Androgen effect on connexin expression in the mammalian female reproductive system: a systematic review

Abstract

The functions of androgen and connexin in the mammalian female reproductive system are suggested to be related. Previous research has shown that androgen affects connexin expression and localization in the female reproductive system, altering its function. However, no definitive conclusion on their cause-effect relationship has been drawn yet. In addition, a high prevalence of women with polycystic ovary syndrome (PCOS), who are characterized by elevated androgen levels and failure of ovulation, has prompted the studies on the relationship between androgen and connexin in the ovaries. This systematic review aims to investigate the effect of androgen on connexin expression in the mammalian female reproductive system. The literature search was conducted using the MEDLINE, EBSCOhost, and Scopus databases and the following keywords: “androgen” or “testosterone” or “androgen blocker” or “anti-androgen” or “androstenedione” or “dehydroepiandrosterone” or “flutamide AND connexin” or “gap junction” or “cell junction”. We only considered in vitro and in vivo studies that involved treatment by androgen or androgen receptor blockers and measured connexin expression as one of the parameters. Our review showed that the exposure to androgen or androgen blocker affects connexin expression but not its localization in the mammalian ovary. However, it is not clear whether androgen downregulates or upregulates connexin expression. Additionally, it is inconclusive whether the upregulation of connexin positively contributes to the ovarian function.

Dishevelled family proteins (DVL1-3) expression in IUGR placentas

“…Steroids (estrogens and androgens) are actively involved in placental functions and pathologies [ 25 , 26 ]. It has been shown that DVL1 and DVL3 proteins could regulate placental aromatase expression and the aromatase gene transcription [ 27 ] that regulate human trophoblast differentiation [ 28 ].…”

Intercellular communication in the cumulus–oocyte complex during folliculogenesis: A review

“…What’s more, androgen may also have an effect on GJs ( Mohd Kamal et al, 2019 ). Clinical studies in PCOS patients have found a correlation between androgen and connexin expression, the expression of CX43 also increased in cultured granulosa cells by adding androstenedione, but the specific regulatory mechanisms have not been studied.…”

AOP key event relationship report: Linking decreased androgen receptor activation with decreased granulosa cell proliferation of gonadotropin-independent follicles

“…AR activation affects the level of connexins, proteins that form gap junctions between granulosa cells and the oocyte and hence regulate intracellular communication; a prerequisite for folliculogenesis [19]. There is evidence connecting AR and connexins 37 and 43, the main connexins involved in granulosa-oocyte communication [19]. Although not conclusive, AR may induce connexin expression, whereas high levels of AR activation, or AR antagonism, can decrease the levels of expression [19].…”

“…Additionally, the AR may regulate folliculogenesis indirectly by interacting with proteins important to the process. These proteins include Insulin Growth Factor (IGF1) and its receptor (IGFR1), follicle-stimulating hormone receptor (FSHR), anti-Müllerian hormone (AMH) and connexins essential for oocyte-granulosa cell communication [14,[16][17][18][19].…”