Steroid Hormone Action In Female Reproduction

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A part of this project focuses on leiomyomata (fibroids) and examines factors related to their pathogenesis, diagnosis and/or potential treatment. We previously investigated the effect of single doses of the agent on the menstrual cycle in women, and showed that doses of 100 or 200 mg retard folliculogenesis and precipitate menses, in the follicular and luteal phase respectively. Two randomized double-blind placebo-controlled clinical trials from our group showed reduction in fibroid size in women receiving CDB 2914 at a daily dose of 10 or 20 mg for three months, as compared to women receiving placebo. One of these studies showed continued efficacy during a second three-month study. We also are using gene arrays to evaluate the pathophysiology of leiomyomata. To evaluate the role of estradiol in depression, we studied asymptomatic postmenopausal women with past perimenopausal depression (PMD) responsive to hormone therapy and asymptomatic postmenopausal women with no history of depression matched for age, body mass index, and reproductive status who served as controls. After 3 weeks of open-label administration of transdermal estradiol (100 g/d), participants were randomized to a parallel design to receive either estradiol (100 g/d; 27 participants) or matched placebo skin patches (29 participants) for 3 additional weeks under double-blind conditions.None of the women reported depressive symptoms during open-label use of estradiol. Women with past PMD who were crossed over from estradiol to placebo experienced a significant increase in depression symptom severity demonstrated using the Center for Epidemiologic Studies-Depression Scale and 17-item Hamilton Depression Rating Scale, with mean (SD) scores increasing from estradiol (ie, 2.4 2.0 and 3.0 2.5) to placebo (8.8 4.9 and 6.6 4.5, respectively p=.0004 for both). Women with past PMD who continued estradiol therapy and all women in the control group remained asymptomatic. Women in both groups had similar hot-flush severity and plasma estradiol levels during use of placebo.In women with past PMD that was previously responsive to hormone therapy, the recurrence of depressive symptoms during blinded hormone withdrawal suggests that normal changes in ovarian estradiol secretion can trigger an abnormal behavioral state in these susceptible women. To evaluate the role of neurosteroids in mood, we stabilized neurosteroid levels by administering the 5α-reductase inhibitor dutasteride to block conversion of progesterone to its neurosteroid metabolite allopregnanolone in women with premenstrual dysphoric disorder (PMDD) and in asymptomatic control women. Sixteen women with prospectively confirmed PMDD and 16 control women participated in one of two separate randomized, double-blind, placebo-controlled, cross-over trials, each lasting three menstrual cycles. After one menstrual cycle of single-blind placebo, participants were randomized to receive, for the next two menstrual cycles, either double blind placebo or dutasteride (low-dose 0.5 mg/day in the first 8 PMDD and 8 control women or high-dose 2.5 mg/day in the second group of women). All women completed the Daily Rating Form (DRF) and were evaluated in clinic during the follicular and luteal phases of each menstrual cycle. Main outcome measures were the DRF symptoms of irritability, sadness, and anxiety. In the low-dose group, no significant effect of dutasteride on PMDD symptoms was observed compared with placebo (ie, symptom cyclicity maintained), and plasma allopregnanolone levels increased in women with PMDD from follicular to the luteal phases, suggesting the absence of effect of the low-dose dutasteride on 5α-reductase. In contrast, the high-dose group experienced a statistically significant reduction in several core PMDD symptoms (ie, irritability, sadness, anxiety, food cravings and bloating) on dutasteride compared with placebo. Dutasteride had no effect on mood in controls. Thus, stabilization of allopregnanolone levels from the follicular to the luteal phase of the menstrual cycle by blocking the conversion of progesterone to its 5α-reduced neurosteroid metabolite mitigates symptoms in PMDD. These data provide preliminary support for the pathophysiologic relevance of neurosteroids in this condition