Effects of Common Life Stresses on Fertility

常见的生活压力对生育能力的影响

• 批准号: 7004274
• 负责人: JUDY L CAMERON
• 金额: $ 19.26万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7004274
• 关键词: Macaca mulatta; behavioral /social science research tag; biological models; confocal scanning microscopy; cooperative study; endorphins; environmental stressor; fertility; gamma aminobutyrate; hormone biosynthesis; immunocytochemistry; in situ hybridization; in vitro fertilization; luteinizing hormone; neuroanatomy; neuropharmacology; progesterone; psychological stressor; reproduction; reproductive hormone; serotonin inhibitor; steroid hormone receptor; stress

The overall goal of this project renewal is 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, medium stress-resilient animals developing stress-induced reproductive dysfunction after sustained stress exposure, and highly stress-resilient animals maintaining normal menstrual cyclicity throughout stress exposure. Interestingly, all monkeys show a significant impairment of fertility with stress exposure. The stress used for these studies is patterned after that documented in women with Hypothalamic Amenorrhea, who generally experience increased psychosocial stress combined with a mild metabolic stress (resulting from dieting and exercise). Monkeys are exposed to a combination of mild psychosocial stress (moving monkeys to a new housing room) + a moderate diet (20% decrease in calorie intake) + moderate exercise (running at a moderate pace for 1 hour, 5 days a week). We identified several stable characteristics associated with stress-sensitivity: lower follicular phase estradiol secretion, lower luteal phase progesterone secretion, higher heart rate, increased anxious behavior, lower activity of the brain serotonin system, and increased gene expression in hypothalamic GABAergic neurons. Our findings suggest that common life stresses have a more significant impact on both circulating levels of reproductive hormones and fertility than previously appreciated, particularly in stress-sensitive individuals. The specific aims of this renewal are: (1) to determine whether increasing brain serotonin levels by chronic treatment with a serotonin reuptake inhibitor (SSRI; a common anti-anxiety medication) will improve stress resilience, (2) identify further differences in neural circuits in stress-sensitive versus stress-resilient individuals, and (3) determine whether stress exposure has a negative impact at the level of the ovary on oocyte viability, early embryo development and ovarian cell steroidogenic capacity. The proposed studies will further our understanding of how common life stresses impact reproductive function, with the long-term goal of developing new treatments to make stress-sensitive individuals more stress resilient.

该项目更新的总体目标是确定常见生活压力（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，应激敏感的动物会迅速出现应激性生殖功能障碍，中等应激抵抗力的动物在应激后会出现应激性生殖功能障碍。持续的压力暴露，以及高度抗压的动物在压力暴露期间保持正常的月经周期。有趣的是，所有猴子都表现出显着的 生育力与压力暴露。这些研究中使用的压力是根据患有下丘脑闭经的女性所记录的压力模式得出的，这些女性通常会经历增加的社会心理压力以及轻微的代谢压力（由节食和运动引起）。猴子承受轻度社会心理压力（将猴子搬到新的住房）+适度饮食（卡路里摄入量减少 20%）+适度运动（每周 5 天，以中等速度跑步 1 小时）。我们确定了与压力敏感性相关的几个稳定特征：卵泡期雌二醇分泌较低、黄体较低 相黄体酮分泌、心率加快、焦虑行为增加、大脑血清素系统活性降低以及下丘脑 GABA 能神经元基因表达增加。我们的研究结果表明，常见的生活压力对生殖激素和生育能力的循环水平的影响比以前认为的更显着，特别是对于压力敏感的个体。此次更新的具体目标是：(1) 确定通过长期使用血清素再摄取抑制剂（SSRI；一种常见的抗焦虑药物）治疗来提高大脑血清素水平是否会提高压力恢复能力，(2) 确定神经回路的进一步差异在压力敏感型与压力恢复型个体中进行比较，以及（3）确定压力暴露是否对卵巢水平的卵母细胞活力产生负面影响，及早 胚胎发育和卵巢细胞类固醇生成能力。拟议的研究将进一步加深我们对常见生活压力如何影响生殖功能的理解，长期目标是开发新的治疗方法，使压力敏感的个体更具压力恢复能力。