Mechanisms of Prevention of Ovarian Cancer by Oral Contraceptives

描述（由申请人提供）：侵袭性上皮性卵巢癌（卵巢癌）的5年生存率低于50%，因为大多数女性被诊断为晚期。然而，有一种有效的化学预防策略。流行病学研究的荟萃分析显示，使用口服避孕药（OC） 5年可使卵巢癌风险降低约40%。这种保护作用随着使用时间的延长而显著增加，并在停止使用后至少持续25年。这种保护作用背后的机制尚不清楚。一种假说认为，这种保护是通过阻断排卵来实现的，但越来越多的证据表明，这可能与促进有利的孕激素环境有关。如果激素暴露在卵巢癌中对可能不同类型的卵巢癌起源细胞的刺激比正常排卵周期中的激素暴露更少，那么使用卵巢癌就有保护作用。OCs的孕激素暴露量高于正常周期，这可以解释保护作用。我们认为，使用OC的主要保护来源是由于它们显著降低了输卵管原膜（FTF）和卵巢皮质包涵囊肿（CICs）中的细胞增殖，这两种细胞可能是卵巢癌的起源细胞。随着癌症风险的增加，增殖的细胞群更容易受到致癌作用的影响，细胞增殖是继发于突变和进展的机会增加。据报道，FTF的增殖几乎局限于月经周期的卵泡期，在排卵后的几天内几乎没有增殖，我们的初步数据显示了相同的模式——OCs可以通过模仿黄体期（孕酮暴露高）来预防FTF中发生的卵巢癌。这种变化是否发生在CICs中尚不清楚。不同类型CICs在月经周期内的细胞增殖尚未研究。OCs对FTF和CICs内增殖的影响也未见研究。我们建议确定“传统”高剂量黄体酮对接受降低风险的双侧输卵管卵巢切除术（RR-BSO）的女性FTF和CICs细胞增殖的影响，并将这些增殖率与接受RR-BSO的女性在正常月经周期内的增殖率进行比较。这项研究的结果将为卵巢癌的使用和预防之间的关系提供重要的信息。它将为进一步研究低剂量黄体酮OCs和新黄体酮制剂OCs的影响奠定基础。我们研究卵巢癌保护机制的长期目标是确定卵巢癌对卵巢癌的保护是否可能随着卵巢癌配方的剂量或黄体酮类型的改变而丧失，如果可能的话，指导卵巢癌形成的发展，进一步提高卵巢癌提供的保护。

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.