Cell type-specific transcriptomic responses to progesterone and bazedoxifene prevent estradiol-driven proliferation in the human endometrium

Menopausal hormone therapy (MHT) combining estrogen with a progestogen protects the endometrium in non-hysterectomized women but increases breast cancer risk, prompting the search for progestogen-free alternatives. Selective estrogen receptor modulators (SERMs), such as bazedoxifene (BZA), offer a potential solution, yet their use for menopausal indications remains debated. MHT evaluations rely largely on mouse models or clinical measurements of endometrial thickness, providing limited mechanistic insight in human tissue. Here, we performed cell-type-specific transcriptomic profiling of patient-derived endometrial xenografts to compare how progesterone and BZA prevent estradiol-induced proliferation. Both treatments act through specific mechanisms: progesterone preserves half of the estradiol-dependent transcriptional response while inducing new programs, whereas BZA broadly abrogates estradiol-driven signaling in epithelial and stromal cells. We further identified cell-specific transcription factors and differential regulation of paracrine/autocrine networks. Overall, this study provides mechanistic and transcriptomic resources from human endometrium, with important implications for the development of improved MHT strategies.