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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 loss in overweight and obese men by lifestyle changes, pharmacotherapy and weight-loss procedures, including bariatric surgery [67]. Independently from the selected strategy, an inverse relation between BMI and T was also confirmed in this setting. In the European Male Ageing Study, a longitudinal survey on 2,736 community-dwelling men aged 40–79 years at baseline followed for a mean of 4.4 ± 0.3 years; a weight decrease of at least 10% (mean decrease of 13.7 kg) was associated with a statistically significant increase in total T (2.9 nmol/L) and SHBG (13.6 nmol/L); in particular, total and free T were associated with a cubic relationship with the percentage of weight loss, whereas this relationship was linear for SHBG [68]. In 58 men with BMI of 36.1 ± 3.8 kg/m², a 9-week of very low calorie diet followed by 12-month maintenance period was associated with a weight loss of 14.3 ± 9.1 kg and an increase in total T, free T and SHBG. In 22 men with BMI 44.9 ± 1.0 kg/m², Roux-en-Y gastric bypass surgery was associated with a BMI reduction of 16.6 ± 1.2 kg/m² and an increase in total T, free T, and SHBG after 2 years of follow-up; a decreased oestradiol was also reported [19]. A weight loss of at least 5–10% is needed for a significant increase of T, as recommended for other strong outcomes in obesity management [67]. As expected, bariatric surgery is more significantly effective in comparison with low-calorie diet, both on weight loss and on androgens [69]. Another option for weight loss is represented by T replacement therapy in hypogonadal subjects. Current guidelines on androgen deficiency syndromes recommend an active assessment of hypogonadism in all subjects with increased body fat and BMI by history and physical examination; if clinically suspected, total T and SHBG should be requested for the laboratory confirmation of the diagnosis [67, 70]. In these patients, T showed to be effective on weight loss and waist circumference reduction. In 362 men with obesity grades I, II and III under T undecanoate for up to 6 years, the mean change in BMI from baseline was –3.99 ± 0.14, –6.58 ± 0.16, and –8.79 ± 0.23 kg/m², respectively; the mean change in waist circumference from baseline was –9.24 ± 0.3, –12.29 ± 0.33, and –12.44 ± 0.36 cm, respectively [71]. In a meta-analysis of observational studies, T replacement therapy has been associated with a weight loss of –3.50 (95% CI –5.21 to –1.80) kg and a waist circumference reduction of –6.23 (95% CI –7.94 to –4.76) cm at 24 months; a significant reduction in fat and an increase in lean mass were reported [72]. A meta-analysis of randomized controlled trials by the same authors confirmed the significant change in body composition (in particular with parenteral T formulations), without any difference in body weight, BMI, and WC [73]. The effect of T is immediate, progressive and sustained [74].

When discussing the relationship between androgen levels and body composition, the attention is usually focused on FM loss, according to the hypogonadal-obesity cycle described above. We believe the increase in FFM to be more clinically relevant: LTM is the major determinant of basal metabolic rate; higher muscle mass is associated with improved physical performance [75, 76]. Thus, T replacement therapy induces weight loss, thanks to the increase of both basal and exercise-associated energy expenditure. For this reason, we routinely offer lifestyle measure, T replacement therapy (if not contraindicated and after treating obstructive sleep apnea syndrome) and gastric balloon, followed by bariatric surgery, to severely obese hypogonadal men. It is interesting to note that T supplementation induces VAT loss also in middle-aged obese men with normal T levels [19]. Rather than performing the replacement therapy with T, it has been proposed to increase androgen levels by targeting directly the hypothalamus: a clinical trial with Anakinra, a receptor antagonist of the pro-inflammatory cytokine interleukin 1 has been recently completed, but no results have been published at the time of writing of the present review [77]. Another option can be represented by treatment with antiestrogen (clomiphene), which has been associated with an improvement in serum T levels and a reduction in weight and insulin resistance in obese men with functional hypogonadism and metabolic disturbances [78].

KS is the most common sex-chromosome disorder, with a prevalence of 1:660 men, and the main cause of hypergonadotropic hypogonadism. Given the same BMI, they are characterized by decreased LTM and increased truncal fat and waist circumference when compared to controls [79]. When they were substituted with T, a non-significant decrease in truncal fat was found, explained by the authors with a possible insufficient replacement therapy [21]. Since to date no evidence that results of T replacement therapy in obese subjects can hardly be replicated in KS is available, it could suggest that other metabolic pathways or different active genes on the extra X chromosome may be involved in the definition of body composition in KS [30, 80, 81].

Prostate cancer is the second most common cancer in men, accounting for 1.1 million new cases and 307,000 deaths in 2012 [82]. Depending on staging, treatment options include watchful waiting, radical prostatectomy, radiation therapy, androgen deprivation therapy (ADT) and chemotherapy. ADT has been shown to be effective on survival outcomes and may be performed with GnRH analogues and androgen-blocking agents. Patients treated with ADT show an increased rate of FFM loss and FM gain when compared to controls. Prospective studies on type of adipose tissue have been inconsistent so far: some describe a prevalent increase of SAT, other of both SAT and VAT [83, 84]. The bulk of these changes occurs during the first 6–9 months of therapy and persists even after 2 years of suspension; a chronic inflammation could contribute to an increase of cardiometabolic risk in these patients [23, 85, 86]. For this reason, current guidelines suggest that T supplementation be cautiously considered even in prostate cancer survivors with low risk of recurrence and after at least 1 year of follow-up after surgery [87].

MtoF are generally treated before orchiectomy with antiandrogen and oestrogens with the aim of inducing feminization; following surgery, an oestrogen supplementation is performed. A significant lessening in FFM along with a rise in SAT and VAT as measured by MRI has been described [88].

Fewer studies have been conducted in hypoandrogenemic women; endogenous androgens are less than one-tenth those of man. One randomized controlled study on T replacement therapy in hypopituitary women showed an improvement in body composition: increased FFM, with no changes in FM and body weight when compared to placebo [81].