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Menopause Matters

Premature Ovarian Failure
Women With Special Needs

JoAnn V. Pinkerton, MD


Women who experience premature ovarian failure (POF) have significantly increased risks of adverse physical and psychological health. By definition, POF is hyper-gonadotropic amenorrhea that occurs in women younger than age 40 years. Although POF usually results in premature menopause, 5% to 10% of women will subsequently experience spontaneous ovulation.¹

In the United States, the incidence rate of POF is approximately 1%; 0.1% will experience POF before the age of 30 years.²

Compared with spontaneous menopause at the average age (51 years), POF-related premature menopause has been shown to increase the osteoporosis and fracture risks in an age-related manner—the younger women are when premature menopause occurs, the greater their risk.^3,4 Cardiovascular risk is also increased. Women who experience premature menopause at age 35 years or younger have approximately a 2.8 relative risk of developing a myocardial infarction.⁵

Causes of POF may be idiopathic or be due to chromosomal changes or autoimmune disorders, such as hypothyroidism, diabetes mellitus, or Addison disease. Fragile X chromosome permutations appear to be an important familial cause of POF with important implications for early loss of fertility.

Because POF has cumulative negative effects over time, it is important for clinicians to make a timely diagnosis and begin appropriate strategies for symptom manage-ment, emotional support, and risk reduction.


Diagnosis

Women with early stage ovarian failure usually have some type of menstrual disorder, such as metrorrhagia, polymenorrhea, oligomenorrhea, or amenorrhea. However, there is no confirming characteristic menstrual history. Because menstrual cycles are relatively stable in most women younger than age 40 years, any change in cycles could be an indication of POF.

Medical history

A woman's medical history should include prior ovarian surgery, chemotherapy, radiation therapy, and any automimmune disorders. Symptoms suggestive of POF include cold intolerance, fatigue and weight gain (hypothyroidism), polyuria and polydypsia (diabetes mellitus), or anorexia, salt craving, and increased skin pigmentation (Addison disease). Other diseases associated with POF include Graves disease, vitiligo, systemic lupus erythamatosus, rheumatoid arthritis, Sjögren syndrome, and inflammatory bowel disease. Additional potential secondary causes of amenorrhea include androgen excess, systemic diseases, eating disorders, narcotic abuse, use of psychotropic drugs, gonorrhea or chlamydia infection, and galactorrhea.

Physical Examination

In most women with suspected POF, the physical examination should include an assessment for signs of atrophic genital changes, such as attenuation of the labia majora or minora, loss of vaginal pallor, increased vaginal pH, vaginal or cervical petechia, decreased vaginal moisture, or friability. However, because intermittent estrogen stimulation is possible, these signs may not be present. The examination should also include other genetic or autoimmune stigmata.

Laboratory Evaluation

Blood work should include tests for follicle-stimulating hormone (FSH). In women younger than age 40 years, amenorrhea for at least 4 months, along with FSH levels in the postmenopausal range (>30 mIU/mL) on two tests at least 1 month apart are strong indicators of ovarian failure. However, 12 consecutive months of amenorrhea is the definitive confirmation of menopause.

Blood work should also include tests for luteinizing hormone, thyroid-stimulating hormone, free thyroxin, fasting glucose, and prolactin. Estradiol assays may be useful. The progestin challenge test is not reliable as some women with POF have intermittent normal estradiol levels leading to withdrawal bleeding. Testing for adrenal insufficiency and specialized enzyme tests depend on clinical concerns, including the woman's family history. In most cases, little additional information is gained from pelvic ultrasound, ovarian biopsy, or antiovarian antibody testing.

Karyotype testing should be performed to identify the presence of a Y chromosome. If found, bilateral gonadectomy is recommended because of concerns of gonadal germ cell neoplasia. DNA testing can detect some abnormalities of the X chromosome that may cause ovarian failure, including fragile X permutations.


Clinical issues

Regardless of the cause, women experiencing POF will require clinical care beyond that provided for women reaching menopause at the typical age. Emotional issues that arise in relation to the POF diagnosis vary greatly from woman to woman and depend on a variety of factors, including concerns about fertility, body image, sexuality, and a feeling of growing old prematurely. Health care providers can determine the cause of mental health stressors, assess options, and recommend appropriate treatment. Reproductive-aged women who want to become pregnant may be referred to a fertility specialist.

Estrogen therapy (ET), adding progestogen (EPT) for women with an intact uterus, may be recommended to relieve symptoms of hot flashes, night sweats, and vaginal dryness, and to lower risk of osteoporosis. Higher doses may be required than those used for women who reach menopause at midlife. Continuation of ET/EPT is often advised until the woman is closer to the average age of menopause (51 years). It should be noted that findings of increased heart disease risk with hormone therapy from the Women's Health Initiative⁶ were based largely on older women (average age 63 years), not women under age 40 years, so the results may not be applicable to this population.

Due to the potential for spontaneous and unexpected pregnancy, sexually active women with POF should be prescribed cyclic EPT that will induce regular menses. If a period is missed on this regimen, a pregnancy test should be performed and EPT discontinued. In women who want to avoid pregnancy, an oral contraceptive would be more appropriate than EPT.

Women who experience premature menopause are at an age when they are more likely to enjoy frequent sexual activity, and they may be more disturbed by any changes in sexual function. For women with declining libido, low-dose androgen therapy may be an option.

Health care providers should encourage women experiencing POF and premature menopause to adopt a more healthful life-style to reduce the health risks related to lower endogenous estrogen levels. Baseline and periodic bone density testing may be required, as well as ongoing monitoring of blood pressure and cholesterol. A wide array of therapies are available to treat osteoporosis, hypertension, and hyper-cholesterolemia.


Conclusion

Premature ovarian failure has significant health implications. Because the health risks are cumulative, an early diagnosis and thoughtful approaches to management can minimize adverse health outcomes.

1. Kalantaridou SN, Davis SR, Nelson LM. Premature ovarian failure. Endocrinol Metab Clin North Am. 1998;27(4):989-1006.
2. Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol. 1986;67(4):604-606.
3. van der Voort DJ, van der Weijer PH, Barentsen R. Early menopause: increased fracture risk at older age. Osteoporos Int. 2003;14(6):525-530.
4. Pouilles JM, Tremollieres F, Bonneu M, Ribot C. Influence of early age at menopause on vertebral bone mass. J Bone Mineral Res. 1994;9(3):311-315.
5. Palmer JR, Rosenberg L, Shapiro S. Reproductive factors and risk of myocardial infarction. Am J Epidemiol. 1992;136(4):408-416.
6. Rossouw JE, Anderson GL, Prentice RL, et al, for the writing group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.

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