Amenorrhea

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence
Clinical recommendation rating References

A female patient with primary amenorrhea and sexual development, including pubic hair, C 1, 18
should be evaluated for the presence of a uterus and vagina.
Women with secondary amenorrhea should receive pregnancy tests. C 1-3, 6
Women with polycystic ovary syndrome should be tested for glucose intolerance. C 21

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-
oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 1313 or
http://www.aafp.org/afpsort.xml.

TABLE 1
Normal Female Pubertal Development

Tanner stage

Developmental stage Breast Pubic hair

(age in years) Anatomic drawing development development

Initial growth acceleration (8 to 10) Elevation of papilla only; no pubic hair 1 1

Thelarche (9 to 11) See adrenarche for stage 2 development 2 1

Adrenarche (9 to 11) 2 2

Peak growth (11 to 13) 3 3

Menarche (12 to 14) 4 4

Adult characteristics (13 to 16) 5 5

Illustrations by Renee Cannon.

Information from references 4 and 5.

April 15, 2006 U Volume 73, Number 8 www.aafp.org/afp American Family Physician 1375
Amenorrhea

7.5 percent of participants had abnormal prolactin levels tive progestogen challenge test signifies an outflow tract
and 4.2 percent had abnormal TSH levels. abnormality or inadequate estrogenization. An estrogen/
If TSH and prolactin levels are normal, a progestogen progestogen challenge test (Table 33,14) can differentiate
challenge test (Table 33,14) can help evaluate for a patent the two diagnoses. A negative estrogen/progestogen chal-
outflow tract and detect endogenous estrogen that is lenge test typically indicates an outflow tract obstruc-
affecting the endometrium. A withdrawal bleed usually tion. A positive test indicates an abnormality within the
occurs two to seven days after the challenge test.3 A nega- hypothalamic-pituitary axis or the ovaries.

TABLE 2
History and Physical Examination Findings Associated with Amenorrhea

Findings Associations

Patient history
Exercise, weight loss, current or previous chronic illness, Hypothalamic amenorrhea
illicit drug use
Menarche and menstrual history Primary versus secondary amenorrhea
Prescription drug use Multiple, depending on medication
Previous central nervous system chemotherapy or radiation Hypothalamic amenorrhea
Previous pelvic radiation Premature ovarian failure
Psychosocial stressors; nutritional and exercise history Anorexia or bulimia nervosa
Sexual activity Pregnancy
Family history
Genetic defects Multiple causes of primary amenorrhea
Pubic hair pattern Androgen insensitivity syndrome
Infertility Multiple
Menarche and menstrual history (mother and sisters) Constitutional delay of growth and puberty
Pubertal history (e.g., growth delay) Constitutional delay of growth and puberty
Physical examination
Anthropomorphic measurements; growth chart Constitutional delay of growth and puberty
Body mass index Polycystic ovary syndrome
Dysmorphic features (e.g., webbed neck, short stature, Turner’s syndrome
widely spaced nipples)
Rudimentary or absent uterus; pubic hair Müllerian agenesis
Striae, buffalo hump, significant central obesity, easy bruising, Cushing’s disease
hypertension, or proximal muscle weakness
Tanner staging (Table 1) Primary versus secondary amenorrhea
Thyroid examination Thyroid disease
Transverse vaginal septum; imperforate hymen Outflow tract obstruction
Undescended testes; external genital appearance; pubic hair Androgen insensitivity syndrome
Virilization; clitoral hypertrophy Androgen-secreting tumor
Review of systems
Anosmia Kallmann syndrome
Cyclic abdominal pain; breast changes Outflow tract obstruction or müllerian agenesis
Galactorrhea; headache and visual disturbances Pituitary tumor
Hirsutism or acne Polycystic ovary syndrome
Signs and symptoms of hypothyroidism or hyperthyroidism Thyroid disease
Vasomotor symptoms Premature ovarian failure

Information from references 2 and 6 through 8.

1376 American Family Physician www.aafp.org/afp Volume 73, Number 8 U April 15, 2006
 Amenorrhea
Evaluation of Primary Amenorrhea
History and physical examination completed
for a patient with primary amenorrhea

Secondary sexual characteristics present

No Yes

Measure FSH and LH levels. Perform ultrasonography of uterus.

FSH and LH < 5 IU per L FSH > 20 IU per L and Uterus absent Uterus present
LH > 40 IU per L or abnormal or normal

Hypogonadotropic Hypergonadotropic Karyotype analysis Outflow obstruction

hypogonadism (Table 4) hypogonadism

No Yes
Karyotype analysis
46,XY 46,XX Evaluate for secondary Imperforate hymen
amenorrhea (Figure 2). or transverse
vaginal septum
Androgen Müllerian
46,XX 45,XO insensitivity agenesis
syndrome

Premature Turner’s
ovarian failure syndrome

Figure 1. Algorithm for the evaluation of primary amenorrhea. (FSH = follicle-stimulating hormone; LH = luteinizing
hormone.)
Information from references 1, 7, 9, and 10.

Gonadotropin levels can further help determine the are present, they should be removed because of the high
source of the abnormality. Elevated follicle-stimulat- risk of malignant transformation after puberty.1
ing hormone (FSH) or luteinizing hormone (LH) levels If a patient has normal secondary sexual characteris-
suggest an ovarian abnormality (hypergonadotropic tics, including pubic hair, the physician should perform
hypogonadism). Normal or low FSH or LH levels suggest MRI or ultrasonography to determine if a uterus is
a pituitary or hypothalamic abnormality (hypogonado- present. Müllerian agenesis (the congenital absence of
tropic hypogonadism). Magnetic resonance imaging a vagina and abnormal uterine development [usually
(MRI) of the sella turcica can rule out a pituitary rudimentary]) causes approximately 15 percent of pri-
tumor. Normal MRI indicates a hypothalamic cause of mary amenorrhea.16 The etiology is thought to involve
amenorrhea.3 embryonic activation of the antimüllerian hormone,
causing malformation of the female genital tract.7,17
Differential Diagnosis of Primary Amenorrhea Patients may have cyclic abdominal pain if there is endo-
Causes of primary amenorrhea should be evaluated in the metrial tissue in the rudimentary uterus, mittelschmerz,
context of the presence or absence of secondary sexual or breast tenderness. An absent or truncated vagina and
characteristics. Table 43,6,15 includes the differential diag- an abnormal adult uterus confirm müllerian agenesis.
nosis of primary amenorrhea. Karyotype analysis should be performed to determine if
the patient is genetically female.8
PRESENCE OF SECONDARY SEXUAL CHARACTERISTICS If the patient has a normal uterus, outflow tract
If a patient with amenorrhea has breast development and obstruction should be considered. An imperforate hymen
minimal or no pubic hair, the usual diagnosis is androgen or a transverse vaginal septum can cause congenital out-
insensitivity syndrome (i.e., patient is phenotypically female flow tract obstruction, which typically is associated with
but genetically male with undescended testes). A karyotype cyclic abdominal pain from blood accumulation in the
analysis is needed to determine proper treatment. If testes uterus and vagina.1 If the outflow tract is patent, the

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Amenorrhea
Evaluation of Secondary Amenorrhea
Patient presenting with secondary
amenorrhea; negative pregnancy test

Check TSH and prolactin levels.

Both normal Normal prolactin level, Normal TSH level,

abnormal TSH level abnormal prolactin level

Progestogen
challenge test Thyroid disease
(Table 3)
Prolactin b 100 ng per mL Prolactin > 100 ng per mL
(100 mcg per L)

Perform MRI to evaluate

Withdrawal bleed No withdrawal bleed Consider other for prolactinoma.
causes (Table 4).

Normogonadotropic Estrogen/progestogen Negative MRI

hypogonadism (Table 4) challenge test (Table 3)

Consider other
causes (Table 4).

Withdrawal bleed No withdrawal bleed

Check FSH and LH levels. Outflow obstruction

FSH > 20 IU per L and FSH and LH < 5 IU per L

LH > 40 IU per L

Hypergonadotropic Perform MRI to evaluate

hypogonadism (Table 4) for pituitary tumor.

Normal MRI: hypogonadotropic

hypogonadism (Table 4)

Figure 2. Algorithm for the evaluation of secondary amenorrhea. (TSH = thyroid-stimulating hormone; MRI = magnetic
resonance imaging; FSH = follicle-stimulating hormone; LH = luteinizing hormone.)
Information from references 1 through 3 and 6.

physician should continue an evaluation similar to that stitutional delay of growth and puberty is indistinguish-
for secondary amenorrhea (Figure 21-3,6).1 able from that associated with hypothalamic or pituitary
failure.10 Watchful waiting is appropriate for constitu-
ABSENCE OF SECONDARY SEXUAL CHARACTERISTICS tional delay of growth and puberty. Kallmann syndrome,
Diagnosis of patients with amenorrhea and no second- which is associated with anosmia, also can cause hypogo-
ary sexual characteristics is based on laboratory test nadotropic hypogonadism.18
results and karyotype analysis. The most common cause Hypergonadotropic hypogonadism (elevated FSH and
of hypogonadotropic hypogonadism (low FSH and LH LH levels) in patients with primary amenorrhea is caused
levels) in primary amenorrhea is constitutional delay of by gonadal dysgenesis or premature ovarian failure.
growth and puberty.16,17 A detailed family history also Turner’s syndrome (45,XO karyotype) is the most com-
may help detect this etiology, because it often is familial. mon form of female gonadal dysgenesis. Characteristic
Hypogonadotropic hypogonadism associated with con- physical findings include webbing of the neck, widely

1378 American Family Physician www.aafp.org/afp Volume 73, Number 8 U April 15, 2006
Amenorrhea
TABLE 4
Causes of Amenorrhea

Hyperprolactinemia Hypergonadotropic hypogonadism Hypogonadotropic hypogonadism

Prolactin b100 ng per mL Gonadal dysgenesis (continued)
(100 mcg per L) Turner’s syndrome* Excessive exercise
Altered metabolism Other* Excessive weight loss or malnutrition
Liver failure Postmenopausal ovarian failure Hypothalamic or pituitary destruction
Renal failure Premature ovarian failure Kallmann syndrome*
Ectopic production Autoimmune Sheehan’s syndrome
Bronchogenic Chemotherapy Normogonadotropic
(e.g., carcinoma) Congenital
Galactosemia
Gonadoblastoma Androgen insensitivity syndrome*
Genetic
Hypopharynx Müllerian agenesis*
17-hydroxylase deficiency syndrome
Ovarian dermoid cyst Hyperandrogenic anovulation
Idiopathic
Renal cell carcinoma Acromegaly
Mumps
Teratoma Androgen-secreting tumor (ovarian or
Pelvic radiation
Breastfeeding adrenal)
Hypogonadotropic hypogonadism
Breast stimulation Cushing’s disease
Anorexia or bulimia nervosa
Hypothyroidism Exogenous androgens
Central nervous system tumor
Medications Nonclassic congenital adrenal hyperplasia
Constitutional delay of growth and puberty*
Oral contraceptive pills Polycystic ovary syndrome
Chronic illness
Antipsychotics Thyroid disease
Chronic liver disease
Antidepressants Outflow tract obstruction
Chronic renal insufficiency
Antihypertensives Asherman’s syndrome
Diabetes
Histamine H2 receptor Cervical stenosis
Immunodeficiency
blockers Imperforate hymen*
Inflammatory bowel disease
Opiates, cocaine Transverse vaginal septum*
Thyroid disease
Prolactin > 100 ng per mL Other
Severe depression or psychosocial stressors
Empty sella syndrome Pregnancy
Cranial radiation
Pituitary adenoma Thyroid disease

*—Causes of primary amenorrhea only.

Information from references 3, 6, and 15.

with no other identified secondary cause. The primary fivefold; therefore, testing for glucose intolerance should
etiology of PCOS is unknown, but resistance to insulin be considered.21-24
is thought to be a fundamental component.21 The primary treatment for PCOS is weight loss
The diagnosis of PCOS is primarily clinical, although through diet and exercise. Modest weight loss can lower
laboratory studies may be needed to rule out other causes androgen levels, improve hirsutism, normalize menses,
of hyperandrogenism (Table 56,21). Significantly elevated and decrease insulin resistance. It may take months to
testosterone or dehydroepiandrosterone sulfate levels see these results, however.21 Use of oral contraceptive
indicate a possible androgen-secreting tumor (ovarian pills or cyclic progestational agents can help maintain
or adrenal). Levels of 17-hydroxyprogesterone can help a normal endometrium. The optimal cyclic progestin
diagnose adult-onset congenital adrenal hyperplasia. regimen to prevent endometrial cancer is unknown,
Cushing’s disease is rare; therefore, patients should only but a monthly 10- to 14-day regimen is recommended.21
be screened when characteristic signs and symptoms Insulin sensitizing agents such as metformin (Gluco-
(e.g., striae, buffalo hump, significant central obesity, phage) can reduce insulin resistance and improve ovula-
easy bruising, hypertension, proximal muscle weakness) tory function.21,25,26
are present.21,22
HYPERGONADOTROPIC HYPOGONADISM
Patients with PCOS have excess unopposed circulat-
ing estrogen, increasing their risk of endometrial cancer Ovarian failure can cause menopause or can occur pre-
threefold.21 The insulin resistance associated with PCOS maturely. On average, menopause occurs at 50 years of
increases a patient’s risk of diabetes mellitus two- to age and is caused by ovarian follicle depletion. Premature

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Amenorrhea
Table 1. Major Causes of Amenorrhea

Outflow tract Pituitary Hypothalamic Other endocrine gland disorders

Congenital Autoimmune disease Eating disorder Adrenal disease
Complete androgen resistance Cocaine Functional (overall energy Adult-onset adrenal hyperplasia
Imperforate hymen Cushing syndrome deficit) Androgen-secreting tumor
Müllerian agenesis Empty sella syndrome Gonadotropin deficiency Chronic disease
(e.g., Kallmann
Transverse vaginal septum Hyperprolactinemia Constitutional delay of puberty
syndrome)
Acquired Infiltrative disease Cushing syndrome
Infection (e.g., meningitis,
Asherman syndrome (e.g., sarcoidosis) Ovarian tumors (androgen
tuberculosis, syphilis)
(intrauterine synechiae) Medications producing)
Malabsorption
Cervical stenosis Antidepressants Polycystic ovary syndrome
Rapid weight loss
Antihistamines (multifactorial)
Primary ovarian insufficiency (any cause)
Antihypertensives Thyroid disease
Congenital Stress
Gonadal dysgenesis (other than Antipsychotics Traumatic brain injury Physiologic
Turner syndrome) Opiates Tumor Breastfeeding
Turner syndrome or variant Other pituitary or central Contraception
Acquired nervous system tumor Exogenous androgens
Autoimmune destruction Prolactinoma Menopause
Chemotherapy or radiation Sheehan syndrome Pregnancy

Information from references 1, 2, and 4 through 11.

HISTORY is short in stature, a karyotype analysis should be per-

Patients should be asked about eating and exercise pat- formed to exclude Turner syndrome.1,15 If the presence
terns, changes in weight, previous menses (if any), medi- of endogenous estradiol secretion is not evident from the
cation use, chronic illness, presence of galactorrhea, physical examination (e.g., breast development), serum
and symptoms of androgen excess, abnormal thyroid estradiol may be measured.7 A complete blood count and
function, or vasomotor instability. Taking a sexual his- comprehensive metabolic panel may be useful if history
tory can help corroborate the results of, but not replace, or examination is suggestive of chronic disease.7
the pregnancy test. Family history should include age at
FURTHER TESTING
menarche and presence of chronic disease. Although it is
normal for menses to be irregular in the first few years Pelvic ultrasonography can help confirm the presence or
after menarche, the menstrual interval is not usually absence of a uterus, and can identify structural abnor-
longer than 45 days.7,12 malities of reproductive tract organs. If a pituitary tumor
is suspected, magnetic resonance imaging (MRI) may be
PHYSICAL EXAMINATION indicated.8 Hormonal challenge (e.g., medroxyproges-
The physician should measure the patient’s height, terone acetate [Provera], 10 mg orally per day for seven
weight, and body mass index, and perform thyroid pal- to 10 days) with anticipation of a withdrawal bleed to
pation and Tanner staging. Breast development is an confirm functional anatomy and adequate estrogeniza-
excellent marker for ovarian estrogen production.1 Acne, tion, has traditionally been central to the evaluation.2
virilization, or hirsutism may suggest hyperandrogen- Some experts defer this testing because its correlation
emia. Genital examination may reveal virilization, evi- with estrogen status is relatively unreliable.1,6,13,16,17
dence of an outflow tract obstruction, or a missing or
malformed organ. Thin vaginal mucosa is suggestive of Differential Diagnosis and Treatment
low estrogen.7 Dysmorphic features such as a webbed ANATOMIC ABNORMALITIES
neck or low hairline may suggest Turner syndrome.13 Müllerian agenesis, a condition characterized by a con-
genital malformation of the genital tract, may present
LABORATORY EVALUATION with normal breast development without menarche,
The initial workup includes a pregnancy test and serum and may be associated with urinary tract defects and
luteinizing hormone, follicle-stimulating hormone, pro- fused vertebrae.18 Other congenital abnormalities that
lactin, and thyroid-stimulating hormone levels. If his- may cause amenorrhea include imperforate hymen and
tory or examination suggests a hyperandrogenic state, transverse vaginal septum. In these conditions, products
serum free and total testosterone and dehydroepiandros- of menstruation accumulate behind the defect and can
terone sulfate concentrations are useful.14 If the patient lead to cyclic or acute pelvic pain. Physical examination,

782  American Family Physician www.aafp.org/afp Volume 87, Number 11 ◆ June 1, 2013
 Amenorrhea
Table 2. Findings in the Evaluation of Amenorrhea

Findings Associations

History
Chemotherapy or radiation Impairment of specific organ (e.g., brain, pituitary, ovary)
Family history of early or delayed menarche Constitutional delay of puberty
Galactorrhea Pituitary tumor
Hirsutism, acne Hyperandrogenism, PCOS, ovarian or adrenal tumor, CAH,
Cushing syndrome
Illicit or prescription drug use Multiple; consider effect on prolactin
Menarche and menstrual history Primary versus secondary amenorrhea; new disease
Sexual activity Pregnancy
Significant headaches or vision changes Central nervous system tumor, empty sella syndrome
Temperature intolerance, palpitations, diarrhea, constipation, Thyroid disease
tremor, depression, skin changes
Vasomotor symptoms Primary ovarian insufficiency, natural menopause
Weight loss, excessive exercise, poor nutrition, psychosocial Functional hypothalamic amenorrhea
stress, diets

Physical examination
Abnormal thyroid examination Thyroid disorder
Anthropomorphic measurements; growth charts Multiple; Turner syndrome, constitutional delay of puberty
Body mass index High: PCOS
Low: Functional hypothalamic amenorrhea
Dysmorphic features (webbed neck, short stature, low hairline) Turner syndrome
Male pattern baldness, increased facial hair, acne Hyperandrogenism, PCOS, ovarian or adrenal tumor, CAH,
Cushing syndrome
Pelvic examination
Absence or abnormalities of cervix or uterus Rare congenital causes
Clitoromegaly Androgen-secreting tumor, CAH
Presence of transverse vaginal septum or imperforate hymen Outflow tract obstruction
Reddened or thin vaginal mucosa Decreased endogenous estrogen
Striae, buffalo hump, central obesity, hypertension Cushing syndrome
Tanner staging abnormal Turner syndrome, constitutional delay of puberty, rare causes

Laboratory testing (refer to local reference values)

Complete blood count and metabolic panel abnormalities Chronic disease
Estradiol Low: Poor endogenous estrogen production (suggestive of poor
ovarian function)
Follicle-stimulating hormone and luteinizing hormone High: Primary ovarian insufficiency, Turner syndrome
Low: Functional hypothalamic amenorrhea
Normal: PCOS, Asherman syndrome, multiple others
Free and total testosterone; dehydroepiandrosterone sulfate High: Hyperandrogenism, PCOS, ovarian or adrenal tumor, CAH,
Cushing syndrome
Karyotype Abnormal: Turner syndrome, rare chromosomal disorders
Pregnancy test Positive: Pregnancy, ectopic pregnancy
Prolactin High: Pituitary adenoma, medications, hypothyroidism, other neoplasm
Thyroid-stimulating hormone High: Hypothyroidism
Low: Hyperthyroidism

Diagnostic imaging
Magnetic resonance imaging of head or sella Tumor (e.g., microadenoma)
Pelvic ultrasonography Morphology of pelvic organs

CAH = congenital adrenal hyperplasia; PCOS = polycystic ovary syndrome.

Adapted with permission from Master-Hunter T, Heiman DL. Amenorrhea: evaluation and treatment. Am Fam Physician. 2006;73(8):1376, with addi-
tional information from references 1, 2, 6, and 7.

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Amenorrhea
Diagnosis of Primary Amenorrhea
Perform history and physical
examination (Table 2) Pregancy test positive – pregnant
(exclude ectopic pregnancy if indicated)
Abnormal TSH level – order thyroid
Pregnancy test; serum LH, FSH, TSH, and function tests and treat thyroid disease
prolactin levels; pelvic ultrasonography or Abnormal prolactin level – magnetic
other laboratory testing if clinically indicated resonance imaging of the pituitary to
exclude adenoma; consider medications

Uterus present?

No

Yes Karyotype; free and total

testosterone levels

Low FSH and LH levels Normal FSH and LH levels Elevated FSH and LH levels
46,XX 46,XY

Functional amenorrhea Consider outflow Primary ovarian insufficiency

(if energy deficit), tract obstruction; also Müllerian agenesis, Androgen insensitivity
constitutional delay of consider all other causes expect female-range syndrome, expect male-
puberty; rarely, primary of amenorrhea with Order karyotype to evaluate serum testosterone range serum testosterone
gonadotropin-releasing normal gonadotropin for Turner syndrome or level level
hormone deficiency levels (Figure 2) presence of Y chromatin

Figure 1. A diagnostic approach to primary amenorrhea. (FSH = follicle-stimulating hormone; LH = luteinizing

hormone; TSH = thyroid-stimulating hormone.)
Information from references 1, 2, 5 through 8, 10, and 11.

as well as ultrasonography or MRI, is key to diagnosis, diagnosed in patients younger than 40 years with amen-
and surgical correction is usually warranted.18 orrhea or oligomenorrhea.6 Other terms, including pre-
Rare causes of amenorrhea include complete andro- mature ovarian failure, are used synonymously with
gen insensitivity syndrome, which is characterized by primary ovarian insufficiency.6,9 Up to 1% of women
normal breast development, sparse or absent pubic and may experience primary ovarian insufficiency. This con-
axillary hair, and a blind vaginal pouch; and 5-alpha dition differs from menopause, in which the average age
reductase deficiency, which is characterized by partially is 50 years, because of age and less long-term predict-
virilized genitalia.1 In these conditions, serum testoster- ability in ovarian function.6,22,23 More than 90% of cases
one levels will be in the same range as those found in unrelated to a syndrome are idiopathic, but they can be
males of the same age.19 The karyotype will be 46,XY, attributed to radiation, chemotherapeutic agents, infec-
and testicular tissue should be removed to avoid malig- tion, tumor, empty sella syndrome, or an autoimmune
nant transformation.20 or infiltrative process.6
A structural cause of secondary amenorrhea is Asher- Patients with primary ovarian insufficiency should be
man syndrome: intrauterine synechiae caused by uter- counseled about possible infertility, because up to 10%
ine instrumentation during gynecologic or obstetric of such patients may achieve temporary and unpredict-
procedures, which can be evaluated and treated with able remission.24 Hormone therapy (e.g., 100 mcg of
hysteroscopy.2,21 daily transdermal estradiol or 0.625 mg of daily conju-
gated equine estrogen [Premarin] on days 1 through 26
PRIMARY OVARIAN INSUFFICIENCY of the menstrual cycle, and 10 mg of cyclic medroxypro-
Primary ovarian insufficiency, a condition character- gesterone acetate for 12 days [e.g., days 14 through 26]
ized by follicle depletion or dysfunction leading to a of the menstrual cycle) 6 until the average age of natu-
continuum of impaired ovarian function, is suggested ral menopause is usually recommended to decrease the
by a concentration of follicle-stimulating hormone in likelihood of osteoporosis, ischemic heart disease, and
the menopausal range (per reference laboratory), con- vasomotor symptoms.9 Combined oral contraceptives
firmed on two occasions separated by one month, and (OCs) deliver higher concentrations of estrogen and

784  American Family Physician www.aafp.org/afp Volume 87, Number 11 ◆ June 1, 2013
 Amenorrhea
Diagnosis of Secondary Amenorrhea
Perform history and physical
examination (Table 2)
Review medications including
contraceptives and illicit drugs Pregnancy test positive – pregnant (exclude
ectopic pregnancy if indicated)
Abnormal TSH level – order thyroid function
Pregnancy test; serum LH, FSH, TSH, and tests and treat thyroid disease
prolactin levels; pelvic ultrasonography or Abnormal prolactin level – MRI of the
other laboratory testing if clinically indicated pituitary to exclude adenoma; consider
medications

Elevated FSH Normal or low FSH and LH levels

and LH levels

Repeat in one
month; consider Evidence of disordered Evidence of high intracranial Evidence of History of obstetric
serum estradiol eating, excessive pressure (e.g., headache, hyperandrogenism or gynecologic
exercise, or poor vomiting, vision changes) procedures; consider
nutritional status induction of
Order serum testosterone, DHEA-S, withdrawal bleed
Primary ovarian
Consider MRI of head to 17-hydroxyprogesterone testing or hysteroscopy
insufficiency, natural
Most likely functional evaluate for neoplasm to evaluate for
menopause; order
amenorrhea, but Asherman syndrome
karyotype, especially
if patient is of short consider chronic illness
stature, to rule out
Turner syndrome or
Elevated 17- Meets criteria Rapid onset of
variant
hydroxyprogesterone for polycystic symptoms or very high
level ovary syndrome serum androgen levels;
consider adrenal and
ovarian imaging to
Consider late-onset Screen for evaluate for tumor
congenital adrenal metabolic
hyperplasia syndrome; treat
accordingly

Figure 2. A diagnostic approach to secondary amenorrhea. (DHEA-S = dehydroepiandrosterone sulfate; FSH =

follicle-stimulating hormone; LH = luteinizing hormone; MRI = magnetic resonance imaging; TSH = thyroid-stimulating
hormone.)
Information from references 1, 2, 4, 6 through 8, 10, and 11.

progesterone than necessary for hormone therapy, may with a classic phenotype including a webbed neck, a low
confer thromboembolic risk, and may theoretically be hairline, cardiac defects, and lymphedema.13,15 Some
ineffective at suppressingfollicle-stimulating hormone patients who have Turner syndrome have only short
for contraceptive purposes in this population; thus, a stature and variable defects in ovarian function (even
barrier method or intrauterine device is appropriate in with possible fertility).6,13,15 Thus, all patients with short
sexually active patients.6,13,25,26 For optimal bone health, stature and amenorrhea should have a karyotype analy-
patients with primary ovarian insufficiency should be sis.15 Because patients require screening for a number of
advised to perform weightbearing exercises and supple- systemic problems, including coarctation of the aorta,
ment calcium (e.g., 1,200 mg daily) and vitamin D3 (e.g., other cardiac lesions, renal abnormalities, hearing
800 IU daily) intake.6,27 problems, and hypothyroidism, and because they may
There is evidence of genetic predisposition to primary require human growth hormone treatment and hormone
ovarian insufficiency, and patients without evidence of a replacement therapy, physicians inexperienced with
syndrome should be tested for FMR1 gene premutation Turner syndrome should consult an endocrinologist.13,15
(confers risk of fragile X syndrome in their offspring)
HYPOTHALAMIC AND PITUITARY CAUSES
and thyroid and adrenal autoantibodies.6,28-30
Turner syndrome, a condition characterized by a The ovaries require physiologic stimulation by pituitary
chromosomal pattern of 45,X or a variant, can present gonadotropins for appropriate follicular development

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