Mechanisms of Prevention of Ovarian Cancer by Oral Contraceptives

口服避孕药预防卵巢癌的机制

• 批准号: 8571076
• 负责人: CELESTE Leigh PEARCE
• 金额: $ 21.68万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8571076
• 关键词: Accounting; Address; BRCA1 gene; Bilateral; Cancer Etiology; Cell Proliferation; Cells; Cessation of life; Chemoprevention; Clear Cell; Contraceptive Usage; Data; Developed Countries; Development; Diagnosis; Disease; Dose; Drug Formulations; Ensure; Environment; Epidemiologic Studies; Epithelial cyst; Epithelial ovarian cancer; Epithelium; Estrogen Therapy; Exposure to; Foundations; Goals; Health; Hormonal; Lesion; Luteal Phase; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Menopause; Menstrual cycle; Meta-Analysis; Metaplastic; Mucinous; Mutation; Neoplastic Cell Transformation; Oral Contraceptives; Ovarian; Ovary; Ovulation; Pattern; Population; Progesterone; Progestins; Proliferating; Regimen; Reporting; Risk; Salpingo-Oophorectomy; Secondary to; Serous; Site; Source; Specimen; Staging; Surface; Uncertainty; Woman; base; cancer risk; cell type; fimbria; high risk; improved; mutation carrier; ovarian cancer prevention; proliferative phase Menstrual cycle; protective effect; screening; tool

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.

描述（由申请人提供）：侵袭性上皮性卵巢癌（卵巢癌）的五年生存率低于 50%，因为大多数女性在诊断时已处于晚期。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，患卵巢癌的风险降低约 40%。保护作用随着 OC 使用时间的延长而显着增强，并在停止使用 OC 后持续至少 25 年。这种保护作用的机制尚不清楚。一种假设是通过阻止排卵来实现保护，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。如果服用口服避孕药期间的激素暴露对可能不同类型的卵巢癌起源细胞的刺激程度低于正常排卵周期中的激素暴露，则使用口服避孕药可以起到保护作用。口服避孕药期间孕激素的暴露量高于正常周期，这可以解释其保护作用。我们认为，使用 OC 提供保护的一个主要来源是它们显着减少了输卵管菌毛 (FTF) 和卵巢皮质包涵囊肿 (CIC) 中的细胞增殖，这两种细胞可能是卵巢癌的起源细胞。增殖的细胞群更容易受到致癌作用的影响，癌症风险增加，细胞增殖继发于突变和进展机会的增加。据报道，FTF 增殖几乎局限于月经周期的卵泡期，在排卵后几天内几乎没有增殖，我们的初步数据显示了相同的模式 - 因此，OC 可以通过模仿 FTF 中出现的卵巢癌来预防 FTF 中出现的卵巢癌。周期的黄体期，黄体酮暴露量较高。 CIC 中是否会发生此类变化尚不清楚。月经周期期间不同类型 CIC 内的细胞增殖尚未进行研究。 OC 对 FTF 和 CIC 内增殖的影响也尚未研究。我们建议确定“传统”高孕激素剂量 OC 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 CIC 细胞增殖的影响，并将这些增殖率与在女性正常月经周期期间也接受 RR-BSO。这项研究的结果将提供有关 OC 使用和预防卵巢癌之间关系的重要信息。它将为进一步研究检查较低孕激素剂量 OC 和采用新孕激素配方的 OC 的效果奠定基础。我们研究 OC 保护机制的长期目标是确定 OC 所提供的对卵巢癌的保护是否可能会随着 OC 配方中所用孕激素剂量或类型的改变而丧失，并且如果可能的话，指导业主立案法团编队的发展，进一步改善业主立案法团提供的保障。