Androgen Receptor Gene Expression in the Primate Ovary: Cellular Localization, Regulation, and Functional Correlations

Abstract

Excess androgens are associated with a characteristic polyfollicular ovarian morphology; however, it is not known to what extent this problem is due to direct androgen action on follicular development vs. interference with gonadotropin release at the level of the pituitary or hypothalamus. To elucidate potential androgen effects on the ovary, we investigated the cellular localization of androgen receptor (AR) messenger ribonucleic acid (mRNA) in rhesus monkey using in situ hybridization. To investigate the regulation of ovarian AR gene expression, we compared the relative abundance of AR transcripts in monkeys during follicular and luteal phases of the menstrual cycle and in monkeys treated with testosterone. To assess potential functional consequences of AR expression in the primate ovary, we compared AR mRNA levels with indexes of follicular cell proliferation and apoptosis in serial sections from individual follicles. AR mRNA expression was most abundant in granulosa cells of healthy preantral and antral follicles in the primate ovary. Theca interna and stromal cells also expressed AR mRNA, but to a lesser degree than granulosa cells. No significant cycle stage effects were noted in AR mRNA levels; however, larger numbers of animals would be necessary to definitively establish a cycle stage effect. AR mRNA level was significantly increased in granulosa cells and was decreased in theca interna and stromal cells of testosterone-treated monkeys. Importantly, granulosa cell AR mRNA abundance was positively correlated with expression of the proliferation-specific antigen Ki-67 (r = 0.91; P < 0.001) and negatively correlated with granulosa cell apoptosis (r = -0.64; P < 0.001). In summary, these data show that primate ovary AR gene expression is most abundant in granulosa cells of healthy growing follicles, where its expression is up-regulated by testosterone. The positive correlation between granulosa AR gene expression and cell proliferation and negative correlation with programmed cell death suggests that androgens stimulate early primate follicle development.

Subfertility and defective folliculogenesis in female mice lacking androgen receptor

“…Nevertheless, a marked decrease in FSHR expression in the ovaries from 10-dayold AR Ϫ/Ϫ mice as well as from 4.5-week-old PMSG-primed AR Ϫ/Ϫ mice supports the previous findings that androgen treatment enhances FSHR expression and that AR expression is associated with follicular proliferation (25,26). Also, the important role of AR in the early stages of follicular growth is elucidated by the in vitro follicle culture experiment that showed that the cultured follicles fail to develop to POFs when AR activity is inhibited by antiandrogen treatment (27).…”

Low testosterone levels in women with diminished ovarian reserve impair embryo implantation rate: a retrospective case-control study

“…It is generally accepted that androgen activates primordial follicles through the phosphatidylinositol 3-kinase-Akt-Foxo3α pathway, promotes follicular development beyond the preantral stage, and reduces follicular atresia by stimulating granulosa cells [14,15]. Thus, androgen supplementation may yield more oocytes, resulting in more embryos and improving pregnancy outcomes in women with DOR [8][9][10][11].…”

Pharmacological profile of MEN 11066, a novel potent and selective aromatase inhibitor

“…Blockade of estrogen synthesis in the early part of the menstrual cycle would increase gonadotropin secretion by decreasing hypothalamus and pituitary estrogen levels and thus the estrogen negative feedback [10,11]. On the other hand, the failed conversion of androgens to estrogens and the consequent accumulation of intraovarian androgens may increase follicular sensitivity to FSH during the early stages of the follicular development [10,11], as already suggested [12][13][14].…”