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）：我们先前的工作表明，经前烦躁不安障碍（PMDD）的女性可能更容易受到烦躁的情绪状态的影响，这是由于性腺激素及其神经活性代谢产物的变化引起的，而不是由绝对水平的本身所致。拟议的研究的一个目的是确定消除无药丸间隔（PFI）并产生稳定的低内源激素水平的连续口服避孕（OC）方案是否会阻止PMDD症状的表达。第二个目标是证明改变激素会引发PMDD中的情感症状，并确定哪些性腺激素及其神经活性代谢产物与症状有关。具有前瞻性确认PMDD的八十一名妇女将被随机分配，并完成三个，13周的治疗组之一：治疗＃1）连续服用20 ug乙基雌二醇/3mg苯甲苯酮[EE/P]；处理＃2）中断EE/P，在第4、8和12周内将安慰剂代替EE/DRP；治疗＃3）连续安慰剂。主要结局指标将是每天在基线和整个治疗中评估的PMDD症状评分。次要措施将包括回应率，情绪和社会调整量表。血清雌二醇（E2）和P的血清水平以及血浆神经活性类固醇，异源性异烷酮，同倍氢酮，妊娠酚酮和硫酸妊娠硫酸盐的水平，在17、21、21、21、21、21、21、21、21、25，以及在预测中，所有有效的调节剂都将在Prestion中进行样本。 EE/P（ARM＃1）将与PMDD症状相对于预处理水平的显着降低，并且相对于安慰剂和中断EE/P（臂＃2和＃3），在治疗的第2个月和第3个月的症状水平较低有关； 2）用中断的OC治疗的妇女（ARM＃2）将显示出类似于接受安慰剂治疗的女性（ARM＃3）的症状的严重程度，尽管峰症状会转移到卵泡阶段，但主要与PFI期间E2的变化相对应； 3）用中断OC治疗的女性PFI期间E2的增加（ARM＃2）将预测该组症状的发展和严重程度； 4）由于OC抑制了神经类固醇的合成，因此从第17-25天到第2-5天，神经活性类固醇的变化的幅度将预测安慰剂组中的PMDD症状，但在接受OCS治疗的女性（手臂＃1和2）中不会预测。这项研究的结果有望提高我们对PMDD的病理生理学的了解，并有助于阐明女性情感失调的底物。确认荷尔蒙变化在沉淀PMDD中的作用将为未来的研究提出治疗靶标。