eMedicine Specialties > Obstetrics and Gynecology > Reproductive Endocrinology and Infertility

Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure: Treatment & Medication

Author: Vaishali Popat, MD, MPH, Fellow in Endocrinology, National Institutes of Health
Coauthor(s): Lawrence M Nelson, MD, MBA, Head of Integrative Reproductive Medicine Unit, Investigator, Intramural Research Program on Reproductive and Adult Endocrinology, National Institutes of Child Health and Human Development, National Institutes of Health
Contributor Information and Disclosures

Updated: Jun 1, 2007

Treatment

Medical Care

Medical treatment of patients with POF/POI should address the following aspects: ovarian hormone replacement, restoration of fertility, and psychological well being of the patient.

  • Management of premature ovarian failure
    • Inform
      • Discuss the test results on a special visit (not by phone).
      • The diagnosis of POF/POI can be particularly traumatic for young women.
      • Use of appropriate terminology is important (use of premature ovarian failure or insufficiency is preferred instead of premature menopause or early menopause).
      • Explain the nature of the disease and advise the patient of sources of information and support.
    • Counsel
      • The ovary is not only a reproductive organ but also is a source of important hormones that help maintain strong bones. Adequate replacement of these missing hormones, a healthy lifestyle, and a diet rich in calcium are essential.
      • POF/POI is not menopause. Spontaneous ovarian activity and pregnancies are possible.
      • Allow the patient enough time to accept the diagnosis. Family planning decisions are best made after the patient has had some time to come to terms with her condition.
      • No proven therapies exist to restore fertility; experimental treatment should be performed only under a review board–approved research protocol.
      • Currently available options to resolve infertility include change of family building plans, such as adoption, ovum donation, or embryo donation.
    • Hormone replacement therapy (HRT)
      • All women with POF/POI should receive cyclical HRT with estrogens and progestins to relieve the symptoms of estrogen deficiency and to maintain bone density.
      • A few women may need HRT even before amenorrhea develops to alleviate menopausal symptoms.
    • Estrogens
      • Estrogens can be administered orally or transdermally. The appropriate dose for young women with ovarian failure has not been established in control studies. According to the authors’ clinical judgment, administer doses twice as high as the recommended dose for HRT for women who are postmenopausal (transdermal estradiol 100-150 mcg instead of 50 mcg daily, conjugated equine estrogens [CEE] 1.25 mg instead of 0.625 mg daily or oral estradiol 2-4 mg instead of 1 mg daily). Such doses usually achieve adequate estrogenization of the vaginal epithelium in young women with POF/POI and help maintain age-appropriate bone density.
      • The estrogens can be administered continuously or cyclically (21 d on, 7 d off). Because no controlled studies compare the efficacy and safety of one method over another, the choice of therapy should come after consideration of the patient's preference and physician's experience.
      • Estrogen replacement therapy does not prevent ovulation and conception in these patients; in fact, it may improve the chance of pregnancy by theoretically lowering the LH level to normal range and preventing premature luteinization of the remaining follicles.5 Patients should be informed that they must obtain a prompt pregnancy test if menstrual bleeding fails to appear when expected.
      • Oral contraceptives provide more sex steroid than is required for replacement, and the authors advise against this approach. Furthermore, owing to the elevated gonadotropin levels, oral contraceptives may not be effective in preventing pregnancy in women with premature ovarian failure.
    • Progestins
      • Progestins should be administered cyclically, 10-14 days each month, to prevent endometrial hyperplasia that unopposed estrogen may cause. Young women with POF/POI have a 5-10% chance of spontaneous pregnancy (unlike women who are postmenopausal). If an expected withdrawal bleeding is missing, a pregnancy test should be performed and a diagnosis of pregnancy should not be delayed.
      • The recommended regimens include medroxyprogesterone 10 mg daily for 10-12 days each month or micronized progesterone 200 mg daily for 10-12 days each month.
    • Androgens
      • Women with ovarian failure have lower levels of free testosterone compared with normally ovulating age-matched controls, but only 13% have levels below the lower limit of normal.6
      • Androgen replacement could be carefully considered for women who have persistent fatigue, low libido, and poor well being despite adequate estrogen replacement and when depression has been ruled out or adequately treated. This should be performed with great caution and for relatively short periods until more data are available.
      • Available medications include oral methyl testosterone 1.25-2.5 mg/d, injectable testosterone esters 50 mg every 6 weeks intramuscularly, and subcutaneous testosterone pellet implants 50 mg every 3-6 months.
    • Restoration of fertility: No intervention has been proven to increase the ovulation rate or restore fertility in patients with POF/POI.
    • Gonadotropin therapy carries a theoretical risk of exacerbating autoimmune premature ovarian failure.
    • The use of prednisone or dexamethasone in an attempt to restore ovarian function in suspected autoimmune ovarian failure is not indicated clinically.
      Use of these agents carries a risk of osteonecrosis. Their use in patients with premature ovarian failure should be confined to studies approved by an institutional review board.
    • Unproven treatments to restore fertility should be avoided because they have the potential of interfering with the development of a spontaneous pregnancy.
    • Patients with POF/POI can have successful pregnancy with a donor egg. A decision to proceed with such a procedure should be made after a fair discussion of different options. The age of the patient is of less importance than the age of the egg donor.
    • Other possibilities include embryo adoption, adoption, or change of life plans.

Surgical Care

Ovarian biopsy is not clinically indicated in women with ovarian failure.

Consultations

  • Consultation with an endocrinologist may be indicated in some cases because of concerns of hypothyroidism or adrenal insufficiency.
  • Patients with infertility due to POF/POI usually have a grief response after hearing the diagnosis. They may benefit from a baseline psychological evaluation and appropriate counseling.
  • Genetic counseling may be needed in some cases.
  • Referral for eye care is indicted in women with symptoms of dry eye.

Diet

Patients with ovarian failure should consume 1200-1500 mg of elemental calcium per day in their diet. If this is not feasible, calcium supplementation is appropriate. An adequate intake of vitamin D also is important.

Activity

Women with POF/POI should be encouraged to engage in weight-bearing exercises for 30 minutes per day, at least 3 days per week, to improve muscle strength and maintain bone mass. Participation in outdoor sports is strongly recommended.

Medication

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Estrogens

Used to achieve adequate estrogenization of vaginal epithelium in young women and to maintain bone density.


Estradiol transdermal system (Alora)

Increases synthesis of DNA, RNA, and many proteins in target tissues.

Adult

Apply 0.05, 0.075, or 0.1 mg/d TD patch twice weekly

Pediatric

Not established

May decrease effect of tricyclic antidepressants and cause worsening of previously well-controlled depression, which seems to be dose-dependent and is reversible with decrease or discontinuation of therapy
Effects may decrease during concomitant therapy with carbamazepine and/or phenytoin, and dose increase may be necessary; estrogens may increase seizures in patients with previously well-controlled epilepsy
Thyroid replacement or suppressive therapy (eg, levothyroxine, triiodothyronine) may need adjustment while taking estrogens because the latter increases SHBG, especially when administered orally, thus leaving less free T4
Tobacco smoking can have antiestrogenic effect by increasing C-2 hydroxylation of estradiol molecule
Estrogens may reduce hypoprothrombinemic effects of anticoagulants
Estrogen levels may be reduced with coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes; an increase in corticosteroid levels may occur when administered concurrently with ethynylestradiol

Documented hypersensitivity; thrombophlebitis; undiagnosed vaginal bleeding; pregnancy; breast cancer; estrogen-dependent neoplasia; chronic liver disease; neuroophthalmologic vascular disease

Pregnancy

X - Contraindicated in pregnancy

Precautions

Reported endometrial cancer risk among users of unopposed estrogen is approximately 2- to 12-fold greater than in nonusers and appears dependent on duration of treatment and dose; greatest risk appears to be associated with prolonged use (increased risks of 15- to 24-fold for 5-10 y or longer); concurrent progestin therapy may offset risk, but overall health impact in women who are premenopausal is not known
Some studies suggest possible increased incidence of breast cancer with higher doses or use for prolonged periods; studies focused on women who are postmenopausal, and conclusions may not be applicable to young women with ovarian failure; good counseling should help young women deficient in estrogen feel comfortable taking estrogens
Therapy during pregnancy is associated with increased risk of fetal congenital reproductive tract disorders and, possibly, other birth defects
Two studies report 2- to 4-fold increase in risk of gallbladder disease requiring surgery in women receiving oral estrogen replacement therapy, similar to 2-fold increase previously noted in users of oral contraceptives; risk from TD estrogens not established
Occasional BP increases attributed to idiosyncratic reactions; other studies show slightly lower BP among estrogen users compared to nonusers; postmenopausal estrogen use does not increase risk of stroke, but BP should be monitored regularly; recent studies indicate that medroxyprogesterone acetate may cause adverse changes in lipoprotein metabolism compared to natural progesteronal
Ongoing debate over long-term cardioprotective effect of estrogens, especially in presence of established cardiovascular disease; complete medical and family histories should be taken before initiating therapy; should be prescribed for no longer than 1 y without physical examination
Studies have shown that women taking estrogen replacement therapy have hypercoagulability, primarily related to decreased antithrombin activity; effect appears dose-dependent and duration-dependent and is less pronounced than with oral contraceptive use; information on hypercoagulability in women who have had previous thromboembolic disease is insufficient
Estrogen use may be associated with massive elevations of plasma triglycerides, leading to pancreatitis and other complications in patients with familial defects of lipoprotein metabolism
May cause fluid retention, careful observation is required when conditions that might be influenced by this factor are present (eg, asthma, epilepsy, migraine, cardiac, renal dysfunction)
Certain patients may develop the following undesirable manifestations of estrogenic stimulation: abnormal uterine bleeding, mastodynia, and mood changes
Drug/lab test interactions include accelerated prothrombin time, partial thromboplastin time, 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 (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), 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 (ie, corticosteroid-binding globulin [CBG], sex hormone-binding globulin [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)


Conjugated equine estrogens (Premarin)

Contains a mixture of estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. Mixture of sodium estrone sulfate and sodium equilin sulfate. Contains as concomitant components, sodium sulfate conjugates, 17-alpha-dihydroequilenin, 17-alpha-estradiol, and 17-beta-dihydroequilenin.
Available in 0.3-mg, 0.625-mg, 0.9-mg, 1.25-mg, and 2.5-mg PO tablets.

Adult

1.25 mg/d PO

Pediatric

<12 years: Not established
12-13 years: 0.3 mg PO qod for as long as 6 mo, increase to adult dose at 6-mo intervals
>13 years: Administer as in adults

May reduce hypoprothrombinemic effect of anticoagulants
Coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes may reduce estrogen levels
Pharmacologic and toxicologic effects of corticosteroids may occur as a result of estrogen-induced inactivation of hepatic P450 enzyme
Loss of seizure control has been noted when administered concurrently with hydantoins

Documented hypersensitivity; known or suspected 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 malignancy or prostatic malignancy in men)

Pregnancy

X - Contraindicated in pregnancy

Precautions

Certain patients may develop undesirable manifestations of excessive estrogenic stimulation (eg, abnormal or excessive uterine bleeding or mastodynia)
Estrogens may cause some degree of fluid retention (caution)
Prolonged unopposed estrogen therapy may increase risk of endometrial hyperplasia

Progestins

When administered orally in the recommended doses to women adequately exposed to exogenous or endogenous estrogen, they transform the proliferative endometrium into a secretory one.


Medroxyprogesterone (Provera)

Derivative of progesterone. Androgenic and anabolic effects have been noted, but apparently is devoid of significant estrogenic activity. Parenterally administered dosage form inhibits gonadotropin production, which, in turn, prevents follicular maturation and ovulation. Available data indicate that this does not occur when the usually recommended PO dose is administered qd.

Adult

10 mg PO qd for 10-12 d monthly

Pediatric

Not established

May decrease effects of aminoglutethimide
May cause increased sulfobromophthalein retention and other hepatic function tests
May cause increase in PT factors VII, VIII, IX, and X
Coadministration with food results in approximate doubling of medroxyprogesterone maximum concentration and increases area under the concentration-time curve (AUC) by 20-30% (clinical significance unknown)
May interfere with pregnanediol determination

Documented hypersensitivity; cerebral apoplexy; undiagnosed vaginal bleeding; thrombophlebitis; liver dysfunction; known or suspected malignancy of breast or genital organs; missed abortion; use as a diagnostic test for pregnancy

Pregnancy

X - Contraindicated in pregnancy

Precautions

Caution in hepatic impairment, migraine, seizure disorders, cerebrovascular disorders, breast cancer, and asthma
In case of breakthrough bleeding; as in all cases of irregular vaginal bleeding, nonfunctional causes (eg, malignancy) should be borne in mind and adequate diagnostic measures are indicated
Patients who have a history of psychic depression should be carefully observed and drug discontinued if depression recurs to serious degree
Patients with diabetes should be observed carefully
Because of occurrence of thrombotic disorders (thrombophlebitis, pulmonary embolism, retinal thrombosis, and cerebrovascular disorders) in patients taking estrogen-progestin combinations and because the mechanism is obscure, physician should be alert to earliest manifestations of these disorders; discontinue medication pending examination if sudden partial or complete loss of vision occurs or if sudden onset of proptosis, diplopia, or migraine occurs; if examination reveals papilledema or retinal vascular lesions, withdraw medication


Progesterone (Prometrium)

Used to prevent endometrial hyperplasia in women with a uterus who are receiving estrogen replacement therapy.

Adult

200 mg PO hs for 12 d sequentially each 28-d cycle

Pediatric

Not established

Ketoconazole may increase bioavailability (clinical relevance of in vitro findings is unknown)

Documented hypersensitivity; cerebral apoplexy; undiagnosed vaginal bleeding; thrombophlebitis; liver dysfunction; known or suspected malignancy of breast or genital organs; missed abortion; use as a diagnostic test for pregnancy

Pregnancy

X - Contraindicated in pregnancy

Precautions

Capsules contain peanut oil and should never be used by patients allergic to peanuts
May cause fluid retention, and conditions that might be influenced by this (eg, epilepsy, migraine, asthma, cardiac or renal dysfunction) require careful observation
Patients who have a history of depression should be observed carefully
Transient dizziness may occur, use caution when driving a motor vehicle or operating machinery (small percentage of women may experience extreme dizziness and/or drowsiness during initial therapy)

Androgens

Responsible for normal growth and the development and maintenance of secondary sex characteristics in males. In addition, androgens have exhibited metabolic activity and may cause retention of nitrogen, sodium, potassium, and phosphorus and decrease urinary excretion of calcium. In the presence of sufficient caloric and protein intake, they will improve nitrogen balance. Androgens also have been reported to stimulate production of RBCs through the enhancement of erythropoietin production. Also increase muscle mass, improve muscle strength, and increase libido.


Methyltestosterone (Android)

Synthetic testosterone derivative with significant androgen activity. Tablets are available in 5-mg, 10-mg, and 25-mg strengths.

Adult

1.2-5 mg PO qd

Pediatric

Not established

May increase effects of anticoagulants
Concurrent administration of oxyphenbutazone may result in elevated serum levels of oxyphenbutazone
In patients with diabetes, metabolic effects of androgens may decrease blood glucose and insulin requirements

Documented hypersensitivity; severe cardiac or renal disease; benign prostatic hypertrophy with obstruction in men; undiagnosed genital bleeding

Pregnancy

X - Contraindicated in pregnancy

Precautions

When administered to pregnant woman, may cause virilization of external genitalia of female fetus (virilization includes clitoromegaly, abnormal vaginal development, and fusion of genital folds to form a scrotallike structure); degree of masculinization related to amount of drug administered and age of fetus (most likely to occur when drugs are administered in first trimester); if patient becomes pregnant, she should be apprised of potential hazard to the fetus
Women should be observed for signs of virilization (deepening of the voice, hirsutism, acne, clitoromegaly, and menstrual irregularities), discontinuation at time of evidence of mild virilism is necessary to prevent irreversible virilization (such virilization is usual following androgen use at high doses); instruct patients to report any adverse effects (eg, hoarseness, acne, changes in menstrual periods, more hair on the face, nausea, vomiting, changes in skin color, ankle swelling)
Because of hepatotoxicity associated with use of 17-alpha-alkylated androgens, LFTs should be obtained periodically; has been associated with development of peliosis hepatis and hepatic neoplasms, including hepatocellular carcinoma (peliosis hepatis can be life-threatening or fatal); cholestatic hepatitis and jaundice occur with 17-alpha-alkylandrogens at a relatively low dose (if cholestatic hepatitis with jaundice appears or if LFTs become abnormal, discontinue therapy and determine etiology); drug-induced jaundice is reversible when medication is discontinued


Testosterone enanthate (Andro LA 200, Delatestryl, Durathate-200)

Derivative of the primary endogenous androgen testosterone. For IM administration. In active form, androgens have a 17-beta-hydroxy group. Esterification of 17-beta-hydroxy group increases duration of action. Hydrolysis to free testosterone occurs in vivo.
Each mL of sterile colorless-to-pale yellow solution provides 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol (chloral derivative) as preservative.

Adult

50 mg IM q6wk

Pediatric

Not established

May increase effects of anticoagulants
Anabolic effects may enhance hypoglycemia
Elevated serum levels of oxyphenbutazone may result with coadministration
May decrease levels of TBG, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4 (free thyroid hormone levels remain unchanged, however, and no clinical evidence of thyroid dysfunction)
Caution when coadministering with ACTH or corticosteroids, especially in patients with hepatic or cardiac disease (enhances tendency toward edema)

Documented hypersensitivity; severe cardiac or renal disease; undiagnosed genital bleeding

Pregnancy

X - Contraindicated in pregnancy

Precautions

Observe women for signs of virilization (eg, deepening of the voice, hirsutism, acne, clitoromegaly, menstrual irregularities); discontinuation of therapy at time of evidence of mild virilism is necessary to prevent irreversible virilization (such virilization is usual following androgen use at high doses and is not prevented by concomitant use of estrogens)
Because androgens may alter serum cholesterol concentration, caution should be used when administering these drugs to patients with a history of MI or coronary artery disease; serial determinations of serum cholesterol should be made and therapy adjusted accordingly

More on Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure

Overview: Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure
Differential Diagnoses & Workup: Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure
Treatment & Medication: Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure
Follow-up: Spontaneous Primary Ovarian Insufficiency and Premature Ovarian Failure
References
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Further Reading

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Keywords

ovaries, reproductive organs, premature ovarian failure, primary ovarian failure, premature menopause, primary ovarian insufficiency, POF, anovulation, endocrine failure

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Contributor Information and Disclosures

Author

Vaishali Popat, MD, MPH, Fellow in Endocrinology, National Institutes of Health
Vaishali Popat, MD, MPH is a member of the following medical societies: American Association of Clinical Endocrinologists, American Diabetes Association, American Medical Association, and Endocrine Society
Disclosure: Nothing to disclose.

Coauthor(s)

Lawrence M Nelson, MD, MBA, Head of Integrative Reproductive Medicine Unit, Investigator, Intramural Research Program on Reproductive and Adult Endocrinology, National Institutes of Child Health and Human Development, National Institutes of Health
Lawrence M Nelson, MD, MBA is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine, Association of Professors of Gynecology and Obstetrics, Endocrine Society, and Society for Experimental Biology and Medicine
Disclosure: Nothing to disclose.

Medical Editor

Thomas Michael Price, MD, Associate Professor of Reproductive Endocrinology, Director of Reproductive Fellowship Training Program, Duke University Medical Center
Thomas Michael Price, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine, Endocrine Society, Phi Beta Kappa, Society for Gynecologic Investigation, and South Carolina Medical Association
Disclosure: Clinical Advisors Group Consulting fee Consulting; MEDA Corp Consulting Consulting fee Consulting; Gerson Lehrman Group Advisor  Consulting fee Consulting; Roche/GSK Spokesperson  Consulting fee Consulting

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

A David Barnes, MD, PhD, MPH, FACOG, Consulting Staff, Department of Obstetrics and Gynecology, Mammoth Hospital, Mammoth Lakes, California, Pioneer Valley Hospital, Salt Lake City, Utah, Warren General Hospital, Warren, Pennsylvania and Mountain West Hospital, Tooele, Utah
A David Barnes, MD, PhD, MPH, FACOG is a member of the following medical societies: American College of Forensic Examiners, American College of Obstetricians and Gynecologists, American Medical Association, Association of Military Surgeons of the US, and Utah Medical Association
Disclosure: Nothing to disclose.

CME Editor

Frederick B Gaupp, MD, Consulting Staff, Department of Family Practice, Hancock Medical Center
Frederick B Gaupp, MD is a member of the following medical societies: American Academy of Family Physicians
Disclosure: Nothing to disclose.

Chief Editor

Bryan D Cowan, MD, Professor and Chairman, Department of Obstetrics and Gynecology, University of Mississippi College of Medicine; Consulting Staff, Department of Obstetrics and Gynecology, Veterans Affairs Medical Center; Medical Director, Wiser Hospital for Women, University of Mississippi Medical Center
Bryan D Cowan, MD is a member of the following medical societies: American Association of Gynecologic Laparoscopists, American College of Obstetricians and Gynecologists, American Gynecological and Obstetrical Society, American Medical Association, American Society for Reproductive Medicine, Association of Professors of Gynecology and Obstetrics, Central Association of Obstetricians and Gynecologists, Endocrine Society, Sigma Xi, Society for Assisted Reproductive Technologies, Society for Gynecologic Investigation, Society for the Study of Reproduction, and Society of Laparoendoscopic Surgeons
Disclosure: Galil None Consulting

 
 
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