MECHANISM OF ACTION OF DIHYDROTESTOSTERONE IN LUTEOLYSIS DURING PREGNANCY

到目前为止，这个实验室的发现表明 双氢睾酮(DHT)抑制黄体孕酮(P)合成和分泌 在怀孕大鼠体内释放。DHT的体内治疗增加了数量 对黄体细胞内的脂滴没有任何影响 线粒体内或血浆孕烯醇酮上的管状脊 水平，表明血浆中P的降低可能是由于 胆固醇转运到线粒体或降低的酯酶 活动。较低的磷水平反过来可能导致抑制 夜间催乳素(PRL)激增，病变可能处于 3β-羟基类固醇脱氢酶(3β-HSD)导致 血浆P水平。体内给药对DHT的作用不明显 促黄体生成素(L H)的释放。此外，在体内 研究还表明，DHT的这种抑制作用可能是由 前列腺素F2pha(PGF2pha)。目前的提案延长了 这些研究将进一步调查这些观察结果，以便 了解双羟色胺抗生育作用的精确部位 在妊娠期间及其抑制细胞内机制 黄体P合成。在目前的提案中，它将是第一个 已确定体内给药DHT是否会导致形态 以及24小时内黄体(CL)的激素变化 治疗对垂体和CL的影响或由于其直接作用 CL的治疗。随后的实验将尝试定义 确切地说，导致黄体P降低的细胞内事件 体内用DHT处理后用24小时制作。黄体含量 游离胆固醇、胆固醇酯、ACAT和胆固醇酯酶 活动将被测量。双羟色胺治疗对黄体的影响 酶，P450scc和3beta-HSD，将通过Northern和 免疫印迹分析贯穿整个研究过程。几个荷尔蒙终点 将由RIA测量。接下来，将确定是否 DHT的抗妊娠作用是由PGF2α介导的。调查结果 从这项拟议的研究中可以提供对生理上的 这种自然分泌物质DHT在控制脑血管疾病中的作用 妊娠期间黄体类固醇激素的生成。

The findings from this laboratory so far suggest that dihydrotestosterone (DHT) inhibits luteal progesterone (P) synthesis and release in pregnant rats. In vivo treatment of DHT increased the number of lipid droplets within the luteal cells without having any effect on tubular cristae within the mitochondria or on plasma pregnenolone levels, indicating that the decrease in plasma P may be due to decreased cholesterol transport to the mitochondria or to decreased esterase activity. The lower P levels, in turn, may lead to inhibition of the nocturnal prolactin (PRL) surge and the lesion may be at the level of 3beta-hydroxy-steroid dehydrogenase (3beta-HSD) resulting in decreased plasma P levels. In vivo administration of DHT has no effect on pituitary luteinizing hormone (LH) release. Furthermore, in vivo studies also suggest that this inhibitory effect of DHT may be mediated by prostaglandin F2alpha (PGF2alpha). The current proposal extends these studies to further investigate these observations so as to understand the precise locus or loci of antifertility action of DHT during gestation and the intracellular mechanisms by which it inhibits luteal P synthesis. In the present proposal, it will be first determined whether in vivo administration of DHT causes morphological and hormonal changes in the corpus luteum (CL) within 24 h due to the effect of treatment on pituitary and CL or due to the direct effect of treatment on CL. Subsequent experiments will attempt to define precisely the intracellular events that lead to decreased luteal P production with 24 h after in vivo DHT treatment. The luteal content of free cholesterol, cholesterol ester, ACAT and cholesteryl esterase activity will be measured. The effects of DHT treatment on luteal enzymes, P450scc and 3beta-HSD, will be quantitated by northern and immunoblot analyses throughout the study. Several hormonal end points will be measured by RIA. Next, it will be determined if the contragestational effect of DHT is mediated by PGF2alpha. The findings from this proposed study could provide an insight into the physiological role of this naturally secreting substance, DHT, in the control of luteal steroidogenesis during pregnancy.