Exploration of the dynamic regulation of the hypothalamic-pituitary-ovarian axis during the estrous cycle

Abstract Background One of the most challenging issues in current assisted reproductive technology is how to optimally counsel and treat patients with poor ovarian response (POR). However, current research predominantly emphasized the ovarian local changes during controlled ovarian hyperstimulation, and the hypothalamic-pituitary-ovarian (HPO) axis as an integrated system in the context of clinical ovulation induction and POR remains underexplored. Investigating the inter-organ interactions and dynamic regulatory characteristics of the HPO axis in response to exogenous gonadotropin stimulation may provide molecular insights into the interaction networks of the HPO axis, and ultimately propose new potential targets for the clinical diagnosis and treatment of ovulatory disorders and POR. Results Fifteen genes were identified as being associated with the dynamic regulation of the HPO axis during the estrous cycle in mice. In the hypothalamus, Il-7; in the pituitary, Oxtr and Cacna1g; and in the ovary, Bmp2, Cyp19a1, Lhcgr, and Fshr were linked to follicular growth regulation. Npy and Inhba cooperatively regulated the release of gonadotropins. Ovarian Amh and Amhr2 were implicated in the regulation of follicular development. Eif4b, Polrmt, and Yy1 were identified as core regulatory factors for granulosa cell proliferation. Rhoa was found to participate in the regulation of cortisol synthesis, thereby modulating both follicular and luteal development. Cortisol and corticosterone levels peaked during P0, while pregnenolone, estrone, 11-deoxycorticosterone, and testosterone peaked during P24-P44. Progesterone levels peaked during H6 and H16. The trends for pregnenolone, estrone, testosterone, and progesterone were observed in mice and mirrored in humans. Conclusion An estrous cycle model of the mouse was successfully established. Fifteen potential genes associated with the dynamic regulation of the estrous cycle by the HPO axis were identified, along with the elucidation of trends in seven estrous cycle-related hormones. Notably, the cyclic change of Il-7 in the hypothalamus during the gonadotropin-synchronized estrous cycle of mice has not been previously reported.