Mechanisms of Prevention of Ovarian Cancer by Oral Contraceptives

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DESCRIPTION (provided by applicant): Five-year survival for invasive epithelial ovarian cancer (ovarian cancer) is less than 50% because most women are diagnosed at an advanced stage. However, there is an effective chemoprevention strategy. Meta-analysis of epidemiological studies shows an approximately 40% reduction in risk of ovarian cancer with 5 years of oral contraceptive (OC) use. The protective effect increases significantly with duration of OC use and continues for at least 25 years after use of OCs is stopped. The mechanism(s) underlying this protective effect are not understood. One hypothesis is that protection is achieved by blocking ovulation, but growing evidence suggests that it may be related to promoting a favorable progestagenic environment. OC use would protect if the hormonal exposure while on OCs was less stimulatory to the possibly different types of cells of origin of ovarian cancer than the hormonal exposure in normal ovulatory cycles. Exposure to progestins is higher while on OCs than in normal cycling and this could explain the protective effect. We propose that a major source of the protection from OC use is due to their significantly reducing cell proliferation in the fallopian tube fimbriae (FTF) and in ovarian cortical inclusion cysts (CICs), two likely cells of origin for ovarian cancer. Proliferating cell populations are more susceptible to carcinogenic effects with the rise in cancer risk with cell proliferation being secondary to increased chances of mutation and progression. FTF proliferation has been reported to be almost confined to the follicular phase of the menstrual cycle with virtually no proliferation within a few days after ovulation and our preliminary data show the same pattern - OCs could thus protect against ovarian cancers arising in the FTF by mimicking the luteal phase of the cycle when progesterone exposure is high. Whether such changes occur in CICs is not known. Cell proliferation within different types of CICs during the menstrual cycle has not been studied. The effect of OCs on proliferation within the FTF and CICs has also not been studied. We are proposing to determine the effect of a 'traditional' high progestin dose OC on cell proliferation in the FTF and CICs in women undergoing a risk-reducing bilateral salpingo-oophorectomy (RR-BSO), and to compare these proliferation rates to the rates during the normal menstrual cycle of women also undergoing an RR-BSO. The results of this study will provide crucial information regarding the relationship between OC use and protection against ovarian cancer. It will lay the foundation for further studies examining the effects of lower progestin dose OCs and OCs with newer progestin formulations. Our long-term goal in studying the mechanism of OC protection is to determine whether it is likely that the protection against ovarian cancer afforded by OCs will be lost with alterations in OC formulation in terms of dose or type of progestin used, and, if possible, to guide development of OC formations to improve further on the protection afforded by OCs.