Flutamide ameliorates uterine decidualization and angiogenesis in the mouse hyperandrogenemia model during mid-pregnancy

Abstract

Background/Aim Patients with polycystic ovary syndrome (PCOS), characterized by anovulation, hyperandrogenemia and polycystic ovaries, are still vulnerable to undergo recurrent pregnancy loss and premature labor even though the ovulatory process is pharmacologically recovered. However, its potential mechanism remains unknown. Thus, our aim was to investigate the effect and mechanism of hyperandrogenemia and flutamide (a non-steroidal anti-androgen) on the embryo implantation and pregnancy during mid-pregnancy. Methods We used a mouse model in which PCOS-like hyperandrogenemia was induced by subcutaneous injection of testosterone propionate. In this model, we observed the effect of hyperandrogenemia and flutamide on the decidualization, angiogenesis and uNK cells by methods of immunohistochemistry, quantitative PCR, western blotting and Dolichos biflorus agglutinin (DBA) lectin staining. Results Testosterone and flutamide treatment did not significantly influence the numbers of implanted embryo compared with the control group. However, different doses of testosterone significantly increased the ratio of resorbed /implanted embryo, decreased the level of prl8a2 mRNA and cyclin D3 protein, inhibited the uterine angiogenesis and reduced the numbers of uNK cells, but combined treatment with flutamide markedly decreased the resorbed embryos, increased expressions of prl8a2 mRNA and cyclin D3 protein and angiogenesis and numbers of uNK cells. Conclusion Flutamide treatment can efficiently ameliorate the hyperandrogenemia-induced the disorders in aspects of decidualization, angiogenesis and uNK cells, which further improve the poor endometrial receptivity in PCOS patients.

Endometriosis and polycystic ovary syndrome are diametric disorders

“…Treatment with metformin, a drug prescribed for diabetes as well as PCOS, improves markers of endometrial receptivity in women with PCOS, including increased uterine blood flow (Palomba et al, 2006 ). Recent research with a hyperandrogenic mouse model showed that angiogenesis and uterine natural killer cells are increased with flutamide treatment, demonstrating that elevated testosterone levels inhibit decidualization (Gong et al, 2019 ).…”

Increased uterine androgen receptor protein abundance results in implantation and mitochondrial defects in pregnant rats with hyperandrogenism and insulin resistance

“…Further, we show that treatment with flutamide effectively reverses DHT + INS-induced deficiencies in endometrial receptivity and decidualization and subsequently increases the numbers of viable fetuses and restores fertility. Likewise, in pregnant mice flutamide treatment elicited a marked reversal of testosterone-induced decreases in decidualization-related gene expression, and it decreased the number of resorbed embryos during implantation [ 60 ]. Furthermore, in women with PCOS, long-term anti-androgen therapy is associated with decreased testosterone levels and improved ovulatory function [ 61 ].…”

Increased Uterine Androgen Receptor Protein Abundance Results in Implantation and Mitochondrial Defects in Pregnant Rats with Hyperandrogenism and Insulin Resistance

“…Further, we show that treatment with utamide effectively reverses DHT + INS-induced de ciencies in endometrial receptivity and decidualization and subsequently increases the numbers of viable fetuses and restores fertility. Likewise, in pregnant mice utamide treatment elicited a marked reversal of testosterone-induced decreases in decidualization-related gene expression, and it decreased the number of resorbed embryos during implantation [54]. Furthermore, in women with PCOS long-term anti-androgen therapy is associated with decreased testosterone levels and improved ovulatory function [55].…”

“…Substantial evidence indicates that PCOS patients have aberrant/altered circulating levels of immune cells and uNK cell abundance in the uterus during the secretory phase of the menstrual cycle [8,66]. In pregnant mice during post-implantation, treatment with testosterone propionate decreased the numbers of uNK cells in the uterus, and the additional treatment with utamide restored the normal distribution of uNK cells [54]. Although the different types of immune cells, including NK cells and macrophages, in humans and rodents express AR [67], whether decidual immune cells also express AR during pregnancy remains unclear [22].…”