Role of Serotonin in Mediating Stress-Induced Infertility

描述(申请人提供)：这笔赠款的总体目标是继续我们的研究，以确定共同的生活压力(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。雌性食蟹猴和女性一样，一年有28天的月经周期，在对压力的反应方面表现出个体差异，压力敏感型动物迅速发展为应激诱导的生殖功能障碍，而具有压力弹性的动物在压力暴露期间保持正常的月经周期。这些研究中使用的压力是以功能性下丘脑闭经(FHA；一种临床症状，占女性不孕症的30%)女性为研究对象的模式，在这些患者中，猴子面临轻度心理压力(搬到新房间)和中度代谢压力(卡路里摄入量减少20%，每天适度跑步一小时，一周五天)。到目前为止，我们已经在非压力条件下对猴子进行了研究。我们发现，与更具应激适应能力的动物相比，应激敏感猴子的5-羟色胺生理性释放较低，中枢5-羟色胺能系统功能下调[色氨酸羟基酶(THP)2基因表达较低，5-羟色胺转运体(SERT)基因表达较少，5-HT-1A受体基因表达较少，5-羟色胺降解基因(MAO-A和MAO-B)表达较少]，下丘脑5HT2A和2C受体表达上调。我们有初步数据表明，在正常月经周期中，用5-羟色胺再摄取抑制剂(SSRI)治疗非应激条件下的应激敏感猴子会增加生殖激素的分泌。在这项赠款申请中，我们将测试SSRI治疗是否可以防止应激导致的生殖轴抑制，从而可能成为治疗应激诱导的不孕不育的一种新疗法。我们将检查SSRI治疗中发生的中枢神经系统的变化。我们还将进行一项小型试验性临床研究，以确定SSRI治疗FHA女性是否能够增加生殖激素的分泌。卡梅隆博士、贝西娅博士和贝尔加博士之间的合作代表着一个独特的机会，可以在适当的动物模型(我们可以在其中检查神经系统)和小型先导性临床研究中测试这种潜在的FHA新疗法。 公共卫生相关性：功能性下丘脑闭经是一种临床症状，占女性不孕症的30%。该项目正在对患有FHA的女性进行一项小型试点项目，以测试FHA的一种新的潜在治疗方法。FHA是一种由于生活压力敏感而导致的不孕不育形式。这种治疗包括使用5-羟色胺再摄取抑制剂治疗，这是一种治疗焦虑的常见方法。

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.