**8.2 Androgen receptor blockers**

Recommendations from the International evidence-based guideline for the assessment and management of Polycystic Ovary Syndrome [7] recommend that AR blockers be used mostly towards the dermatological manifestations of the syndrome, not the metabolic ones. AR blockers can be used in addition to OCPs and insulin sensitizers to ameliorate excessive hair growth or hirsutism. Antiandrogen monotherapy is not recommended because of its teratogenic potential [124]. In the US, the AR blocker most commonly used in the clinic is spironolactone [124]. Spironolactone is also a progesterone and mineralocorticoid receptor blocker. Blockade of the mineralocorticoid receptor causes a diuretic effect that potentially can cause serious side effects such as hyperkalemia and hypotension [124]. Other potent antiandrogens are flutamide and cyproterone acetate. Cyproterone acetate is not currently available in the US and recently has been linked to an increased risk of meningioma among high dose users [125]. Flutamide use has been associated with severe hepatoxicity, and it is not FDA-approved for use in women with PCOS. Bicalutamide, an androgen receptor blocker, has been used in combination with OCPs in a study where hirsutism was the primary endpoint [126]. Safe, effective, and specific AR blockers are necessary to positively impact the management of the cardiometabolic risk factors in women with PCOS.

## **8.3 Insulin sensitizers**

Metformin is the most frequent insulin sensitizer agent used in women with PCOS [124, 127]. Obesity exacerbates the IR in women with PCOS, and weight loss in women with PCOS ameliorates it. However, weight loss is very difficult to achieve and sustain. Since insulin resistance is present in obese and lean women with PCOS, it has been proposed to be the key factor in mediating the adverse cardiovascular risk profile observed in PCOS subjects. Metformin has been used for years to treat insulin resistance in women with PCOS. The effectiveness of metformin to improve IR and prevent T2DM in women with PCOS is unclear. Metformin reduces the risk of progression from insulin resistance to T2DM in only 30% of patients in the Diabetes Prevention Trial [128]. Metformin can lower testosterone levels; thereby, some of the beneficial effects in women with PCOS may be due to lowering their androgen levels [129]. A recent metanalysis showed no effect of metformin on indexes of fasting insulin, homeostasis model assessment of insulin resistance, sex hormone-binding globulin, high-density lipoprotein cholesterol, total cholesterol, triglycerides, fasting blood glucose, and androstenedione in overweight women with PCOS [130]. Long-term prospective randomized controlled trials assessing the effect of metformin on cardiovascular morbidity and mortality in women with PCOS are not available at present.

## **8.4 Incretins**

Glucagon-like peptide-1 (GLP-1) is an incretin that potentiates the foodmediated release of insulin leading to a decrease in plasma glucose levels and delaying gastric emptying, and exerting satiety effects. Several short-term clinical trials showed that administration of GLP-1 receptor agonists caused significant improvement in metabolic abnormalities and also cause weight loss in women with PCOS [131]. Similar beneficial effects of GLP-1 were observed in hyperandrogenic female rats [132]. In contrast, we recently reported that administration of the GLP-1 receptor agonist (GLP-1 RA) liraglutide to a model of postmenopausal PCOS, elicits several beneficial metabolic effects but the BP-lowering effect of GLP-1 RA was blunted compared with control rats [64]. These results suggest that GLP-1 RA treatment could improve DHT-induced metabolic and BP abnormalities in reproductiveaged PCOS. It is possible to hypothesize that GLP-1 RA's BP-lowering effect in PCOS animals could be mediated by estrogens, which are significantly decreased in postmenopausal PCOS rodents, leading to the lack of effect in those aging animals. This concept of a role for estrogens in the age-differential effect of GLP-1 RA in BP regulation in PCOS is an exciting hypothesis that needs to be tested.
