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）：这项资助的总体目标是继续我们的研究，以确定共同生活压力的机制（即，节食、适度运动和心理压力）损害生殖轴的活动和生育能力。雌性食蟹猴和女性一样，一年中有28天的月经周期，它们对压力的反应存在个体差异，压力敏感的动物会迅速发展出压力诱导的生殖功能障碍，而压力适应性强的动物在整个压力暴露过程中保持正常的月经周期。用于这些研究的压力模式是在患有功能性下丘脑闭经（FHA;一种占女性不孕症30%的临床病症）的女性中记录的，其中猴子暴露于轻度心理压力（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，每天适度跑步1小时）。到目前为止，我们已经研究了非应激条件下的猴子。我们已经发现，应激敏感的猴子具有较低的5-羟色胺生理释放，中枢神经系统功能的下调[如较低的色氨酸羟化酶（THP）2基因表达、较低的5-羟色胺转运体（SERT）基因表达、较低的5 HT-1A受体基因表达和较低的5-羟色胺降解基因表达所示（MAO-A和MAO-B）]，以及下丘脑中5 HT 2A和2C受体的上调，与更具应激弹性的动物相比。我们有初步的数据表明，在非应激条件下，用5-羟色胺再摄取抑制剂（SSRI）治疗应激敏感的猴子，可以增加正常月经周期中的生殖激素分泌。在这项资助申请中，我们将测试SSRI治疗是否可以预防应激诱导的生殖轴抑制，从而可能成为治疗应激诱导的不孕症的新疗法。我们将研究SSRI治疗引起的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SSRI治疗FHA女性是否能够增加生殖激素分泌。卡梅隆博士、Bethea博士和贝尔加博士之间的合作代表了一个独特的机会，可以在适当的动物模型中测试这种潜在的FHA新疗法，我们可以在其中检查神经系统，并在小型试点临床研究中进行测试。 公共卫生相关性：功能性下丘脑闭经是一种临床疾病，占女性不孕症的30%。该项目正在测试一种新的潜在治疗FHA的方法，FHA是一种由于对生活压力敏感而导致的不孕症，在雌性猴子中进行了一个小型的FHA女性试点项目。这种治疗包括使用血清素再摄取抑制剂，这是一种常见的焦虑治疗方法。