Stress and Sex: Characterizing the Distinct Impacts of Various Stressors on Female Reproductive Function

Abstract

Most adults experience stress in one form or another, whether it be systemic stress caused by brain injury or psychological stress caused by a perceived environmental threat. Stress of excessive intensity or prolonged duration can adversely impact health, namely by dysregulating the hypothalamic-pituitary-adrenal (HPA) axis. However, while substantial research supports an inhibitory effect of stress on hypothalamic-pituitary-gonadal (HPG) axis function, information is lacking regarding its effects in females, particularly the impact of adulthood stress on estrous cycle regularity.

This PhD thesis includes a set of studies (two systematic reviews and three original studies) aiming to better characterize the impact of various adulthood stressors on HPG axis function and reproductive outputs. The first and second chapters systematically reviewed the existing evidence on the association between adulthood psychological stress and disruptions to ovarian cyclicity in humans and rodents, respectively. The first chapter showed the majority of the 41 included studies to report an association between elevated psychological stress and irregular menstruation in adult women. Similarly, the second chapter found that over half of the 32 included papers detected an adverse impact of psychological stress models on the rodent estrous cycle, and shows altered estradiol (E2) levels and high basal corticosterone (CORT) are often observed in tandem with such cycle disruptions. The third chapter assessed HPG axis function in female Wistar rats exposed to global cerebral ischemia (GCI). We studied post-ischemic estrous cycle regularity and HPG axis reactivity through expression of estrogen receptor alpha (ERα), gonadotropin-inhibitory hormone (GnIH), and kisspeptin (Kiss1), and found a transient interruption of the estrous cycle (persistent diestrus) lasting on average 11 days and enduring dysregulation to HPG neuroendocrine function 25 days post ischemia. The fourth chapter evaluated the impact of social stressors (isolation, crowding, and social instability) in adult female Wistar rats on sexual functioning, fertility, estrous cycling, and all levels of the HPG axis (namely hypothalamic immunofluorescent expression of ERα, GnIH, and Kiss1, serum levels of pituitary and gonadal hormones, ovarian histology). Our data uncovered distinct impairment profiles following social stress exposure in rats, with the isolation condition leading to increased hopping behaviours, alterations to the reproductive organs, and elevated follicle-stimulating hormone (FSH) levels. Exposure to crowding reduced GnIH and ERα immunoreactivity, in addition to decreasing days spent in proestrus, whereas social instability led to reductions in estrous cyclicity, uterine horn weight, and ovarian reserve. The fifth chapter expanded on the previous findings by providing an in-depth assessment of the home-cage dynamics during instability and crowding stress, and assessed whether individual differences in play fighting in females were associated with altered stress and reproductive outcomes. This study uncovered distinctive patterns of play fighting in crowded and social instability exposed rats. Additionally, significant differences in adrenal gland weights and days spent in estrus were noted between high and low playing rats, suggesting play fighting to contribute to such physiological outcomes. Together, this series of experiments contributed to characterizing HPG axis dysfunction following different types of adulthood stress and should help future researchers select the most relevant models for studying impacts of stress on female reproductive function.