Involvement of androgens in ovarian health and disease

Abstract

In women, ovary and adrenal gland produce androgens. Androgens are essential drivers of the primordial to antral follicle development, prior to serving as substrate for estrogen production in the later stages of folliculogenesis. Androgens play a crucial role in the follicular-stromal intertalk by fine tuning the extracellular matrix and vessel content of the ovarian stroma. Local auto-and paracrine factors regulate androgen synthesis in the pre-antral follicle. Androgen excess is a hallmark of polycystic ovary syndrome and is a key contributor in the exaggerated antral follicle formation, stromal hyperplasia and hypervascularity. Hyperandrogenaemia overrides the follicular-stromal dialog, resulting in follicular arrest and disturbed ovulation. On the other hand, androgen deficiency is likely to have a negative impact on fertility as well, and further research is needed to examine the benefits of androgen-replacement therapy in subfertility.

Keywords: androgen; angiogenesis; folliculogenesis; polycystic ovary syndrome; stroma.

Figure 1

Working model for androgen action in the pre-antral follicle. Androgens are secreted by theca cells from the secondary stage on, and amplify their local effects by increasing their own receptor expression and activity. Androgens induce the expression of FSH-R and prime the follicle for further FSH-driven follicular growth and maturation. We postulate that androgens stimulate AMH secretion that in turn inhibits FSH-induced aromatase expression thereby maintaining a predominantly androgenic intrafollicular milieu. In this scenario the growing follicle is ‘protected’ from premature selection by FSH.

Figure 2

Working model for androgen action on endothelial cells. In steroid-producing cells, ligand-activated AR induces HIF-1 (Hypoxia-inducible factor 1) expression. HIF-1 is a transcription factor for VEGF. Secreted VEGF binds membrane receptors on the neighboring endothelial cells and potently stimulates proliferation.

Figure 3

Working model for excess androgen action on follicle and stroma in PCOS. In PCOS, the disturbed balance between androgens, AMH and FSH leads to antral follicular arrest. Circulating FSH-levels are insufficient to reach the increased FSH-threshold of the follicles and selection for dominance does not occur. The hypervascular, rigid and inflammatory cortex negatively impacts the follicular dynamics. Exaggerated blood supply, partly mediated by local androgen overproduction, fuels the whole process. The blue ovals indicate follicles, red circles blood vessels, yellow squares inflammatory cells and green bowed lines stand for connective tissue.