Role of Serotonin in Mediating Stress-Induced Infertility

血清素在调节压力引起的不孕症中的作用

• 批准号: 8294451
• 负责人: JUDY L CAMERON
• 金额: $ 45.55万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-10 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294451
• 关键词: Accounting; Address; Adult; Amenorrhea; Animal Model; Animals; Anxiety; Applications Grants; Autoreceptors; Behavior Disorders; CRH gene; Citalopram; Clinical; Clinical Research; Collaborations; Data; Diet; Down-Regulation; Eating; Estradiol; Female; Female infertility; Fertility; Functional disorder; Funding; Gene Expression; Goals; Grant; Hour; Hypothalamic structure; Impairment; Incidence; Individual Differences; Infertility; Intake; Life Stress; Macaca fascicularis; Mediating; Menstrual cycle; Metabolic stress; Modeling; Moderate Exercise; Molecular; Monkeys; Monoamine Oxidase A; Monoamine Oxidase B; National Institute of Child Health and Human Development; Neurons; Oregon; Ovarian; Pattern; Periodicity; Physiological; Pilot Projects; Pituitary Gland; Primates; Progesterone; Psychological Stress; Psychometrics; Receptor Gene; Reproduction; Reproductive Physiology; Research; Role; Running; Selective Serotonin Reuptake Inhibitor; Serotonin; Stimulus; Stress; System; TDO2 gene; Testing; Therapeutic; Therapeutic Effect; Tryptophan 5-monooxygenase; Up-Regulation; Woman; Work; common treatment; experience; functional hypothalamic amenorrhea; median eminence; neural circuit; neurochemistry; nonhuman primate; novel; prevent; programs; public health relevance; raphe nuclei; receptor; relating to nervous system; reproductive; reproductive axis; reproductive function; reproductive hormone; response; reuptake; serotonin transporter

DESCRIPTION (provided by applicant): The overall goal of this grant is to continue our studies to determine the mechanisms by which common life stresses (i.e., dieting, moderate exercise and psychological stress) impair activity of the reproductive axis and fertility. Female cynomolgus monkeys, which like women have 28-day menstrual cycles throughout the year, show individual differences in responsiveness to stress, with stress-sensitive animals rapidly developing stress-induced reproductive dysfunction, and stress-resilient animals maintaining normal menstrual cyclicity throughout stress exposure. The stress used for these studies is patterned after that documented in women with Functional Hypothalamic Amenorrhea (FHA; a clinical condition which accounts for as much as 30% of female infertility) in which monkeys are exposed to a mild psychological stress (moving to a new room) and a moderate metabolic stress (a 20% decrease in calorie intake and moderate running for an hour a day, 5 days a week). To date, we have studied monkeys in non-stressed conditions. We have found that stress-sensitive monkeys have lower physiological release of serotonin, a down regulation of function in the central serotonergic system [as indicated by lower tryptophan hydroxylase (THP) 2 gene expression, less serotonin transporter (SERT) gene expression, less 5HT-1A receptor gene expression, and less expression of genes degrading serotonin (MAO-A and MAO-B)], as well as an up-regulation of 5HT2A and 2C receptors in the hypothalamus, compared to more stress-resilient animals. We have preliminary data showing that treatment of stress-sensitive monkeys in a nonstressed condition with a serotonin reuptake inhibitor (SSRI) increases reproductive hormone secretion in a normal menstrual cycle. In this grant application we will test whether SSRI treatment can prevent stress-induced suppression of the reproductive axis and thus may be a novel therapy for treatment of stress-induced infertility. We will examine changes in central neural systems that occur with SSRI therapy. We will also run a small pilot clinical study to determine if SSRI therapy in women with FHA is able to increase reproductive hormone secretion. This collaboration between Drs. Cameron, Bethea and Berga represents an unique opportunity to test this potential new therapy for FHA both in an appropriate animal model in which we can examine neural systems, and in a small pilot clinical study. PUBLIC HEALTH RELEVANCE: Functional Hypothalamic Amenorrhea is a clinical condition that accounts for as much as 30% of female infertility. This project is testing a new potential treatment for FHA, a form of infertility due to sensitivity to life stresses, in female monkeys with a small pilot project in women with FHA. This treatment involves treatment with a serotonin reuptake inhibitor, a common treatment for anxiety.

描述（由申请人提供）：这笔赠款的总体目标是继续我们的研究，以确定常见生活压力（即节食、适度运动和心理压力）损害生殖轴活动和生育能力的机制。雌性食蟹猴与女性一样，全年有 28 天的月经周期，对压力的反应表现出个体差异，压力敏感的动物会迅速发展出压力引起的生殖功能障碍，而压力恢复的动物在整个压力暴露过程中都保持正常的月经周期。这些研究中使用的压力是根据患有功能性下丘脑闭经（FHA；一种临床病症，导致女性不孕症的 30%）的女性记录的压力模式，其中猴子承受轻度心理压力（搬到新房间）和中度代谢压力（卡路里摄入量减少 20%，每周 5 天、每天 1 小时适度跑步）。迄今为止，我们已经在无压力条件下研究了猴子。我们发现，应激敏感猴的血清素生理释放量较低，中枢血清素能系统功能下调[如色氨酸羟化酶 (THP) 2 基因表达较低、血清素转运蛋白 (SERT) 基因表达较少、5HT-1A 受体基因表达较少以及降解血清素的基因（MAO-A 和 MAO-B）表达较少]， 与更具抗压能力的动物相比，下丘脑中 5HT2A 和 2C 受体的上调。我们的初步数据表明，在非应激条件下用血清素再摄取抑制剂（SSRI）治疗应激敏感的猴子可以增加正常月经周期中生殖激素的分泌。在本次拨款申请中，我们将测试 SSRI 治疗是否可以预防压力引起的生殖轴抑制，因此可能是治疗压力引起的不孕症的一种新疗法。我们将检查 SSRI 治疗中枢神经系统的变化。我们还将进行一项小型试点临床研究，以确定 FHA 女性的 SSRI 治疗是否能够增加生殖激素的分泌。博士之间的合作。 Cameron、Bethea 和 Berga 提供了一个独特的机会，可以在适当的动物模型（我们可以在其中检查神经系统）和小型试点临床研究中测试这种潜在的 FHA 新疗法。 公众健康相关性：功能性下丘脑闭经是一种临床病症，占女性不孕症的 30%。该项目正在雌性猴子身上测试一种针对 FHA 的新潜在治疗方法，FHA 是一种由于对生活压力敏感而导致的不孕症，并在患有 FHA 的女性中进行了一个小型试点项目。这种治疗涉及使用血清素再摄取抑制剂进行治疗，这是治疗焦虑症的常见方法。