Amenorrhea

Background: Primary amenorrhea is defined as the failure of menses to occur by age 16 years. Secondary amenorrhea is defined as the cessation of menses once they have begun. Oligomenorrhea is defined as menses occurring at intervals longer than 35 days. No consensus has been reached regarding the point at which oligomenorrhea becomes amenorrhea. Some authors suggest the absence of menses for 6 months constitutes amenorrhea, but the basis for this recommendation is unclear. Practically speaking, a woman aged 20-40 years who experiences loss of an established regular menstrual pattern should have an evaluation to seek the cause.

This article addresses the evaluation and treatment of women with amenorrhea who have no evidence of androgen excess. Women with amenorrhea who do have evidence of androgen excess, such as hirsutism, virilization, or sexual ambiguity, should be evaluated differently from women with amenorrhea alone.

Pathophysiology: Regular and predictable menstrual cycles occur if the ovarian hormones estradiol and progesterone are secreted in an orderly fashion in response to stimulation by the hypothalamus and pituitary. Circulating estradiol stimulates growth of the endometrium. Progesterone, produced by the corpus luteum formed after ovulation, transforms proliferating endometrium into secretory endometrium. If pregnancy does not occur, this secretory endometrium breaks down and sheds during the ensuing menstrual period.

Amenorrhea occurs if the hypothalamus and pituitary fail to provide appropriate gonadotropin stimulation to the ovary, resulting in inadequate production of estradiol or in failure of ovulation and progesterone production. Amenorrhea can also occur if the ovaries fail to produce adequate amounts of estradiol despite normal and appropriate gonadotropin stimulation by the hypothalamus and pituitary. In some cases, the hypothalamus, pituitary, and ovaries all may be functioning normally, yet amenorrhea occurs because of adhesions in the endometrial cavity or an obstruction to the cervicovaginal outflow tract.

Frequency:

• In the US: Each year, approximately 5% of menstruating women experience 3 months of secondary amenorrhea.

• Internationally: No evidence indicates that the prevalence of amenorrhea varies according to national origin or ethnic group. However, local environmental factors related to nutrition and the prevalence of chronic disease undoubtedly have an effect. For instance, the age of the first menses varies by geographic location, as demonstrated by a World Health Organization study comparing 11 countries, which reported a median age of menarche of 13-16 years across centers.

Mortality/Morbidity: The regular occurrence of menses is a sign of good health. It means that the hypothalamic-pituitary-ovarian axis is functioning normally to produce ovarian hormones and support ovulation. The ovary functions as both an endocrine organ and a reproductive organ. When menstrual cycle regularity is lost, this means the ovaries are not functioning normally in either their endocrine role or their reproductive role. Loss of menstrual regularity has been associated with reduced bone density and increased fracture rates. Thus, loss of menstrual regularity has associated morbidity and may contribute to increased mortality.

• Regular menses is a sign that the ovaries are producing normal amounts of estrogen, androgens, and progesterone. These sex hormones play an important role in building and maintaining bone mass. Late menarche has been associated with a 3-fold increase in the risk of wrist fracture. Menstrual cycle duration of longer than 31 days has been associated with a 2-fold increase in wrist fracture. Similar correlations exist for the risk of hip fracture, a potentially fatal occurrence.

• Regular menses is also a sign that the ovaries support ovulation and that they contain a normal store of primordial follicles. Primordial follicles are composed of an oocyte surrounded by a single layer of granulosa cells. The number of primordial follicles in the human ovary peaks during the fifth gestational month at approximately 7 million. After this initial finite pool is in place, no additional primordial follicles are formed. In some cases, loss of menstrual regularity is an early sign of declining fertility and impending premature ovarian failure. Also in some cases, this follicle depletion progresses to cause irreversible infertility. Approximately 10% of women evaluated for amenorrhea in a tertiary center are found to have premature ovarian failure.

Race: No evidence suggests that the incidence of either primary or secondary amenorrhea is related to race.

Sex: Amenorrhea occurs only in women.

Age: A large study by Treolar et al (1967) demonstrated that by age 20 years, women have established remarkably regular and persistent patterns of menstrual cycle length with little variation on an individual basis. Relatively stable and predictable menstrual cycle length then continues until age 40 years.

According to the findings from the Treolar et al study, fewer than 2 menses in a 90-day interval (>95th percentile) in a woman aged 20-40 years is distinctly abnormal. Further, more than 3 menses in a 90-day interval in these women is also distinctly abnormal. Finally, menstrual bleeding for more than 10 days in women in this age group is also distinctly abnormal.

As women age, a remarkably steady decline occurs in mean menstrual cycle length. The shortening cycle length may be physiologically linked in some way to the well-established decline in the number of primordial follicles remaining in the pool as women age.

While the overall median menstrual cycle length is 28 days, cycle length gradually declines from age 20 years to age 40 years. At age 20 years, the median cycle length is 29 days, and by age 40 years, this has declined to 27 days. Further shortening of the menstrual cycle length is a well-recognized early sign of impending menopausal transition.

• In the first year after menarche, the fifth percentile for menstrual cycle length is 23 days and the 95th percentile is 90 days. By the fourth year after menarche, the 95th percentile for cycle length has declined from 90 days to approximately 50 days. Menstrual cycle length is certainly more variable for females in their teens than for women aged 20-40 years. However, by 7 years after menarche, cycles are more stable; the fifth percentile in cycle length is 27 days, and the 95th percentile is 38 days.

• In the year preceding menopause, the fifth percentile for cycle length is 25 days and the 95th percentile is approximately 150 days. Four years before menopause, the fifth percentile for cycle length is 23 days and the 95th percentile for cycle length is significantly more regular, at approximately 40 days. Menstrual cycle length is certainly more variable during the years preceding the menopausal transition than during the age span of 20-40 years.

Treatment
Medical Care: Medical care needs are defined by the etiology of the menstrual cycle disturbance and the desires of the patient. Ideally, treatment should be directed at correcting the underlying pathology. In the case of outflow tract abnormalities, surgery may be indicated. In other cases, correcting the underlying pathology should restore normal ovarian endocrine function and prevent the development of osteoporosis. Likewise, correcting the underlying pathology should restore ovulation and permit women interested in achieving pregnancy to maintain fertility.

• Dopamine agonists are effective in treating hyperprolactinemia. In most cases, this treatment restores normal ovarian endocrine function and ovulation .
  

• Hormone replacement therapy is required to maintain bone density in patients whose underlying pathology cannot be reversed to restore normal endocrine function.

• Gonadotropin therapy or the use of pulsatile GnRH therapy is required to induce ovulation for patients with infertility whose underlying pathology cannot be reversed.

• Women with evidence of hyperandrogenism and disordered menses have many other medical issues that must be addressed.

Surgical Care: Some pituitary and hypothalamic tumors may require surgery and, in some cases, radiation therapy. Asherman syndrome requires hysteroscopic lysis of the intrauterine adhesions. The surgical procedure required for other outflow tract abnormalities depends on the specific clinical situation.

Consultations: The causes of menstrual cycle disturbance leading to the development of amenorrhea are so diverse that in some complex cases, the situation is best addressed by a multidisciplinary team. For example, a patient with complete androgen resistance (testicular feminization) would benefit from the involvement of experts in endocrinology, human genetics, psychiatry, and reproductive surgery.

• General internal medicine specialist: In certain cases in which an underlying chronic disease process is present, the insights of an internist may be needed.

• Medical endocrinologist: In cases of pituitary/hypothalamic tumor, other endocrine disorders (eg, central hypothyroidism, central adrenal insufficiency) may be involved. Generally, the expertise of a medical endocrinologist is required to assist in the treatment of patients who require neurosurgery to treat the underlying condition. In cases of hyperthyroidism or Cushing syndrome, the expertise of a medical endocrinologist is required to treat the underlying pathology.

• Geneticist: With hereditary causes of amenorrhea, such as Kallmann syndrome, a geneticist's expertise can be helpful for the extended family and in counseling patients regarding the disorder.

• Psychiatrist: Cases of major depression, anorexia nervosa, bulimia nervosa, or other major psychiatric disorders warrant consultation with a psychiatrist.

• Reproductive surgeon: In some unusual cases, such as with vaginal agenesis, consult with a reproductive surgeon with extensive experience in the specific disorder.

• Nutritionist: In many cases, exercise-induced amenorrhea is due to an imbalance in energy intake and expenditure. Nutritional counseling to increase energy intake without reducing exercise is a means of reversing the underlying pathology. Women who are underweight or who appear to have nutritional deficiencies should receive nutritional counseling and can be referred to a multidisciplinary team specializing in eating disorders.

Diet: Women with findings suggestive of an eating disorder should be evaluated by a multidisciplinary team with special expertise in these disorders. Nutritional counseling alone is inadequate therapy for these women.

In some cases, nutritional deficiencies induced by dieting and exercise can cause amenorrhea even in the absence of a psychiatric disorder. Strict fat restriction often plays a role. Frequently, simply explaining the need to balance energy expenditure with energy intake resolves the problem. In this situation, nutritional counseling may be all that is required.

Activity: More than 8 hours of vigorous exercise a week may cause amenorrhea. As noted above, in some cases this resolves with appropriate adjustment of the diet.

Medication
Dopamine agonists are the only medical therapy specifically approved to reverse an underlying pathology that leads amenorrhea. In most cases, dopamine agonists effectively reduce hyperprolactinemia.

Gonadotropin therapy or pulsatile GnRH therapy is indicated in women who desire fertility yet remain anovulatory because of an unresolved hypothalamic/pituitary disorder.

For some women with oligomenorrhea or amenorrhea who do not wish to become pregnant, oral contraceptives are a good choice to restore menstrual cyclicity and provide estrogen replacement. Document the absence of pregnancy before oral contraceptive therapy is begun.

In patients with amenorrhea or oligomenorrhea, induce withdrawal bleeding with an injection of progesterone or the administration of 5-10 mg of medroxyprogesterone for 10 days. Therapy is then begun with an oral contraceptive containing ethinyl estradiol and a progestin, such as norethindrone and levonorgestrel.

Hormone replacement therapy, consisting of an estrogen and a progestin, is needed for women in whom estrogen deficiency remains because ovarian function cannot be restored. The role of androgen replacement is unclear at this time and is the subject of ongoing investigation.

Drug Category: Estrogens -- Administered transdermally, transvaginally, or orally. Appropriate dose for young women with ovarian failure has not been established. The authors recommend full replacement doses for young women. Generally, this is approximately twice as high as doses recommended for hormone replacement therapy in normally postmenopausal women. The authors prefer to administer estradiol by skin patch. This avoids the first-pass effect of oral estrogen on the liver. No controlled studies are available to compare the efficacy and safety of one method over another. Therefore, the choice of therapy should follow consideration of the patient's preferences and the physician's experience.

Drug Name	Estradiol (Alora, Climara, Esclim, Vivelle-dot, Estrace) -- Increases synthesis of DNA, RNA, and many proteins in target tissues. TD patch available as Alora (0.05, 0.075, and 0.1 mg/d, applied twice weekly), Climara (0.025, 0.05, 0.075, and 0.1 mg/d, applied once weekly), Esclim (0.025, 0.0375, 0.05, 0.075, 0.1 mg/d, applied twice weekly), and Vivelle-dot (0.037, 0.05, 0.075, 0.1 mg/d, applied twice weekly). If TD patch not tolerated, PO form may be used.
Adult Dose	100 mcg/d TD patch or 2 mg/d PO in cyclic regimen of q3wk on and 1 wk off
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; thrombophlebitis; neuroophthalmologic vascular disease; undiagnosed vaginal bleeding; pregnancy; breast cancer; estrogen-dependent neoplasia; chronic liver disease
Interactions	May reduce hypoprothrombinemic effects of anticoagulants Levels may be reduced with coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes Possible increase in corticosteroid levels when administered concurrently Use with hydantoins may cause spotting, breakthrough bleeding, and pregnancy Increase in fluid retention caused by estrogen intake may reduce seizure control In isolated cases, may decrease effect of TCAs and therefore cause worsening of previously well-controlled depression (phenomenon seems to be dose-dependent and is reversible with decrease or discontinuation of estrogen) Thyroid replacement or suppressive therapy may need adjustments because estrogen increases SHBG, thus leaving less free T4 (active hormone) available Tobacco smoking can have antiestrogenic effect by increasing the C-2 hydroxylation of estradiol molecule
Pregnancy	X - Contraindicated in pregnancy
Precautions	Reported endometrial cancer risk among those on unopposed estrogen is approximately 2- to 12-fold greater than those who are not; appears dependent on duration of treatment and on estrogen dose; greatest risk appears associated with prolonged use (increased risks of 15- to 24-fold for 5-10 y or more); concurrent progestin therapy may offset this risk but overall health impact in premenopausal women is unknown Some studies suggest possible increased incidence of breast cancer in women taking estrogen therapy at higher doses or for prolonged periods; these studies have focused on postmenopausal women; conclusions may not be applicable to young women with ovarian failure Counseling should help young women deficient in estrogen to feel comfortable taking estrogens; estrogen therapy during pregnancy is associated with an increased risk of fetal congenital reproductive tract disorders and possibly other birth defects Two studies have reported a 2- to 4-fold increase in risk of gallbladder disease requiring surgery in women receiving oral estrogen replacement therapy, similar to the 2-fold increase previously noted in users of oral contraceptives (risk from TD estrogens not established) Occasional blood pressure increases during therapy have been attributed to idiosyncratic reactions to estrogens; other studies showed slightly lower blood pressure compared with those not on therapy; postmenopausal use does not increase risk of stroke; nonetheless, blood pressure should be monitored at regular intervals May lead to severe hypercalcemia in patients with breast cancer and bone metastases; if hypercalcemia occurs, discontinue therapy and take appropriate measures to reduce serum calcium level Addition of a progestin to estrogens may cause adverse effects on lipoprotein metabolism (lowering HDL and raising LDL), which could diminish cardioprotective effect of therapy Possible enhancement of mitotic activity in breast epithelial tissue, although few epidemiological data are available to address this point; take complete medical and family history before initiation of therapy; as a general rule, should be prescribed for no longer than 1 y without another physical examination Some studies have shown that women on therapy have hypercoagulability, primarily related to decreased antithrombin activity; effect appears dose- and duration-dependent and is less pronounced than that associated with oral contraceptive use Insufficient information on hypercoagulability in women with previous thromboembolic disease; may be associated with massive elevations of plasma triglycerides, leading to pancreatitis and other complications in patients with familial defects of lipoprotein metabolism; because may cause some degree of fluid retention, careful observation required when conditions that might be influenced by this factor are present (eg, asthma, epilepsy, migraine, cardiac, renal dysfunction) Certain patients may develop undesirable manifestations of estrogenic stimulation (eg, abnormal uterine bleeding, mastodynia); may be poorly metabolized in patients with impaired liver function and should be administered with caution; accelerated PT, aPTT, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity Increased thyroid-binding globulin leading to increased circulating total thyroid hormone, as measured by protein-bound iodine, T4 levels (by column or by radioimmunoassay), or T3 levels by radioimmunoassay; free T4 and free T3 concentrations are unaltered Other binding proteins may be elevated in serum (eg, corticosteroid-binding globulin and SHBG, leading to increased circulating corticosteroids and sex steroids, respectively); free or biologically active hormone concentrations are unchanged; other plasma proteins may be increased (eg, angiotensinogen/renin substrate, alpha1-antitrypsin, ceruloplasmin); increases plasma HDL and HDL-2 subfraction concentrations, reduces LDL cholesterol concentration, and increases triglyceride levels; reduces response to metapyrone test; reduces serum folate concentration Long-term continuous administration of natural and synthetic estrogens in certain animal species increases frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver Generally, any drug should be administered to breastfeeding women only when clearly necessary because many drugs are excreted in human milk; administration to breastfeeding women has been shown to decrease quantity and quality of milk

Drug Name	Estrogens, conjugated (Premarin) -- Some cannot tolerate TD patch. Use conjugated equine estrogens to achieve adequate estrogenization of vaginal epithelium in young women and adequately maintain bone density.
Adult Dose	1.25 mg/d PO
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; known or possible pregnancy; breast cancer, undiagnosed abnormal genital bleeding, active thrombophlebitis, or thromboembolic disorders; history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when used in treatment of breast or prostatic malignancy)
Interactions	May reduce hypoprothrombinemic effect of anticoagulants; coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes may reduce levels; pharmacologic and toxicologic effects of corticosteroids may occur as a result of estrogen-induced inactivation of hepatic P-450 enzyme; loss of seizure control has been noted when administered concurrently with hydantoins
Pregnancy	X - Contraindicated in pregnancy
Precautions	Certain patients may develop undesirable manifestations of excessive estrogenic stimulation (eg, abnormal or excessive uterine bleeding or mastodynia); may cause some degree of fluid retention (exercise caution); prolonged unopposed estrogen therapy may increase risk of endometrial hyperplasia

Drug Category: Progestins -- Stop endometrial cell proliferation, allowing organized sloughing of cells after withdrawal. No long-term controlled studies compare efficacy of medroxyprogesterone with oral progesterone in protecting the endometrium from neoplasia at the doses of estrogen generally required for replacement in young women. The authors recommend use medroxyprogesterone as first-line therapy because of longer-term clinical experience with this agent.

Drug Name	Medroxyprogesterone (Provera, Cycrin, Depo-Provera, Amen) -- Administer cyclically 12 d/mo to prevent endometrial hyperplasia that unopposed estrogen may cause. In young women, regular withdrawal bleeding is preferable because even young women with premature ovarian failure have a 5-10% chance of spontaneous pregnancy (unlike postmenopausal women). If an expected withdrawal bleeding is absent, perform a pregnancy test (and a timely diagnosis of pregnancy will not be missed). Other causes of amenorrhea may also remit spontaneously and result in an unexpected pregnancy.
Adult Dose	10 mg PO qd for first 12 d of menstrual cycle
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; cerebral apoplexy, vaginal bleeding from undiagnosed cause, thrombophlebitis, liver dysfunction, pregnancy, missed abortion, breast or genital malignancies
Interactions	May decrease effects of aminoglutethimide; slightly decreases clearance of digoxin; increases liver enzymes when coadministered with tamoxifen; increases half-life of warfarin
Pregnancy	X - Contraindicated in pregnancy
Precautions	Be alert to earliest manifestations of thrombotic disorders (eg, thrombophlebitis, cerebrovascular disorders, pulmonary embolism, retinal thrombosis); if these occur or are suspected, discontinue drug immediately Discontinue medication pending examination with sudden, partial, or complete loss of vision or with sudden onset of proptosis, diplopia, or migraine; if examination reveals papilledema or retinal vascular lesions, withdraw medication Perform physical examination (including special attention to breast, pelvic organs, and Papanicolaou smear); may cause some degree of fluid retention, and conditions that might be influenced by this (eg, epilepsy, migraine, asthma, cardiac or renal dysfunction) require careful observation In case of breakthrough bleeding, as in all cases of irregular bleeding per vagina, bear in mind nonfunctional causes; in cases of vaginal bleeding from an unknown cause, adequate diagnostic measures are indicated Carefully observe patients with history of depression and discontinue drug if depression recurs to serious degree; carefully observe diabetic patients receiving progestin therapy; advise pathologist of progestin therapy when relevant specimens are submitted Because of occurrence of thrombotic disorders (eg, thrombophlebitis, pulmonary embolism, retinal thrombosis, cerebrovascular disorders) in patients taking estrogen-progestin combinations and because mechanism is obscure, be alert to earliest manifestation of these disorders Administer any drug to breastfeeding women only when clearly necessary because many drugs are excreted in human milk; detectable amounts of progestin have been identified in milk

Drug Name	Progesterone (Prometrium) -- Used to prevent endometrial hyperplasia
Adult Dose	For women with a uterus receiving estrogen therapy: 200 mg/d PO for 2 d sequentially per 28-d cycle
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; caps contain peanut oil and should never be used by patients allergic to peanuts; known or suspected pregnancy; thrombophlebitis thromboembolic disorders, cerebral apoplexy, or patient with a history of these conditions; severe liver dysfunction or disease; known or suspected malignancy of breast and genital organs; undiagnosed vaginal bleeding; missed abortion; as a diagnostic test for pregnancy
Interactions	Ketoconazole inhibits metabolism by human liver microsomes (clinical relevance unknown)
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May cause some degree of fluid retention; thus, conditions that might be influenced by this factor (eg, epilepsy, migraine, asthma, cardiac or renal dysfunction) require careful observation Patients with history of depression should be carefully observed Transient dizziness may occur in some patients; caution when driving a motor vehicle or operating machinery; small percentage of women may experience extreme dizziness and/or drowsiness during initial therapy; for these women, bedtime dosing is advised