Continuous OC Treatment in PMDD: Steroid Hormone Mechanisms

经前抑郁症 (PMDD) 的持续 OC 治疗：类固醇激素机制

• 批准号: 7656813
• 负责人: SUSAN S. GIRDLER
• 金额: $ 53.88万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-11 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7656813
• 关键词: Address; Affective; Affective Symptoms; Age; Allopregnanolone; Animals; Anti-Anxiety Agents; Anxiety; Appearance; Back; Beck depression inventory; Behavior; Contraceptive Usage; Controlled Study; Data; Development; Diagnosis; Disease; Disease remission; Dose; Double-Blind Method; Effectiveness; Estradiol; Ethinyl Estradiol; Exhibits; Exposure to; Figs - dietary; Functional disorder; Future; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Hormonal; Hormonal Change; Hormones; Human; Impairment; Intervention; Knowledge; Low Dose Oral Contraceptives; Luteal Phase; Measures; Menstrual cycle; Modeling; Mood Disorders; Moods; Morbidity - disease rate; Names; Oral Contraceptives; Outcome Measure; Ovarian; Ovarian Ablation; Periodicity; Peripheral; Placebo Effect; Placebos; Plasma; Precipitation; Pregnanolone; Premenstrual Tension; Progesterone; Protocols documentation; Public Health; Publishing; Randomized; Rattus; Regulation; Relative (related person); Reporting; Research; Role; Sampling; Serum; Severities; Social Adjustment; Steroids; Symptoms; Syndrome; Treatment Efficacy; Treatment Protocols; Upper arm; Withdrawal; Woman; Work; base; clinical efficacy; drospirenone; effective therapy; efficacy testing; experience; functional disability; neurosteroids; open label; pill; pregnenolone sulfate; premenstrual dysphoric disorder; prevent; primary outcome; proliferative phase Menstrual cycle; prospective; receptor; reproductive; reproductive hormone; response; secondary outcome; steroid hormone; tetrahydrodeoxycorticosterone; therapeutic target; time use

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.

描述（由申请人提供）：我们之前的工作表明，患有经前烦躁不安障碍（PMDD）的女性可能更容易受到性激素及其神经活性代谢物变化引起的烦躁情绪状态，而不是由绝对水平本身引起的。拟议研究的一个目的是确定持续口服避孕药（OC）方案是否消除无药间隔（PFI）并产生稳定的低内源性激素水平，以防止经前抑郁症状的表达。第二个目标是证明激素的变化会触发经前抑郁症的情感性症状，并确定哪些性激素及其神经活性代谢物与症状有关。81名确诊为经前抑郁症的女性将被随机分配并完成三个为期13周的治疗组之一：治疗组1)持续给予20 ug炔雌醇/3mg屈螺酮[EE/P]；治疗2)中断EE/P，在第4、8和12周用安慰剂代替EE/DRP；治疗方案3：持续安慰剂。主要结果测量将是每日在基线和整个治疗期间评估的经前不悦症总症状评分。次要测量包括反应率、情绪和社会适应量表。血清雌二醇（E2）和P的水平，以及血浆中神经活性类固醇、异孕酮、异四氢doc、孕酮和硫酸孕烯醇酮的水平，以及GABAA受体的所有有效调节剂，将在治疗前的第17、21、25、2和5天以及治疗第3个月取样。主要预测是：1)与预处理水平相比，持续的EE/P（第1组）将与经前抑郁症状的显著减少相关，并且与安慰剂和中断的EE/P（第2组和第3组）相比，治疗的第2和第3个月的症状水平较低相关；2)接受中断OC治疗的女性（第2组）将表现出与接受安慰剂治疗的女性（第3组）相似的症状严重程度，并且将继续表现出症状的周期性，尽管症状高峰将转移到卵泡期，主要与PFI期间诱导的E2变化相对应；3)接受中断性OC治疗的女性在PFI期间E2的升高（第2组）将预测该组症状的发展和严重程度；4)由于OCs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可以预测安慰剂组的经前抑郁症状，但不能预测接受OCs治疗的妇女（第1组和第2组）。这项研究的结果有望提高我们对经前不悦症病理生理学的认识，并有助于阐明女性情感失调的基础。确认激素变化在诱发经前不悦症中的作用将为今后的研究提供治疗靶点。