EFFECT OF SRIs ON GONADAL STEROIDS

描述（由申请人提供）：该R21申请旨在研究一种新的假设：5-羟色胺再摄取抑制剂（SRI）抗抑郁药抑制性腺类固醇激素的产生。我们有初步证据表明，SRI治疗降低了类固醇激素17-OH双烯醇酮和17 α-OH孕酮的循环水平，它们是性腺类固醇合成途径中的中间前体，并且SRI治疗还可以降低下游雄激素DHEA和雄烯二酮的水平。为了证实该试验数据并开始确定该作用是否是SRI的特异性特征，将在健康志愿者女性中比较用SRI氟西汀长期治疗对性腺类固醇前体激素17 α-OH阿替诺龙的作用与非SRI安非他酮的作用。 作为性腺类固醇活性的潜在功能测定，我们还将比较氟西汀和安非他酮对同一组健康女性性功能的影响，并调查循环17-OH双烯醇酮水平的变化是否与抗抑郁药治疗期间性功能的变化有关。很少有研究性腺类固醇激素活性的变化是否在SRI治疗期间的性副作用的病理生理学中发挥作用，或者性副作用的严重程度是否在月经周期中变化。本研究将使用健康女性志愿者，以避免精神疾病对性功能以及下丘脑-垂体-肾上腺和卵巢轴活性的混杂影响。受试者将接受一个月的基线激素采样，然后随机接受两个月的氟西汀或安非他酮治疗。在研究的所有三个月内，将在月经周期的三个阶段（卵泡早期、排卵期、黄体中期）进行血样采集和性功能评估。 本研究旨在扩大我们对SRI作用机制的理解。如果氟西汀而不是安非他酮治疗与循环中17-OH双烯醇酮水平的降低相关，则将在未来的研究中检查这种效应对SRI治疗PMDD和OCD的不同临床疗效的潜在重要性。这项研究也可能导致PMDD和OCD的神经基础治疗的发展。目前，对于30%对SRI治疗无反应的PMDD和OCD受试者，几乎没有替代的药理学策略。

DESCRIPTION (provided by applicant): This R21 application is intended to investigate a novel hypothesis: that serotonin reuptake inhibitor (SRI) antidepressants suppress production of gonadal steroid hormones. We have preliminary evidence that SRI treatment reduces circulating levels of the steroid hormones 17-OH pregnenolone and 17a-OH progesterone which are intermediary precursors in the gonadal steroid synthesis pathway, and that SRI treatment may also reduce levels of the downstream androgenic hormones DHEA and androstenedione. To confirm this pilot data and to begin to determine whether this effect is a specific characteristic of SRIs, the effect of chronic treatment with an SRI, fluoxetine, on the gonadal steroid precursor hormone 17a-OH pregnenolone will be compared to the effect of a non-SRI, bupropion, in healthy volunteer women. As a potential functional assay of gonadal steroid activity, we will also compare the effects of fluoxetine and bupropion on sexual functioning in the same group of healthy women, and investigate whether changes in circulating 17-OH pregnenolone levels are related to changes in sexual function during antidepressant treatment. There has been little study of whether changes in gonadal steroid hormone activity play a role in the pathophysiology of sexual side effects during SRI treatment, or whether severity of sexual side effects varies across the menstrual cycle. Healthy female volunteers will be used for this study to avoid the confounding effects of psychiatric illness on sexual function and on the activity of the hypothalamic-pituitary-adrenal and ovarian axes. Subjects will undergo one month of baseline hormonal sampling and then will be randomized to two months of treatment with either fluoxetine or bupropion. Blood sampling and sexual function assessments will occur in three phases of the menstrual cycle (early follicular, ovulatory, mid-luteal) in all three months of the study. This study is intended to expand our understanding of the mechanism of action of SRIs. If fluoxetine, but not bupropion treatment, is associated with a reduction in circulating levels of 17-OH pregnenolone, the potential importance of this effect to the distinct clinical efficacy of SRIs for PMDD and OCD will be examined in future studies. This research also may lead to development of hormonally based treatments for PMDD and OCD. Currently, for the 30% of subjects with PMDD and OCD who do not respond to SRI treatment, there are few, if any, alternative pharmacologic strategies.