Chronic Intermittent Hypoxia Dysregulates the Hypothalamic-Pituitary-Gonadal Axis in a Sex Specific Manner

Background: Obstructive sleep apnea (OSA) affects approximately 10-26% of adults in the United States. OSA is characterized by intermittent cycles of hypoxia followed by rapid episodes of reoxygenation and is clinically classified by the apnea-hypopnea index (AHI). The prevalence of OSA is higher in males and menopausal females who typically present with a high ratio of androgens to estrogens, suggesting sex hormones may play a role in the pathophysiology of OSA. Circulating sex hormones are secreted by the hypothalamic-pituitary gonadal (HPG) axis. However, it is unclear to what extent OSA modulates the HPG axis. The objective of this study was to evaluate the HPG axis in male and female rats exposed to chronic intermittent hypoxia (CIH), an in vivo model of OSA. We hypothesized that CIH would decrease circulating sex hormones and impair the HPG axis in a sex-dependent manner. Methods: A model of CIH was used to simulate a mild form of OSA (10 hypoxic events per one hour, AHI= 10) in young adult Long Evans male and female rats. To measure the HPG axis, we quantified circulating steroid hormones using Milliplex technology and assessed protein concentrations of follicle stimulating hormone receptors (FSH-R) in the pituitary gland. Additionally, we performed histological analysis on gonadal tissues to examine changes in cellular morphology. Results: There were significant interaction effects of sex and CIH on circulating estradiol and progesterone. Post-hoc analysis demonstrated that CIH decreased estradiol in female rats and progesterone in male rats. Additionally, male rats had higher circulating testosterone compared to females. Notably, there were significant sex and CIH differences in the pituitary FSH-R where CIH decreased pituitary FSH-R in female rats. However, there were no significant main effects of sex or CIH on the concentrations of circulating follicle stimulating hormone. Exposure to CIH decreased the average number of secondary ovarian follicles in female rats, but did not affect the number of corpus luteum or antral follicles present in the ovary. In male rats, exposure to CIH did not affect the area of Sertoli cells or the distance between seminiferous vesicles. Conclusions: Our findings suggest that both males and females have impairments in the HPG axis following exposure to CIH. However, the mechanisms driving these differences are sex dependent, such that females demonstrated changes in circulating hormones, pituitary hormone receptors, and gonadal cell morphology, whereas males demonstrated changes in circulating hormones. These findings may provide a potential mechanism where OSA negatively impacts reproductive function by dysregulating the HPG axis in young adult males and females. NIH R01 NS0091359, UNTHSC Seed Grant, NIH T32 AG020494 to SM, AHA 22POST-903250 to JLB, AHA 22PRE-900431 to JG This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.