Approach To The Patient With Delayed Puberty

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Approach to the patient with delayed puberty

Authors: William F Crowley, Jr, MD, Nelly Pitteloud, MD
Section Editors: Peter J Snyder, MD, Amy B Middleman, MD, MPH, MS Ed, Mitchell E Geffner, MD
Deputy Editors: Alison G Hoppin, MD, Kathryn A Martin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2020. | This topic last updated: Jul 23, 2018.
INTRODUCTION
Delayed puberty is defined clinically as the absence of the first signs of pubertal development beyond the normal range for the population. In the
United States, this means the absence of breast development by age 12 years in girls, or absence of testicular enlargement by age 14 years in
boys. However, there are clear racial and ethnic variations in the timing of puberty, such as earlier onset of puberty in African American girls
compared with Caucasian counterparts [1]. These racial, social, and ethnic differences should be incorporated into decisions regarding the
evaluation and therapy of pubertal disorders.
The most common cause of delayed puberty is a functional defect in production of gonadotropin-releasing hormone (GnRH) from the
hypothalamus. This may be due to physiologic individual variation, known as constitutional delay of growth and puberty, or other functional
defects, such as undernutrition or chronic illness. The GnRH deficiency leads to defective secretion of gonadotropins (luteinizing hormone [LH]
and follicle-stimulating hormone [FSH]) from the anterior pituitary, which results in inadequate steroid secretion by the gonads. Other causes of
delayed puberty include a variety of hypothalamic, pituitary, and gonadal disorders. (See "Causes of primary amenorrhea" and "Causes of
primary hypogonadism in males".)
The evaluation and management of an adolescent with delayed puberty is discussed in this topic review. Other clinical presentations of
hypogonadism are discussed elsewhere:
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● (See "Evaluation and management of primary amenorrhea".)

● (See "Evaluation and management of secondary amenorrhea".)
● (See "Clinical features and diagnosis of male hypogonadism".)
DEFINITIONS
Delayed puberty — Delayed puberty is defined clinically by the absence or incomplete development of secondary sexual characteristics
bounded by an age at which 95 percent of children of that sex and culture have initiated sexual maturation. However, there are wide ranges
within and across populations as to the order and temporal sequences that occur during puberty, especially in girls. In girls, this is due in part to
the fact that some features of early sexual maturation (pubic hair, axillary hair and odor, and acne) are manifestations of adrenal activity
(adrenarche), which typically occurs about six months after the start of true puberty (ie, ovarian maturation, heralded by breast development).
Hence, some girls have early breast development, but little else for some time, whereas others follow the typical sequencing of events as
described by Tanner's pioneering work quite precisely.
In the United States, the upper 95th percentile for initial pubertal development is 12 years for girls (breast development being the first sign, Tanner
stage B2), and 14 years for boys (increase in testicular size being the first sign, Tanner stage G2). Onset of pubic hair is not usually included in
this definition because this is typically a sign of adrenarche, rather than true puberty. (See "Normal puberty".)
Stalled puberty — Puberty can be considered "stalled" if it was started but not completed within about four years of the first signs of pubertal
development. About 95 percent of healthy children complete pubertal development within four years [2]. In the clinical setting, the clinician may
choose to initiate an evaluation before this threshold is reached, if there is no evidence of pubertal progression for a sustained period of time (eg,
for two or more years).
Hypogonadism — Hypogonadism describes impairment of any or all functions of the gonads, including production of testosterone and sperm in
men, and estradiol, progesterone, and ova in females.
● Primary hypogonadism is characterized by high serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
(See 'Primary hypogonadism' below.)

● Secondary hypogonadism, also known as hypogonadotropic hypogonadism, is characterized by low or normal serum LH and FSH
concentrations. (See 'Secondary (hypogonadotropic) hypogonadism' below.)
EPIDEMIOLOGY
By definition, delayed puberty occurs in approximately 5 percent of apparently healthy individuals in a given population. The relative frequency of
various causes of delayed puberty was described in a retrospective study of adolescents presenting to an academic center with delayed puberty
[3]:
● Secondary (hypogonadotropic) hypogonadism:
• Constitutional delay of growth and puberty (CDGP) – 53 percent of subjects (63 percent of males and 30 percent of females).
• Functional hypogonadotropic hypogonadism – 19 percent.
• Other causes of hypogonadotropic hypogonadism (eg, isolated gonadotropin-releasing hormone [GnRH] deficiency, including Kallman
syndrome, or a central nervous system tumor) – 12 percent.
● Primary hypogonadism – 13 percent.
● Unclassified – 3 percent.
ETIOLOGY
It is useful to classify hypogonadism pathophysiologically according to the circulating levels of the gonadotropins, which are luteinizing hormone
(LH) and follicle-stimulating hormone (FSH) (table 1):
Primary hypogonadism — Primary hypogonadism is characterized by low gonadal steroids with high serum concentrations of LH and FSH.
This may be caused by a variety of gonadal diseases, including Turner syndrome or Klinefelter syndrome, gonadal injury from chemotherapy,
radiotherapy, autoimmune or postinfectious injury, cryptorchidism, or disorders of testosterone biosynthesis. Rarely, it is caused by defects in LH
and FSH receptors on the membrane of the gonadal cells. (See "Causes of primary hypogonadism in males" and "Pathogenesis and causes of
spontaneous primary ovarian insufficiency (premature ovarian failure)".)
Secondary (hypogonadotropic) hypogonadism — Secondary hypogonadism is characterized by low or normal serum LH and FSH
concentrations. These disorders are characterized by deficient gonadotropin-releasing hormone (GnRH) secretion, which leads to decreased
secretion of LH and FSH from the anterior pituitary, which results in inadequate gonadal steroid secretion. This category is sometimes called
"central" hypogonadism.
Causes of secondary hypogonadism include:
Constitutional delay of growth and puberty — This is the most common cause of delayed puberty; this is thought to be a transient
functional defect in production of GnRH from the hypothalamus, due to individual variations that can be genetic. Constitutional delay of growth
and puberty (CDGP) tends to have familial patterns of inheritance, often following an autosomal dominant pattern such that family members often
have a history of being "late bloomers," with a late growth spurt or late puberty compared with their peers. (See "Causes of short stature", section
on 'Constitutional delay of growth and puberty'.)
Isolated GnRH deficiency — Isolated GnRH deficiency, also known as idiopathic hypogonadotropic hypogonadism or congenital GnRH
deficiency, can be caused by a variety of genetic mutations. Some patients have associated anosmia or hyposmia (reduced sense of smell),
known as Kallmann syndrome, or other congenital anomalies including midline defects (cleft lip/palate), neurosensory hearing loss, synkinesia
(alternating mirror movements), unilateral renal agenesis, or skeletal defects including syndactyly and ectrodactyly (lobster claw deformity). The
clinical presentation varies but may include microphallus and/or cryptorchidism in males at birth, and absent or stalled pubertal development
during adolescence in both sexes. These disorders may have familial patterns of inheritance, although many cases appear to be sporadic
because of the variable clinical presentation. The hypogonadism is usually permanent but may occasionally remit [4]. (See "Isolated
gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Genetics'.)
Isolated GnRH deficiency is a diagnosis of exclusion. In patients with unexplained hypogonadotropic hypogonadism, a presumptive diagnosis of
isolated GnRH deficiency can be made in patients with suggestive physical features (microphallus and/or cryptorchidism, anosmia, unilateral
renal agenesis, synkinesia, or skeletal defects); or a family history of isolated GnRH deficiency; or if puberty remains absent by age 18 years.
(See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Diagnosis'.)

In patients lacking individual phenotypic features who are younger than 18 years, it may be difficult to distinguish isolated GnRH deficiency from
CDGP. Furthermore, these disorders may have some degree of genetic overlap. This is suggested by the observation of higher rates of CDGP in
families with isolated GnRH deficiency [5], and reports that some cases of apparent CDGP are associated with heterozygous mutations in a gene
associated with isolated GnRH deficiency [6].
Other forms of functional hypogonadotropic hypogonadism — This may be associated with an underlying medical condition such as poor
nutrition (including anorexia nervosa), chronic illness (eg, inflammatory bowel disease, celiac disease), hypothyroidism, and excessive exercise.
Affected patients typically have delayed but spontaneous pubertal development.
Hypothalamic or pituitary disease — Hypothalamic or pituitary disorders, such as malformations, hemochromatosis, injury, or tumors
(especially craniopharyngioma), can cause secondary hypogonadism.
EVALUATION
Measurement of serum gonadotropin levels can often differentiate primary from secondary hypogonadism. During adolescence, it can be difficult
to make a definitive diagnosis of a specific cause of delayed puberty associated with secondary hypogonadism. Because most of these disorders
have in common a decrease in gonadotropin-releasing hormone (GnRH) secretion and/or its action, no single test except for serial observations
over time reliably distinguishes patients with constitutional delay of growth and puberty (CDGP), who will eventually progress spontaneously
through puberty, from patients with other causes of delayed puberty, particularly those with isolated GnRH deficiency [7-9]. In addition, because
10 to 15 percent of cases of well-documented isolated GnRH deficiency undergo spontaneous reversals after being treated with sex steroids,
these distinctions between CDGP and isolated GnRH deficiency are becoming less absolute [4]. (See "Isolated gonadotropin-releasing hormone
deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Reversal of IHH'.)
As a result, the first step in the evaluation is a complete history and physical examination to determine whether further biochemical testing or
imaging studies are needed.
History — Key elements of the history are:

● Is pubertal development totally absent, or did it start and then "stall"? – Assessment of the patient's growth pattern up to the time of
evaluation is critical, with review of the height-for-age growth chart and calculation of height velocity (cm/year), compared with his or her
peers of the same chronological age (figure 1A-B). Similarly, inquire about whether there have been any signs of pubertal development.
Isolated androgen-mediated sexual characteristics (such as pubic and/or axillary hair, acne, and apocrine odor) may be the first signs of
puberty, but usually reflect adrenarche. (See "Causes of short stature".)
Patients with CDGP have delayed (not stalled) pubertal development, with slow progression of growth, adrenarche, gonadal maturation, and
bone age compared with their peers. In contrast, adolescent-aged patients with tumors in the hypothalamic-pituitary region may present with
stalled pubertal development.
● Are there nutritional habits, intense exercise, or medical illness that delayed the onset or slowed the tempo of puberty? –
Undernutrition or high-intensity exercise (eg, long-distance running) are common causes of pubertal delay in otherwise healthy adolescents.
Delays in sexual maturation and height velocity often can be the first clinical signs of underlying disorders, such as inflammatory bowel
disease, hypothyroidism, or psychosocial deprivation [10]. Patients with inflammatory bowel disease often have gastrointestinal symptoms
such as loose or bloody stools or abdominal pain, but the symptoms may be subtle. (See "Growth failure and poor weight gain in children
with inflammatory bowel disease", section on 'Pubertal delay' and "Clinical presentation and diagnosis of inflammatory bowel disease in
children".)
Chronic opioid use is associated with hypogonadism. (See "Causes of secondary hypogonadism in males", section on 'Opiates'.)
● Are there any congenital abnormalities or neurologic symptoms? – Some patients with isolated GnRH deficiency have associated
anomalies including microphallus, cryptorchidism, midline defects, synkinesia, or renal agenesis. Neurologic symptoms such as headache,
visual disturbances, dyskinesia, seizures, and intellectual disability (mental retardation) strongly suggest a central nervous system disorder.
(See 'Hypothalamic or pituitary disease' above and "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic
hypogonadism)", section on 'Congenital abnormalities'.)
● Is there a family history of delayed or absent of puberty? – A family history of delayed puberty is common in both CDGP and isolated
GnRH deficiency, and in some cases the disorders may have similar genetic mechanisms (see 'Isolated GnRH deficiency' above). In CDGP,
parents or siblings give a history of being "late bloomers," with a late growth spurt or late puberty compared with their peers. This typically

has an autosomal dominant mode of inheritance, with or without incomplete penetrance [11]. Isolated GnRH deficiency can be inherited in an
autosomal dominant, autosomal recessive, or X-linked recessive manner. (See "Isolated gonadotropin-releasing hormone deficiency
(idiopathic hypogonadotropic hypogonadism)".)
● Does the patient have a normal sense of smell? – Absent or reduced sense of smell (anosmia or hyposmia) strongly suggests Kallmann
syndrome, which is a subtype of isolated GnRH deficiency [12-14]. (See 'Isolated GnRH deficiency' above.)
Physical examination — Careful assessments of height, weight, arm span, and secondary sex characteristics are the most relevant aspects of
the physical examination. Early signs of sexual development unnoticed by the patient (such as testicular growth) may permit reassurance and
avoidance of a costly evaluation in the otherwise normal child. Serial measurements of height and testicular size or breast development made
over one or two years will help to confirm the presence or absence of pubertal changes and their progression, and clarify the diagnosis.
Both standing height and arm span should be measured to determine if eunuchoid body proportions are present, indicated by an arm span
exceeding the height by more than 5 cm. This finding suggests delayed epiphyseal closure secondary to hypogonadism (eg, due to Klinefelter
syndrome). Increased arm span is also a feature of Marfan syndrome, but Marfan syndrome is not associated with hypogonadism. The height
should be plotted on growth charts that include normal growth patterns with centiles or standard deviation scores (figure 2A-B) to place the
current height in the proper developmental context and to allow comparison with both current and subsequent bone age determination. The
height velocity should be carefully documented for at least six months or longer, if possible.
Secondary sexual characteristics should be staged according to the sexual maturity ratings, also known as Tanner staging (picture 1 and picture
2A-B) [15]. In boys, testicular size should be measured by a Prader orchidometer (picture 3). Particular attention also should be paid to the
symmetry of the testes, as gonadal tumors can occur in several intersex disorders presenting at puberty with asymmetrical gonadal development
and defects in sexual maturation; suspected abnormalities should be further evaluated by ultrasonography. (See "Normal puberty", section on
'Sexual maturity rating (Tanner stages)' and 'Additional testing' below.)
The earliest signs of pubertal development are a testicular volume of greater than or equal to 4 mL in boys (figure 3) (corresponding to about 2.0
to 3.1 cm in testicular length), and the appearance of breast buds in girls. If either of these features is present, the patient and family can be
reassured that puberty will most likely progress. However, longitudinal follow-up is essential, since some children exhibit some initial signs of

pubertal development, but then pubertal progression stops or stalls. This includes some children with genetic causes of isolated GnRH
deficiency.
All girls should be carefully evaluated for features associated with Turner syndrome (table 2). In some individuals with Turner syndrome, the
presenting feature is delayed pubertal development, usually with longstanding short stature and generally without other obvious clinical features
of Turner syndrome (see "Clinical manifestations and diagnosis of Turner syndrome", section on 'Typical features'). As a result, any girl with
unexplained significant pubertal delay and primary hypogonadism (elevated levels of luteinizing hormone [LH] and follicle-stimulating hormone
[FSH]) should have genetic testing for Turner syndrome. (See 'Additional testing' below.)
Initial testing — For patients with some signs of pubertal development (eg, breast buds by age 12 years in girls, or testicular enlargement by
age 14 years in boys) and no evidence of underlying disease, general laboratory screening is appropriate but not essential. These patients
should be followed clinically in three- to six-month intervals, and tested if puberty does not progress.
Patients with absent, stalled, or very delayed puberty should undergo a bone age determination and additional lab testing as outlined in the
following section.
Bone age — A radiograph of the left hand and wrist to evaluate bone age should be obtained at the initial visit to assess skeletal maturation
and repeated over time if needed. This provides valuable information about the relationship between chronologic age and skeletal maturation, the
potential for future skeletal growth, and allows a preliminary prediction of adult height. These results are useful when making decisions about
possible interventions (eg, whether or not to initiate hormonal therapy for patients with CDGP). However, the bone age does not help to
distinguish between different causes of delayed puberty.
Patients with CDGP typically have bone ages delayed by approximately 20 percent compared with chronological age. Skeletal development
progresses slowly without the presence of pubertal levels of gonadal steroids because sex steroids are required for epiphyseal closure.
General laboratory tests — Children with delayed puberty should be evaluated for the possibility of nutritional disorders, celiac disease, or
occult chronic illnesses (eg, chronic inflammatory bowel disease, anorexia nervosa, or hepatic disease) that may affect hypothalamic GnRH
secretion [16], by performing the following tests:

● Complete blood count, erythrocyte sedimentation rate, blood urea nitrogen, creatinine, and liver function tests (alanine aminotransferase
[ALT] and aspartate aminotransferase [AST]).
● To screen for celiac disease, measure immunoglobulin A (IgA) antibodies to tissue transglutaminase (tTG). Celiac disease is common and
occasionally presents with delayed growth and puberty, with few or no other symptoms. (See "Epidemiology, pathogenesis, and clinical
manifestations of celiac disease in children" and "Diagnosis of celiac disease in children".)
Endocrine tests — The hormonal evaluation should include the following tests:
● LH, FSH, estradiol, and testosterone – Random (unstimulated) measurements of serum LH and FSH, together with estradiol (girls) or
testosterone (boys), should be obtained to distinguish between primary and secondary hypogonadism. These measurements should be
interpreted based upon the normative data provided by the testing laboratory.
• Elevated serum LH and FSH concentrations indicate primary hypogonadism. These hormones are usually sufficiently elevated by
adolescence to be easily distinguished from normal adolescents without hypogonadism. This is particularly true for FSH levels, which
provide the greatest discriminate value in this age group. Girls with elevated gonadotropins should be further evaluated for Turner
syndrome. (See 'Additional testing' below.)
• Low or normal serum LH and FSH values in the setting of low levels of testosterone or estradiol in the adolescent age range are
consistent with either CDGP or isolated GnRH deficiency. This pattern would also be seen with other forms of functional
hypogonadotropic hypogonadism (eg due to medical illness) or hypothalamic-pituitary disorders. (See 'Other forms of functional
hypogonadotropic hypogonadism' above and 'Hypothalamic or pituitary disease' above.)
GnRH stimulation testing is not recommended because it does not help distinguish between CDGP and isolated GnRH deficiency, as there
is significant overlap of LH and FSH responses between the two groups of patients [17-19]. Several reports have suggested stimulation tests
with other GnRH agonists, such as buserelin, are better at differentiating between these groups of patients [20,21]. In most cases, however,
the distinction between CDGP and isolated GnRH deficiency remains ambiguous and can be resolved only with time and serial
observations. In some patients, therapy may be initiated prior to determining the diagnosis. (See 'Therapy' below.)

● Prolactin – A random measurement of serum prolactin should be obtained to detect hyperprolactinemia, which can present clinically as
"stalled" puberty. An elevated prolactin level can result from a lactotroph adenoma (prolactinoma) or from any hypothalamic or pituitary
disorder that interrupts hypothalamic inhibition of prolactin secretion. Patients with hyperprolactinemia (unless clearly related to a prolactin-
raising medication) should be further evaluated by imaging of the hypothalamus and the pituitary region by head magnetic resonance
imaging (MRI). (See "Causes of hyperprolactinemia" and "Causes, presentation, and evaluation of sellar masses".)
● Insulin-like growth factor 1 (IGF-1) – Measurement of IGF-1 is often suggested to help exclude the possibility of growth hormone
deficiency as a cause of the delayed puberty. The growth hormone deficiency may be isolated, or associated with other pituitary hormone
deficiencies. The results should be compared with the normal range for the child's pubertal stage (and/or bone age), rather than
chronological age. Growth hormone deficiency is unlikely if the IGF-1 result is normal. However, a low IGF-1 level does not mean that the
patient has growth hormone deficiency, as low levels are seen in many other disorders, including undernutrition, hypothyroidism, renal
failure, and other chronic illnesses. (See "Diagnosis of growth hormone deficiency in children", section on 'IGF-1 and IGFBP-3'.)
● Thyroid function tests – Tests for hypothyroidism, which delays puberty by as yet unknown mechanisms, should be obtained, particularly if
height velocity has suddenly slowed and the bone age is significantly delayed. Both thyroid-stimulating hormone (TSH) and free thyroxine
(T4) should be measured. Serum TSH is elevated in primary hypothyroidism, but is usually normal or low in secondary hypothyroidism (ie,
due to hypothalamic or pituitary disease). As a result, serum free T4 should be measured to assess for central hypothyroidism. (See
"Laboratory assessment of thyroid function".)
Additional testing — Depending upon the clinical findings and the results of the hormonal testing, additional evaluation may include the
following:
Patients with high LH and FSH — Patients with elevated gonadotropins have primary hypogonadism. A karyotype or comparative genomic
hybridization array should be performed in every patient with primary hypogonadism to evaluate the possibility of Klinefelter syndrome in boys
and Turner syndrome in girls. Girls with Turner syndrome may present with delayed puberty/primary amenorrhea. Boys with Klinefelter syndrome
rarely present with delayed puberty. They more typically present with incomplete puberty and other physical findings that suggest the diagnosis
(gynecomastia, testes smaller than 5 mL in volume, and/or cryptorchidism). (See "Clinical manifestations and diagnosis of Turner syndrome",
section on 'Diagnosis' and "Causes of primary hypogonadism in males", section on 'Klinefelter syndrome'.)

Patients with low or normal LH and FSH — Patients with low or normal LH and FSH have secondary or hypogonadotropic hypogonadism.
Additional evaluation in these patients depends upon their clinical presentation:
● Head MRI should be obtained if associated neurologic symptoms or signs suggest a process involving the brain (eg, headaches, visual
disturbances, and/or midline defects), or if the laboratory studies are consistent with hypothalamic or pituitary disease (eg, mildly elevated
prolactin, central adrenal insufficiency, and/or central hypothyroidism). If a sellar mass is identified, the patient should be further evaluated for
pituitary hormone deficiencies. In addition, clinicians may request special imaging (with thin cuts through the olfactory region) to assess the
presence or hypoplasia/absence of the olfactory bulb, nerves, and tracts, which can provide insight into the possibility of Kallmann
syndrome. (See "Diagnostic testing for hypopituitarism" and "Isolated gonadotropin-releasing hormone deficiency (idiopathic
hypogonadotropic hypogonadism)", section on 'Diagnosis'.)
● In patients who report anosmia, an olfactory function test can be used ("smell kit") to point toward a diagnosis of Kallmann syndrome. (See
'Isolated GnRH deficiency' above.)
● If isolated GnRH deficiency is strongly suspected because of anosmia or associated congenital anomalies (eg, midline defects [cleft
lip/palate], neurosensory hearing loss, synkinesia, unilateral renal agenesis, or skeletal defects including syndactyly), referral for panels of
genetic testing is appropriate. By contrast, in patients without these features, genetic testing usually is not warranted during adolescence.
This is because a majority of patients with secondary hypogonadism and no other abnormalities will have CDGP. (See "Isolated
gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Diagnosis'.)
● Serum inhibin B can be used as a biochemical index of gonadal function in boys. For individuals with secondary (hypogonadotropic)
hypogonadism with no clear cause, a very low level of inhibin B is more likely to be associated with isolated GnRH deficiency with absent
puberty, rather than CDGP [22]. However, inhibin B levels are not useful to distinguish between CDGP and milder forms of isolated GnRH
deficiency. For boys, serial measurements of inhibin B can help to monitor pubertal progression, as a supplement to measurements of
testicular volume.
● Evaluation for iron overload in patients with risk factors, by measuring serum transferrin saturation and ferritin, can be done in clinically
appropriate situations. Iron overload can cause secondary (hypogonadotropic) hypogonadism. Risk factors include:
• Children with a history of blood transfusion therapy (eg, those with hemoglobinopathies).
• Boys or girls with risk factors for juvenile hereditary hemochromatosis, which include a family history of consanguinity or iron overload,
or unexplained liver or cardiac disease. Juvenile hemochromatosis is rare but has been most commonly reported in Italy. In contrast with
other forms of hereditary hemochromatosis, it can present in adolescents or young adults. (See "HFE and other hemochromatosis
genes", section on 'Hemojuvelin (HJV)' and "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on
'Indications for testing'.)
THERAPY
Patients with specific cause of delayed puberty — If a specific underlying disorder can be identified (table 1), therapy should be targeted at
that disorder. As examples, thyroid hormone replacement in hypothyroidism, effective treatment of inflammatory bowel disease, dopamine
agonist treatment of lactotroph adenomas, and excision of craniopharyngiomas can result in prompt initiation or resumption of sexual maturation
in the appropriate clinical circumstances.
For patients with primary gonadal failure, such as Turner or Klinefelter syndrome, sex hormone therapy is a component of management. (See
"Management of Turner syndrome in children and adolescents" and "Testosterone treatment of male hypogonadism".)
Patients with presumed constitutional delay of growth and puberty — A majority of patients with pubertal delay will have secondary
hypogonadism without evidence of underlying disease. For this group of patients, the most likely causes are either constitutional delay of growth
and puberty (CDGP) or isolated gonadotropin-releasing hormone (GnRH) deficiency. Distinguishing between these disorders is often impossible
during the initial evaluation, unless specific associated features of isolated GnRH deficiency are present. In many cases, the diagnosis is
resolved only with serial observations. (See 'Isolated GnRH deficiency' above and "Isolated gonadotropin-releasing hormone deficiency
(idiopathic hypogonadotropic hypogonadism)", section on 'Diagnosis'.)
In view of these diagnostic difficulties, the initial therapeutic approach is similar for both disorders [23,24]. The two major options are "watchful
waiting" with reassurance and psychological support for the patient and family, or short-term hormonal therapy, with testosterone in boys and
estrogen in girls.
Hormonal therapy

Indications and goals — Short-term hormonal therapy may be appropriate for boys older than 14 years, or girls older than 12 years who
show few or no signs of puberty, and if the pubertal delay is severe or if the patient's psychosocial concerns about the delay play a prominent role
that cannot be resolved by reassurance and education alone. The short-term use of exogenous testosterone in boys or estrogen in girls does not
appear to have any long-term sequelae, except that the hormone-induced skeletal maturation might result in some loss of adult height.
Short-term therapeutic goals include:
● Attainment of age-appropriate secondary sex characteristics to ameliorate the patient's concern about his/her appearance relative to peers,
a particular problem for boys in communal settings that require disrobing such as in showers and gym classes, but one that occurs to some
degree in both sexes.
● Induction of a growth spurt without inducing premature epiphyseal closure. This goal requires frequent (eg, every six months) longitudinal
monitoring of bone age during therapy.
● Potential induction of a "reversal" of their GnRH deficiency, whether congenital or functional; sex steroid hormone therapy has been
demonstrated to induce puberty even in some cases in which the GnRH deficiency has a genetic etiology [4].
For patients who turn out to have isolated GnRH deficiency that does not "reverse" spontaneously, the long-term goals of therapy are to maintain
the serum concentrations of sex steroids within the normal adult range and, eventually, to induce fertility if and when the patient desires. (See
"Induction of fertility in men with secondary hypogonadism" and "Isolated gonadotropin-releasing hormone deficiency (idiopathic
hypogonadotropic hypogonadism)".)
Testosterone therapy — Testosterone can be administered by several routes, and patient preferences should be consulted. The most
reliable and well-tested approach is to use intramuscular (IM) injections of testosterone esters [25-34]. An oral preparation of testosterone
undecanoate is available in some countries, but the levels of testosterone achieved with this preparation seem to be slightly more erratic
compared with parenterally administered testosterone. The use of testosterone gel transdermally seems appealing because of its efficacy and
convenience in adult males with hypogonadism, but it has not yet been widely tested or approved in males younger than age 18 years. (See
"Testosterone treatment of male hypogonadism", section on 'Choice of testosterone regimen'.)

Testosterone doses should initially be relatively low (eg, 50 mg of IM testosterone enanthate or testosterone cypionate once a month). Such a
dose (about 15 to 25 percent of the adult dose) is usually sufficient to achieve early virilization and growth over time (ie, three to six months),
without unduly advancing epiphyseal maturation (bone age). (See "Testosterone treatment of male hypogonadism".)
One approach is to administer testosterone enanthate or cypionate (50 mg IM once monthly) for six months and then to reassess endogenous
gonadal function and size six months later. In many patients, this therapy is associated with pubertal development, indicated by testicular
enlargement and increasing testosterone concentrations after the cessation of therapy. Testicular enlargement and increasing testosterone
concentrations demonstrate that follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are present in sufficient quantities, and
excludes testicular pathology. It is unclear whether the pubertal development is spontaneous or is triggered by the testosterone exposure.
Controlled studies in this area are difficult to conduct but do support the notion that testosterone exposure may hasten the hypothalamic GnRH
secretion required for puberty.
Although exogenous sex steroid administration accelerates epiphyseal maturation [32], most studies indicate that judicious treatment with low
doses of sex steroids for limited periods of time does not adversely affect adult height [24-27,30,33]. The use of relatively low doses of
testosterone, and treating for limited periods of time, maximizes the likelihood that a boy will reach his "predicted" final height.
In one report, for example, 15 boys with CDGP were treated with testosterone enanthate (50 mg/month) for a mean of 1.2 years [24]. Mean
height velocity increased from the 3rd percentile for mean bone age to above the 90th percentile, and mean testicular volume rose from 5.9 to
11.3 mL during therapy. The increase in testicular volume during the course of testosterone therapy was accompanied by endogenous GnRH
secretion and the occurrence of spontaneous puberty. Skeletal maturation increased only in the boys with an initial bone age below the group
mean. After cessation of therapy, bone age and sexual development proceeded normally and the boys ultimately achieved their predicted mean
height. Similar results have been reported in other studies [25,30,33]. Thus, it is unusual for a boy with CDGP to require more than two three- to
six-month courses of testosterone therapy before spontaneous puberty occurs.
In contrast, most boys with other forms of hypogonadotropic hypogonadism demonstrate little or no pubertal development with low-dose
testosterone, and pubertal progress usually stops with cessation of therapy. After the age of 18 years in those patients without any organic or
obvious pathologic causes, isolated (congenital) GnRH deficiency is the most likely diagnosis. However, approximately 10 percent of patients
with isolated GnRH deficiency appear to undergo a spontaneous reversal following even a brief course of sex steroid exposure. This reversal is

heralded by testicular enlargement, or the ability to sustain a normal testosterone concentration off of treatment or following a missed prescription
refill [4].
Estradiol therapy — In girls, estradiol may be given orally or transdermally. Initial doses are lower than those used for replacement
therapy in adults. Guidelines suggest starting with very low doses of estradiol and gradually increasing the dose. Our approach, using
transdermal 17-beta estradiol patch, is as follows:
● Start with a transdermal matrix 17-beta estradiol patch that is designed to deliver 25 mcg/day. Cut into quarters to deliver approximately 6.25
mcg/day per piece. For all doses, wear the patch continuously, and change the patch as directed on the manufacturer's insert (typically twice
weekly).
● Month 6: Increase to one-half patch (12.5 mcg/day 17-beta estradiol).
● Month 12: Increase to three-fourth quarters patch (18.75 mcg/day 17-beta estradiol).
● Month 18: Increase to full patch (25 mcg/day 17-beta estradiol).
● Month 24: Continue estradiol and add cyclic progestin 200 mg, given on days 1 to 12 of the calendar month (if breast development is
adequate).
In girls with Turner syndrome, estradiol therapy is typically started at age 11 to 12 years. In this case, some experts use even lower initial doses
(eg, cutting a smaller portion of the patch and wearing this only at night). (See "Management of Turner syndrome in children and adolescents",
section on 'Induction of puberty'.).
The initial estradiol doses used are below those required to induce menstruation. We add cyclic progestin therapy after two years of estradiol or
when breakthrough bleeding occurs on unopposed estradiol. Our first choice for progestin therapy is oral micronized progesterone 200 mg days
1 to 12 of the calendar month. The progestin should not be added until there is substantial breast development that is not solely confined to the
areolae, and full contour breast growth has plateaued, because premature initiation of progestin therapy can compromise ultimate breast growth.
Once breast growth has plateaued during serial evaluation and menstruation has been established, estradiol therapy can be discontinued
intermittently for one- to three-month periods to determine if spontaneous menstruation occurs, which should happen in girls with CDGP.

Patients who do not develop spontaneous menstruation and who are older than age 18 years likely have isolated (congenital) GnRH deficiency.
In this case, full adult replacement therapy with both estrogen and progesterone should be initiated. Doses and principles of therapy are similar to
those for women with primary ovarian insufficiency. Additional details on progestin therapy and maintenance hormone therapy are found
separately. (See "Management of spontaneous primary ovarian insufficiency (premature ovarian failure)".)
Growth hormone therapy — The value of growth hormone therapy in patients without documented growth hormone deficiency is
controversial. Serum growth hormone and insulin-like growth factor 1 (IGF-1) concentrations are usually low for chronological age in patients with
CDGP (but not if corrected for the normal range for bone age) and increase in response to testosterone or estrogen therapy. Patients with
isolated (congenital) GnRH deficiency are typically not growth hormone-deficient and do not benefit from growth hormone therapy, since sex
steroids will prompt normal increases in their growth axis. Although the administration of growth hormone is less likely to induce epiphyseal
closure than sex steroids and may therefore add to adult height, children with delayed puberty grow well when treated with sex steroids alone.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See
"Society guideline links: Normal puberty and related disorders".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written
in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and
are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can
also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topic (see "Patient education: Late puberty (The Basics)")
SUMMARY
● Delayed puberty is defined clinically by the absence or incomplete development of secondary sexual characteristics bounded by an age at
which 95 percent of children of that sex and culture have initiated sexual maturation. In the United States, the upper 95th percentile for initial
pubertal development is 12 years for girls (breast development being the first sign), and 14 years for boys (increase in testicular size being
the first sign), but with considerable differences in racial and ethnic subpopulations. (See 'Delayed puberty' above.)
● Primary hypogonadism is characterized by low levels of gonadal hormones and high levels of luteinizing hormone (LH) and follicle-
stimulating hormone (FSH). Secondary hypogonadism is characterized by low levels of gonadal hormones and low to normal concentrations
of LH and FSH, and typically is caused by impaired secretion of hypothalamic gonadotropin-releasing hormone (GnRH) (table 1). The most
common cause of delayed puberty is constitutional delay of growth and puberty (CDGP), which is a transient defect in production of GnRH
from the hypothalamus, due to physiologic individual variation. CDGP may be difficult to distinguish from isolated (congenital) GnRH
deficiency. (See 'Etiology' above.)
● No test reliably distinguishes patients with CDGP (who will eventually progress spontaneously through puberty) from patients with other
causes of delayed puberty, particularly isolated GnRH deficiency. The most valuable components of an assessment are a focused history
and physical examination, and observation over time. Some patients with isolated GnRH deficiency have anosmia or associated congenital
anomalies, including midline defects (cleft lip/palate), neurosensory hearing loss, synkinesia, unilateral renal agenesis, or skeletal defects
including syndactyly and ectrodactyly. (See 'Evaluation' above.)
● The history helps determine whether pubertal development is totally absent or had started but then "stalled." Patients with CDGP have
delayed (not stalled) growth, adrenarche, sexual development, and bone age. The history should also solicit information about underlying
chronic disease, congenital anomalies, family history of pubertal development, and sense of smell. (See 'History' above.)
● The physical examination includes accurate determination of Tanner stage of pubertal development (picture 1 and picture 2A-B), as well as
measurements of height and weight, and of testicular size in boys. Height velocity should be calculated from serial measurements of height
over six months or more. (See 'Physical examination' above.)
● Determination of bone age at the initial evaluation provides valuable information about the relationship between chronologic age and skeletal
maturation. Children with CDGP typically have bone ages approximately 20 percent younger than their actual age. (See 'Bone age' above.)
● Laboratory evaluation for a patient with delayed puberty should include measurement of serum testosterone in boys and estradiol in girls, LH
and FSH, prolactin, thyroid-stimulating hormone (TSH), and free thyroxine (T4). Most patients should also be screened for chronic diseases
that may cause pubertal delay, using a complete blood count, erythrocyte sedimentation rate, liver function tests, and serologic testing for
celiac disease. In selected patients, head magnetic resonance imaging (MRI) or evaluation for iron overload is appropriate. Patients with
primary hypogonadism (elevated LH and FSH) should undergo diagnostic testing for Turner syndrome (girls) or Klinefelter syndrome (boys).
(See 'Initial testing' above and 'Additional testing' above.)
● If a specific underlying disorder can be identified (table 1), therapy should be targeted at that disorder.
● In most patients with secondary hypogonadism and no other abnormalities, the distinction between CDGP and isolated (congenital) GnRH
deficiency remains uncertain, and can be resolved only with serial observations. Short-term hormonal therapy with testosterone in boys and
with estradiol in girls may be appropriate when the pubertal delay is severe or the patient's psychosocial concerns about the delay play a
prominent role that cannot be addressed by reassurance and education alone. (See 'Therapy' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Herman-Giddens ME, Slora EJ, Wasserman RC, et al. Secondary sexual characteristics and menses in young girls seen in office practice:
a study from the Pediatric Research in Office Settings network. Pediatrics 1997; 99:505.
2. Argente J. Diagnosis of late puberty. Horm Res 1999; 51 Suppl 3:95.
3. Sedlmeyer IL, Palmert MR. Delayed puberty: analysis of a large case series from an academic center. J Clin Endocrinol Metab 2002;
87:1613.

4. Raivio T, Falardeau J, Dwyer A, et al. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med 2007; 357:863.
5. Waldstreicher J, Seminara SB, Jameson JL, et al. The genetic and clinical heterogeneity of gonadotropin-releasing hormone deficiency in
the human. J Clin Endocrinol Metab 1996; 81:4388.
6. Zhu J, Choa RE, Guo MH, et al. A shared genetic basis for self-limited delayed puberty and idiopathic hypogonadotropic hypogonadism. J
Clin Endocrinol Metab 2015; 100:E646.
7. Rosenfield RL. Clinical review 6: Diagnosis and management of delayed puberty. J Clin Endocrinol Metab 1990; 70:559.
8. Kaplowitz PB. Delayed puberty. Pediatr Rev 2010; 31:189.
9. Boepple PA. Precocious and delayed puberty. Curr Opin Endocrinol Diabetes 1995; 2:111.
10. Pugliese MT, Lifshitz F, Grad G, et al. Fear of obesity. A cause of short stature and delayed puberty. N Engl J Med 1983; 309:513.
11. Sedlmeyer IL, Hirschhorn JN, Palmert MR. Pedigree analysis of constitutional delay of growth and maturation: determination of familial
aggregation and inheritance patterns. J Clin Endocrinol Metab 2002; 87:5581.
12. Balasubramanian R, Dwyer A, Seminara SB, et al. Human GnRH deficiency: a unique disease model to unravel the ontogeny of GnRH
neurons. Neuroendocrinology 2010; 92:81.
13. Mitchell AL, Dwyer A, Pitteloud N, Quinton R. Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying
theory. Trends Endocrinol Metab 2011; 22:249.
14. Balasubramanian R, Crowley WF Jr. Isolated GnRH deficiency: a disease model serving as a unique prism into the systems biology of the
GnRH neuronal network. Mol Cell Endocrinol 2011; 346:4.
15. Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch
Dis Child 1976; 51:170.

16. Marshall JC, Kelch RP. Low dose pulsatile gonadotropin-releasing hormone in anorexia nervosa: a model of human pubertal development.
J Clin Endocrinol Metab 1979; 49:712.
17. Kelch RP, Hopwood NJ, Marshall JC. Diagnosis of gonadotropin deficiency in adolescents: limited usefulness of a standard gonadotropin-
releasing hormone test in obese boys. J Pediatr 1980; 97:820.
18. Savage MO, Preece MA, Cameron N, et al. Gonadotrophin response to LH-RH in boys with delayed growth and adolescence. Arch Dis
Child 1981; 56:552.
19. Harman SM, Tsitouras PD, Costa PT, et al. Evaluation of pituitary gonadotropic function in men: value of luteinizing hormone-releasing
hormone response versus basal luteinizing hormone level for discrimination of diagnosis. J Clin Endocrinol Metab 1982; 54:196.
20. Wilson DA, Hofman PL, Miles HL, et al. Evaluation of the buserelin stimulation test in diagnosing gonadotropin deficiency in males with
delayed puberty. J Pediatr 2006; 148:89.
21. Ghai K, Cara JF, Rosenfield RL. Gonadotropin releasing hormone agonist (nafarelin) test to differentiate gonadotropin deficiency from
constitutionally delayed puberty in teen-age boys--a clinical research center study. J Clin Endocrinol Metab 1995; 80:2980.
22. Coutant R, Biette-Demeneix E, Bouvattier C, et al. Baseline inhibin B and anti-Mullerian hormone measurements for diagnosis of
hypogonadotropic hypogonadism (HH) in boys with delayed puberty. J Clin Endocrinol Metab 2010; 95:5225.
23. Brook CG. Management of delayed puberty. Br Med J (Clin Res Ed) 1985; 290:657.
24. Richman RA, Kirsch LR. Testosterone treatment in adolescent boys with constitutional delay in growth and development. N Engl J Med
1988; 319:1563.
25. Soliman AT, Khadir MM, Asfour M. Testosterone treatment in adolescent boys with constitutional delay of growth and development.
Metabolism 1995; 44:1013.
26. Wilson DM, Kei J, Hintz RL, Rosenfeld RG. Effects of testosterone therapy for pubertal delay. Am J Dis Child 1988; 142:96.

27. Butler GE, Sellar RE, Walker RF, et al. Oral testosterone undecanoate in the management of delayed puberty in boys: pharmacokinetics
and effects on sexual maturation and growth. J Clin Endocrinol Metab 1992; 75:37.
28. Adan L, Souberbielle JC, Brauner R. Management of the short stature due to pubertal delay in boys. J Clin Endocrinol Metab 1994; 78:478.
29. Albanese A, Kewley GD, Long A, et al. Oral treatment for constitutional delay of growth and puberty in boys: a randomised trial of an
anabolic steroid or testosterone undecanoate. Arch Dis Child 1994; 71:315.
30. Büyükgebiz A. Treatment of constitutional delayed puberty with a combination of testosterone esters. Horm Res 1995; 44 Suppl 3:32.
31. Bergadá I, Bergadá C. Long term treatment with low dose testosterone in constitutional delay of growth and puberty: effect on bone age
maturation and pubertal progression. J Pediatr Endocrinol Metab 1995; 8:117.
32. Albanese A, Stanhope R. Predictive factors in the determination of final height in boys with constitutional delay of growth and puberty. J
Pediatr 1995; 126:545.
33. Arrigo T, Cisternino M, Luca De F, et al. Final height outcome in both untreated and testosterone-treated boys with constitutional delay of
growth and puberty. J Pediatr Endocrinol Metab 1996; 9:511.
34. Raivio T, Dunkel L, Wickman S, Jänne OA. Serum androgen bioactivity in adolescence: a longitudinal study of boys with constitutional
delay of puberty. J Clin Endocrinol Metab 2004; 89:1188.
Topic 5814 Version 22.0

GRAPHICS
Causes of delayed puberty
Primary hypogonadism - High FSH and LH

Congenital
Chromosomal abnormalities (Turner syndrome - 45,XO; Klinefelter syndrome - 47,XXY)
Anorchia (vanishing testis)
Acquired
Autoimmune or postinfectious
Following trauma or surgery
Chemotherapy, radiation therapy
Secondary hypogonadism - Low to normal FSH and LH

Acquired
Tumors
Benign tumors and cysts
Craniopharyngiomas
Germinomas, meningiomas, gliomas, astrocytomas
"Functional" gonadotropin deficiency

Constitutional delay of growth and puberty (CDGP)
Chronic systemic disease
Acute illness
Malnutrition
Hypothyroidism, hyperprolactinemia, diabetes mellitus, Cushing's disease
Anorexia nervosa, bulimia
Infiltrative diseases
Hemochromatosis
Granulomatous diseases
Histiocytosis
Head trauma
Pituitary apoplexy
Drugs - Marijuana
Congenital

Isolated GnRH deficiency (also known as idiopathic hypogonadotropic hypogonadism)
Without anosmia
With anosmia (Kallmann syndrome)
Associated with adrenal hypoplasia congenita
GnRH deficiency associated with mental retardation/obesity

Laurence-Moon-Biedl syndrome
Prader-Willi syndrome
Idiopathic forms of multiple anterior pituitary hormone deficiencies
Congenital brain malformations causing GnRH or gonadotropin deficiencies (often associated with craniofacial anomalies)
FSH: follicle stimulating hormone; LH: luteinizing hormone; GnRH: gonadotropin-releasing hormone.
Graphic 62372 Version 7.0

Height velocity in American boys


Height velocity by age for American boys. The main set of curves (black lines) is centered on
the population with average timing of peak growth velocity (around 13.5 years for boys) and
show an approximate trajectory for individual children with this average pubertal timing. The
2 other curves outline a trajectory (50 th percentile) for a child with "early" (solid blue) or
"late" (solid orange) timing of peak growth velocity.
Other height velocity curves (not shown here) have been developed that reflect population
averages; those curves are substantially flatter than the trajectory followed by any individual
patient [1]. Those curves are based on data from a more recent and ethnically diverse
population of children and are valuable for understanding overall growth patterns in the
population but are less appropriate for evaluation of the growth of an individual patient.
SD: standard deviations.
Reference:
1. Kelly A, Winer KK, Kalkwarf H, et al. Age-based reference ranges for annual height velocity in
US children. J Clin Endocrinol Metab 2014; 99:2104.
Reproduced with permission from: Tanner JM, Davies S. Clinical longitudinal standards for height and
height velocity for North American children. J Pediatr 1985; 107:317. Copyright © 1985 Elsevier.

Height velocity in American girls


Height velocity by age for American girls. The main set of curves (black lines) is centered on
the population with average timing of peak growth velocity (around 11.5 years for girls) and
show an approximate trajectory for individual children with this average pubertal timing. The
2 other curves outline a trajectory (50 th percentile) for a child with "early" (solid blue) or
"late" (solid orange) timing of peak growth velocity.
Other height velocity curves (not shown here) have been developed that reflect population
averages; those curves are substantially flatter than the trajectory followed by any individual
patient [1]. Those curves are based on data from a more recent and ethnically diverse
population of children and are valuable for understanding overall growth patterns in the
population but are less appropriate for evaluation of the growth of an individual patient.
SD: standard deviations.
Reference:
1. Kelly A, Winer KK, Kalkwarf H, et al. Age-based reference ranges for annual height velocity in
US children. J Clin Endocrinol Metab 2014; 99:2104.
Reproduced with permission from: Tanner JM, Davies S. Clinical longitudinal standards for height and
height velocity for North American children. J Pediatr 1985; 107:317. Copyright © 1985 Elsevier.

Stature-for-age percentiles, boys, 2 to 20 years, CDC growth charts:

United States

CDC: Centers for Disease Control and Prevention.

From National Health Center for Health Statistics in collaboration with the National Center for Chronic
Disease Prevention and Health Promotion (2000).

Stature-for-age percentiles, girls, 2 to 20 years, CDC growth charts:

United States

CDC: Centers for Disease Control and Prevention.

From National Health Center for Health Statistics in collaboration with the National Center for Chronic
Disease Prevention and Health Promotion (2000).

Sexual maturity rating (Tanner staging) of pubic hair and

external genitalia development in boys


Stages of pubic hair development in boys:

Stage 1: Prepubertal, with no pubic hair.
Stage 2: Sparse, straight pubic hair along the base of the penis.
Stage 3: Hair is darker, coarser, and curlier, extending over the mid-pubis.
Stage 4: Hair is adult-like in appearance, but does not extend to thighs.
Stage 5: Hair is adult in appearance, extending from thigh to thigh.
Stages of external genitalia development in boys:
Stage 1: Prepubertal.
Stage 2: Enlargement of testes and scrotum; scrotal skin reddens and changes
in texture.
Stage 3: Enlargement of penis (length at first); further growth of testes.
Stage 4: Increased size of penis with growth in breadth and development of
glans; testes and scrotum larger, scrotal skin darker.
Stage 5: Adult genitalia.
Figure from: Roede MJ, van Wieringen JC. Growth diagrams 1980: Netherlands third
nation-wide survey. Tijdschr Soc Gezondheids 1985; 63:1. Reproduced with permission
from the author.

Sexual maturity rating (Tanner staging) of breast

development in girls
Stages in breast development in girls.

Stage 1: Prepubertal, with no palpable breast tissue.
Stage 2: Development of a breast bud, with elevation of the papilla and
enlargement of the areolar diameter.

Stage 3: Enlargement of the breast, without separation of areolar contour from
the breast.
Stage 4: The areola and papilla project above the breast, forming a secondary
mound.
Stage 5: Recession of the areola to match the contour of the breast; the papilla
projects beyond the contour of the areola and breast.
nation-wide survey. Tijdschr Soc Gezondheids 1985; 63:1. Reproduced with
permission from the author.

Sexual maturity rating (Tanner staging) of pubic hair

development in girls
Stages of development in pubic hair in girls.

Stage 1: Prepubertal with no pubic hair.
Stage 2: Sparse, straight hair along the lateral vulva.
Stage 3: Hair is darker, coarser, and curlier, extending over the mid-pubis.

Stage 4: Hair is adult-like in appearance, but does not extend to the thighs.
Stage 5: Hair is adult in appearance, extending from thigh to thigh.
nation-wide survey. Tijdschr Soc Gezondheids 1985; 63:1. Reproduced with
permission from the author.

Prader orchidometer
Photo of a Prader orchidometer for measuring testicular size. On physical examination, the patient's testicular volume is estimated
by palpation and comparison with the models on the orchidometer. Each of the beads is labeled with its volume, ranging from 1 to
25 mL. Prepubertal sizes are 1 to 3 mL, pubertal sizes are 4 to 12 mL, and adult sizes are 12 to 25 mL.

Testicular volume in each pubertal stage
Testicular volume in adolescents as a function of pubertal stage. These data are

from serial evaluations of 539 boys, ages 10 to 15 years; the subjects were
evaluated every 6 months over 3 years. Pubertal stage represents the sexual
maturity rating (Tanner stage of pubertal development).
Reproduced with permission from: Biro FM. Physical growth and development. In:
Principles of Adolescent Medicine, Friedman SB, Fisher M, Schonberg SK. Mosby-Year
Book, Inc, 1997. Figure 6-3, p.31. Copyright ©1997 Elsevier.

Approximate incidence of major clinical abnormalities in Turner syndrome
Abnormalities Frequency (percent) Abnormalities Frequency (percent)
Skeletal growth disturbances Other features
Short stature 95 to 100 Cardiac malformations up to 50
Growth failure 90 to 95 Elongated transverse aortic arch 40 to 50

Increased upper-to-lower segment ratio >90 Aortic valve abnormalities 15 to 30
Defective dental development, malocclusion up to 75 (primarily bicuspid aortic valve)
Characteristic facies with micrognathia 60 Coarctation of the aorta 7 to 17
Cubitus valgus 50 Pulmonary venous abnormalities 13 to 15
Kyphosis 50 Systemic venous abnormalities 8 to 13

(such as persistent left superior vena cava)
Short neck 40
Ventricular septal defects 1 to 4
Genu valgum 35
Atrial septal defects 1 to 2
High arched palate 35
Coronary artery abnormalities up to 2
Widely spaced nipples, broad chest 30 to 35
Hypoplastic left heart <1
Short metacarpals 35
Electrocardiographic abnormalities (minor) 50
Scoliosis 10 to 20
Prolonged QTc interval 21 to 36
Madelung deformity 5
Renal and renovascular anomalies 20 to 30
Lymphatic obstruction
Collecting system malformations ~20
Low posterior hairline 40
Horseshoe kidney 10
Edema of hands/feet 20 to 30
Hypertension 30
Characteristic dermatoglyphics 30
Ocular abnormalities
Webbed neck 25
Myopia or hyperopia 20 to 50
Earlobe anomalies (eg, rotated) 15 to 20
Strabismus 15 to 30
Nail dysplasia 10
Amblyopia >15
Germ cell chromosomal defects
Ptosis 10 to 30
Infertility 95
Ears and hearing
Ovarian failure 90
Recurrent otitis media 50 to 70
Gonadal dysgenesis 85 to 90
Sensorineural hearing loss 50 (by adulthood)
Gonadoblastoma 5
Conductive hearing loss 10 to 40

Cholesteatoma 5
Skin
Multiple pigmented nevi 25
Vitiligo 5
Alopecia 5
Autoimmune
Thyroiditis 15 to 30
(rate increases with age)
Celiac disease 6
Inflammatory bowel disease 4
References:
1. Gravholt CH, Juul S, Naeraa RW, Hansen J. Morbidity in Turner syndrome. J Clin Epidemiol 1998; 51:147.
2. Sylvén L, Hagenfeldt K, Bröndum-Nielsen K, von Schoultz B. Middle-aged women with Turner's syndrome. Medical status, hormonal treatment and social life. Acta Endocrinol
(Copenh) 1991; 125:359.
3. Lippe B. Turner syndrome. Endocrinol Metab Clin North Am 1991; 20:121.
4. Gøtzsche CO, Krag-Olsen B, Nielsen J, et al. Prevalence of cardiovascular malformations and association with karyotypes in Turner's syndrome. Arch Dis Child 1994; 71:433.
5. Kim HK, Gottliebson W, Hor K, et al. Cardiovascular anomalies in Turner syndrome: spectrum, prevalence, and cardiac MRI findings in a pediatric and young adult population.
AJR Am J Roentgenol 2011; 196:454.
6. Mortensen KH, Andersen NH, Gravholt CH. Cardiovascular phenotype in Turner syndrome--integrating cardiology, genetics, and endocrinology. Endocr Rev 2012; 33:677.
7. Bondy CA, Van PL, Bakalov VK, et al. Prolongation of the cardiac QTc interval in Turner syndrome. Medicine (Baltimore) 2006; 85:75.
8. Bondy CA, Ceniceros I, Van PL, et al. Prolonged rate-corrected QT interval and other electrocardiogram abnormalities in girls with Turner syndrome. Pediatrics 2006;
118:e1220.
9. Bondy CA, Turner Syndrome Study Group. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2007;
92:10.

Contributor Disclosures
William F Crowley, Jr, MD Equity Ownership/Stock Options: Dare Bioscience [Endocrinology (Transvaginal ring delivery systems)]. Consultant/Advisory
Boards: Dare Bioscience [Endocrinology (Transvaginal drug delivery systems)]. Nelly Pitteloud, MD Nothing to disclose Peter J Snyder,
MD Grant/Research/Clinical Trial Support: AbbVie [Hypogonadism]; Novartis [Cushing's]. Consultant/Advisory Boards: AbbVie [Hypogonadism]; Novartis
[Cushing's]; Pfizer [Acromegaly]. Amy B Middleman, MD, MPH, MS Ed Grant/Research/Clinical Trial Support: Pfizer [Meningococcal serogroup B vaccine
(Creation and preliminary evaluation of educational materials)]. Mitchell E Geffner, MD Grant/Research/Clinical Trial Support: Novo Nordisk [Growth].
Consultant/Advisory Boards: Daiichi-Sankyo [Type 2 diabetes]; Novo Nordisk, Nutritional Growth Solutions, and Pfizer [Growth]; Spruce Biosciences [CAH].
Other Financial Interest: McGraw-Hill [Pediatric endocrinology textbook royalties]; Ascendis data safety monitoring board [Growth]; Tolmar data safety
monitoring board [Precocious puberty]; Millendo data safety monitoring board [Prader-Willi syndrome]. Alison G Hoppin, MD Nothing to disclose Kathryn A
Martin, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review
process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

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● (See "Evaluation and management of primary amenorrhea".)

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● Secondary (hypogonadotropic) hypogonadism:

• Functional hypogonadotropic hypogonadism – 19 percent.

● Primary hypogonadism – 13 percent.

Causes of secondary hypogonadism include:

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History — Key elements of the history are:

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Short-term therapeutic goals include:

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● Month 6: Increase to one-half patch (12.5 mcg/day 17-beta estradiol).

● Month 18: Increase to full patch (25 mcg/day 17-beta estradiol).

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SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

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● Basics topic (see "Patient education: Late puberty (The Basics)")

Use of UpToDate is subject to the Subscription and License Agreement.

2. Argente J. Diagnosis of late puberty. Horm Res 1999; 51 Suppl 3:95.

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8. Kaplowitz PB. Delayed puberty. Pediatr Rev 2010; 31:189.

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Topic 5814 Version 22.0

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Causes of delayed puberty

Primary hypogonadism - High FSH and LH

Chromosomal abnormalities (Turner syndrome - 45,XO; Klinefelter syndrome - 47,XXY)

Anorchia (vanishing testis)

Following trauma or surgery

Chemotherapy, radiation therapy

Secondary hypogonadism - Low to normal FSH and LH

"Functional" gonadotropin deficiency

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GnRH deficiency associated with mental retardation/obesity

Idiopathic forms of multiple anterior pituitary hormone deficiencies

Graphic 62372 Version 7.0

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Height velocity in American boys

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SD: standard deviations.

Graphic 96367 Version 6.0

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Height velocity in American girls

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SD: standard deviations.