Androgen Hormones in PMDD

描述（由申请人提供）：经前焦虑障碍是一种复杂的情绪和身体症状，影响5-8%的绝经前妇女。由于症状仅限于月经周期的黄体期，因此周期中生殖激素的变化被认为会引发症状。然而，激素波动产生PMDD症状的机制仍不清楚。到目前为止，很少有研究的作用，雄激素在PMDD。虽然雄激素的循环水平在黄体期不会上升，但雄激素前体，包括孕酮和炔雌醇酮，在黄体期确实会上升，并且可以在大脑和其他组织中转化为雄激素。PMDD患者对局部合成雄激素的敏感性增加可能导致几种突出的PMDD症状，包括易怒、情绪不稳定和腹胀。在这项R34探索性治疗开发申请中，我们建议通过进行初步治疗疗效研究来阐明雄激素在PMDD中的作用。将在一项安慰剂对照研究中检测特异性雄激素受体拮抗剂氟替卡松治疗PMDD的疗效。将招募64名符合DSM-IV PMDD标准的受试者，并通过两个月的前瞻性每日评级进行确认。受试者将随机接受两个月的氟替卡松或安慰剂治疗。这项研究将能够确定这种治疗的效应量，这对于设计更大规模的临床试验是必要的，并且还将提供关于这种治疗的耐受性的数据。如果有初步证据表明这种抗雄激素治疗有效，并且治疗耐受性良好，将计划进行全面的临床试验。如果治疗显示出疗效证据，但耐受性不佳，将研究阻断雄激素活性的替代方法。这项研究也将提供证据，是否雄激素，通过雄激素受体的作用，在PMDD的病理生理学中发挥作用。

DESCRIPTION (provided by applicant): Premenstrual dysphoric disorder is a disabling complex of mood and physical symptoms that affects 5-8% of premenopausal women. Because symptoms are limited to the luteal phase of the menstrual cycle, fluxes in reproductive hormones during the cycle are thought to precipitate symptoms. However, the mechanisms through which hormonal fluctuations produce symptoms of PMDD remain unclear. To date, there has been little study of the role of androgen hormones in PMDD. Although circulating levels of androgen hormones do not rise in the luteal phase, androgen precursors, including progesterone and pregnenolone, do rise in the luteal phase and can be converted to androgens in brain and other tissues. Increased sensitivity to locally synthesized androgens in women with PMDD could lead to several prominent PMDD symptoms, including irritability, mood lability, and bloating. In this R34 exploratory treatment development application, we propose to clarify the role of androgen hormones in PMDD by conducting a pilot treatment efficacy study. The efficacy of a specific androgen receptor antagonist, flutamide, for treatment of PMDD will be tested in a placebo-controlled study. 64 subjects will be recruited who meet DSM-IV criteria for PMDD, confirmed by two months of prospective daily ratings. Subjects will be randomized to two months of treatment with either flutamide or placebo. This study will enable determination of an effect size for this treatment, which is necessary for design of a larger scale clinical trial, and will also provide data regarding the tolerability of this treatment. If there is preliminary evidence of efficacy of this anti-androgen treatment, and the treatment is well-tolerated, a full-scale clinical trial will be planned. If the treatment shows evidence of efficacy, but is not well-tolerated, alternative methods of blocking androgen hormone activity will be investigated. This study will also provide evidence as to whether androgen hormones, acting through androgen receptors, play a role in the pathophysiology of PMDD.