**2. Androgen synthesis in PCOS**

In women, the concentration of plasmatic androgens is higher than of estrogens [13]. Excess androgens are secreted by the ovaries in most women with PCOS, but in 20–30% of them, excess androgens are also secreted by the adrenal gland. Plasma levels of total and free testosterone (T), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and androstenedione are significantly elevated in PCOS [2, 14]. Androstenedione, DHEA, and DHEAS are pro-hormones synthesized by the adrenal gland, they circulate at a higher concentration than T. Those pro-hormones could be converted into more potent T and DHT in the adipose tissue, liver, and the skin [3, 15]. Depending on the type of androgens measured, hyperandrogenemia is present in ~80% of PCOS diagnosed cases [16]. Recently, a study showed that the 11-oxygenated androgens, 11β-hydroxyandrostenedione, 11-ketoandrostenedione, and 11-ketotestosterone, represent the majority of circulating androgens in women with PCOS [17]. Moreover, 11β-hydroxyandrostenedione, 11-ketoandrostenedione circulating levels positively correlate with circulating insulin and IR assessed by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) in women with PCOS [17]. The HOMA-IR is an index of IR calculated according to the formula: fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5 [18]. The HOMA-IR is extensively used in epidemiological studies, but rarely in the clinical setting. On the other hand, the hyperinsulinemic eulgycemic clamp is considered the gold standard to determine IR; but, unfortunately, it is impractical for routine use in the clinic [19]. Local production or activation of androgens at the tissular level have been reported, and they may constitute a key factor in the cardiometabolic abnormality in these patients. For example, the subcutaneous adipose tissue in women with PCOS has a higher concentration of androgens than in control subjects [20, 21]. Testosterone can be converted to its more biologically active form, DHT, by the 5α-reductase, and to estradiol by the aromatase. DHT is more biologically active than testosterone, binding to the androgen receptor (AR) with a 2-fold higher affinity and a 5-fold decreased dissociation rate compared to testosterone [22]. The synthesis of androgens in women is complex. The local activation of androgens is not well understood during normal physiology or diseases such as PCOS.

## **3. Androgen receptor in PCOS**

AR is a member of the steroid hormone receptor superfamily, a class of receptors that function through their ability to regulate the transcription of specific genes. It contains an N-terminal transactivation domain, a central DNA-binding domain, and a C-terminal ligand-binding domain [23]. Androgens act by binding to the

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

AR and subsequently translocate to the nucleus to act as a transcription factor and promote gene expression. The unbound AR is inactive in the cytoplasm as a large dynamic heterocomplex, together with heat shock proteins (Hsp70 and Hsp90) and their co-chaperones [24]. Ligand binding dissociates the AR from heat shock proteins, causing its activation and translocation to the nuclei to exert its transcription regulatory role.

Androgen actions in the cardiovascular system could be genomic or nongenomic [25], although most of the basic research data available derived from experiments performed in male rats. The activity of AR is modulated by a polyglutamine tract of variable size in its N-terminal transactivation domain. This polyglutamine tract is encoded by a highly polymorphic CAG repeat sequence in exon 1 of the AR gene located on the X-chromosome. Shorter CAG repeats lengths in exon 1 of the AR gene are associated with a stronger transcriptional activity of the AR. The shorter CAG repeats have been associated with the androgen actions in male conditions such as prostate cancer [24] and benign prostatic hyperplasia [26]. Moreover, abnormal expansion of the CAG repeat length leads to Kennedy's disease, which is associated with hypogonadism and impaired spermatogenesis in men [27, 28]. However, studies in women with PCOS did not find significant differences in the mean values of CAG repeat sizes compared to controls [29, 30]. The fundamental role of AR in the development of metabolic and reproductive features of PCOS was demonstrated by the lack of effect of DHT in AR knockout (ARKO) mice, supporting the fundamental concept that androgen excess, via AR activation, is a key factor in PCOS [31]. More recent studies further demonstrated that AR signaling pathways within the brain and adipocytes are key in the physiopathology of metabolic PCOS characteristics [32]. Pharmacological strategies safely targeting the brain and adipocyte AR-could constitute a novel and effective way to ameliorate the cardiometabolic complications in PCOS.
