Abstract

Analysis of epidemiologic data on cancers of the breast, ovary and endometrium; the effects of endogenous hormones on cell proliferation; and current carcinogenesis concepts, suggest that hormonal contraceptives can be developed that will reduce lifetime risk of all 3 cancers. The 'unopposed-estrogen hypothesis' accounts for endometrial cancer risk factors. Ovarian cancer risk is closely related to the total frequency of ovulation. The risk of breast cancer can be explained by an 'estrogen-plus-progestogen hypothesis'. On the basis of this analysis an hormonal contraceptive regimen has been developed consisting of a gonadotropin-releasing hormone agonist (GnRHA) plus continuous low-dose add-back estrogen and a short course of progestogen every fourth month. The total dose of add-back estrogen is estimated to be approximately 38% that in present-day low-dose combination-type oral contraceptives (COCs). The total dose of progestogen is approximately 15% that in COCs. This regimen prevents ovulation and should thus reduce ovarian cancer risk. It also reduces the exposure of the endometrium to unopposed estrogen, and the exposure of the breast to estrogen-plus-progestogen. It is estimated that use of such a regimen for 10 years will only reduce lifetime risk of endometrial cancer by one-sixth, but lifetime risk of ovarian cancer is estimated to be reduced by two-thirds, and lifetime risk of breast cancer is estimated to be reduced by one-half.

PIP:

Epidemiologic studies of breast, ovarian, and endometrial cancer and physiologic studies of epithelial tissues from which these cancers originate indicate that medical researchers can develop interventions to reduce women's risk of these 3 cancers. They already know that use of combined oral contraceptives considerably reduced the risk of endometrial and ovarian cancer. The key etiologic factors for endometrial and breast cancer are ovarian steroid hormones. Specifically, any estrogen not checked by progestogen stimulate cell division in the epithelial tissue of the endometrium thus increasing the risk of cancer. Yet estrogen and progestogen induces significantly more cell division in the epithelial tissue of the terminal duct lobular unit (from which many breast cancers originate) than does just estrogen. Ovulation damages the ovarian surface making it the leading etiologic factor for ovarian cancer. Medical researchers at the University of Southern California (USC) have designed a prototype contraceptive regimen which should prevent all 3 cancers. They re presently testing it in a clinical trial at USC. The prototype regimen consists of administration of the gonadotropin releasing hormone agonist (GnRHA) leuprolide acetate depot on day 1 of each 28-day cycle, 0.625 mg of oral conjugated equine estrogens (CEE) on Monday-Saturday (24 days) per each 28-day cycle, and 10 mg of oral medroxyprogesterone acetate (MCA) for 13 days every 4th cycle. The GnRHA reduces the risk of all 3 cancers. CEE prevents bone mineral loss, possible increase in cardiovascular disease risk, menopausal symptoms, and urogenital atrophy. MCA reverses endometrial hyperplasia and prevents increased risk of endometrial cancer. The predicted relative reduction in lifetime breast cancer risks over 5,10, and 15 years for the prototype regimen are 31%, 53%, and 70%, respectively. For endometrial cancer, they are 18%, 33%, and 45%, respectively. For ovarian cancer, they are 41%, 67%, and 84%. This regimen should also reduce the incidence or severity of hormonally mediated benign gynecologic disorders. Further research on such a regimen is needed.