Chronic social isolation, crowding, and instability distinctly impact reproductive function in adult female Wistar rats

Abstract

Social stressors represent highly relevant stress models which remain understudied in females. Concordantly, little is known of the impact of different types of social stress on female reproductive functioning, despite close interactions between the hypothalamic-pituitary-adrenal (HPA) axis and hypothalamic-pituitary-gonadal (HPG) axis. This study provides a comprehensive assessment of reproductive functioning in female rats following exposure to three social stress paradigms. 112 regularly cycling adult female Wistar rats were exposed to 21 days of isolation, crowding, social instability, control housing (daily cage changes) or regular housing. Rats were then euthanized (in proestrus or diestrus) or underwent paced-mating and fertility assessments. Estrous cyclicity, uterine horn weight, hypothalamic expression of kisspeptin (Kiss1), gonadotropin-inhibitory hormone (GnIH), estrogen receptors alpha (ERα), and glucocorticoid receptors (GR), serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), progesterone (P4), and corticosterone (CORT), as well as ovarian follicle counts were assessed. Findings show isolation to increase hopping behaviors, decrease early follicle counts, uterine weight, and GnIH, as well as increase FSH levels. In crowded rats, expression of GnIH and ERα were reduced, paralleled by fewer days spent in proestrus and increased hopping behaviors. Following instability, rats presented decreased estrous cyclicity, reduced uterine weight, and diminished ovarian reserve, despite minimal changes at the hypothalamic level. Paced mating exposure increased CORT in all groups except instability and crowding. Overall, social stressors presented distinct consequences on reproduction, highlighting their relevance as stress models and the importance of gaining a better understanding of social stress-induced reproductive dysfunction in females.