Novel contraceptive targets to inhibit ovulation: the prostaglandin E2 pathway
Novel contraceptive targets to inhibit ovulation: the prostaglandin E2 pathway
复制标题
DOI：
10.1093/humupd/dmv026
复制
发表时间：
2015-09-01
影响因子：
13.3
通讯作者：
Duffy, Diane M.
中科院分区：
文献类型：
--
作者：
Duffy, Diane M.
背景：前列腺素E2(PGE2)是一种重要的卵泡内排卵调节剂。与单基因、单蛋白质合成多肽信号分子的概念不同，生物活性PGE2的产生和代谢需要控制多种蛋白质的表达，正确的亚细胞定位，协调PGE2的合成和代谢，以及前列腺素在细胞内外的运输，以促进PGE2的作用和降解。卵泡内PGE2升高是成功排卵所必需的，因此破坏PGE2的合成、代谢或转运可能会产生有效的避孕策略。方法：本文综述了1987-2014年间发表的环氧合酶抑制剂抑制妇女和猕猴排卵的病例报道和研究。这些发现是在描述卵巢细胞中前列腺素合成和代谢酶以及前列腺素转运体的mRNA、蛋白质和活性水平的研究的背景下讨论的。结果：促黄体生成素的排卵峰调节排卵卵泡内PGE2合成-代谢-运输途径的每个组成部分的表达。来自原代卵巢细胞和癌细胞株的数据表明，酶和转运蛋白可以协同作用，优化生物活性PGE2水平。卵泡内PGE2升高介导了包括卵丘扩张、卵泡破裂和卵母细胞释放在内的关键排卵事件。前列腺素-过氧化物合成酶2(Ptgs2)的抑制剂(也称为环氧合酶-2或COX2)会降低女性的排卵率。对猕猴的研究表明，Ptgs2抑制剂可以降低卵丘扩张、卵母细胞释放、卵泡破裂、卵母细胞核成熟和受精的比率。一种Ptgs2抑制剂在模拟紧急避孕时降低了繁殖猕猴的怀孕率。然而，当模拟每月避孕药的使用时，Ptgs2抑制剂并没有阻止猴子怀孕。结论：单独使用Ptgs2抑制剂可能适合用作紧急避孕药。然而，这类药物不太可能作为月度避孕药有效。抑制额外的PGE2合成酶或调节PGE2的代谢或运输也具有减少卵泡PGE2和防止排卵的潜力。针对PGE2合成-代谢-转运途径的多种成分的方法可能需要有效地阻止排卵，并导致为妇女开发新的避孕选择。针对PGE2的治疗也可能影响子宫紊乱，除了避孕外，还可能对妇女的健康有好处。
BACKGROUND: Prostaglandin E2 (PGE2) is an essential intrafollicular regulator of ovulation. In contrast with the one-gene, one-protein concept for synthesis of peptide signaling molecules, production and metabolism of bioactive PGE2 requires controlled expression of many proteins, correct subcellular localization of enzymes, coordinated PGE2 synthesis and metabolism, and prostaglandin transport in and out of cells to facilitate PGE2 action and degradation. Elevated intrafollicular PGE2 is required for successful ovulation, so disruption of PGE2 synthesis, metabolism or transport may yield effective contraceptive strategies.METHODS: This review summarizes case reports and studies on ovulation inhibition in women and macaques treated with cyclooxygenase inhibitors published from 1987 to 2014. These findings are discussed in the context of studies describing levels of mRNA, protein, and activity of prostaglandin synthesis and metabolic enzymes as well as prostaglandin transporters in ovarian cells.RESULTS: The ovulatory surge of LH regulates the expression of each component of the PGE2 synthesis-metabolism-transport pathway within the ovulatory follicle. Data from primary ovarian cells and cancer cell lines suggest that enzymes and transporters can cooperate to optimize bioactive PGE2 levels. Elevated intrafollicular PGE2 mediates key ovulatory events including cumulus expansion, follicle rupture and oocyte release. Inhibitors of the prostaglandin-endoperoxide synthase 2 (PTGS2) enzyme (also known as cyclooxygenase-2 or COX2) reduce ovulation rates in women. Studies in macaques show that PTGS2 inhibitors can reduce the rates of cumulus expansion, oocyte release, follicle rupture, oocyte nuclear maturation and fertilization. A PTGS2 inhibitor reduced pregnancy rates in breeding macaques when administered to simulate emergency contraception. However, PTGS2 inhibition did not prevent pregnancy in monkeys when administered to simulate monthly contraceptive use.CONCLUSION: PTGS2 inhibitors alone may be suitable for use as emergency contraceptives. However, drugs of this class are unlikely to be effective as monthly contraceptives. Inhibitors of additional PGE2 synthesis enzymes or modulation of PGE2 metabolism or transport also hold potential for reducing follicular PGE2 and preventing ovulation. Approaches which target multiple components of the PGE2 synthesis-metabolism-transport pathway may be required to effectively block ovulation and lead to the development of novel contraceptive options for women. Therapies which target PGE2 may also impact disorders of the uterus and could also have benefits for women's health in addition to contraception.