The Hypothalamic-Pituitary-Ovarian Axis, Ovarian Disorders, and Brain Aging

Heather Valera, Angela Chen, Kathryn J Grive
Endocrinology, Volume 166, Issue 10, October 2025, bqaf137
https://doi.org/10.1210/endocr/bqaf137

Abstract

The hypothalamic-pituitary-ovarian (HPO) axis is a complex endocrine feedback mechanism controlling ovulation in female vertebrates. Balance of the HPO axis requires correct secretion of sex steroids from the ovarian follicle to inhibit release of gonadotropins from the pituitary. Several conditions of ovarian dysfunction such as menopause, primary ovarian insufficiency, and polycystic ovary syndrome involve imbalances in the HPO axis, contributing to infertility. Intriguingly, these disorders also share a higher incidence of cognitive and emotional dysregulations, as well as a heightened risk of certain neurodegenerative conditions with age. It is understood that estradiol exerts neuroprotective functions, but gonadotropin signaling is less understood. High concentrations of circulating follicle-stimulating hormone (FSH) and luteinizing hormone (LH) have shown to contribute to neurodegenerative disease states, but are not addressed as part of traditional hormone replacement therapy. To identify the mechanistic connections between ovarian disorders and heightened susceptibility of the brain to pathological aging, a multisystem experimental approach is required, considering each HPO axis player as an individual effector. In this review, we will summarize current knowledge on the effects of estradiol, progesterone, FSH, and LH on neuronal susceptibility to pathology. We will describe ways in which the HPO axis becomes imbalanced during ovarian dysfunction, and how systemic inflammation can become an additional HPO axis effector. Finally, we will recommend solutions to the presented gaps in knowledge, and suggest avenues of future research to pursue development of therapeutics targeting both ovarian and brain health in patients.

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