Endometrial dysfunction in PCOS. Insights from a mouse model, human endometrial transcriptomics, and organoids

The beginning of every pregnancy depends on a delicate dialogue between the embryo and the uterus. At the heart of this process is the endometrium, the inner lining of the uterus, which changes throughout the menstrual cycle to become receptive to an implanting embryo. If these changes are disturbed, implantation may fail, leading to infertility, pregnancy loss, or complications later in pregnancy.
Polycystic ovary syndrome (PCOS) is the most common hormonal condition in women, characterized by high levels of male hormones, irregular menstrual cycles and polycystic ovarian morphology. PCOS is often associated with difficulties in becoming pregnant and with unfavourable pregnancy outcomes. While much research has focused on the ovaries and hormone production in PCOS, the role of the uterus and endometrium has been less studied. Increasing evidence, however, suggests that the endometrium itself is affected in PCOS, but the underlying mechanisms are not well understood.
This thesis aimed to explore how PCOS alters the endometrium and, in turn, affects fertility and placental health. First, endometrial changes in a PCOS mouse model with early-onset obesity were investigated. In addition, gene activity in human endometrial tissue was examined, and lab-grown ‘mini-organs’ (organoids) were developed from PCOS endometrium. The studies revealed that endometrial cells in PCOS have altered gene activity linked to inflammation, hormone signaling and tissue structure. It was also found that the endometrial cells have defects in their energy metabolism. Overall, these changes interfere with the endometrium’s ability to support embryo implantation and early placental development.
Both in mice and in women, excess weight was found to aggravate endometrial dysfunction, suggesting that obesity and PCOS together exert a “double burden” on fertility, yet also normal weight women experienced endometrial abnormalities.
Taken together, this thesis highlights the uterus as a key player in the reproductive difficulties of PCOS. It shows how excess male hormones and body weight interact to disrupt the endometrium and placenta, offering new insights into why pregnancy complications are more common in women with this condition. By identifying specific endometrial pathways and cell functions that are impaired, the results point to potential therapeutic targets to improve fertility and pregnancy outcomes in women with PCOS.