Molecular effects of estrogenic treatments on estrogen receptor αlpha signaling in the human endometrium

The endometrium is a highly sensitive estrogenic organ, composed by epithelial and stromal cells. Sexual hormones, as estrogens, mainly produced by the ovaries, are key regulators of the physiological growth and differentiation of the uterine tissue, through paracrine interactions occurring between estrogen receptor positive (ER+) cells from the epithelium and the stroma. In addition, estrogens remain the most powerful treatment to circumvent menopause symptoms. Their use as menopause hormone treatment (MHT) remains controversial since estrogen-only preparations are associated to an increased risk of endometrial cancers that is prevented by the addition of a progestogen. Nevertheless, formulations based on estrogen and progestogen increase the risk of breast cancer. A better understanding of the ER signaling occurring upon estrogen or analogs treatments in stromal and epithelial cells of the endometrium, is thus crucial to develop a new safer generation of MHT. Thus, we have developed 3D organoids and patient-derived xenograft (PDX) from human endometrium samples to characterize at the transcriptomic and the histological levels the impact of estrogenic treatments on both epithelial (EpCAM+) and stromal (CD90+) cells. Our results emphasized that depending on the nature of the estrogen used, the transcriptional activity of stromal and epithelial cells of the endometrium can be modulated. These results will provide important resources for understanding how different estrogen affects endometrial health and function. This will contribute to pave the way for the development of new safer MHT.