Hyperandrogenism in Women. Группа авторов

Чтение книги онлайн.

СКАЧАТЬ before and after cross-sex hormonal therapy owing to the gender reassignment, confirmed results found in animal studies: visceral and subcutaneous adipocytes of male-to-female transsexuals (MtoF) after combined antiandrogen and oestrogens showed a significant reduction in basal lipolytic activity along with an increase in cells size, whereas diametrically opposite results were found in the adipocytes coming from female-to-male transsexuals (FtoM) after T supplementation [39].

      The Role of the AR

Given that T acts through the AR, its expression and function could also play a role. In female and male rats, AR and oestrogen receptor (ERα and ERβ) densities vary according to the type of adipose tissue rather than the sex, with VAT showing higher AR density than SAT. Moreover, in vitro studies in mouse-derived cell models (3T3-L1), oestrogens seem to raise both AR and ERα, highlighting the fact that oestrogens can positively modulate both androgens and oestrogens action on adipose tissue; glucocorticoids stimulate the AR expression, even though they inhibit the androgen effects by means of inducing the inactivation of DHT to 5α-androstane-3α,17β-diol (AD) especially in VAT in both sexes [40, 41].

The first exon of AR is involved in the transactivation of the receptor and is characterized by a polymorphism: a higher number of CAG repeats is associated with lower transcriptional activity [42]. In adolescent males, low and intermediate CAG repeats is associated with higher VAT; in adult men, it negatively correlates with muscle mass but not with VAT [43]. Unfortunately, results on this topic are still conflicting, as other studies found no correlation between AR polymorphism and body composition [44–46].

      Androgen Metabolism in Adipose Tissue

In adipose tissue, one of the main steroid-converting enzymes is aldo-keto reductase 1C (AKR1C) family which encompass 3 members (AKR1C1, AKR1C2, and AKR1C3) showing different substrate specificity. In men, AKR1C2 (3α-hydroxysteroid dehydrogenase), in particular, converted DHT into AD and, then, in ADG (inactivation androgens pathway) and its expression is increased in SAT when compared to VAT. Therefore, in the eugonadal male, the VAT adipogenesis is inhibited, given that DHT is poorly inactivated. Conversely, in obese men ARK1C2 expression is increased in VAT when compared to lean subjects and, moreover, visceral adipocytes are characterized by higher density of AR when compared to subcutaneous. Thus, hypogonadism, which occurs in men with severe obesity, facilitates fat deposition in VAT [15, 47]. On the other hand, in obese women as well as in those with PCOS, AKR1C3 converts A into T (activation androgens pathway) through its 17β-hydroxysteroid-dehydrogenase activity [48]. In vitro (adipose cellular supernatant) and in vivo (adipose tissue microdialysis) studies showed that AKR1C3 expression in the adipose tissue of PCOS is increased by insulin resistance [49].

Another key enzyme in androgen metabolism is 5α-reductase, in particular the type 1 isoform: it is expressed in different tissues, including the adipose one of both sexes, and converts T into DHT. Indeed, its inhibition by means of dutasteride (an inhibitor of both isoforms of 5α-reductase) facilitates fat deposition, in particular, in the liver of adult men, while its induction leads to hirsutism in obese women with PCOS [50–53].

      A third class of enzymes is represented by UDP-glucuronosyl transferase (mainly UGT2B17 and UGT2B15) which is involved in the glucuronidation of 5α-end metabolites such as ADG and ADTG (inactivation androgens pathway). Since 5α-reductase activity is difficult to quantify in clinical practice, the glucoronate metabolites above quoted have been proposed as its indirect parameter. Indeed, both ADG and ADTG positively correlate with BMI in overweight adult men, whereas this correlation is negative in obese women without hirsutism and in severely obese hypogonadal men (BMI >40 kg/m²), indicating that 5α-reductase activity is very sensitive either to the circulating androgens or to those locally produced in the target tissues [20, 51, 54].

Adipose tissue is regarded as the major source of endogenous oestrogens after the gonads in both sexes, thanks to the aromatase activity, having C19 steroids as substrate [12, 55]. Given that its contribution increases with age and considering the expression of ER in adipose tissue, regional differences in aromatase expression (higher in SAT of thighs and buttocks than in VAT) have been associated with distribution of FM (i.e., gynoid fat distribution) [56, 57].

In conclusion, beside the thought of adipose tissue as a steroid reservoir, it should be considered an organ with intense enzyme activity by androgen synthesis, inactivation and conversion to oestrogens, co-regulating their metabolic clearance and production rates, eventually [58–60].

      Androgen Deficiency and Body Composition: Clinical Studies

      Several clinical conditions can be taken into account when describing the interaction between androgen deficiency and body composition. As specific clinical examples, obesity, Klinefelter syndrome (KS), prostate cancer and MtoF in men and hypopituitarism in women are reviewed in the present paragraph.

Obesity is the epidemic public health problem of the century: it is estimated that 1.9 billion adults are overweight and 600 million are obese worldwide [61]. In men, obesity and androgen levels reciprocally influence each other, as described in the “hypogonadal-obesity cycle”: obese subjects have higher VAT; VAT is characterized by aromatase activity, converting T to oestradiol as already stated; oestradiol suppress LH release, worsening T deficiency; low T favours differentiation of FM, instead of FFM [20, 62]. Moreover, visceral adiposity is associated with hyperinsulinism and insulin resistance, leading to decreased synthesis of sex hormone binding globulin (SHBG) in the liver and T in Leydig cells [19, 21, 63, 64]. Finally, obesity and metabolic syndrome have been associated with low-grade inflammation in the hypothalamus and impairment of the GnRH via the kisspeptin pathway induced by tumour necrosis factor-α [65, 66]. Current guidelines on obesity management recommend weight СКАЧАТЬ