Absence of menstruation-either because it never began or later ceased.
Amenorrhea is traditionally categorized as primary (menarche has not occurred by age 16) or secondary (menses has not occurred for >= 3 mo in women who have had menses), although often this distinction is not clinically useful. A functional approach is more helpful.

An acceptable definition of amenorrhea is failure of menarche by age 15, irrespective of the presence or absence of secondary sexual characteristics, or the absence of menstruation for 6 months in a woman with previous periodic menses. However, women who do not fulfill these criteria should be evaluated if (1) the patient and/or her family are greatly concerned, (2) no breast development has occurred by age 13, or (3) any sexual ambiguity or virilization is present. Amenorrhea is commonly categorized as either primary (the woman has never menstruated) or secondary (when menstruation has been present for a variable period of time in the past and has ceased). However, some disorders can cause either primary or secondary amenorrhea. For example, most women with gonadal dysgenesis have primary amenorrhea, but some have a few follicles and ovulate for short periods so that pregnancy occurs rarely. Furthermore, patients with chronic anovulation (PCOS) usually have secondary amenorrhea but on occasion have primary amenorrhea. For these reasons, categorization of amenorrhea into primary and secondary types is less helpful than a classification based on the underlying physiologic derangements: (1) anatomic defects, (2) ovarian failure, and (3) chronic anovulation with or without estrogen present.

Etiology
Amenorrhea-except that occurring before puberty, during pregnancy or early lactation, and after menopause-is pathologic. Amenorrhea indicates failure of hypothalamic-pituitary-gonadal-uterine interaction to produce cyclic changes in the endometrium, resulting in menses. Amenorrhea may be caused by anatomic abnormalities; hypothalamic, pituitary, or other endocrine dysfunction; ovarian failure; or genetic defects. Depending on its cause, amenorrhea may be accompanied by other abnormalities, such as hirsutism, obesity, and galactorrhea.

Chronic anovulation is the most common form of amenorrhea among women of reproductive age who are not pregnant. No anatomic abnormalities of the target organs preclude menstruation. Chronic anovulation may be viewed as a steady state in which the monthly rhythm manifested by menses is no longer operational. The term chronic anovulation implies that functional ovarian follicles remain and that cyclic ovulation can be induced or reinitiated with appropriate management. The hypothalamic-pituitary unit appears intact, but a functional derangement results in abnormal gonadotropin secretion. Chronic anovulation can result from hypothalamic, pituitary, or other endocrine dysfunction or from inappropriate hormonal feedback. Evidence suggests that the hypothalamic form is a heterogeneous group of disorders that produce similar manifestations and to which emotional and physical stresses, diet, body composition, exercise, environment, and other unknown factors contribute in varying degrees. Inappropriate feedback may result from abnormal buffering involving sex hormone binding globulin (eg, in liver disease), excessive extraglandular production of estrogen (eg, in obesity), functional androgen excess (ovarian or adrenal), or such disorders as polycystic ovary syndrome. Chronic anovulation is characterized by low to normal levels of gonadotropins, relative hypoestrogenism, and amenorrhea; however, irregular, profuse uterine bleeding may occur because of unopposed estrogenic stimulation (see Dysfunctional Uterine Bleeding, below).

The polycystic ovary syndrome (sometimes termed hyperandrogenic chronic anovulation) is a benign disorder. It may cause amenorrhea but is usually characterized by irregular menses, mild obesity, and hirsutism, typically beginning in the pubertal years and worsening with time. Most patients have abundant cervical mucus on examination and elevated free estrogens. Levels of most circulating androgens tend to be mildly elevated. The ovaries may be enlarged with smooth, thickened capsules or may be normal in size. Typically, the ovaries contain many 2- to 6-mm follicular cysts, and thecal hyperplasia surrounds the granulosa cells. Large cysts containing atretic cells may be present. Hirsutism should be evaluated. The diagnostic evaluation aims to identify a cause (eg, a neoplasm) that can be treated definitively.

Diagnosis
Delayed menses should be evaluated if a girl shows no signs of puberty by age 13, if menarche has not occurred by age 16, or if >= 5 yr have passed without menarche since the onset of puberty. Women of reproductive age who have had menses should be evaluated if they are amenorrheic for >= 3 mo, have < 9 menses a year, or are concerned about a change in menstrual pattern.

History and physical examination can often determine the cause of amenorrhea. Pregnancy should first be ruled out. Patients should be asked about abnormal growth and development, family history of genetic anomalies, dietary and exercise habits, lifestyle, and environmental stresses. Evidence of psychologic disturbances should be sought.

Noting hormonal alterations of the pubertal process and of secondary sexual characteristics is central to the diagnosis. Signs of virilization (masculinization) due to increased androgen secretion (hyperandrogenism), especially hirsutism (an increase in hair stimulated by androgens), may occur. Other signs of hyperandrogenism include temporal balding, voice deepening, increased muscle mass, clitoromegaly, increased libido, and a decrease in feminine secondary sexual characteristics (defeminization), such as decreased breast size and vaginal atrophy. Galactorrhea (nonpuerperal secretion of milk) may occur.

The breasts should be inspected and development noted using the Tanner method. While the patient is seated, breast secretions should be elicited by applying pressure to all sections of the breast beginning at the base and moving toward the nipple. Secretions should be examined microscopically for thick-walled, perfectly round fat globules of varying sizes, which prove the discharge is milk.

The distribution and quantity of hair should be considered in light of the family history. Hypertrichosis (excessive growth of hair on the extremities, head, and back) must not be mistaken for true hirsutism and virilization. The stage of pubic hair development should be noted.

Abnormal genitalia suggest disorders of sexual differentiation, such as female or male pseudohermaphroditism and mullerian duct abnormalities.

Internal abnormalities may obstruct menstrual blood flow, causing hematocolpos (accumulation of menstrual blood in the vagina) and hematometra (distention of the uterus). A bulging vagina and a pelvic mass are typically felt during abdominal and rectal examinations (which can also detect other pelvic pathology, such as tumors), but determining whether the cause is vaginal agenesis, a vaginal septum, or an imperforate hymen may be difficult. In these disorders, the external genitalia and other secondary sexual characteristics develop normally (because ovarian function is normal); however, about 15 to 40% of patients with vaginal agenesis or a vaginal septum also have urinary tract and skeletal abnormalities.

In androgen insensitivity syndrome (testicular feminization), the external genitalia may appear normal, but pubic and axillary hair is decreased, breast development is incomplete, and the vagina varies in length, with no identifiable cervix or uterus.

If an intersex disorder is suspected, karyotype should be determined. Fusion of the labia and enlargement of the clitoris (with or without formation of a penile urethra) occur in women exposed to androgens during the first 3 mo of fetal development and in patients with congenital adrenal hyperplasia, true hermaphroditism, or drug-induced virilization. Development of significant clitoromegaly postnatally requires marked hormonal stimulation and, if there is no history of exogenous steroid use, strongly suggests an androgen-secreting tumor.

Visual inspection of the vaginal mucosa and the cervical mucus is important because they are exquisitely sensitive to estrogen. Influenced by estrogen, the vaginal mucosa progresses during sexual maturation from a shiny, bright-red tissue with sparse, thin secretions to a dull, gray-pink rugated surface with copious, thick secretions.

A progestational challenge can help assess the competence of the outflow tract and the level of endogenous estrogens. Medroxyprogesterone acetate 5 to 10 mg/day po for 5 days or progesterone 100 to 200 mg IM in oil is given. Bleeding confirms the presence of normal endometrium and of sufficient estrogen to stimulate endometrial growth, and it helps establish the diagnosis (eg, women with chronic anovulation bleed, whereas those with premature ovarian failure do not). If bleeding does not occur, giving orally active estrogen (eg, conjugated estrogens 2.5 mg/day for 21 days, plus medroxyprogesterone acetate 5 to 10 mg po for the last 5 of those days) produces bleeding if there is no uterine abnormality. Women with Asherman’s syndrome or with tuberculosis affecting the endometrium may not bleed.

Laboratory Findings
Basal serum levels of follicle-stimulating hormone (FSH), prolactin, and thyroid-stimulating hormone (TSH) should be measured in all women with amenorrhea to confirm the clinical impression. Prolactin is increased in > 30% of amenorrheic women. If prolactin is increased (generally, > 20 ng/mL [> 888 pmol/L]), it should be remeasured because it can be increased by nonspecific stimuli, including stress, sleep, and food ingestion. If thyroid function is normal and prolactin is increased, further evaluation is warranted to rule out a prolactin-secreting pituitary hormone and other disorders. Increased TSH (> 5 mU/L) without increased prolactin indicates primary hypothyroidism. However, in primary hypothyroidism, increased secretion of thyrotropin-releasing hormone stimulates production of prolactin as well as TSH in some women. Increased FSH (> 30 IU/L) suggests ovarian failure.

If prolactin, TSH, and FSH levels are normal or low, further evaluation is based on the clinical presentation. Thyroid hormone levels should be measured if thyroid dysfunction is suspected. Total serum testosterone and dehydroepiandrosterone sulfate (DHEAS) should be measured in hirsute women. Testosterone levels > 200 ng/dL suggest an androgen-producing tumor, most commonly of ovarian origin. If DHEAS levels are twice as high as the upper limit of normal for the laboratory, the patient should be evaluated for an adrenal neoplasm. If neither testosterone nor DHEAS is markedly elevated, extensive testing is unnecessary because serious causes have been eliminated. Mildly elevated levels of testosterone and/or DHEAS suggest polycystic ovary syndrome, but levels are sometimes normal in hirsute women with this syndrome because the metabolic clearance rates of androgens and the levels of proteins that bind androgens are altered.

Adult-onset forms of congenital adrenal hyperplasia should be considered if a woman has severe hirsutism beginning at puberty, a strong family history of hirsutism, a stature shorter than expected compared with other family members, or serum DHEAS levels of >= 500 ÞÌg/dL. Levels of 17-hydroxyprogesterone are elevated in women with congenital adrenal hyperplasia. If Cushing’s syndrome is suspected, the patient should be screened for cortisol excess.

Measuring basal levels of serum luteinizing hormone (LH) may help differentiate polycystic ovary syndrome from hypothalamic or pituitary dysfunction. In polycystic ovary syndrome, circulating LH levels are often increased, increasing the ratio of LH to FSH. In hypothalamic or pituitary dysfunction, LH and FSH levels are normal or decreased.

X-rays of the sella turcica are indicated for euthyroid women with hyperprolactinemia and for women with low gonadotropin levels (typically < 7 IU/L for LH and FSH), regardless of the prolactin level, to rule out a pituitary neoplasm. Sellar x-rays should not be obtained for hypothyroid women with mild hyperprolactinemia and amenorrhea-galactorrhea because the sella turcica returns to normal size after thyroid hormone replacement. CT or MRI of the sella can determine if the patient has suprasellar extension of a pituitary neoplasm or the empty-sella syndrome (in which the sella turcica is enlarged but contains mainly CSF). Formal visual field testing is indicated when a pituitary neoplasm is >= 10 mm in diameter on x-ray or there is evidence of suprasellar extension. Pituitary testing, especially of adrenal and thyroid function, is warranted when a large tumor is present or panhypopituitarism is suspected.

Ultrasonography and CT can usually localize an androgen-producing neoplasm before surgical excision. Selective adrenal and ovarian vein angiography, which are rarely indicated, should be performed only in specialized centers. Neoplasms should be biopsied during surgery to assess malignant potential.

Treatment
Treatment depends on the cause. No ideal therapy for polycystic ovary syndrome exists. Patients may require therapy to induce ovulation if pregnancy is desired, to prevent estrogen-induced endometrial hyperplasia, or to minimize hirsutism and long-term effects of hyperandrogenism (eg, cardiovascular disease, hypertension).

For women who have polycystic ovary syndrome and desire pregnancy, clomiphene citrate 50 to 100 mg/day for 5 days is the first choice to induce ovulation because of its simplicity and high success rate (75% ovulation rate, 35 to 40% pregnancy rate). Other methods to induce ovulation include exogenous gonadotropin, human purified FSH, pulsatile administration of gonadotropin-releasing hormone (GnRH), ovarian wedge resection, and ovarian drilling. Wedge resection and drilling are used only when all other methods fail, especially when fertility is an issue, because pelvic adhesions can form after surgery.

For anovulatory women who have polycystic ovary syndrome, are not hirsute, and do not desire pregnancy, an intermittent progestin (eg, medroxyprogesterone acetate 5 to 10 mg/day po for 10 to 14 days q 1 to 2 mo) or oral contraceptives should be given to reduce the increased risk of endometrial hyperplasia and cancer and to minimize circulating androgen levels. Oral contraceptives should be given only to women who are premenopausal, do not smoke, and do not have other significant risk factors. Women using intermittent progestins should be cautioned about the need for contraception because of the possible (although unproven) association of birth defects with these hormones if taken early in pregnancy.

For anovulatory women who have polycystic ovary syndrome, are hirsute, and do not desire pregnancy, physical treatments (eg, bleaching, electrolysis, plucking, waxing, depilation) should be encouraged. No drug therapy is ideal or completely effective. Oral contraceptives are the first line of therapy for mild hirsutism. They suppress gonadotropin and sex hormone secretion and increase production of sex hormone binding globulin, thus reducing biologically active free testosterone levels. Results, often slight, are not seen for several months. All formulations appear equally effective, but oral contraceptives with minimal androgenic adverse effects are preferred. When oral contraceptives are undesired or contraindicated, an oral progestin (medroxyprogesterone acetate 5 to 20 mg/day) can be used. Adverse effects of progestins may include mastodynia, bloating, and depression.

Other drugs used to treat hirsutism include cyproterone acetate, a potent progestin and an antiandrogen, which appears to control hirsutism in 50 to 75% of affected women. It is used to treat hirsute women worldwide but is not approved in the USA because it causes breast cancer in beagles and fetal anomalies when given to pregnant rats. Spironolactone is a mild diuretic that inhibits the biosynthesis of androgens and competes with androgens for their receptors in target tissues. Doses of 100 to 200 mg/day po are effective. Adverse effects include initial diuresis, postural changes (eg, syncope, hypotension), mastodynia, and irregular uterine bleeding. Its long-term effects are unknown, as are its effects on a developing fetus; thus, contraception should be used.

Glucocorticoids are not indicated for most hirsute women because no advantage of adrenal over ovarian suppression has been shown and because the source of excess androgen in most hirsute women is largely ovarian. Glucocorticoids should be used only for documented adrenal hyperfunction or enzyme defects in the steroidogenic pathway. GnRH agonists and antagonists may be useful in the treatment of hirsutism. These drugs suppress gonadotropins and thus sex hormone secretion, producing a medical oophorectomy. Effective topical antiandrogens are being sought.

For women with hypothalamic dysfunction, psychologic counseling or a change in lifestyle often induces ovulation. Clomiphene citrate rarely induces ovulation. If these measures are ineffective, treatment with exogenous gonadotropins or pulsed therapy with GnRH may be required.

For the prevention of osteoporosis, women who have chronic hypothalamic or pituitary anovulation and low levels of circulating estrogen and do not desire pregnancy may be given oral conjugated estrogens 0.625 to 1.25 mg/day, esterified estrogens 0.625 to 1.25 mg/day, micronized estradiol-17ÞÂ 0.5 to 1.0 mg/day, or transdermal estradiol-17ÞÂ 0.05 to 0.1 mg applied twice weekly plus medroxyprogesterone acetate 5 to 10 mg given daily on the first 12 to 14 days of each month or medroxyprogesterone acetate 2.5 mg daily throughout the month. Sexually active women can use oral contraceptives as replacement therapy.

Evaluation of Amenorrhea

On physical examination, attention should be given to three features: (1) the degree of maturation of the breasts, pubic and axillary hair, and external genitalia; (2) the current estrogen status; and (3) the presence or absence of a uterus. Pregnancy should be excluded in all women with amenorrhea; it is prudent to perform a suitable pregnancy screening test even when the history and physical examination are not suggestive. Once that is done, the cause of amenorrhea can frequently be diagnosed clinically. For example, Asherman’s syndrome is suggested by a history of curettage in a woman who previously menstruated; in women with primary amenorrhea and sexual infantilism, the essential differential diagnosis is between gonadal dysgenesis and hypopituitarism; and the diagnosis of gonadal dysgenesis (Turner’s syndrome) or of anatomic defects of the outflow tract (mu"llerian agenesis, testicular feminization, and cervical stenosis) is frequently suggested on the basis of physical findings. When a specific cause is suspected, it is appropriate to proceed directly to confirm the diagnosis (obtaining a chromosomal karyotype or measurement of plasma gonadotropins). It is also useful to measure serum prolactin and FSH levels during the initial evaluation.

Estrogen status is evaluated by determining if the vaginal mucosa is moist and rugated and if the cervical mucus can be stretched and shown to fern upon drying. If these criteria are indeterminate, a progestational challenge is indicated, most often the administration of 10 mg medroxyprogesterone acetate by mouth once or twice daily for 5 days or 100 mg progesterone in oil intramuscularly. (It should be emphasized that progestogen should never be administered until pregnancy is excluded.) If estrogen levels are adequate (and the outflow tract is intact), menstrual bleeding should occur within 1 week of ending the progestogen treatment. If withdrawal bleeding occurs, the diagnosis is chronic anovulation with estrogen present, usually caused by PCOS.

If no withdrawal bleeding or only minimal vaginal spotting occurs, the nature of the subsequent workup depends on the results of the initial prolactin assay. If plasma prolactin is elevated, or if galactorrhea is present, radiography of the pituitary should be undertaken. When the plasma prolactin level is normal in an anovulatory woman with estrogen absent and with elevated FSH levels, the diagnosis is ovarian failure. If the gonadotropins are in the low or normal range, the diagnosis is either hypothalamic-pituitary disorder or an anatomic defect of the outflow tract. As indicated previously, the diagnosis of outflow tract disorder is usually suspected or established on the basis of the history and physical findings. When the physical findings are not clear-cut, it is useful to administer cyclic estrogen plus progestogen (1.25 mg oral conjugated estrogens per day for 3 weeks, with 10 mg medroxyprogesterone acetate added for the last 7 to 10 days of estrogen treatment), followed by 10 days of observation. If no bleeding occurs, the diagnosis of Asherman’s syndrome or another anatomic defect of the outflow tract is confirmed by hysterosalpingography or hysteroscopy. If withdrawal bleeding occurs following the estrogen-progestogen combination, the diagnosis of chronic anovulation with estrogen absent (functional hypothalamic amenorrhea) is suggested. Radiologic evaluations of the pituitary-hypothalamic areas may be indicated in the latter cases - irrespective of the prolactin level - because of the risk of overlooking a pituitary-hypothalamic tumor and because the diagnosis of functional hypothalamic amenorrhea is one of exclusion.