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.
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