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].
Androgen Excess and Body Composition: Clinical Studies
Three scenarios can be considered when describing the effect of androgen excess on body composition: in women, FtoM and PCOS; in both men and women, doping.
FtoM is the most common gender dysphoria; in this condition, a person with a female gender at birth has a male identity. It has a prevalence of 1:30,400 females, which is one third when compared to the prevalence of the MtoF transsexualism (1:11,900 males), based on the Netherlands and Belgium data [89]. Medical management is based on T administration; the following effects on body composition have been consistently reported: increase in body weight and muscle mass; quick depletion of SAT, with slower accumulation of VAT occurring in 1–3 years. Interestingly morphological changes include enlarged ovaries with a polycystic morphology [30, 89–91].
PCOS is the most common ovarian disorder associated with androgen excess in women. According to Rotterdam criteria, it can be diagnosed when 2 criteria are found between chronic oligo/anovulation, clinical or biochemical hyperandrogenism and polycystic ovaries on US, after excluding other aetiologies such as congenital adrenal hyperplasia, androgen-secreting tumours, Cushing syndrome, thyroid dysfunction, and hyperprolactinaemia; based on the combination of criteria, 4 phenotypes can be further classified [92]. Clinical series reported an association between PCOS and being overweight or obese; obesity is associated with insulin resistance; insulin has been shown to increase androgen synthesis by ovaries acting synergistically with LH and by adrenal glands with adrenocorticotropin (androgens further boosts VAT gain [93–95]. Other authors reported an increased androgens production by theca cells even when isolated in culture. The reciprocal association between insulin resistance and hyperandrogenism/ovulatory dysfunction are supported by the following evidence: metformin and bariatric surgery induce insulin sensitizing and weight loss, which are usually associated with decreased Ferriman-Gallwey score, androgen levels and in some patients to the resolution of PCOS; flutamide (a pure anti-androgen indicated for hirsutism) is associated with decreased VAT and insulin resistance [96].
Doping