Continuous OC Treatment in PMDD: Steroid Hormone Mechanisms

描述（由申请人提供）：我们之前的工作表明，经前焦虑障碍（PMDD）女性可能更容易受到由性腺激素及其神经活性代谢物变化引起的焦虑情绪状态的影响，而不是由绝对水平本身引起的。这项研究的目的之一是确定一个连续的口服避孕药（OC）方案，消除无药丸间隔（PFI），并产生稳定的，低内源性激素水平将防止PMDD症状的表达。第二个目标是证明激素的变化触发PMDD的情感症状，并确定哪些性腺激素及其神经活性代谢物与症状相关。将81名具有前瞻性证实的PMDD的女性随机化并完成三个13周治疗组中的一个：治疗#1）连续施用20 μ g炔雌醇/3 mg屈螺酮[EE/P];治疗#2）中断EE/P，在第4、8和12周期间用安慰剂代替EE/DRP;治疗#3）连续安慰剂。主要结果测量将是在基线和整个治疗期间每天评估的PMDD症状总评分。次要指标包括反应率、情绪和社会适应量表。雌二醇（E2）和P的血清水平，以及神经活性类固醇、别孕烯醇酮、别四氢DOC、孕烯醇酮和硫酸双烯醇酮（GABAa受体的所有有效调节剂）的血浆水平将在预处理时的周期第17、21、25、2和5天以及治疗第3个月期间取样。主要预测是：1）相对于治疗前水平，持续EE/P（第1组）将与PMDD症状显着减轻相关，并且与安慰剂和中断EE/P相比，治疗第2个月和第3个月的症状水平较低相关（2号和3号臂）; 2）用中断OC治疗的女性（组#2）将显示与用安慰剂治疗的女性（组#3）相似的症状严重性，并且将继续显示症状的周期性，尽管峰值症状将转移到卵泡期，主要对应于PFI期间诱导的E2的变化; 3）在接受中断OC治疗的女性（组#2）中，PFI期间E2的增加将预测该组中症状的发展和严重程度;和4）由于OC抑制神经类固醇的合成，从第17 - 25天到第2- 5天神经活性类固醇的变化幅度将预测安慰剂组中的PMDD症状，但在用OC治疗的妇女（组#1和组#2）中不能预测。本研究的结果有望推进我们对PMDD病理生理学的认识，并有助于阐明女性情感失调的底物。激素变化在PMDD诱发中的作用的确认将为未来的研究提供治疗靶点。

DESCRIPTION (provided by applicant): Our prior work indicates that women with premenstrual dysphoric disorder (PMDD) may be more vulnerable to dysphoric mood states induced by changes in gonadal hormones and their neuroactive metabolites, and not resulting from absolute levels per se. One objective of the proposed research is to determine if a continuous oral contraceptive (OC) regimen that eliminates the pill free interval (PFI) and produces stable, low endogenous hormone levels will prevent the expression of PMDD symptoms. A second objective is to demonstrate that changing hormones trigger affective symptoms in PMDD, and to establish which gonadal hormones and their neuroactive metabolites are associated with symptoms. Eighty one women with prospectively confirmed PMDD will be randomized and complete one of three, 13 week treatment arms: Treatment #1) continuous administration of 20 ug ethinyl estradiol/3mg drospirenone [EE/P]; Treatment #2) interrupted EE/P, substituting placebo for EE/DRP during weeks 4, 8, & 12; Treatment #3) continuous placebo. The primary outcome measure will be the total PMDD symptom score assessed daily at baseline and throughout the treatments. Secondary measures will include Response Rate, mood and social adjustment scales. Serum levels of estradiol (E2) and P, as well as plasma levels of neuroactive steroids, allopregnanolone, allotetrahydroDOC, pregnanolone and pregnenolone sulfate, all potent modulators of the GABAA receptor will be sampled on cycle days 17, 21, 25, 2, & 5 at pretreatment and also during treatment month 3. Primary predictions are: 1) Continuous EE/P (arm #1) will be associated with a significant reduction in PMDD symptoms relative to pretreatment levels, and will be associated with lower symptom levels in months 2 and 3 of treatment relative to both placebo and interrupted EE/P (arms #2 and #3); 2) Women treated with interrupted OC (arm #2) will show symptom severity similar to women treated with placebo (arm #3), and will continue to show cyclicity of symptoms though there will be a shift in peak symptoms to the follicular phase, corresponding primarily to the changes in E2 induced during the PFI; 3) the increase in E2 during the PFI in women treated with interrupted OC (arm #2) will predict the development and severity of symptoms in that group; and 4) since OCs suppress the synthesis of neurosteroids, the magnitude of the change in neuroactive steroids from days 17 - 25 to days 2- 5 will predict PMDD symptoms in the placebo group, but not in the women treated with OCs (arms #1 and #2). The results of this study are expected to advance our knowledge on the pathophysiology of PMDD and help illuminate a substrate for affective dysregulation in women. Confirmation of the role of hormonal change in precipitating PMDD will suggest therapeutic targets for future research.