Implicating androgen excess in propagating metabolic disease in polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) has been traditionally perceived as a reproductive disorder due to its most common presentation with menstrual dysfunction and infertility. However, it is now clear that women with PCOS are at increased risk of metabolic dysfunction, from impaired glucose tolerance and type 2 diabetes mellitus to nonalcoholic fatty liver disease and cardiovascular disease. PCOS is characterised by androgen excess, with cross-sectional data showing that hyperandrogenism is directly complicit in the development of metabolic complications. Recent studies have also shown that C11-oxy _C19 androgens are emerging to be clinically and biochemically significant in PCOS, thus emphasising the importance of understanding the impact of both classic and C11-oxy _C19 androgens on women's health. Here we discuss androgen metabolism in the context of PCOS, and dissect the role played by androgens in the development of metabolic disease through their effects on metabolic target tissues in women.

Keywords: C11-oxy C19 androgens; PCOS; adipose tissue; androgens; diabetes; metabolic disease; obesity.

Figure 1.

Iceberg phenomenon: PCOS has been traditionally perceived as a primarily reproductive disorder. On a superficial level, clinical consequences of this condition include subfertility, irregular menses and signs and symptoms of androgen excess. However, clinicians should be aware of the significantly increased risk of metabolic complications across the female lifespan in women with PCOS, underpinned by androgen excess and insulin resistance.

Figure 2.

Adrenal, ovarian and peripheral androgen metabolism in PCOS. Androgenic precursors are secreted predominantly by the adrenal glands, and activated to potent androgens in the ovaries and peripheral tissues. Expression of key androgen-activating enzymes in peripheral tissues such as adipose tissue highlight an important role for extra-adrenal and -ovarian androgen generation.

Figure 3.

Impact of androgen excess on metabolic target tissues- (A) Increased fat accumulation in the hepatocytes in response to androgen excess, eventually resulting in NAFLD, (B) Androgen excess is proportionally related to beta-cell dysfunction, (C) Ectopic lipid accumulation in skeletal muscle with androgen excess influences glucose-regulating pathways resulting in insulin resistance, (D) under the influence of androgens, women with PCOS have been shown to have more central obesity phenotypes.