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）：侵入性上皮卵巢癌（卵巢癌）的五年生存率小于50％，因为大多数女性在晚期被诊断出。但是，有一个有效的化学预防策略。流行病学研究的荟萃分析显示，使用5年口服避孕（OC）使用卵巢癌风险约40％。随着OC的使用持续时间，保护效应显着增加，并且在使用OCS后至少持续25年。该保护作用的基础机制尚不清楚。一个假设是通过阻止排卵来实现保护，但越来越多的证据表明，它可能与促进有利的孕激素环境有关。如果OC在OCS上的激素暴露对卵巢癌起源的类型类型的刺激性与正常排卵周期中的激素暴露相比，则OC使用可以保护。在OC上，暴露于孕激素高于正常循环中的孕激素，这可以解释保护作用。我们建议，防止OC的主要来源是由于它们在输卵管纤维中（FTF）和卵巢皮质包容性囊肿（CICS）中显着降低了细胞的增殖，这是两个可能起源的细胞卵巢癌。增殖细胞群体更容易受到致癌作用的影响，癌症风险的增加，细胞增殖是突变和进展的机会增加的。据报道，FTF的增殖几乎局限于月经周期的卵泡相，在排卵后几天内几乎没有增殖，我们的初步数据显示出相同的模式 - 因此，OC可以通过模拟孕酮敞口时的酸性周期来预防FTF中产生的卵巢癌。在CIC中是否发生这种变化尚不清楚。在月经周期中不同类型的CIC中的细胞增殖尚未研究。还没有研究OC对FTF和CICS中增殖的影响。我们提议确定“传统”高孕激素剂量OC对FTF的细胞增殖和经历降低风险的双侧salpingo-opopopopopopopopopopophororycome（RR-BSO）的细胞增殖的影响，并将这些增殖率与正常妇女的率在经历RR-BSO的正常男性周期中进行比较。这项研究的结果将提供有关OC使用与卵巢癌的保护之间关系的关键信息。它将为进一步的研究奠定基础，以研究具有较新的孕激素制剂的较低孕激素剂量OC和OC的影响。我们研究OC保护机制的长期目标是确定OCS提供的卵巢癌的保护是否可能会随着使用剂量或使用的孕激素类型而改变的OC所提供的卵巢癌，并且如果可能的话，可以指导OC形成的开发以进一步改善OCS提供的保护。