**7. Hyperandrogenism is a key factor mediating insulin resistance in PCOS**

IR is recognized as a significant contributor to metabolic homeostasis disturbances in women with PCOS, especially in obese individuals, due to increased lipid accumulation in muscle and liver from impaired insulin signaling. Decreased insulin sensitivity and glucose tolerance have been reported in women with PCOS versus healthy individuals in several studies [84]. Additionally, both metabolic syndrome and hyperinsulinemia have a characteristic increase in low-grade inflammation markers [85], which has also been observed in women with PCOS [86]. IR prevalence among women with PCOS is varied between different measurement methods but is reported to be between 40% and 70%, approximately [87]. Women with insulin receptor mutations, and thus high levels of insulin, develop severe hyperandrogenemia [88].

Hyperandrogenism and or hyperandrogenemia is present in about 80% of women with PCOS [89]. Both circulating testosterone and its precursor androstenedione have been shown in positive association with the severity of metabolic dysfunction in women with PCOS [90]. The prevalence of type 2 Diabetes Mellitus (T2DM) in the US is 10-times higher among young women with PCOS compared to

#### *Androgens and Cardiovascular Risk Factors in Polycystic Ovary Syndrome DOI: http://dx.doi.org/10.5772/intechopen.96005*

age-matched, normal-cycling women [91]. Insulin and insulin signaling can influence androgens in women with PCOS. Insulin can stimulate the ovaries of theca cells to produce androgens. This dysfunctional androgen stimulation is suggested to induce hyperandrogenism in women with PCOS in a positive feedback mechanism with hyperinsulinemia. Specifically, the P450c17 (CYP17A1) enzyme in the theca cells has been addressed as having modulated activity in response to insulin and IGF. This is specifically relevant to PCOS because the enzyme is necessary for the production of androgens [92]. Additionally, high circulating plasma insulin may itself influence androgen availability due to its suppression of sex hormone-binding globulin (SHBG) synthesis, a steroid transport protein, and subsequent increase in the bioavailability of unbound testosterone [93]. PCOS patients have been shown to have reduced SHBG level [94], that could lead to increases in free T. In addition to its role in glucose homeostasis and metabolism, in the central nervous system insulin can effectively modulate food intake and signal satiety. Insulin has also been shown to influence gonadotropin-releasing hormone (GnRH) in the hypothalamic neurons by increasing its expression and activity [95]. In PCOS, GnRH pulse frequency modifications and subsequent LH timing alterations have been suggested as another potential trigger to prevent inhibition of androgens and lead to their increased biosynthesis [96, 97]. This relationship illustrates the importance of the interplay between the neuroendocrine system, insulin, and androgen production in women with PCOS. Clinically, in a randomized controlled trial, women with PCOS treated for three months with Resveratrol, a natural polyphenol able to reduce androgen production via CYP17A1, showed a 30% reduction in fasting insulin and increased insulin sensitivity [98]. Together, these findings suggest the potential therapeutic importance of androgen targeted drugs to treat IR in PCOS patients.

The main target tissues of insulin action and subsequent insulin resistance and dysfunction include white adipose tissue, skeletal muscle, and the liver. Androgens play a significant role in each of these insulin-responsive target tissues in women.

#### **7.1 Androgen actions on the adipose tissue**

Androgens regulate several different aspects of adipose cell function and lipid accumulation and are themselves synthesized by the adipose tissue. Adipose tissue is known to play a role in whole-body insulin sensitivity, inflammation, and intracellular stress. The adipose tissue is crucial for the storage of lipids, and adipocytes are the primary storage cells to serve this purpose. The adipose tissue can also release adipokines, like leptin and adiponectin, which may directly influence insulin sensitivity, inflammatory response, fatty acid oxidation, sex steroids, and even energy expenditure. Several adipokines are dysregulated in PCOS [99]. Women with high androgens have been shown to display a fat distribution pattern more similar to men, with increased abdominal visceral adipose accumulation [100]. Although the expansion of the subcutaneous adipose depot is also associated with PCOS [101]. Additionally, after administration of androgen antagonists, women with PCOS were shown to lose visceral adiposity, which suggests that androgens have a role in fat distribution [102]. This increased adiposity is considered to be due to a hypertrophic adipocyte expansion compared to a hyperplasic response, which is more highly indicative of metabolic syndrome. Hypertrophy of adipocytes is influenced by androgens directly by increasing visceral adipocyte mass. Women with PCOS have an increase in adipocyte size [103]. Androgens influence adipogenesis by limiting the differentiation of preadipocytes. In preadipocytes taken from the subcutaneous adipose depots of healthy women were shown to have impaired insulin-induced glucose uptake in response to testosterone [104]. This study suggests that androgens, via the androgen receptor, mediate insulin resistance in adipocytes. Interestingly, the relationship between circulating testosterone and elevated fasting insulin in PCOS is independent of adiposity [105], supporting that insulin resistance is intrinsic to PCOS and may be mediated by hyperandrogenemia independently of obesity.

## **7.2 Androgens actions on the skeletal muscle**

Glucose can be used as a primary fuel source in the skeletal muscle when insulin is high, instead of fatty acids, or can be stored in the form of glycogen for future periods of exercise. Glucose may enter the skeletal muscle in response to insulin by the specific cell surface transporter GLUT4. Skeletal muscle alone may show insulin resistance, which is defined as a reduced ability for glucose uptake and glycogen storage in response to insulin. Skeletal muscle serves as a primary organ for glucose disposal [87].

Several studies suggest that adiponectin and lower AMPK phosphorylation may be important in skeletal muscle-specific insulin resistance in PCOS [106], even in non-obese hyperandrogenic women. Adiponectin is an adipokine that has an inverse relationship with a degree of adiposity. Adiponectin has both insulin-sensitizing properties, including skeletal muscle, and is decreased by androgens [107].

Androgens have been shown to alter lean muscle mass. Both healthy and women with PCOS who exercised using resistance strength training, which focuses on skeletal muscle contractions, along with aerobic training showed reduced fasting glucose concentration and serum testosterone profiles [108]. Together, this suggests the potential to target the skeletal muscle to improve insulin-sensitive tissue sensitivity and improve hyperandrogenemia.

### **7.3 Androgens actions on the liver**

Of crucial importance following a meal, glucose is allowed entry into the liver and stored as glycogen in the liver due to the effects of insulin. In a healthy adult, storage is especially important to help varying energy levels in the body to prevent blood glucose from changing rapidly between meals and allow it to be released when energy is needed.

Hyperandrogenemia in PCOS has been associated with several different disturbances of the liver. Alanine aminotransferase (ALT), often used as a clinical biomarker of liver injury, has been shown in positive association to androgen levels in young women with PCOS [109]. Women with PCOS with high androgens display a distinct metabolic phenotype different than women with normal levels of androgens. There is evidence that women with PCOS are at an increased risk of developing a spectrum of nonalcoholic fatty liver disease, the most common liver disease. Women with PCOS and obesity have an increased risk for NAFLD [110]. Interestingly, even after adjusting for BMI, other PCOS cohorts have shown that hyperandrogenemic women with PCOS have a significantly higher liver fat than women with normal levels of androgens [111]. Those findings suggest that androgens may be an independent risk factor for steatosis and the development of NAFLD.
