, 9 diagnosis/investigations, 14
thyroid-associated ophthalmopathy, 9 drug-induced thyroiditis, 20
thyroid component of, 8 epidemiology/etiology, 13
thyroid-directed T-cell-mediated autoimmunity, 8 Hashimoto’s thyroiditis, 15–17
Growth hormone deficiency, 80 management/treatment, 14–15
Growth hormone-releasing hormone (GHRH), 124 myxedema coma, 14
Gynecomastia, 233–235 painful subacute thyroiditis, 18
postpartum and painless thyroiditis, 17–18
Hansen’s disease, 53 during pregnancy, 14
Hashimoto’s thyroiditis, 8, 15–17 Reidel’s thyroiditis, 18–20
High-density lipoprotein cholesterol (HDL-C), 249 subclinical, 15
Hirschsprung’s disease, 279 suppurative thyroiditis, 18
Hormone replacement treatment (HRT), 193, 216–218 thyroiditis, 15
Human plasma apolipoproteins, 254
Hurthle cell cancer, 33–34 Idiopathic hyperaldosteronism (IHA), 156
Hypercholesterolemia, 256–258, 263 Insular thyroid cancer, 34
Hyperlipoproteinemias, 255 Invasive anaplastic thyroid cancer, 35
Hyperprolactinemia, 235
Hyperthyroidism, 4 Jod–Basedow disease, 5
Hypogonadism
male, 219–228 Kallmann syndrome, 200
5-alpha reductase deficiency, 221–222 Klinefelter’s syndrome, 220
aging, 225–227
incomplete androgen insensitivity syndrome, 220–221 LAMB (lentigines, atrial myxoma, blue nevi) syndrome, 294
meta-analyses, 227–228 Laurence–Moon–Bardet Biedl syndrome, 200
metabolic consequences and treatment, 227 Li–Fraumeni syndrome, 180
primary, 220 Lipemia retinalis, 259
primary hypogonadotropic, 200 Lipid disorders
secondary, 222–224 atherosclerosis, 255
Hypolipoproteinemias, 255 clinical presentation, 255–261
Hypoparathyroidism; see also Metabolic bone disorders definition/overview, 249, 250
brachydactyly, 105 diagnosis, 262–263
clinical presentation, 105–106 differential diagnosis, 261–262
definition/overview, 103 endogenous pathway, 254
diagnosis, 106 etiology, 249, 251–253
differential diagnosis, 106 exogenous pathway, 254
etiology, 103 future directions, 269
management/treatment, 107 hyperlipoproteinemias, 251
pathophysiology, 103–105 hypolipoproteinemias, 253
radiographs, 104 management/treatment, 263–268
Hypopituitarism pathophysiology, 252, 254–255
GH deficiency, 142 therapeutic modalities for dyslipidemia, 265–268
gonadotropin deficiency, 142 Lipid keratopathy, 257
hormone deficiencies, 142 Lipoprotein (A), 269
TSH deficiency, 142 Low-density lipoprotein cholesterol (LDL-C), 266
Hypothalamic amenorrhea, 200 Luteinizing hormone (LH), 124
Hypothalamic obesity, 80 Luteinizing hormone-releasing hormone (LHRH), 124
Hypothalamic-pituitary disorders Lymphocytic hypophysitis; see also Pituitary adenomas
acromegaly, 130–135 clinical presentation, 140
Cushing disease and ectopic ACTH syndrome, 135–139 definition/overview, 140
hypothalamic hormones, 124 diagnosis, 140
Index 313
management, 140 tumors associated with, 271, 272

pathophysiology, 140 Von Hippel–Lindau disease, 296–297
Lynch syndrome, 180 Multiple endocrine neoplasia type 2 (MEN-2), 165, 278–281
clinical presentation, 279–281
Marble bone disease, 119 definition/overview, 278–279
McCune–Albright syndrome, 168–170 marfanoid body habitus, 280
characteristic cafe-au-lait macules, 292 MTC in MEN2A, 281
clinical presentation, 292–294 mucosal neuromas of tongue, 280
definition/overview, 291–294 neuromas in, 281
fibrous dysplasia, 293 pathophysiology, 279
pathophysiology, 291–292 pheochromocytoma, 283–285
precocious puberty, 293 primary hyperparathyroidism, 285
Medication-induced hyperprolactinemia, 235 RET gene, 279
Medullary thyroid cancer (MTC), 34, 281–283 type 2A (MEN-2A), 165
calcitonin in, 282 type 2B (MEN-2B), 165
diagnosis, 281–282
DOPA-positive disease, 283 NAME (nevi, atrial myxoma, ephelides) syndrome, 294
management and treatment, 282–283 Necrobiosis lipoidica diabeticorum; see also Diabetes mellitus
in MEN2A, 281 clinical presentation, 52
prognosis, 283 definition/overview, 52
Menopause, 214–219 diagnosis, 53
alternatives to HRT, 217–218 differential diagnosis, 53
breast cancer, 216 etiology, 52
cardiovascular disease, 217 management/treatment, 53
cognitive function, 216–217 pathophysiology, 52
diabetes, 217 with telangiectasia, 53
guidelines, 219 Nephropathy; see also Diabetes mellitus
nonprescription ‘herbal’ remedies, 218–219 clinical presentation, 46
risks and benefits of HRT, 216 definition/overview, 44
Metabolic bone disorders diagnosis, 46
hypoparathyroidism and pseudohypoparathyroidism, differential diagnosis, 46
103–107 etiology, 44
osteomalacia, 114–119 glomerulus, 45
osteoporosis, 90–97 management/treatment, 46–47
Paget’s disease, 107–114 pathophysiology, 45–46
primary hyperparathyroidism, 98–103 Neuropathy, 47–51; see also Diabetes mellitus
sclerotic bone disorders, 119–123 clinical presentation, 48–50
Metabolic syndrome (MBS), 40, 41, 206 definition/overview, 47
Microalbuminuria, 44 diagnosis, 51
Mild autonomous cortisol excess (MACE), 189 differential diagnosis, 51
Milk-alkali syndrome, 99 esophagus, absence of contractions, 49
Mineralocorticoid receptor antagonists (MRAs), 160 etiology, 47
Multiple endocrine neoplasia type 1 (MEN1) management/treatment, 51
autoimmune polyendocrine syndromes, 289–291 neurogenic bladder, 50
carcinoid syndrome, 286–289 pathophysiology, 47–48
Carney complex, 294–295 in a sural nerve, 48
clinical presentation and management, 273–278 tertiary contractions in the esophagus, 49
cutaneous lesions, 275–276, 278 Nodular hyperplasia, 169
enteropancreatic, 273–275 Nonalcoholic fatty liver disease (NAFLD), 206
other, 276–278 Nonfunctioning or glycoprotein-secreting tumors, 139–142
parathyroid, 273 clinical presentation, 139
pituitary, 275, 278 definition/overview, 139
definition/overview, 270, 271 diagnosis, 139
diagnosis, 272 management/treatment, 139–140
McCune–Albright syndrome, 291–294
medullary thyroid cancer, 281–283 Obesity
metastatic insulinoma, 277 definition, 74
multiple endocrine neoplasia type 2, 278–281 endocrine-disrupting chemicals, 78
multiple pancreatic islet cell tumors, 274 endocrinopathies leading, 80
pancreas glucagonoma, 276 epidemiology, 74–76
pancreatic neuroendocrine tumor, 275 pathophysiology, 76
pathophysiology, 271–272 in adults, 77
prognosis and screening, 272 anti-obesity therapies, 78
314 Index
CDC’s DNPAO, 74, 75 pharmacologic therapy, 96–97

development, age, and weight gain, 78–79 radiograph of shoulder, 93–97, 102
dietary factors, 79–80 raloxifene, 96
drugs, 80 romosozumab, 97
genetics, 76 secondary osteoporosis, 92
monogenic obesity, 76, 78 teriparatide, 97
neuroendocrine dysregulation, 76–78 Osteoporosis circumscripta, 111
polygenic obesity, 78
sedentary lifestyles, 80 Paget’s disease, 107–114; see also Metabolic bone disorders
sleep, 80 arm of a patient, 112
surgical therapy, 85, 87 bisphosphonates for treatment, 113
treatment bowing leg, 111
adjustable gastric banding, 86 clinical presentation, 108
chronic weight medical management selection, 84 definition/overview, 107
with diet, exercise, and lifestyle, 83 diagnosis, 109
healthy plate model, 82 differential diagnosis, 109
liraglutide, 83 hematoxylin and eosin, 108
lorcaserin, 83 lateral spine, 110
medical pharmacotherapy, 83 long bone, 112
naltrexone/bupropion, 85 management/treatment, 112–114
orlistat, 83 normal and pagetic bone, 109
pharmacotherapy, selection and duration of, 85 pathophysiology, 108
phentermine/topiramate, 83, 85 skull, 111
prevention, 82 subcutaneous calcitonin, 113
Roux-en-Y gastric bypass (RYGB), 87 tibia and fibula, 110
sleeve gastrectomy, 86 Papillary thyroid cancer (PTC), 29–33, 38
weight gain, medications, 81 Parkinson’s disease, 220, 238
Orphan Annie eyes, 32 Pemberton’s sign, 22
Osteomalacia, 114–119; see also Metabolic bone disorders Peripheral vascular disease (PVD), 65
bone biopsy revealing osteomalacia, 116 Pheochromocytoma, 161–167
clinical presentation, 115 adrenal imaging, 163, 165–167
definition/overview, 114 biochemical testing, 163–165
diagnosis, 116 clinical features, 161–162
differential diagnosis, 116 definition, 161
etiology, 114 diagnosis, 162–163
hypophosphatemic rickets, 114 functional, 161, 162
lower extremity, 119 management/treatment, 163–167
management/treatment, 118–119 metastatic pheochromocytoma, 166–167
pathophysiology, 115 pheochromocytoma-associated syndromes, 164–166
pseudovitamin D deficiency, 114 preoperative management, 163–164
rickets, 117, 118 surgical management and follow-up, 164
Osteomyelitis, 63, 64 in MEN2, 283–285
Osteopetrosis congenita, 119 diagnosis, 283–284
Osteopetrosis tarda, 119 management and treatment, 284–285
Osteoporosis, 90–97; see also Metabolic bone disorders suspected, 162, 163
abaloparatide, 97 Pituitary adenomas, 125–127; see also Hypothalamic-
bone biopsies, 94 pituitary disorders
bone remodeling unit, 93 clinical manifestations of pituitary tumors, 125
clinical presentation, 91, 92 definition/overview, 125
combination therapy, 93 empty sella syndrome, 141
denosumab, 97 etiology, 125
diagnosis, 93, 94 GH-secreting adenoma, 127
differential diagnosis, 93 hypopituitarism, 142
dual-energy x-ray absorptiometry, 94, 95 lymphocytic hypophysitis, 140
estrogen/progesterone replacement therapy, 96 nonfunctioning or glycoprotein-secreting tumors and TSH
etiology, 91 adenomas, 139–142
FRAX, 91 pituitary macroadenoma, 126
kyphosis, 95 pituitary microadenoma, 126
medical management, 102–103 Pituitary apoplexy, 143–144; see also Hypothalamic-pituitary
oral bisphosphonates, 97 disorders
osteitis fibrosis, 102 clinical presentation, 143
pathophysiology, 91 definition/overview, 143
Index 315
diagnosis, 143 in MEN2, 285

differential diagnosis, 143 nephrolithiasis, 101
etiology, 143 pathophysiology, 98–99
management/treatment, 143–144 Sestamibi scan, 100
Sheehan’s syndrome, 144 Primary hypogonadotropic hypogonadism, 200
Pituitary gigantism, 68 Primary pigmented nodular adrenal disease (PPNAD), 168,
Pituitary macroadenoma, 126 170
Pituitary microadenoma, 126 Prolactin (PRL), 124
Pituitary neuroendocrine tumors (PitNETs), 125 Prolactinoma, 127–130; see also Hypothalamic-pituitary
Plasma aldosterone concentration (PAC), 158 disorders
Plasma renin activity (PRA), 158 definition/overview, 127
Pleiotropic syndromes, 76 diagnosis, 128
Plummer’s disease, 20 differential diagnosis, 128, 129
Polycystic ovarian morphology (PCOM), 204 management/treatment, 129–130
Polycystic ovarian syndrome (PCOS), 204, 206–208; see also pathophysiology and clinical presentation, 127–128
Amenorrhea Psammoma bodies, 32
acanthosis, 208 Pseudo-Cushing syndrome, 173–174
acne and hirsutism, 208 Pseudohypoparathyroidism, see Hypoparathyroidism
cardiometabolic consequences, 210–211
clinical cardiovascular disease events, 211–212 Reidel’s thyroiditis, 18–20
clinical presentation, 207–208 Reproductive disorders (male and female)
diagnosis, 208–209 clinical presentation, 235–236
familial clustering, 206–207 etiology, 235
GWAS of, 206 evaluation of guidelines, 213
management, 209–210 future investigation, 213
pathophysiology, 205–206 guidelines, 228–233
subtypes of, 206 gynecomastia, 233–235
Posterior pituitary, 144; see also Hypothalamic-pituitary hyperprolactinemia, 235
disorders imaging, 237
central diabetes insipidus, 145–146 invasive pituitary adenoma, 241
common ADH-related syndromes, 144 laboratory measurement, 236–237
COVID-19 and pituitary disease, 146 male hypogonadism, 219–228
Prader–Willi syndrome, 55, 76, 200, 222–223 medication-induced hyperprolactinemia, 235
Primary aldosteronism, 155–161 menopause, 214–219
aldosterone secretion radiation, 240–241
APAs, 156, 157 alternative/investigational drugs, 240
physiology and pathophysiology, 156–157 guidelines, 240–241
causes of, 156 treatment, 237–240
clinical presentation, 157–158 management of dopamine-resistant tumors, 239
definition, 155–156 medical therapy, 238–239
diagnosis, 158–160 surgery, 239–240
confirmatory tests, 159 Retinal hemangioblastoma, 296
familial hyperaldosteronism, 160 Retinal–renal syndrome, 46
lateralizing studies, 159–160 Retinopathy, 40–44; see also Diabetes mellitus
screening tests, 158–159 anti-VEGF therapies, 41
management/treatment, 160 clinical presentation, 41–42
primary hyperaldosteronism, 158 diagnosis, 42–43
unilateral aldosterone excess, 159, 160 etiology, 41
Primary amenorrhea; see also Amenorrhea hard exudates, 43
constitutional retardation of puberty, 194 management/treatment, 43–44
imperforate hymen, 194–195 neovascularization of the disc, 42
pure ovarian dysgenesis, 197 normal fundus, 42
Turner syndrome, 196 pathophysiology, 41
Primary hyperparathyroidism (PHPT), 98–103, 273; see also preretinal hemorrhage, 43
Metabolic bone disorders vascular leakage, 44
band keratopathy, 99
clinical presentation, 99 Schmidt’s syndrome, 289
definition/overview, 98 Sclerotic bone disorders, 119–123; see also Metabolic bone
diagnosis, 100 disorders
differential diagnosis, 99–100 biopsy of sclerotic bone, 122
etiology, 98 clinical presentation, 120–121
hands revealing subperiosteal bone resorption, 101 definition/overview, 119
316 Index
diagnosis, 121 hypoparathyroidism, 19

differential diagnosis, 121 painful subacute thyroiditis, 18, 19
epidemiology and etiology, 119–120 postpartum and painless thyroiditis, 17–18
management/treatment, 121–123 Reidel’s thyroiditis, 18–19
pathophysiology, 120 suppurative thyroiditis, 18
radiograph of the pelvis and hip, 123 Thyroid lymphoma, 36
radiograph of the tibia with a sclerotic pseudofracture, 122 Thyroid nodules
Secondary amenorrhea; see also Amenorrhea anaplastic carcinoma histology, 27
fragile X syndrome, 202 chest X-ray for large goiter, 23
functional hypothalamic amenorrhea (HA), 202–203 definition/overview, 20–24
hyperprolactinemia, 202 diagnosis/investigations, 24–26
PCOS, 202 differential diagnosis, 24
pituitary and hypothalamic tumors and infiltrative FNA biopsy, 24
disease, 202 follicular adenoma, 27
premature ovarian failure, 201 follicular carcinoma, 26
uterine dysfunction (Asherman’s syndrome), 201 goiter, 22, 23
Sheehan’s syndrome, 144, 202 large pendulous cystic nodule, 22
Silent disease, see Osteoporosis macrofollicle and microfollicle, 25
SIM1 syndrome, 76 management/treatment, 26–27
Skin manifestations in diabetes mellitus, 51; see also Diabetes papillary carcinoma, 26
mellitus retrosternal goiter, 21
Small interfering RNA (siRNA) therapy/inclisiran, 267 thyroid scintigraphy, 25
Stevens–Johnson syndrome, 59 thyroid ultrasound, 24
Suppurative thyroiditis, 18 thyrotoxicity, 20
Werner & Ingbar’s The Thyroid, 21
Tangier disease, 261, 263, 264 Thyroid-stimulating hormone (TSH), 4, 124
Testicular feminization syndrome, see Androgen insensitivity Thyrotoxicosis
syndrome C-cells, 3
Thyroid clinical presentation, 5
anatomy, 1–3 colloid, 3
C-cell, 4 definition, 4
factors influencing, 4 diagnosis/investigations, 5–6
histology, 3–4 etiology, 5
hormone synthesis, 4 hyperthyroidism, 4, 5
hyperthyroidism, 1 Jod–Basedow disease, 5
muscle fibers, hyoid bone, 2 lid retraction or ‘thyroid stare,’ 5
thyroglossal duct cysts, 2 management/treatment, 7
Thyroid-associated dermopathy, 9 potential adverse reactions, 7
Thyroid-associated ophthalmopathy, 9 thionamides, 7
Thyroid cancer right sagittal thyroid ultrasound, 6
clinical presentation, 36 signs of, 5
definition/overview, 28 subclinical hyperthyroidism, concerns, 7
diagnosis, 37 uptake of radioiodine in Graves’ disease, 6
differential diagnosis, 37 Thyrotropin-releasing hormone (TRH), 4, 124
etiology, 28 Total thyroidectomy, 30
FNA, 37 Transgender patients, endocrinologic care of
genetic abnormalities, 28 acne vulgaris, 305, 306
guiding principles, 38 adverse outcomes, 303–305
history and physical examination findings, 36 bilateral mastectomy, 306
management/treatment, 38–39 diagnosis of gender dysphoria, 302
papillary thyroid cancer, 28, 29, 31 feminizing hormone therapy, 303–304
pathophysiology, 28–29 fertility, 302
radionucleotide scanning, 37 introduction and terminology, 301–302
recombinant thyrotropin alfa, 39 long-term monitoring, 303–305
well-differentiated, see Well-differentiated thyroid cancer masculinizing hormone therapy, 304–306
Thyroid-directed T-cell-mediated autoimmunity, 8 pediatric and adolescent gender care, 302–303
Thyroiditis, 15 surgical options for transgender patients, 306–307
amiodarone-induced thyroid dysfunction, 20 T-scores, 94
antithyroid autoantibodies, 17 TSH adenomas, 139–142
drug-induced thyroiditis, 20
forms of, 15–16 Urine free cortisol (UFC), 173
Hashimoto’s thyroiditis, 15–17 Uterine dysfunction, 201
Index 317
Vitiligo, 150, 151, 201 papillary thyroid cancer, 29–33, 38

Von Basedow’s disease, 7 psammoma bodies, 32
Von Hippel–Lindau disease, 166, 296–297 thyroid lymphoma, 36
total thyroidectomy, 30
WAGR syndrome, 76 Wermer’s syndrome, see Multiple endocrine neoplasia type 1
Well-differentiated thyroid cancer (MEN1)
anaplastic thyroid cancer, 35 WHO Classification of Endocrine and Neuroendocrine
calcifications, 32 Tumors, 125
cystic neck mass, 33 Wilson’s disease, 106
fine needle aspiration biopsy, 30 Women’s Health Initiative (WHI), 216
follicular adenocarcinoma, 34
follicular cell cancer, 33 X chromosome, 196
Hurthle cell cancer, 33–34
insular thyroid cancer, 34 Y chromosome, 196, 198, 219, 220
invasive anaplastic thyroid cancer, 35
medullary thyroid cancer, 34 Z-scores, 94

Atlas of Clinical Endocrinology and Metabolism

Uploaded by

Copyright:

Available Formats

Atlas of Clinical Endocrinology and Metabolism

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Atlas of Clinical Endocrinology and Metabolism

Uploaded by

Copyright:

Available Formats

Atlas of Clinical Endocrinology

First edition published 2024

and by CRC Press

CRC Press is an imprint of Taylor & Francis Group, LLC

© 2024 Taylor & Francis Group, LLC

Library of Congress Cataloging‑in‑Publication Data

ISBN: 9780367608354 (hbk)

4 Metabolic Bone Disorders 90

5 Hypothalamic-Pituitary Disorders 124

6 Adrenal Disorders 147

7 Male and Female Reproductive Disorders 192

8 Lipid Disorders 249

9 Neuroendocrine Tumors and Genetic Endocrine Disorders: Multiple Endocrine

10 Endocrinologic Care of Transgender Patients 301

Marriam Ali, MD Maria Fleseriu

Jason L. Gaglia, MD, MMSc

Rhoda H. Cobin, MD Ikram Haque, MD

Mary Ann Emanuele, MD Natasha S. Kadakia, DO

Sarah Kanbour, MD Louis G. Portugal, MD

Jason L. Gaglia and Jeffrey R. Garber

TABLE 1.1 Factors Influencing Total Thyroid Hormones Levels

The production of thyroid hormone is normally controlled by the hypothalamic–pituitary–thyroid

TABLE 1.2 Forms of Thyroiditis

Postpartum and Painless Thyroiditis

HASHIMOTO’S POSTPARTUM SILENT SUBACUTE SUPPURATIVE

Painful Subacute Thyroiditis

TABLE 1.4 Amiodarone-Induced Thyroid Dysfunction

FIGURE 1.28 Papillary carcinoma. (Courtesy of Dr. Tad Wieczorek.)

FIGURE 1.29 Follicular carcinoma. (Courtesy of Dr. Tad Wieczorek.)

FIGURE 1.30 Follicular adenoma. (Courtesy of Dr. Tad Wieczorek.)

FIGURE 1.31 Anaplastic carcinoma histology. (Courtesy of Dr. Tad Wieczorek.)

Louis G. Portugal and Alexander J. Langerman

Well-Differentiated Thyroid Cancer

Follicular Cell Cancer

Hurthle Cell Cancer

Insular Thyroid Cancer

Medullary Thyroid Cancer

Anaplastic Thyroid Cancer

Alalah Mazhari, Mary Ann Emanuele,

FIGURE 2.1 Normal fundus. (Courtesy of Dr. Mark Dailey.)

FIGURE 2.3 Hard exudates. (Courtesy of Dr. Mark Dailey.)

FIGURE 2.4 Large preretinal hemorrhage. (Courtesy of Dr. Mark Dailey.)

angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, renin–angiotensin system

FIGURE 2.11 Neurogenic bladder. (Courtesy of Dr. Laurie Lomasney.)

NECROBIOSIS LIPOIDICA DIABETICORUM

FIGURE 2.16 Axillary intertrigo. (Courtesy of Dr. Eva Parker.)

COMMON DRUG REACTIONS

THE DIABETIC FOOT

FIGURE 2.22 Radiograph of a Charcot foot. (Courtesy of Dr. Laurie Lomasney.)

FIGURE 2.26 Distal ischemic ulcer. (Courtesy of Dr. Ronald Sage.)

FIGURE 2.27 Severe ischemic ulceration. (Courtesy of Dr. Ronald Sage.)

FIGURE 2.29 Radiograph showing osteomyelitis. (Courtesy of Dr. Laurie Lomasney.)

CARDIOVASCULAR DISEASE IN DIABETES

FIGURE 2.31 Ruptured atherosclerotic plaque. (Courtesy of Dr. Henry Brown.)

FIGURE 2.32 Postischemic subendocardial fibrosis. (Courtesy of Dr. Henry Brown.)

Secondary Causes of Diabetes

EXCESS CORTISOL STATES: CUSHING’S SYNDROME

Therapeutic Options for T2DM

Cheung et al., Kidney International (2021), PMID 33637203/DOI 10.1016/j.kint.2020.10.026

Marriam Ali and Sobia Sadiq