EXTRAADRENAL MINERALOCORTICOSTEROID FORMATION-METABOLISM

中华绒毛虫生物活性类固醇激素的腺外形成 等离子体携带的前体被认为是一种重要的 生理学和病理生理学中的内分泌现象 人类的过程。最近发现的最新例子 一种有效的类固醇激素在腺外的形成 组织是脱氧皮质酮(DOC)的生物合成来源 血浆孕酮。人们还认识到，生物活性 类固醇激素可在作用部位的组织中原位形成。 在腺外形成的情况下也是如此。 DOC是因为肾上腺外类固醇21-羟基酶活性 在据信对……有反应的组织中可见 矿物皮质类固醇，如肾脏、皮肤、肠道和淋巴组织 纸巾。唯一的是，等离子体转化的传递常数 黄体酮与DOC在人群中的差异非常显著(20倍或 更多)，但在给定的人中它是时不时地恒定的 与血浆孕酮浓度无关。这些 几个发现支持肾上腺外的可能性 DOC可能通过以下途径在病理生理过程中发挥作用 常规方法难以检测到的机制 确定是否存在矿质皮质类固醇的方法 太过分了。这项研究的长远目标是：(I) 进一步定义DOC、DOC-SO4的来源和代谢 女性中的21-羟基孕烯醇酮(及其硫酸酯)， 男人和人类胎儿，并识别和表征 肾上腺外组织细胞色素P-450(S)催化 孕酮和其他C21-类固醇底物的21-羟基化反应 以及(Ii)评估在肾上腺外形成的DOC的作用 生理或病理生理过程中的组织。致信地址 第一个目标，我们试图确定delta5-3beta- 羟基-C21-类固醇也是血浆前体 肾上腺外21-羟基酶活性以及是否有更多 一种肾上腺外21-羟基酶，例如一种 优先催化Delta4-3-的21-羟基化 酮-C21-类固醇和另一种(或其他)催化21- β-β-羟基-C21-甾体的羟基化。特别是， 我们试图确定DOC-SO4的来源，它存在于 在人类妊娠中浓度很高(但不是源于 血浆DOC)，并确定是否Delta5-3-Delta-羟基- C21-类固醇可作为血浆来源的前体 男性和绝经后女性的肾上腺外DOC。致信地址 第二个目标，我们建议排卵期的女性是理想的 由于循环、可预测和引人注目的原因，可供研究的模型 卵巢中孕酮产生的变化 周而复始。不同人群肾上腺外DOC形成的差异 排卵的女性可能是选择的差异的根本原因 女性在经前阶段的反应 卵巢周期的周期。特别是，我们问是否有一个角色 肾上腺外DOC在经前期发病机制中的作用 综合症。

The extraglandular formation of bioactive steroid hormones from plasma-borne precursors is recognized as an important endocrinologic phenomenon in physiologic and pathophysiologic processes in humans. The most recently discovered example of the formation of a potent steroid hormone in extraglandular tissues is the biosynthesis of deoxycorticosterone (DOC) from plasma progesterone. It also is recognized that biologically active steroid hormones may be formed in situ in tissue sites of action. This also is true in the case of the extraglandular formation of DOC because extraadrenal steroid 21-hydroxylase activity is demonstrable in tissues believed to be responsive to the action of mineralocorticosteroids, e.g., kidney, skin intestine, and lymphoid tissues. Uniquely, the transfer constant of conversion of plasma progesterone to DOC among persons varies strikingly (20-fold or more), but it is constant in a given person from time-to-time irrespective of the plasma concentration of progesterone. These several findings are supportive of the possibility that extraadrenal DOC may serve a role in pathophysiological processes through mechanisms that would be difficult to detect by conventional means of ascertaining the existence of mineralocorticosteroid excess. The long-range goals of the research proposed are (i) to define further the origin and metabolism of DOC, DOC-SO4, and 21-hydroxypregnenolone (and sulfate esters thereof) in women, men, and the human fetus and to identify and characterize the cytochrome P-450(s) of extraadrenal tissues that catalyzes the 21-hydroxylation of progesterone and other C21-steroid substrates and (ii) to evaluate the role of DOC that is formed in extraadrenal tissues on physiologic or pathophysiologic processes. To address the first goal, we seek to ascertain whether delta5-3beta- hydroxy-C21-steroids also serve as plasma precursors for extraadrenal 21-hydroxylase activity and whether there is more than one extraadrenal 21-hydroxylase enzyme, for example, one that preferentially catalyzes the 21-hydroxylation of delta4-3- keto-C21-steroids and another (or other) that catalyzes the 21- hydroxylation of delta-3beta-hydroxy-c21-steroids. In particular, we seek to identify the source of DOC-SO4, which is present in high concentration in human pregnancy (but is not derived from plasma DOC), and to ascertain whether delta5-3delta-hydroxy- C21-steroids can serve as plasma-borne precursors of extraadrenal DOC in men and postmenopausal women. To address the second goal, we suggest that ovulatory women are ideal models for study because of cyclic, predictable, and striking changes in progesterone production that occur during the ovarian cycle. Variations in extraadrenal DOC formation among ovulatory women may be fundamental to differences in selected responses that women experience during the premenstrual phase of the ovarian cycle. In particular, we ask whether there is a role for extraadrenal DOC in the pathogenesis of the premenstrual syndrome.