Long-term post-ovariectomy mouse model recapitulates hypothalamic transcriptomic changes observed during the menopausal transition in women

Menopause significantly impacts women’s health, yet hypothalamic changes during this transition remain poorly understood. We analyzed gene expression in human hypothalamic samples across menopausal transition, revealing significant changes in inflammatory pathways, KNDy neuron signaling, and thermoregulatory genes. This analysis also identified novel central markers of menopause, including AKAP5 and CDKN1A ( p21 ). To further investigate these changes, we developed a novel mouse model based on long-term (4 months) post-ovariectomy (OVX) that mimics the gonadotropin and temperature fluctuations of menopausal transition. Remarkably, the posterior hypothalamus of 4-month post-OVX mice closely mirrored the transcriptional changes observed in women at the late peri-/early post-menopausal age range (ages 51-55). Both species exhibited increased inflammatory signaling and glial activation, alongside altered KNDy neuron activity. Our findings provide new insights into the central mechanisms of menopausal symptoms and offer a valuable preclinical model for testing interventions.