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During menstruation, an inner layer of the endometrium is selectively shed, while an outer, progenitor-containing layer is preserved to support repeated regeneration. Progress in understanding this compartmentalization has been hindered by the lack of suitable animal models, as mice and rats do not menstruate. Here, we present transgenic mouse models that recapitulate the key anatomical, functional, and transcriptional features of human menstruation through targeted chemogenetic activation of premenstrual differentiation. Using single-cell spatial transcriptomics, we define a new paradigm for spatially regulated fibroblast differentiation that drives pre-menstrual endometrial layering and ultimately determines the extent of tissue shedding. Our results revise a century-old view of endometrial shedding and regeneration and establish new transgenic mice as powerful tools to advance menstruation research.