Systematic characterization of the ovarian landscape across mouse menopause models

Abstract

Menopause affects not only fertility but also systemic health. Yet mechanisms underlying this coupling are still poorly understood, partly due to the absence of robust, age-relevant preclinical models with comprehensive molecular and phenotypic characterization. To address this, we systematically compared three candidate mouse models of menopause: (1) intact aging, (2) chemical ovarian follicle depletion using 4-vinylcyclohexene diepoxide (VCD) administered at multiple ages, and (3) Foxl2 haploinsufficiency, a genetic model based on a gene linked to human premature ovarian failure. Through histology, serum hormone profiling, single-cell transcriptomics and machine-learning approaches, we identify both shared and model-specific features of follicle loss, endocrine disruption, and transcriptional remodeling. Our comparative framework enables informed selection of context-appropriate preclinical rodent models to study menopause and the broader physiological consequences of ovarian aging. TeaserThis systematic characterization of mouse menopause models lays the groundwork for future preclinical work on the systemic impacts of menopause.