Systematic characterization of the ovarian landscape across mouse menopause models.

Menopause not only affects fertility but also has widespread impact on systemic health. Yet, the molecular mechanisms underlying this process are not fully 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 transcription factor linked to human premature ovarian failure. Through histology, serum hormone profiling, single-cell transcriptomics and machine-learning approaches, we uncovered both shared and model-specific features of follicle loss, endocrine disruption, and transcriptional remodeling. The VCD and Foxl2 haploinsufficiency models revealed distinct patterns of hormonal and immune alterations not captured by intact aging alone. This comparative framework enables informed selection of context-appropriate preclinical rodent models to study menopause and the broader physiological consequences of ovarian aging.