Targeting metabolism in the management of PCOS: Metformin and beyond

Impact of androgen excess on metabolism

Hyperandrogenism is the main feature of PCOS and is also partly responsible for the development of metabolic disturbances. Androgens exert their effects at both central and peripheral levels on a variety of tissues . They have diverse effects on white adipose tissue. First of all, high androgen concentrations shift the pattern of fat distribution. Women with PCOS exhibit male pattern fat accumulation with increased visceral adiposity . This altered fat deposition pattern has detrimental metabolic consequences and is a major risk factor for the development of metabolic syndrome . The exact mechanism of the fat redistribution caused by hyperandrogenism remains largely unknown. Rodent studies have shown that exposure to excess androgens was associated with increased adipocyte size in both visceral and subcutaneous fat depots . When adipocytes enlarge, the microenvironment of adipose tissue changes, tissue hypoxia occurs, proinflammatory cytokines and free fatty acids are released, macrophage recruitment begins, and eventually IR emerges. In addition, IR and exceeding adipose tissue capacity trigger the release of free fatty acids and triglycerides into the circulation, causing ectopic fat accumulation in skeletal muscle, liver and pancreas ( Fig. 1 ). As a result, ectopic fat accumulation further aggravates IR in these peripheral tissues . Hyperandrogenism also affects adipocyte differentiation by suppressing adipogenesis via the Wnt signaling pathway . Another potential mechanism of adipogenesis suppression is related to a ligand-enhanced coactivator, activation of androgen receptor-associated protein 70 (ARA70). Peroxisome proliferator-activated receptor-γ (PPAR-γ) activates ARA70 and induces adipogenesis. When activated by androgens, the androgen receptor competes with PPAR-γ to bind ARA70, which leads to blunted PPAR-γ effects on ARA70 and decreased adipogenesis . This impairment further complicates the lipid storage capacity of adipose tissue and contributes to IR. Androgens also alter adipokine dynamics. Androgen excess leads to a decrease in circulating levels of insulin sensitizer adipokines, such as adiponectin . Apart from white adipose tissue, androgens can modify brown adipose tissue as well. Uncoupling protein-1 levels are decreased by the effect of androgen excess, resulting in lower brown adipose tissue activity in women with PCOS .

Androgen excess also decreases insulin sensitivity in the skeletal muscle in women with PCOS . Androgens reduce insulin-mediated glucose transport in skeletal muscle by affecting the insulin-signaling pathway at different levels. Androgen excess decreases insulin receptor phosphorylation in skeletal muscle cells of women with PCOS, which leads to IR . Hyperandrogenemia may also lead to impaired insulin secretion. Pancreatic β cell failure has been demonstrated in female mice following exposure to androgens .

Androgen receptors are expressed in various parts of the central nervous system . Through their actions on the central nervous system, androgens can modify metabolic homeostasis . In an experimental mouse model, key metabolic and reproductive traits of PCOS including irregular menses, obesity, and dyslipidemia, did not develop after dihydrotestosterone treatment in neuron-specific androgen receptor knockout mice . These data suggest that the direct action of androgens on the brain is associated with metabolic and reproductive disturbances in PCOS.

Impact of altered metabolic status on androgen action

Although IR is more severe in overweight and obese individuals with PCOS, it is also frequently seen in lean PCOS subjects . Due to decreased sensitivity to insulin in specific tissues such as adipose tissue, muscle and liver, a higher amount of insulin is required, and compensatory hyperinsulinemia emerges. However, women with PCOS exhibit a specific form of IR called selective IR. Despite the existence of IR in adipose tissue, muscle and liver, hypothalamo-pituitary-ovarian (HPO) axis remains sensitive to insulin actions .

Insulin upregulates gonadotropin-releasing hormone (GnRH) expression in hypothalamus and enhances gonadotropin response to GnRH at pituitary level. Increased gonadotropin stimulates ovarian androgen secretion and contributes to ovarian dysfunction. Ovary is also affected by hyperinsulinemia. Insulin acts like a co-gonadotropin and induces ovarian steroidogenesis. Moreover, not only ovarian steroid production but also adrenal steroid production is increased due to excess insulin activity. Insulin indirectly provokes corticotropin-releasing hormone (CRH) secretion from the hypothalamus and potentiates the hypothalamo-pituitary-adrenal axis. Finally, insulin inhibits sex hormone-binding globulin (SHBG) synthesis and secretion in liver, and leads to increased free (bioavailable) androgen levels ( Fig. 1 ) .

Metabolic dysfunction and PCOS phenotype

The clinical presentation of PCOS is not uniform. Four different phenotypes of PCOS have been defined so far; phenotype A: Hyperandrogenism (HA) + ovulatory dysfunction (OD) + polycystic ovarian morphology (PCOM), phenotype B: HA + OD, phenotype C: HA + PCOM and phenotype D: OD + PCOM . Although HA seems to be a key factor in the pathophysiology of PCOS and the main predictor of the associated metabolic dysfunction, different pathophysiological processes may be involved in different PCOS phenotypes, especially in nonhyperandrogenic phenotype (phenotype D).

Identification of phenotype in each PCOS patient is important. Cardiometabolic risks appear to be particularly higher and more severe in PCOS phenotypes characterized with hyperandrogenism and anovulation. Metabolic disturbances, such as glucose intolerance may develop earlier than expected in these phenotypes, especially in the presence of accompanying obesity . Therefore, phenotypic characteristics of the patients should be considered while deciding which intervention to choose and when, in order to treat metabolic disturbances in PCOS.