Role of Serotonin in Mediating Stress-Induced Infertility

描述（由申请人提供）：这项资助的总体目标是继续我们的研究，以确定日常生活压力（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，全年的月经周期为28天，它们对压力的反应存在个体差异，压力敏感型动物迅速发展为压力引起的生殖功能障碍，而压力复原型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模式是根据功能性下丘脑闭经（FHA；一种临床上占女性不孕症30%的情况）的女性记录的，在这种情况下，猴子暴露于轻度心理压力（搬到一个新的房间）和中度代谢压力（卡路里摄入量减少20%，每周5天，每天适度跑步一小时）。到目前为止，我们已经在非压力条件下研究了猴子。我们发现，应激敏感猴的生理5 -羟色胺释放较低，中枢5 -羟色胺能系统功能下调[表现为色氨酸羟化酶（THP） 2基因表达较低，5 -羟色胺转运体（SERT）基因表达较低，5HT-1A受体基因表达较低，降解5 -羟色胺基因（MAO-A和MAO-B）表达较低]，下丘脑5HT2A和2C受体表达上调。与更能适应压力的动物相比。我们有初步的数据显示，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。在这项拨款申请中，我们将测试SSRI治疗是否可以预防应激性生殖轴抑制，从而可能成为治疗应激性不孕症的新疗法。我们将检查中枢神经系统在SSRI治疗中发生的变化。我们还将进行一项小规模的试点临床研究，以确定SSRI治疗FHA女性是否能够增加生殖激素分泌。博士之间的合作。Cameron， Bethea和Berga代表了一个独特的机会来测试这种潜在的FHA新疗法，既可以在适当的动物模型中检查神经系统，也可以在一个小型的试点临床研究中进行。

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.