PROGESTERONE METABOLISM/ACTION AND PREMENSTRUAL SYNDROME

所描述的研究旨在检验以下命题：(I) 女性在肝外代谢方面存在很大差异 血浆孕酮对具有不同作用的生物活性产物的作用(II) 有多个经前综合征(PMS)，和(Iii)经前 残疾是由黄体酮及其生物活性引起的。 代谢物。黄体中期孕酮(P) 女性的卵巢周期是大量产生的，即40-50 已知的血浆P的生物活性代谢物包括：(I)a 矿物皮质类固醇，即脱氧皮质酮(DOC)，它是 由肝外、肾上腺外血浆P的21-羟基化产生 组织，和(Ii)3α/β-还原-5α-孕酮，它们起作用 通过GABA/A的P受体非依赖性非基因组机制 (γ-氨基丁酸)受体-氯离子通道复合体的调节 GABA的神经抑制作用。我们已经确定， 血浆P向DOC转化的转移常数[p]P-DOC变化 在正常人中广泛存在(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。从最近的发现来看，我们估计 血浆磷清除的50%是由新陈代谢引起的 肝外组织和80%-90%的肝外P代谢 最初的收益是5α-还原，得到5α-二氢- 孕酮(5α-DHP)。反过来，70%的血浆5α-DHP清除率 发生在肝外部位，可产生3α/β-还原-5α- 孕酮类化合物，在选定的组织中具有生物活性，特别是在大脑中。 我们还发现，生物活性5α-的肝外失活- 孕酮是由特殊的5α-孕酮-6α-完成的- 羟基酶分布广泛，但仅限于 肝外组织，脑、乳房和皮肤中含量明显较高。 重要的是，我们还发现5α-DHP的肝外代谢， 和[p]P，DOC一样，女性之间的差异很大。我们建议测试一下 假设肝外P代谢的不同模式 生物活性代谢产物与经前期复发相关 严重程度不同的症状，可能导致多种症状 集群。提出的研究目标是：(I)界定 与遗传变异无关的因素，可能调节 P/5α-DHP在妇女中的代谢；(Ii)建立 排卵妇女P/5α-DHP先天差异的原因(S) 代谢；(Iii)研究和比较黄曲霉毒素的体内代谢 P/5α-DHP治疗30例无症状妇女，其中5例肥胖 25例严重经前综合征患者，即黄体晚期焦虑症 (LLPDD)；和(Iv)比较P/5α在体内的代谢模式。 DHP在这些女性中具有P/5α-DHP的特异性活性 同一女性皮肤成纤维细胞中的代谢酶。 我们预测，编码该基因的基因存在多态性。 代谢P/5α-DHP的肝外酶及其差异 由此产生的酶活性引起速率的变化(S) P的生物活性代谢物的形成，因此， 经前综合症。P/5α-DHP在人与人之间差异的原因 新陈代谢可以通过体内和体外研究来确定 建议。

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.