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The aim of this study was to investigate uterine lesions, uterine endocrine status and expression of genes involved in uterine differentiation in a rat model of polycystic ovary syndrome (PCOS). The possible involvement of the androgen receptor (AR) was also investigated. PCOS rats showed an increased incidence of uterine epithelial and glandular lesions and elevated serum testosterone level, which was not detected in uterine tissue. Uterine 17β-estradiol, estrone and progesterone were detected in 100%, 75% and 50% of the animals, respectively. This was associated with a decrease in Star and an increase in Hsd17b2, Srd5a1 and Cyp19a1, suggesting that uterine steroids are not synthesized de novo in PCOS and that alterations in these enzymes may explain the absence of testosterone and low progesterone. In addition, ESR2 decreased and AR increased, suggesting possible steroid receptor crosstalk. Genes associated with uterine differentiation, PTEN and WNT5a, also showed reduced expression. PCOS rats treated with flutamide, an AR antagonist, were similar to PCOS rats in terms of uterine lesions, serum steroid levels, ESR2, PTEN and WNT5a expression. However, testosterone, AR and aromatase levels were similar to control rats, with decreased expression of ESR1 and HOXA10, suggesting that these expressions are AR dependent. Our results suggest that the primary cause of the observed uterine lesions in the PCOS rat model is the altered endocrine status and consequently changes in genes related to uterine differentiation., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2024. Published by Elsevier B.V.)

The effects of androgens on the uterus have been poorly studied and they need to be clarified to understand why androgen excess, such as observed in women with polycystic ovary syndrome (PCOS), is a risk factor for the development of endometrial hyperplasia, cancer, and infertility. Thus, uterine histomorphology in a PCOS experimental model was evaluated. Beginning at weaning, female rats were injected daily with dehydroepiandrosterone (DHEA, 6 mg/100 g body weight) or vehicle (sesame oil) for 20 consecutive days. On postnatal day 41 (PND41), DHEA-treated animals showed high serum testosterone levels. In addition, uterine histological analysis showed a significant increase in luminal epithelial height and glandular density without changes in cell proliferation. The thickness of the subepithelial stroma and myometrium also increased in these animals. The effect of DHEA on uterine thickness was accompanied by a significant reduction in cell density in both tissue compartments (subepithelial stroma and myometrium). Cell proliferation was not altered in the myometrium, whereas a decrease in the proliferative activity was seen at PND41 in the subepithelial stroma of DHEA animals. The analysis of the extracellular space showed that the changes in the thickness of the subepithelial stroma and myometrium were related to an increase in the organization of collagen fibers and water imbibition. The latter was associated with higher aquaporin 3 and 8 expression. This study provides evidence to further the understanding of PCOS-associated hyperandrogenism effects on uterine architecture. This could have implications for the regulation of uterine function and the development of uterine lesions.