The role of androgens in follicle maturation and ovulation induction: friend or foe of infertility treatment?

Abstract

Background: Effects of androgens on follicle maturation have been controversial for some time. Here, we review the potential of their applications in improving human ovulation induction, based on human and animal data, reported in the literature.

Methods: We reviewed the published literature for the years 2005-2011, using relevant key words, in PubMed, Medline and Cochrane reviews, and then performed secondary reviews of referenced articles, which previously had not been known or preceded the searched time period. A total of 217 publications were reviewed.

Results: Contrary to widely held opinion, recent data, mostly developed in the mouse, convincingly demonstrate essential contribution of androgens to normal follicle maturation and, therefore, female fertility. Androgens appear most engaged at preantral and antral stages, primarily affect granulosa cells, and exert effects via androgen receptors (AR) through transcriptional regulation but also in non-genomic ways, with ligand-activated AR modulating follicle stimulating hormone (FSH) activity in granulosa cells. While some androgens, like testosterone (T) and dehydroepiandrosterone (DHEA), appear effective in improving functional ovarian reserve (FOR) in women with diminished ovarian reserve (DOR), others may even exert opposite effects. Such differences in androgens may, at least partially, reflect different levels of agonism to AR.

Discussion: Selective androgens appear capable of improving early stages of folliculogenesis. They, therefore, may represent forerunners of a completely new class of ovulation-inducing medications, which, in contrast to gonadotropins, affect follicle maturation at much earlier stages.

Figure 1

Synergism between androgen and FSH. The figure depicts the potential synergism of androgens and follicle stimulating hormone (FSH) during early folliculogenesis. Here in detail depicted only on pre-antral and early antral follicles, the figure is meant to demonstrate the high concentration of androgen receptor (AR) at pre-antral to antral stages, declining thereafter [10,15-17]. High concentrations of AR at these stages are strongly suggestive of peak androgen effects at these stages of folliculogenesis. Androgens primarily affect granulosa cells [21] through transcriptional regulation via AR but do so also via non-genomic ways, with ligand-activated AR modulating FSH activity in granulosa cells. The box in the right lower quadrant schematically demonstrates the synergism between androgens and FSH, based on Lenie and Smitz [10], practically creating a feed back loop.Synergism between androgens and FSH suggests the possibility of new pharmacologic approaches to ovulation induction, utilizing this synergism in early folliculogegesis to improve oocyte numbesr and quality. For further detail, see text.