Physiological and Pathological Androgen Actions in the Ovary

Abstract

Androgens, although traditionally thought to be male sex steroids, play important roles in female reproduction, both in healthy and pathological states. This mini-review focuses on recent advances in our knowledge of the role of androgens in the ovary. Androgen receptor (AR) is expressed in oocytes, granulosa cells, and theca cells, and is temporally regulated during follicular development. Mouse knockout studies have shown that AR expression in granulosa cells is critical for normal follicular development and subsequent ovulation. In addition, androgens are involved in regulating dynamic changes in ovarian steroidogenesis that are critical for normal cycling. Androgen effects on follicle development have been incorporated into clinical practice in women with diminished ovarian reserve, albeit with limited success in available literature. At the other extreme, androgen excess leads to disordered follicle development and anovulatory infertility known as polycystic ovary syndrome (PCOS), with studies suggesting that theca cell AR may mediate many of these negative effects. Finally, both prenatal and postnatal animal models of androgen excess have been developed and are being used to study the pathophysiology of PCOS both within the ovary and with regard to overall metabolic health. Taken together, current scientific consensus is that a careful balance of androgen activity in the ovary is necessary for reproductive health in women.

Figure 1.

AR actions in granulosa cells. AR works through genomic (dashed lines) and nongenomic (solid lines) pathways to promote growth and differentiation of granulosa cells, suppress apoptosis and, in dominant follicles, increase steroid synthesis. The effects of granulosa growth factors IGF1, GDF9, and FSH are all enhanced in the presence of androgens through extranuclear activity of AR. At the gene level, AR induces the expression of antiapoptotic miRNA miR125b, multiple steroidogenic enzymes, GDF9, and FSH receptor, and regulates the activity of DNA methyltransferase Ezh2 through modulation of Ezh2 phosphorylation as well as transcriptional regulation of the miRNA miR101 (24–28, 33).