WENDY R. BREWSTER, MD PHILIP J. DiSAIA, MD
Ninety percent of women will live to the climacteric age, compared to only 30 percent 200 years ago. Attrition and aging of ovarian follicles results in termination of the maturation of granulosa cells, which are responsible for estrogen production. Sources of estrogen in the pre-menopausal woman are several fold, including direct production of estradiol by the ovaries as well as the extraglandular aromatization in adipose cells of androstenedione created in the adrenal glands and ovary. The hallmark of menopause is a drop in ovarian production of estriol and testosterone. Peripheral aromatiza-tion of other steroids not produced by the ovaries is an additional source of estrogen in all women. However, this source is not sufficient in most women to prevent the symptoms characteristic of estrogen deprivation.
Given the current population, 30 million women in the United States will spend approximately 40 percent of their lifetime in the post-menopausal period. These women have a lifetime risk of one in eight of developing breast cancer. Thus, a considerable number of American women are likely to have a history of breast cancer treatment and at the same time be potential candidates for hormone-replacement therapy. In the last decade, indications for chemotherapy as adjuvant treatment to surgery have widened and now encompass many more premenopausal women.1 Adjuvant therapy for breast cancer includes the use of alkylating agents and other drugs that cause amenorrhea in 84 percent of women aged 35 to 44 years. Other studies indicate that this treatment causes permanent ovarian failure in 86 percent of women > 40 years of age.2 As a result, a larger number of women will potentially be rendered menopausal in the fourth, and fifth decades of their lives, which has serious consequences in terms of the risk of cardiovascular disease and osteoporosis.
The major concern of many physicians in prescribing estrogen-replacement therapy (ERT) for breast cancer survivors is the theory that metastatic quiescent tumor foci might be activated and the "fire" of breast cancer ignited by the "fuel" estrogen. Other fears are that estrogen might cause a second primary in the already environmentally/genetically primed contralateral breast or might change breast density and mask new mammographic findings. These concerns are in part based upon epi-demiologic studies demonstrating a relationship between duration of postmenopausal estrogen replacement and breast cancer.3,4 Also, surgical oophorectomy is beneficial in a subset of premenopausal breast cancer patients, and estrogen withdrawal has also been observed to promote regression of metastatic breast cancer lesions.5 Despite very limited clinical data to support these concerns, it remains standard practice to prohibit breast cancer survivors from receiving ERT.
The well-substantiated benefits of estrogen replacement therapy must be balanced against theoretical concerns. Arguments in support of the safety of ERT are based on several natural experiments and observations, discussed in detail below.
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