Steroid Hormone Action In Female Reproduction

类固醇激素在女性生殖中的作用

• 批准号: 9150061
• 负责人: Lynnette Nieman
• 金额: $ 7.23万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9150061
• 关键词: Affective Symptoms; Age; Allopregnanolone; Anxiety; Behavioral; Biological Markers; Blinded; Body mass index; Clinic; Control Groups; Controlled Clinical Trials; Cross-Over Trials; Data; Depressed mood; Development; Diagnosis; Dose; Double-Blind Method; Dutasteride; Endometrium; Epidemiologic Studies; Estradiol; Female; Fibroid Tumor; Functional disorder; Genes; Genetic Crossing Over; Genetic Markers; Gonadal Steroid Hormones; Growth; Hamilton Rating Scale for Depression; Hormones; Hot flushes; Leiomyoma; Luteal Phase; Maintenance; Menstrual cycle; Menstruation; Mental Depression; Moods; Outcome Measure; Ovarian; Oxidoreductase; Participant; Pathogenesis; Perimenopause; Periodicity; Physiological; Placebo Control; Placebos; Plasma; Play; Postmenopause; Pregnancy; Progesterone; Quality of life; Randomized; Recording of previous events; Recurrence; Reporting; Reproduction; Role; Severities; Single-Blind Study; Symptoms; Transdermal substance administration; Withdrawal; Woman; Women' s Group; depressive symptoms; design; experience; folliculogenesis; food craving; hormone therapy; implantation; inhibitor/antagonist; neurosteroids; open label; premenstrual dysphoric disorder; proliferative phase Menstrual cycle; randomized placebo controlled trial; receptor; reproductive; secondary outcome; skin patch; steroid hormone; trial design

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

该项目的一部分侧重于平滑肌瘤（肌瘤），并研究了与其发病机理，诊断和/或潜在治疗有关的因素。 我们先前先前研究了单剂量的剂对女性月经周期的影响，并表明在卵泡和黄体期中，分别在100或200 mg延迟卵泡发生和沉淀月经的剂量。 与接受安慰剂的妇女相比，我们组的两项随机双盲安慰剂控制的临床试验显示，接受CDB 2914的女性的肌瘤大小降低了三个月，持续了三个月。其中一项研究表明，在第二次三个月的研究中持续疗效。我们还使用基因阵列来评估平滑肌的病理生理学。 为了评估雌二醇在抑郁症中的作用，我们研究了对激素治疗有效的绝经后妇女（PMD），对激素疗法有反应和无症状的绝经后妇女，其抑郁症没有抑郁史，伴有年龄，体重指数和繁殖状态的抑郁症患者。经过3周的透皮雌二醇（100 g/d）开放标签后，参与者被随机分配给平行设计，以接收雌二醇（100 g/d; 27名参与者）或匹配的安慰剂皮肤贴剂（29名参与者）（29个参与者）在双盲状态下又有3周的另外3周。过去从雌二醇到安慰剂的妇女使用流行病学研究 - 抑郁量表和17个Intem Hamilton抑郁评分量表的抑郁症状严重程度显着增加，平均值（SD）得分从雌二醇（IE，2.4 2.0和3.0 2.5）到8.8 4.9 4.5和6.6 4.5，平均值（SD）分数增加。过去的PMD妇女继续雌二醇治疗，对照组中的所有女性仍然无症状。两组中的女性在使用安慰剂期间都有相似的热液液严重程度和血浆雌二醇水平。在过去的PMD女性中对激素疗法有反应，在盲激素戒断期间抑郁症状的复发表明，卵巢雌二醇分泌的正常变化会触发这些敏感女性的异常行为状态。 为了评估神经类固醇在情绪中的作用，我们通过施用5α-还原酶抑制剂Dutasteride来稳定神经类固醇水平，以阻止孕激素向其神经类固醇代谢产物异源性雌激素的转化率，并在具有过症的女性膜质障碍（PMDD）和无症状对照女性中。有16名具有前瞻性确认PMDD和16名对照妇女的妇女参加了两个单独的随机，双盲，安慰剂对照的交叉试验之一，每个试验持续了三个月经周期。经过一个单盲安慰剂的月经周期后，参与者被随机接收，在接下来的两个月经周期中，即双盲安慰剂或Dutasteride（前8个PMDD中的低剂量0.5 mg/天，以及8个对照女性或高剂量的女性或高剂量2.5 mg/day，第二组女性）。所有妇女均完成了每日评级表（DRF），并在每个月经周期的卵泡和黄体阶段进行了诊所评估。主要结果指标是DRF易怒，悲伤和焦虑的症状。在低剂量组中，与安慰剂（IE，维持症状循环性）相比，未观察到Dutasteride对PMDD症状的显着影响，并且PMDD女性的血浆异源性水平增加了卵泡阶段，这表明低剂量荷兰氏菌对5α-雷神酶的作用缺乏效应。相比之下，与安慰剂相比，高剂量组的几种核心PMDD症状（即烦躁，悲伤，焦虑，焦虑，食物渴望和腹胀）的统计学显着降低。 Dutasteride对控件中的情绪没有影响。因此，通过阻止孕酮向其5α还原神经类固醇代谢产物的转化来减轻PMDD的症状，从卵泡稳定到月经周期的黄体阶段。这些数据在这种情况下为神经类固醇的病理生理相关性提供了初步支持

项目成果

Endometrial Indian hedgehog expression is decreased in women with endometriosis.

患有子宫内膜异位症的女性子宫内膜 Indian Hedgehog 表达降低。

• DOI: 10.1016/j.fertnstert.2011.05.018
• 发表时间: 2011
• 期刊: Fertility and sterility
• 影响因子: 6.7
• 作者: Smith,Kathryn;Alnifaidy,Redab;Wei,Qingxiang;Nieman,LynnetteK
• 通讯作者: Nieman,LynnetteK

Endometrial effects of a single early luteal dose of the selective progesterone receptor modulator CDB-2914.

• DOI: 10.1016/j.fertnstert.2008.12.057
• 发表时间: 2010-04
• 期刊: Fertility and sterility
• 影响因子: 6.7
• 作者: Stratton P;Levens ED;Hartog B;Piquion J;Wei Q;Merino M;Nieman LK
• 通讯作者: Nieman LK

Novel hormone treatment of benign metastasizing leiomyoma: an analysis of five cases and literature review.

• DOI: 10.1016/j.fertnstert.2013.01.147
• 发表时间: 2013-06
• 期刊: FERTILITY AND STERILITY
• 影响因子: 6.7
• 作者: Lewis, Erin I.;Chason, Rebecca J.;DeCherney, Alan H.;Armstrong, Alicia;Elkas, John;Venkatesan, Aradhana M.
• 通讯作者: Venkatesan, Aradhana M.

Efficacy and tolerability of CDB-2914 treatment for symptomatic uterine fibroids: a randomized, double-blind, placebo-controlled, phase IIb study.

• DOI: 10.1016/j.fertnstert.2010.09.059
• 发表时间: 2011-02
• 期刊: FERTILITY AND STERILITY
• 影响因子: 6.7
• 作者: Nieman, Lynnette K.;Blocker, Wendy;Nansel, Tonja;Mahoney, Sheila;Reynolds, James;Blithe, Diana;Wesley, Robert;Armstrong, Alicia
• 通讯作者: Armstrong, Alicia

Magnetic resonance imaging and transvaginal ultrasound for determining fibroid burden: implications for research and clinical care.

• DOI: 10.1016/j.ajog.2008.12.037
• 发表时间: 2009-05
• 期刊: AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
• 影响因子: 9.8
• 作者: Levens, Eric D.;Wesley, Robert;Premkumar, Ahalya;Blocker, Wendy;Nieman, Lynnette K.
• 通讯作者: Nieman, Lynnette K.