With the increase in life span that is expected in the 1990s, one third or more of a woman's life may occur after menopause. The benefits of and guidelines for estrogen replacement therapy have been well established for postmenopausal women. However, few guidelines exist for estrogen supplementation or hormone therapy in the perimenopausal age group. The “perimenopausal decade,” which usually includes the years between 45 and 55, can be a difficult decade with respect to menstrual symptoms and cycle variability. It is a time when hot flushes may intermittently occur, premenstrual syndrome often intensifies and menstrual cycles may have no predictability.^1–4 Unplanned pregnancy is also possible.Although the addition of estrogen appears to alleviate many of these climacteric symptoms during the perimenopausal years, two major questions remain: Is estrogen supplementation safe? Which estrogen regimen is most effective in this age group?

Noncontraceptive Health Benefits of Oral Contraceptives

Prevention of Osteoporosis

Osteoporosis is a major health problem that results in significant morbidity and mortality. Over 25 million people are afflicted with osteoporosis in the United States, with an annual estimated cost of $7 billion to $10 billion.⁵ Twelve to 20 percent of women who have a hip fracture die within two to three months of the fracture, and at least 50 percent require assistance to perform daily activities after a hip fracture. After 30 years of age, bone resorption gradually exceeds bone formation, and the process leading to osteoporosis begins, long before menopause.⁵ Therefore, interventions to maximize formation of bone mass during the perimenopausal years are essential.

In addition to adequate calcium supplementation and weight-bearing exercise, the use of low-dose oral contraceptives appears to be associated with a significant increase in bone density. Data from several studies suggest that perimenopausal administration of low-dose oral contraceptive pills can help prevent the acceleration of bone turnover and substantially reverse the decreasing bone density and resultant osteoporosis that occur during the menopausal years.^5–7

Ovarian and Endometrial Cancer Prevention

As a result of reports that have appeared in the lay press over the past few years, ovarian cancer is a significant fear among perimenopausal and postmenopausal women, even though its actual incidence is very low. Unfortunately, no proven screening test for ovarian cancer exists, and neither CA-125 screening nor periodic pelvic ultrasound examinations have been especially helpful. Recent studies have indicated that the risk of developing ovarian cancer is reduced in women who have used oral contraceptives compared with women who have never used them.⁸ The largest investigation to date, the Cancer and Steroid Hormone Study (CASH), showed a decrease averaging 40 percent in the development of ovarian cancer in women who had taken oral contraceptives.⁹ A protective effect has been observed with as little as three to six months of oral contraceptive use, with further decreases in risk seen with longer periods of use. For example, use of oral contraceptives for seven years or longer confers about a 60 to 80 percent reduction in the risk of developing ovarian cancer.⁸

Another benefit of low-dose oral contraceptive use during the perimenopausal years is a reduction in the risk of endometrial cancer. Several studies indicate that oral contraceptives protect against endometrial cancer in a duration-dependent manner. The CASH study reported that after 12 to 23 months of oral contraceptive use, the age-adjusted risk of developing endometrial cancer was 40 percent less than the risk in women who have never used oral contraceptives. After 10 or more years of oral contraceptive use, the risk is 60 percent less.^8,10

Other Suggested Benefits of Oral Contraceptives

The use of oral contraceptives also provides protection against benign breast disease, ectopic pregnancy, salpingitis, dysmenorrhea and iron deficiency anemia.¹¹ Growing evidence suggests that oral contraceptive use may protect against other conditions, including colorectal cancer, uterine fibroid tumors, toxic shock syndrome, Alzheimer's disease and rheumatoid arthritis. However, these particular findings remain unproved.¹¹

Controversies Related to Oral Contraceptive Use

Oral Contraceptives and Stroke

Although it is known that oral contraceptive use increases the risk of venous thromboembolism, epidemiologic data on the possible association between oral contraceptives and the risk of stroke are now available.¹² No substantial risk of ischemic or hemorrhagic stroke was found with use of low-dose oral contraceptives in healthy young women. In addition, no increased risk of stroke was reported in healthy nonsmoking women, regardless of age. Effective screening for smoking and untreated hypertension in perimenopausal women can limit, if not eliminate, the risk of arterial diseases associated with the use of low-dose oral contraceptives.

The possible relationship between low-dose oral contraceptives and stroke in patients with migraine was not addressed. Evidence from two case-controlled studies^13,14 suggests that some women with migraines have a higher risk of stroke. This increased risk is concentrated among women with migraine who also have an aura or peripheral neurologic symptoms. However, neither study mentions the dosage of oral contraceptives used. It is important for the clinician to individualize the decision to use oral contraceptives in women with migraines. In women with common migraines (migraines without aura and without focal neurologic symptoms), it is likely that clinicians can safely prescribe low-dose combination oral contraceptives. These patients require close follow-up. If the frequency or the intensity of migraine headaches increases, the patient must discontinue use of low-dose oral contraceptives. Occasionally, a clinician might want to prescribe low-dose oral contraceptive pills (such as LoEstrin) in a patient with complicated migraines. Before this decision is made, it may be prudent to consult a neurologist.¹⁵

Oral Contraceptives and Lipids

Low-dose oral contraceptives probably do not adversely affect lipid levels in most women. In one study,¹⁶ oral contraceptive use in perimenopausal women consisted of 20 μg of ethinyl estradiol and 150 μg of desogestrel. In this study, total serum cholesterol levels decreased, and high-density lipoprotein (HDL) cholesterol levels increased. Triglyceride levels, which often increase as a result of the estrogen component of oral contraceptives, were not affected in this study.

Oral Contraceptives and Breast Cancer

A recent collaborative study¹⁷ from 54 centers in 26 countries analyzed a total of 53,297 women with breast cancer and 100,239 women without breast cancer to assess the potential relationship between breast cancer and use of low-dose oral contraceptives. The overall risk of breast cancer in patients who had used oral contraceptives was 1.07—a very slight, although statistically significant, elevation. The cases of breast cancer in women who had previously used oral contraceptives were more localized, with less metastases, than the tumors in patients who had never used oral contraceptives.¹⁷ This constellation of findings may reflect the fact that the impact of oral contraceptive use may be similar to the effects of pregnancy. In both cases, the hormonal environment may accelerate a nidus of malignant cells that is already present, but at the same time change the remaining breast cells in a way that protects against breast cancer transformation later in life.^15,18

Choice of Estrogen Regimen

The perimenopausal years are often characterized by episodes of erratic estrogen production leading to unpredictable hot flushes.¹⁹ Available evidence in this age group suggests that any particular menstrual cycle is relatively independent from previous cycles. Therefore, many perimenopausal women may benefit from a constant hormonal environment to counteract erratic ovarian function and prevent pregnancy. An estrogen dosage equal to 0.625 mg of conjugated equine estrogens is effective in postmenopausal women. However, this dosage may not be an appropriate estrogen supplementation for perimenopausal women. Women who are perimenopausal occasionally ovulate, and the low dose of estrogen and progesterone commonly used postmenopausally does not reliably suppress ovulation and, thus, does not eliminate the potential of unplanned pregnancy. Secondly, oral contraceptives may contain four to 10 times the equipotent estrogen dose of commonly prescribed post-menopausal estrogen therapy regimens. Therefore, for women in the perimenopausal years who are receiving oral contraceptives, it is important to identify when menopause occurs, so that the amount of estrogens prescribed can be reduced to safer levels.

The best solution to this dilemma may prove to be the use of low-dose oral contraceptives.⁶ Table 1 lists equivalent doses of various estrogen preparations.

Contraindications to oral contraceptive use in women over 35 years of age include smoking, untreated hypertension, history of deep venous thrombosis, pulmonary embolus, stroke, estrogen-dependent neoplasia, undiagnosed abnormal genital bleeding and cholestatic jaundice of pregnancy or jaundice with previous pill use. It is important to recognize, however, that a family history of estrogen-dependent neoplasia is not a contraindication to the use of oral contraceptive medication.

Changing from Oral Contraceptives to ‘Traditional’ Estrogen Therapy

To determine the onset of menopause in women receiving oral contraceptives, levels of follicle-stimulating hormone (FSH) must be measured to identify the rise that occurs in response to ovarian failure. Evaluation of the FSH level on the sixth day of the placebo week during oral contraceptive use can help define the best time to change to traditional estrogen replacement therapy (Table 2). When the FSH level is in the menopausal range, the change can be made from low-dose oral contraceptive pills to traditional estrogen replacement therapy.^20–22 In some postmenopausal women, FSH measurements do not reliably increase even after two weeks without oral contraceptives. In these women, estradiol levels will usually indicate a menopausal status. One small study²⁰ of 12 women showed that a combination of FSH level and serum estradiol reliably predicted menopause and an appropriate time to begin hormone replacement therapy.

Estrogen supplementation in the form of low-dose oral contraceptive pills taken during the perimenopausal years may not be appropriate in everyone, but in many women it can ease the emotional and physical transition into the menopausal years, while at the same time providing some of the noncontraceptive benefits of hormonal contraceptives.