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Amenorrhea
is absence of menstruation. The cause is usually endocrine dysfunction
resulting in anovulation, often with mild estrogen deficiency
and hyperandrogenism. Diagnosis is clinical and by pregnancy testing,
measurement of hormone levels, and a progesterone challenge. Treatment
aims to correct any underlying disorder and minimize excess androgenic
effects.
Amenorrhea is abnormal except before puberty, during pregnancy, during early lactation, and after menopause. 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).
Etiology
Amenorrhea has many causes, typically divided into anovulatory and ovulatory (see Table 1: Menstrual Abnormalities: Causes of Amenorrhea ).
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Table 1
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Causes of Amenorrhea
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Cause
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Examples
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Cause
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Examples
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Ovulatory amenorrhea
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Isolated gonadotropin deficiency*
Panhypopituitarism*
Pituitary tumors* (eg, Forbes-Albright syndrome)
Antipsychotic drugs (eg, olanzapine )
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Genital anatomic abnormalities
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Acquired endometrial lesions (eg, Asherman's syndrome, endometrial TB)
Cervical stenosis (rare)
Imperforate hymen
Male pseudohermaphroditism
Transverse vaginal septum
Vaginal and uterine aplasia
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Ovarian failure
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Autoimmune disorders
Chemotherapy and pelvic irradiation
Congenital thymic aplasia
Galactosemia
Gonadal dysgenesis
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Anovulatory amenorrhea
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Hypothalamic dysfunction
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Anorexia nervosa*
Excessive exercise
Hypothalamic chronic anovulation*
Kallmann's syndrome
Prader-Willi syndrome
Psychogenic factors (eg, severe stress)
Tumors (eg, hamartomas, craniopharyngiomas, gliomas)
Weight loss (acute)
Undernutrition (chronic)
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Other endocrine dysfunction
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Congenital or adult-onset adrenal virilism
Cushing's syndrome*
Drug-induced virilization (by antidepressants)
Hyperthyroidism*
Hypothyroidism*
Liver disorders (chronic)
Obesity*
Polycystic ovary syndrome*
Tumors producing androgens, estrogens , or human chorionic gonadotropin*
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Pituitary dysfunction
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Amenorrhea-galactorrhea (hyperprolactinemia)*
Benign pituitary adenoma
Hypopituitarism* (eg, due to Sheehan's syndrome, head trauma, or tumor)
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Genetic disorders
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Androgen insensitivity syndrome
Turner's syndrome (see Chromosomal Anomalies: Turner's Syndrome)
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*These disorders cause chronic anovulation.
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Anovulatory amenorrhea, in which both ovulation and menses are absent, is the most common and results from functional rather than structural causes. The hypothalamic-pituitary axis is intact and ovaries are functional, but gonadotropin secretion is decreased, resulting in mild estrogen deficiency. Causes are hypothalamic, pituitary, ovarian, or other endocrine dysfunction and some genetic disorders. Hypothalamic causes may be multifactorial and may include unknown factors. Endocrine causes may involve inappropriate hormonal feedback, which can result from altered levels of free testosterone , other androgens, or estrogen (see Table 1: Menstrual Abnormalities: Causes of Amenorrhea) due to lack of sex hormone–binding globulin (eg, in chronic liver disorders), excessive extraglandular production of estrogen (eg, in obesity), ovarian or adrenal androgen excess, or polycystic ovary syndrome.
Ovulatory
amenorrhea, which is less common, results from anatomic genital abnormalities in women with normal hormonal function. Many congenital anatomic abnormalities physically obstruct menstrual flow through the uterine outflow tract, causing amenorrhea. Hematocolpos (accumulation of menstrual blood in the vagina), which can cause the vagina to bulge, and hematometra (accumulation of blood in the uterus), which can cause uterine distention or a mass, may also occur. Because ovarian function is normal, the external genitals and other secondary sexual characteristics develop normally; however, some congenital disorders (eg, that cause vaginal aplasia or a vaginal septum) also cause urinary tract and skeletal abnormalities.
Diagnosis
Girls are evaluated if no signs of puberty occur by age 13 or if menarche has not occurred by age 16 or ≥ 5 yr since the onset of puberty. Women of reproductive age should have a pregnancy test after missing one menses; they are evaluated for amenorrhea if they are not pregnant and have missed menstrual cycles for ≥ 3 mo, have < 9 menses a year, or have a sudden change in menstrual pattern.
History and physical
examination:
The history should address the possibility of pregnancy, risk factors (eg, abnormal growth and development, family history of genetic defects, dietary deficiencies, excessive exercise, environmental stresses), and symptoms of endocrine disorders, particularly virilization (eg, increased libido).
Virilization reflects excess androgen effects, suggesting true hermaphroditism, pseudohermaphroditism, gonadal dysgenesis, polycystic ovary syndrome, a virilizing ovarian or adrenal tumor, Cushing's syndrome, adrenal virilism, or a genetic disorder. Signs of virilization include hirsutism, temporal balding, voice deepening, increased muscle mass, clitoral enlargement, and a decrease in previously normally developed secondary sexual characteristics (defeminization), such as decreased breast size and vaginal atrophy. Hypertrichosis (excessive growth of hair on the extremities, head, and back), which is common in some families, is differentiated from true hirsutism, which is characterized by excess hair on the upper lip and chin and between the breasts. Obesity in hirsute women may suggest polycystic ovary syndrome but is nonspecific. Moon facies, truncal obesity, abdominal striae, and thin extremities may indicate Cushing's syndrome.
Absence or delayed development of secondary sexual characteristics (breasts, pubic and axillary hair, genitals) suggests absent or decreased estrogen levels. Staging breast and pubic hair development using the Tanner method (see Fig. 2: Female Reproductive Endocrinology: Puberty—when female sexual characteristics develop. ; see Fig. 3: Female Reproductive Endocrinology: Diagrammatic representation of Tanner stages I to V of human breast maturation.) helps in evaluation of secondary sexual characteristics.
With the patient seated, the physician checks for breast secretion by applying pressure to all sections of the breast, beginning at the base and moving toward the nipple. Galactorrhea (breast milk secretion not temporally associated with childbirth—see Pituitary Disorders: Galactorrhea) suggests hyperprolactinemia, which usually reflects a pituitary disorder.
Pelvic examination may detect anatomic genital disorders or signs of such disorders (eg, bulging vagina, uterine mass). Ambiguous genitals may indicate virilization, true hermaphroditism, or male or female pseudohermaphroditism. Fused labia and an enlarged clitoris (clitoromegaly) usually indicate exposure to androgens during the 1st 3 mo of fetal development, suggesting congenital adrenal virilism (see Endocrine Disorders in Children: 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 anabolic steroid use, strongly suggests an androgen-secreting tumor, most of which originate in the ovaries. If the cervix and uterus appear absent, external genitals appear normal, and secondary sexual characteristics are not fully developed, androgen insensitivity syndrome (testicular feminization) is considered.
Testing:
Routine testing includes a pregnancy test, a progesterone challenge, and measurement of hormone levels. If a genetic defect is suspected (eg, in primary amenorrhea), karyotype is determined.
The progesterone challenge helps assess contributions of estrogen deficiency, structural endometrial lesions, and uterine outflow obstruction to amenorrhea. Medroxyprogesterone 5 to 10 mg po once/day for 5 days or progesterone 5 to 10 mg IM once/day for 5 to 10 days is given. If bleeding occurs, amenorrhea is probably not caused by significant estrogen deficiency, an endometrial lesion, or uterine outflow obstruction; chronic anovulation is often the cause. If bleeding does not occur, estradiol and follicle-stimulating hormone (FSH) levels can be measured to confirm primary or secondary estrogen deficiency and distinguish between them. If results are normal, oral estrogen (usually an oral contraceptive) is given; if bleeding does not occur, amenorrhea is probably caused by an endometrial abnormality (eg, Asherman's syndrome, TB affecting the endometrium) or by uterine outflow obstruction (eg, by a congenital anatomic genital abnormality).
Serum levels of FSH, prolactin, and thyroid-stimulating hormone (TSH) are measured in all women with amenorrhea. Increased FSH (> 30 IU/L) suggests ovarian failure. Decreased FSH (< 7 IU/L) suggests a pituitary tumor. Prolactin is increased (usually > 20 ng/mL [> 888 pmol/L]) in > 30% of women with amenorrhea), often spuriously; consequently, high levels must be confirmed a few weeks later. If prolactin is persistently increased and TSH is normal (< 5 mU/L), a prolactin-secreting pituitary tumor may be the cause. Increased TSH indicates primary hypothyroidism if the prolactin level is normal and possibly even if it is elevated, because primary hypothyroidism increases prolactin secretion in some women.
If FSH level is normal and prolactin and TSH levels are normal or low, further evaluation is based on clinical presentation. If hypothyroidism is suspected, thyroid hormone levels are measured. If virilization is suspected, total serum testosterone and dehydroepiandrosterone sulfate (DHEAS) levels are measured. Testosterone levels > 200 ng/dL suggest an ovarian androgen-producing tumor. DHEAS levels that are modestly increased may suggest an adrenal tumor. If women have a serum DHEAS level of ≥ 500 μg/dL, severe hirsutism that began at puberty, a strong family history of hirsutism, or shorter stature than expected in relation to family members, adult-onset forms of adrenal virilism (see Adrenal Disorders: Adrenal Virilism) are considered.
Mildly elevated levels of testosterone or DHEAS suggest polycystic ovary syndrome, but levels can be elevated in women with hypothalamic or pituitary dysfunction and are sometimes normal in hirsute women with polycystic ovary syndrome. The cause of elevated levels can be determined by measuring basal serum luteinizing hormone (LH). In polycystic ovary syndrome, circulating LH levels are often increased, increasing the ratio of LH to FSH. If LH or FSH levels are < 7 IU/L, hypothalamic or pituitary dysfunction, particularly a pituitary tumor, is considered.
Treatment
Treatment is directed at the underlying disorder when possible. Therapy may also be required to induce ovulation if pregnancy is desired (see Infertility: Ovulatory Dysfunction), to minimize hirsutism and long-term effects of hyperandrogenism (eg, cardiovascular disorders, hypertension), to treat symptoms of estrogen deficiency (see Menopause), and to prevent osteoporosis due to estrogen deficiency.
For hirsutism with elevated testosterone levels (the most common type), physical treatments (eg, bleaching, electrolysis, plucking, waxing, depilation) are encouraged. Eflornithine cream 13.9% bid may help remove unwanted facial hair. No systemic drug is ideal or completely effective; oral contraceptives are used initially. They suppress gonadotropin and sex hormone secretion and increase production of sex hormone–binding globulin, thus reducing biologically active free testosterone . Results are delayed for several months and are rarely dramatic. All formulations appear equally effective, but oral contraceptives with minimal androgenic adverse effects are preferred (see Family Planning: Oral Contraceptives). If oral contraceptives are contraindicated or not desired, an oral progestin ( medroxyprogesterone 5 to 20 mg once/day) can be used. Contraception is recommended because medroxyprogesterone has possible, although unproven, teratogenic effects. Progestins may cause breast pain, bloating, and depression. Gonadotropin-releasing hormone agonists and antagonists (eg, leuprolide 3.75 mg IM q mo, goserelin 3.6 mg sc q 28 days) may also help by suppressing gonadotropins and thus sex hormone secretion.
If neither testosterone nor DHEAS levels are elevated, spironolactone 100 to 200 mg po once/day can be used. It inhibits androgen synthesis and competes for androgen receptors in target tissues. It may cause diuresis, orthostatic hypotension, breast pain, and irregular uterine bleeding; contraception is recommended.
Last full review/revision November 2005
Content last modified November 2005
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