PROGESTERONE METABOLISM/ACTION AND PREMENSTRUAL SYNDROME

所描述的研究旨在验证以下命题：（i） 女性在肝外代谢方面存在很大差异， 血浆孕酮对生物活性物质具有不同的作用，（ii） 有多种经前综合征（PMS），和（iii）经前 残疾是由孕激素及其生物活性物质的作用引起的 代谢物。 妊娠（P），在黄体中期， 女性的卵巢周期，大量产生，即，40-50 mg/24 h。 已知的血浆P的生物活性代谢物包括： 盐皮质类固醇，即，脱氧皮质酮（DOC）， 由肝外、肾上腺外血浆P的21-羟基化产生 组织，和（ii）3 α/β-还原的-5 α-孕烷醇酮，其作用 通过P受体非依赖性，非基因组机制，通过GABA/A （γ-氨基丁酸）受体-氯离子通道复合物调节 GABA的神经抑制作用。 我们已经确定， 血浆P转化为DOC的转移常数[p] P-DOC变化 在正常人中广泛（30倍），因此占了很大的比例。 排卵期妇女DOC形成率的变化 卵巢周期的黄体期。 根据最近的发现，我们估计 50%的血浆P清除率是由代谢引起的， 肝外组织和80 - 90%的肝外磷代谢 首先进行5 α-还原，得到5 α-二氢- 孕酮（5 α-DHP）。 反过来，70%的血浆5 α-DHP清除率 发生在肝外部位，产生3 α/β-还原型-5 α- 孕烷醇酮，其在选定的组织，特别是脑中具有生物活性。 我们还发现，肝外失活的生物活性5 α- 孕烯醇酮是由特殊的5 α-孕烯醇酮-6 α- 羟化酶广泛分布，但仅限于 在肝外组织中，并且在脑、乳房和皮肤中特别高。 重要的是，我们还发现5 α-DHP的肝外代谢， 像[p] P、DOC一样，在女性中差异很大。 我们建议测试 假设肝外磷代谢的各种模式， 生物活性代谢物与经前综合征的复发相关 可能导致多种症状不同严重程度的症状 集群 提出的研究目标是（一）定义 独立于遗传变异的可能调节因素 P/5 α-DHP代谢的妇女;（ii）建立性质和 排卵期妇女P/5 α-DHP固有差异的原因 （iii）研究和比较以下物质的体内代谢： P/5 α-DHP在30例无症状女性中的表达，其中5例为肥胖， 25名患有严重经前综合症的女性，即，黄体晚期焦虑障碍 （LLPDD）;和（iv）比较P/5 α-β-D的体内代谢模式。 这些妇女中的DHP具有P/5 α-DHP的特异性活性 同一个女人的皮肤成纤维细胞中的代谢酶。 我们预测，有多态性的基因编码的 代谢P/5 α-DHP肝外酶及其差异 在由此产生的酶活性中， 形成P的生物活性代谢物，从而， 经前综合症。 P/5 α-DHP的这些人与人之间差异的原因 代谢可以通过体内和体外研究确定 提出了

The research described is designed to test the propositions that (i) there are wide variations among women in the extrahepatic metabolism of plasma progesterone to bioactive products with diverse actions, (ii) there are multiple premenstrual syndromes (PMS), and (iii) premenstrual disabilities are caused by the actions of progesterone and its bioactive metabolites. Progesterone (P), during the mid-luteal phase of the ovarian cycles of women, is produced in massive amounts, viz., 40-50 mg/24 h. The known bioactive metabolites of plasma P include: (i) a mineralocorticosteroid, viz., deoxycorticosterone (DOC), which is produced by 21-hydroxylation of plasma P in extrahepatic, extraadrenal tissues, and (ii) the 3alpha/beta-reduced-5alpha-pregnanolones, which act by way of P receptor-independent, nongenomic mechanisms via the GABA/A (gamma-aminobutyric acid) receptor-chloride channel complex to modulate the neuroinhibitory action of GABA. We have established that the transfer constant of conversion of plasma P to DOC, [p]P-DOC, varies widely (by 30-fold) among normal persons, thus accounting for the great variation in the rate of DOC formation among ovulatory women during the luteal phase of the ovarian cycle. From recent findings, we estimate that 50% of plasma P clearance is accounted for by metabolism in extrahepatic tissues and that 80-90% of this extrahepatic P metabolism proceeds initially by 5alpha-reduction to give 5alpha-dihydro- progesterone (5alpha-DHP). In turn, 70% of plasma 5alpha-DHP clearance occurs in extrahepatic sites to give 3alpha/beta-reduced-5alpha- pregnanolones, which are bioactive in selected tissues, notably brain. We also find that the extrahepatic inactivation of the bioactive 5alpha- pregnanolones is accomplished by peculiar 5alpha-pregnanolone-6alpha- hydroxylase enzymes that are widely distributed, but exclusively in extrahepatic tissues and are notably high in brain, breast, and skin. Importantly, we also find that the extrahepatic metabolism of 5alpha-DHP, like [p]P,DOC, varies widely among women. We propose to test the hypothesis that various patterns of extrahepatic P metabolism to bioactive metabolites are correlated with the recurrence of premenstrual symptoms of varying severity that may result in multiple symptom clusters. The goals of the research presented are (i) to define the factors, which are independent of genetic variation, that may regulate P/5alpha-DHP metabolism in women; (ii) to establish the nature and cause(s) of inherent differences among ovulatory women in P/5alpha-DHP metabolism; (iii) to investigate and compare the in vivo metabolism of P/5alpha-DHP in 30 asymptomatic women, 5 of whom are obese, with that in 25 women with severe PMS, i.e., the late luteal phase dysphoric disorder (LLPDD); and (iv) compare the pattern of in vivo metabolism of P/5alpha- DHP in these women with the specific activities of P/5alpha-DHP metabolizing enzymes in skin fibroblasts of the same woman. We predict that there is polymorphism of the genes that encode the extrahepatic enzymes that metabolize P/5alpha-DHP and that differences in enzyme activities resulting therefrom cause variations in the rate(s) of formation of bioactive metabolites of P and, thereby, the symptoms of PMS. The cause of these person-to-person variations in P/5alpha-DHP metabolism can be identified by the in vivo and in vitro studies proposed.