Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders, affecting 7–12 % of women of reproductive age (Skiba et al., 2018). The diagnostic criteria for PCOS are oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenism and polycystic ovaries (Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group, 2004 Rotterdam ESHRE/ASRM‐sponsored PCOS consensus workshop group, 2004). Clinical observations suggest that, in women with PCOS, hormone abnormalities lead to an increased risk of endometrial hyperplasia and carcinoma, and pregnancy complications (Barry et al., 2014; Yu et al., 2016). Moreover, in women with PCOS, the incidence of endometrial hyperplasia is higher than 35% (Cheung, 2001) and the risk of endometrial cancer is three times higher (Haoula et al., 2012). In obese women, this risk is also three-fold higher, important data considering that obesity is a predominant feature in PCOS (Shafiee et al., 2014). However, the reason why women with PCOS have higher the risk of developing uterine abnormalities is not yet completely understood.

In PCOS women, androgen excess is a common finding (Dumesic and Lobo, 2013). This excess (also called hyperandrogenemia) can increases estrogen levels by its peripheral conversion, leading to a higher exposure of the endometrium to estrogen (Hosseinzadeh et al., 2021). However, some women with PCOS showed 17β-estradiol (E2) level similar to those of healthy women (Codner et al., 2007). It has been described that exposure to high or chronic levels of estrogens results in development of endometrial cancer (Kaaks et al., 2002; Zukerberg et al., 2004). Most endometrial cancers occur due to an unopposed estrogen environment (Nees et al., 2022). In PCOS, estrogen stimulation is not sufficiently counterbalanced by progesterone (P4) due to anovulation or oligo-ovulation (Shang et al., 2012; Dumesic and Lobo, 2013). On the other hand, the target tissue response to hormones also depends on their in-situ availability, which is partly regulated by the activity of tissue steroidogenic enzymes. Several studies have demonstrated that the activity of enzymes related to steroid metabolism in the endometrium of women with PCOS differs from that observed in the normal endometrium (Bacallao et al., 2008; Leon et al., 2008). In the endometrium of PCOS women, Bacallao et al. (2008) showed a decreased relationship between the activities of steroid sulfatase (STS) and estrogen sulfotransferase (ETS), whereas Leon et al. (2008) found an increase in STS activity and a decrease in ETS. Bacallao et al. (2008) also described an increased ratio between the mRNAs of 17β-hydroxysteroid dehydrogenase (Hsd17b) types 1 and 2 in the endometrium of PCOS women versus the normal endometrium. In another study, Margarit et al. (2010) found that the HSD17B1 and HSD17B2 levels in anovulatory PCOS patients were significantly higher than those in fertile women. Regarding aromatase, results are contradictory. Some researchers have reported that aromatase is undetectable in the endometrium of PCOS and normal women (Bacallao et al., 2008; Leon et al., 2008), whereas others have shown that the levels of endometrial aromatase in PCOS patients are higher than those in normal women (Zhao et al., 2014).

Changes in steroid metabolism in the endometrium may alter the expression of hormone-responsive genes associated with uterine development and differentiation, such as homeobox gene A10 (Hoxa10), phosphatidylinositol 3, 4, 5-trisphosphate 3-phosphatase (Pten), wingless-related MMTV integration site member 5a and 7a (Wnt5a and Wnt7a) and β-catenin (Ctnnb1) (Mutter et al., 2000; Cermik et al., 2003; Al Naib et al., 2016). Regarding Hoxa10, endometrial biopsies from women with PCOS have demonstrated decreased Hoxa10 (Cermik et al., 2003; Kara et al., 2019). Regarding PTEN, although a common finding in endometrial cancer or endometrial hyperplasia is the loss of PTEN gene expression (Djordjevic et al., 2012; Yang et al., 2015), Shafiee et al. (2016) found a significant up-regulation in PCOS women with endometrial cancer. Regarding the members of the Wnt family, studies in a PCOS rat model have shown that Wnt4, Wnt5a, and Wnt7a are not modified in the uterus, whereas, in PCOS women, some authors have shown a higher expression of Wnt3 as well as of Ctnnb1 (Mehdinejadiani et al., 2019; Zhang et al., 2017).

In a PCOS rat model, we have recently demonstrated an increase in uterine thickness and water content and alterations in collagen remodeling, cell proliferation and apoptosis (Bracho et al., 2019). These abnormalities were associated with modified expression of aquaporins, Insulin-like Growth Factor-I (Igf1), PTEN and steroid receptors (Bracho et al., 2020). In this study, employing the same animal model, our objective was to examine histomorphological uterine lesions in the luminal and glandular epithelium. Additionally, we aimed to assess tissue steroid pathways by measuring steroid levels, the enzymes responsible for steroidogenesis, and their specific receptors. Furthermore, we evaluated hormone-responsive genes associated with uterine differentiation and function. To explore the potential involvement of the androgen pathway in the uterine lesions of PCOS rats, we included a group treated with flutamide (F), which acts as an androgen receptor (AR) blocker.