Prenatally androgenized PCOS mice have ovary-independent uterine dysfunction and placental inflammation aggravated by high-fat diet

Polycystic ovary syndrome (PCOS) is a common hyperandrogenic and metabolic condition in women. The syndrome is linked to subfertility and pregnancy complications, yet the independent effects of exposure to hyperandrogenism and obesity on endometrial function remain unclear. Here, PCOS-like mice were generated using prenatal androgenization (PNA) with dihydrotestosterone, followed by a prepubertal high-fat (HF) or standard diet. In ovariectomized mice, PNA impaired uterine closure during the implantation window, disrupted decidualization, and altered extracellular matrix- and inflammation-related gene expression. The effects were aggravated by HF diet. In naturally mated, ovary-intact mice, PNA and HF diet affected decidual and placental gene expression, suggestive of placental dysfunction and inflammation, and induced fetal growth restriction. This study underlines the role of the uterus in adverse pregnancy outcomes in PCOS and identifies possible underlying mechanisms for future studies. Pre-pregnancy interventions targeting metabolic health and hyperandrogenism should be the next steps to optimize PCOS pregnancy outcomes. We sought to examine how prenatal androgenization (PNA) and/or excessive body weight affect uterine function during the pre-pregnancy phase and throughout pregnancy in mice. To achieve this, we conducted three experimental scenarios: the window of implantation, artificial decidualization, and natural pregnancy. Uterine and placental tissues were collected from PNA and control mice, both on high-fat and normal diets. RNA sequencing (RNAseq) was performed on the samples, after which the impact of PNA was assessed by comparing PNA-affected tissues to controls, and the influence of diet evaluated by comparing tissues from mice on high-fat versus normal diets.