Investigating progesterone resistance in endometriosis and adenomyosis using endometrial assembloids

Details

Supervisors

Dolmans, Marie-Madeleine

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

enEndometriosis and adenomyosis are chronic gynecological disorders affecting approximately 10-20% of women of reproductive age. These pathologies are primarily driven by hormonal dysregulation, notably local hyperestrogenism and progesterone resistance. The latter plays a key role in lesion persistence, impaired endometrial receptivity and poor response to first-line hormonal therapies. A deeper understanding of this phenomenon is therefore essential to improve therapeutic strategies. The aim of this study was to investigate progesterone resistance and its underlying mechanisms in eutopic endometrium of patients with endometriosis and adenomyosis using endometrial assembloids. Endometrial assembloids are a three-dimensional in vitro model combining primary endometrial epithelial organoids with stromal cells, replicating key physiological and morphological features of the in vivo endometrium, including hormonal responsiveness. In this study, assembloids were either left unstimulated as control or stimulated hormonally to mimic the different phases of the menstrual cycle. Progesterone responsiveness was assessed through morphological and molecular analyses, including evaluation of glycodelin, prolactin, leukemia inhibitory factor, homeobox A10 and 17β-hydroxysteroid dehydrogenase type 2 expression. Cell proliferation and steroid receptor expression were also explored. Endometrial assembloids were successfully generated from eutopic endometrial biopsies and were able to reproduce both epithelial and stromal organization of native endometrium. Assembloids derived from healthy endometrium were shown to respond to progesterone by expressing secretory morphological transformation and inducting progesterone-responsive markers, pointing to preserved hormonal responsiveness. By contrast, assembloids derived from adenomyosis and endometriosis patients exhibited an impaired and heterogeneous response to progesterone, with attenuated secretory transformation and altered regulation of progesterone-responsive markers. Overall, this study demonstrates that endometrial assembloids constitute a relevant and promising in vitro model to investigate progesterone responsiveness in eutopic endometrium from endometriosis and adenomyosis patients. This will serve to enhance our understanding of disease-specific mechanisms underlying impaired endometrial function.