Progressive hypothalamic neuroinflammation in ovariectomized mice parallels aging-related transcriptomic changes in the female human hypothalamus.

The hypothalamic changes that occur after the loss of ovarian estrogen remain poorly characterized. Here, we performed a comprehensive temporal characterization of the mouse hypothalamus after ovariectomy (OVX), combining physiological measurements with bulk RNA-seq of the posterior hypothalamus (PH) and preoptic area at 14 days and 4 months after OVX. Serum luteinizing hormone levels rose progressively and then declined, and core temperature peaked early and subsequently normalized, recapitulating the endocrine and thermoregulatory dynamics of reproductive aging in humans. Transcriptomic analysis revealed time-dependent activation of inflammatory pathways, glial markers, and KNDy neuron-related gene networks, with the most pronounced changes emerging at 4 months after OVX, particularly in the PH. Immunofluorescence confirmed increased neurokinin B release, declining KNDy neuronal activity, and heightened astrocytic reactivity in the arcuate nucleus after prolonged estrogen withdrawal. To contextualize these findings, we analyzed publicly available human hypothalamic RNA-seq data across chronological age. Age-related transcriptomic patterns, including progressive inflammatory signaling, glial activation, and altered KNDy gene expression, showed significant correlation with the OVX mouse model, particularly at the pathway level. These findings establish a temporal framework for hypothalamic molecular changes after estrogen withdrawal, identify conserved neuroinflammatory signatures across species, and provide a preclinical platform for testing interventions targeting menopause-associated hypothalamic dysfunction.