eMedicine Specialties > Obstetrics and Gynecology > Reproductive Endocrinology and Infertility
Amenorrhea, Primary: Treatment & Medication
Updated: Aug 14, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
Medical care needs are defined by the etiology of the amenorrhea 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.
- Dopamine agonists are effective in treating hyperprolactinemia. In most cases, this treatment restores normal ovarian endocrine function and ovulation (see Prolactinoma).
- Hormone replacement therapy is required to achieve peak bone density in patients whose underlying pathology cannot be reversed to restore normal endocrine function.
- Women with evidence of hyperandrogenism and disordered menses have many other medical issues that must be addressed (see Polycystic Ovarian Syndrome).
Surgical Care
Some pituitary and hypothalamic tumors may require surgery and, in some cases, radiation therapy (see Pituitary Macroadenomas). The surgical procedure required for other outflow tract abnormalities depends on the specific clinical situation (see Imperforate Hymen).
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.
- Geneticist: With hereditary causes of amenorrhea, such as Kallmann syndrome, a geneticist's expertise can be helpful in counseling patients and their families regarding the disorder.
- 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.
- Psychiatrist: Cases of major depression, anorexia nervosa, bulimia nervosa, or other major psychiatric disorders warrant consultation with a psychiatrist (see Anorexia Nervosa).
- 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.
- General internal medicine specialist: In certain cases in which an underlying chronic disease process is present, the insights of an internist may be needed.
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
Hormone replacement therapy, consisting of an estrogen and a progestin, is recommended for women with estrogen deficiency.17 Girls with primary amenorrhea typically do not have symptoms of estrogen deficiency. However, with inadequate estrogen exposure over time, these patients are at increased risk for developing osteoporosis and possibly other health issues.
Young women in whom secondary sex characteristics have failed to develop fully should be exposed initially to very low doses of estrogen in an attempt to mimic the gradual pubertal maturation process. A typical regimen consists of an estrogen with a dosage equivalent to 25 mcg/day of transdermal estradiol (approximately 0.3 mg of conjugated equine estrogen) given unopposed (ie, no progestogen) daily for 6 months with incremental dose increases at 6-month intervals until the required maintenance dose is achieved. Gradual dose escalation allows time to balance estrogen supplementation with need to grow in height, develop secondary sexual characters, and often results in optimal breast development. It also allows time for the young woman to adjust psychologically to her physical maturation.18
Cyclic progestogen therapy, given 12-14 days per month, should be instituted once vaginal bleeding begins.
Parenteral estrogen (transdermal or vaginal) is the preferred route of administration because it avoids first-pass liver metabolism. Moreover, it is less likely to increase sex hormone binding globulin (SHBG) and has little or no effect on circulating lipids, coagulation parameters, or C-reactive protein. However, no long-term 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.
The role of androgen replacement is unclear at this time and is the subject of ongoing investigation.19
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.
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
100 mcg/d TD patch or 2 mg/d PO in cyclic regimen of q3wk on and 1 wk off
Pediatric
Not established
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
Documented hypersensitivity; thrombophlebitis; neuroophthalmologic vascular disease; undiagnosed vaginal bleeding; pregnancy; breast cancer; estrogen-dependent neoplasia; chronic liver disease
Pregnancy
X - Contraindicated; benefit does not outweigh risk
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
Estrogens, conjugated (Premarin)
Use in patients who refuse or do not tolerate other forms of estrogen. Use oral estrogen to achieve adequate estrogenization of vaginal epithelium in young women and adequately maintain bone density.
Adult
1.25 mg/d PO
Pediatric
Not established
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
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)
Pregnancy
X - Contraindicated; benefit does not outweigh risk
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
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.
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
10 mg PO qd for first 12 d of menstrual cycle
Pediatric
Not established
May decrease effects of aminoglutethimide; slightly decreases clearance of digoxin; increases liver enzymes when coadministered with tamoxifen; increases half-life of warfarin
Documented hypersensitivity; cerebral apoplexy, vaginal bleeding from undiagnosed cause, thrombophlebitis, liver dysfunction, pregnancy, missed abortion, breast or genital malignancies
Pregnancy
X - Contraindicated; benefit does not outweigh risk
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
Progesterone (Prometrium)
Used to prevent endometrial hyperplasia
Adult
For women with a uterus receiving estrogen therapy: 200 mg/d PO for 2 d sequentially per 28-d cycle
Pediatric
Not established
Ketoconazole inhibits metabolism by human liver microsomes (clinical relevance unknown)
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
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
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
More on Amenorrhea, Primary |
| Overview: Amenorrhea, Primary |
| Differential Diagnoses & Workup: Amenorrhea, Primary |
 Treatment & Medication: Amenorrhea, Primary |
| Follow-up: Amenorrhea, Primary |
| Multimedia: Amenorrhea, Primary |
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Further Reading
Keywords
amenorrhea, primary amenorrhea, secondary amenorrhea, hypothalamic amenorrhea, pituitary amenorrhea, menstruation, absence of menstruation, gonadotropin-releasing hormone, GnRH, follicle-stimulating hormone, FSH, luteinizing hormone, LH, hypothalamus-pituitary-ovarian axis, HPO, gonadal dysgenesis, Turn syndrome, spontaneous primary ovarian insufficiency, POI, premature ovarian failure, POF, premature menopause, Swyer syndrome, 46,XY gonadal dysgenesis, 46,XX gonadal dysgenesis, polycystic ovarian syndrome, vaginal agenesis, mullerian dysgenesis, Mayer-Rokitansky-Kuster-Hauser syndrome, MRKH
