The controversy surrounding exogenous hormone use and breast cancer risk is predicated on the concept that breast carcinogenesis is a hormone-dependent process. The ability to control breast cancer with hormonal manipula tion has been recognized since 1986, when Beatson reported on oophorectomy as a successful treatment for this disease.45 Since that time several other epidemiologic, experimental and clinical lines of evidence have developed that also support this concept.46
It is well established that menstrual factors resulting in exposure of the breast to increased numbers of ovulatory estrogen cycles over a lifetime, such as early menarche (<13 years), late menopause (> 50 years), and nulliparity can increase the risk of breast cancer.46,47 Conversely, bilateral oophorectomy at a young age and interruptions of the menstrual cycle in the form of multiple pregnancies may confer a protective effect.48
The impact of pregnancy on the risk of breast cancer is strongest in the case of the first pregnancy occurring at a young age (before 20 years). The rate of proliferation of the ductal epithelium is normally high after puberty. The hormonal influences associated with pregnancy induce a process of terminal ductal and lobular stem cell differentiation, theoretically rendering the breast more resistant to carcinogenesis.47,48 Henderson and colleagues hypothesized that completion of a full-term pregnancy is crucial for this protective effect because the rapid increase in free estradiol during the first trimester of pregnancy is "equivalent to several ovulatory cycles over a relatively short period of time." They hypothesized that failure to over-ride this estrogenic surge with the subsequent hormonal changes of advanced pregnancy (as occurs with first-trimester abortions) can result in increased risk of breast cancer.49
It is also well established that estrogen and progesterone exert proliferative effects on human breast tissue49,50 and that estrogen can promote mammary tumorigenesis in animal models as well as in in vitro tissue cultures.47-51 Postmenopausal obesity has been associated with increased breast cancer risk, and this relationship appears to be mediated by age-related variations in estrogen metabolism. In the post-
menopausal woman, androstenedione, synthesized in the adrenal gland, is the principal estrogen precursor following the decline of ovarian function. Increased conversion of androstened-ione to estrone by fat cells that results in elevated levels of this predominant postmenopausal estrogen is reputed to be the underlying explanation for the increased risk of breast cancer seen in obese postmenopausal women.47-52 In contrast, in premenopausal obese women, derangement of the estrogen-progesterone balance and subsequent menstrual disturbances result in a decreased risk of breast cancer.50,53
Male breast cancer is also likely to be related to factors resulting in abnormalities of estrogen metabolism, such as liver disease or genetic defects such as Klinefelter's syndrome.53-55
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