EFFECTS OF COMMON LIFE STRESSES ON FERTILITY

共同生活压力对生育力的影响

• 批准号: 8125587
• 负责人: JUDY L CAMERON
• 金额: $ 6.69万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8125587
• 关键词: Address; Amenorrhea; Animals; Anxiety; Behavior; Brain; Butyric Acids; Cells; Characteristics; Chronic; Clinic; Corticotropin-Releasing Hormone; Diet; Embryonic Development; Endorphins; Estradiol; Female; Fertility; Functional disorder; Gene Expression; Goals; Grant; Heart Rate; Homogeneously Staining Region; Hour; Housing; Hypothalamic structure; Impairment; In Situ Hybridization; In Vitro; Individual; Individual Differences; Infertility; Intake; Life Stress; Luteal Phase; Macaca fascicularis; Maintenance; Menstrual cycle; Messenger RNA; Metabolic stress; Moderate Exercise; Monkeys; Monoamine Oxidase A; Monoamine Oxidase B; Neurons; Norepinephrine; Oocytes; Ovarian; Ovarian Steroid Hormone; Ovary; Pathway interactions; Pattern; Periodicity; Pharmaceutical Preparations; Physiological; Pregnancy Rate; Pro-Opiomelanocortin; Progesterone; Psychological Stress; Psychosocial Stress; Regimen; Research; Running; Selective Serotonin Reuptake Inhibitor; Serotonin; Stress; System; Testing; Tryptophan 5-monooxygenase; Tyrosine 3-Monooxygenase; Woman; base; design; diet and exercise; experience; gamma-Endorphin; granulosa cell; improved; in vivo; neural circuit; neuromechanism; neuropeptide Y; noradrenergic; oocyte maturation; prevent; proliferative phase Menstrual cycle; raphe nuclei; receptor; relating to nervous system; reproductive; reproductive axis; reproductive function; reproductive hormone; research study; response; serotonin transporter; stress resilience; trend

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 stressinduced 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.

这个项目更新的总体目标是确定共同生活压力的机制(即， 节食、适度运动和心理压力)会损害生殖轴的活动和生育能力。 雌性食蟹猴和女性一样，一年有28天的月经周期，表现出 应激反应的个体差异，应激敏感的动物迅速发展为应激诱导 生殖功能障碍，中等应激恢复能力的动物发展应激诱导的生殖 持续应激后的功能障碍，高度应激恢复能力的动物保持正常 应激暴露期间的月经周期。有趣的是，所有的猴子都表现出明显的 压力暴露下的生育能力。这些研究中使用的压力是按照女性的记录进行的。 患有下丘脑闭经的患者，他们通常会经历更多的心理社会压力，并伴有 轻微的代谢压力(由节食和锻炼引起)。猴子暴露在温和的混合气体中 心理社会压力(将猴子转移到新的住所)+适度饮食(减少20%的卡路里 摄入量)+适度运动(一周5天，以中等速度跑步1小时)。我们确定了几个 与应激敏感相关的稳定特征：卵泡期雌二醇分泌较低，黄体较低 黄体酮分泌期，心率加快，焦虑行为增加，大脑活动减少 5-羟色胺系统，并增加下丘脑GABA能神经元基因表达。我们的发现 表明共同的生活压力对生殖的两个循环水平都有更显著的影响 荷尔蒙和生育能力比以前认识到的更高，特别是在压力敏感的人身上。具体的 这次更新的目的是：(1)确定慢性治疗是否会增加大脑5-羟色胺水平 一种5-羟色胺再摄取抑制剂(SSRI；一种常见的抗焦虑药物)将提高压力韧性，(2) 确定压力敏感型个体与应激恢复型个体在神经回路上的进一步差异，以及(3) 及早确定应激暴露是否在卵巢水平对卵母细胞存活率产生负面影响 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推动我们的 了解常见的生活压力如何影响生殖功能，长期目标是 开发新的治疗方法，使压力敏感者更具压力弹性。