Effects of testosterone treatment on body fat and lean mass in obese men on a hypocaloric diet: a randomised controlled trial
The major novel findings of this RCT are that, among obese men with low to low-normal testosterone submitted to a weight loss program, testosterone treatment decreased total fat mass and visceral adipose tissue, and protected against loss of total and appendicular lean mass. At the end of the initial 10-week VLED phase, while men lost substantial amounts of weight similar to previous successful VLED studies [11], there were no differences in weight loss or body composition changes between the two groups. However, differences emerged in the weight maintenance phase, during which men receiving testosterone maintained weight loss (P?=?0.62), while there was marginal weight regain in the placebo group (P?=?0.06). At study end, there were marked differences in body composition between groups, and men receiving testosterone had greater reductions of fat mass (–2.9 kg) and visceral fat area (–2678 mm2) compared to placebo. After the VLED phase, men receiving testosterone regained lean mass (3.3 kg, P??0.001) in contrast to placebo (0.8 kg, P?=?0.29), so that at study end, lean mass was 3.4 kg higher in testosterone-treated men. Overall, our results indicate that, compared to men receiving placebo who lose both fat and muscle mass during diet, testosterone treatment shifts this weight loss to almost exclusive fat mass loss.
Our trial has several strengths distinguishing it from previous testosterone trials, most importantly, the successful implementation of a rigorous weight loss program and the exclusive focus on men with established obesity. By contrast, previous RCTs examining the effects of testosterone on body composition recently meta-analysed [8] were neither designed for weight loss nor had obesity as a selection criterion. Moreover, only a few studies, not all placebo controlled, have combined testosterone treatment with lifestyle measures. A recent meta-analysis of these studies [17] suggested that testosterone treatment may have added benefits on body composition, consistent with our findings. We confirmed lowered baseline testosterone levels using LCMS/MS technology [12], used intramuscular testosterone eliminating compliance issues for a relatively long duration in a double-blind placebo controlled design, and attrition rate was relatively low. Compared to men completing the study, non-completers had lost less body weight and less fat mass at the end of the VLED phase of the study. Therefore, if anything, this would be expected to underestimate the benefits of testosterone treatment, especially as the drop-out rate was higher among men assigned to placebo compared to testosterone treatment.
Although it may be expected that the effects of testosterone treatment are attenuated in the context of a rigorous weight loss program, the reduction of fat mass observed here compares favourably with the 1.6–2.0 kg reduction reported in meta-analyses of RCTs not incorporating weight loss measures [18, 19]. This may be because we focused on obese men with a confirmed low testosterone receiving effective testosterone treatment. This may also explain the robust increase in lean mass of 3.4 kg, compared to 1.6–2.7 kg in previous meta-analyses [18, 19]. Testosterone treatment did not prevent the loss of lean mass during the 10-week VLED suggesting that testosterone treatment lacks anabolic actions during acute severe caloric restriction. However, 10 weeks of treatment may be too short to manifest changes in body composition, since testosterone-mediated changes in lean mass are evident only after several months [18, 19].
Testosterone treatment significantly reduced the metabolically important visceral fat even in the context of a weight loss program. Previous RCTs of testosterone therapy, while not incorporating a weight loss program, did not find a consistent reduction in visceral fat [14, 15, 20, 21], most likely because of small trial size [15], use of oral testosterone therapy [20], or less precise methodology to quantify visceral adipose tissue [20]. None of these RCTs specifically targeted obese men.
Interestingly, the differences in body composition were evident despite the modest increase in endogenous testosterone levels in placebo-treated men similar to previous weight loss studies [22]. Indeed, this increase by 2.9 nmol/L in TT and 30.3 pmol/L in free testosterone with 10.8 % weight loss was very similar to that reported in a meta-analysis of low caloric diet studies [23]. Thus, the endogenous rise in testosterone subsequent to diet appears not to be sufficient to prevent diet-associated loss of lean mass.
What are the potential mechanisms by which testosterone treatment leads to these changes in body composition? Testosterone, via androgen receptor signalling, inhibits stem cell differentiation into adipocytes and favours myogenesis [6]. Androgen receptor signalling in mature adipocytes promotes lipolysis [24] and activates anabolic pathways in myocytes [25]. The effect on fat mass may also be mediated by aromatisation to estradiol [26]. Testosterone may also have motivational effects leading to increased physical activity; in RCTs, testosterone treatment reduces fatigue and inertia [27], and androgen-deficient mice have decreased voluntary activity [28]. We advised subjects to perform at least 30-minutes of moderate-intensity exercise each day. Subjects completed exercise questionnaires and accelerometer testing, with feedback given, to reinforce and encourage participation in exercise. Both men receiving testosterone and placebo increased their activity during the weight loss phase. However, only men receiving testosterone (P?=?0.03) but not placebo (P?=?0.28) maintained increased activity levels at study end, suggesting that increased physical activity may have contributed to the observed changes in body composition in testosterone-treated men.
Supervised exercise programs may promote loss of fat mass and attenuate loss of muscle mass during weight loss, but are less effective than caloric restriction to achieve weight loss. Exercise interventions are not well characterised for obese men with low testosterone and require high volume interventions, which may be difficult to achieve even in a dedicated RCT [29]. Only few studies have randomised obese men receiving caloric restriction to exercise programs. The effects of testosterone reported here compare favourably; systematic reviews have estimated that the addition of exercise to energy restriction increases the loss of fat mass by 1.6 kg [30] but does not fully protect against the loss of lean mass that occurs with diet, reducing this by 50 % [2]. In the Look Ahead study, men, despite assignment to an intensive lifestyle intervention, lost 2.5 kg of lean mass in the first study year [31].
Metabolic parameters, evidenced by decreases in HOMA-IR, HbA1c, triglycerides, and increases in HDL levels improved in both groups. Testosterone treatment had no added benefit, despite resulting in changes in body composition expected to be metabolically favourable. Our study was not designed to examine this outcome, and men enrolled were relatively healthy, with a low proportion of men being diabetic or dyslipidaemic at baseline.
Consistent with previous studies, we observed a significant increase in haematocrit in testosterone-treated men. Overall, serious adverse events were few and not statistically different between groups, although this study was not powered to assess safety. Ten percent of the participants assigned to testosterone treatment had an increase of above 1 ?g/L in PSA during the study, similar to the 6 % among men allocated to testosterone in the recent testosterone trials [32]. However, the significance of this biochemical increase is uncertain, and although definitive long-term studies are lacking, the current evidence does not suggest that testosterone treatment leads to clinically meaningful adverse prostate outcomes.
Limitations include the enrolment of relatively healthy men motivated to lose weight subjected to a professionally administered diet and frequent monitoring. Despite preservation of lean mass, testosterone treatment, with the exception of increased grip strength, did not affect muscular performance. Previous studies have suggested that testosterone treatment improves physical performance primarily in frail, mobility-limited men [33, 34]. Although we did not include a supervised exercise program, exercise recommendations were reinforced at every visit, and men assigned to testosterone but not placebo, had increased activity levels. We selected participants based on a TT of less than 12 nmol/L to include men with modestly reduced levels typical of the majority of obese men [3]. This allowed us to capture the large population in whom testosterone treatment (be it replacement or pharmacological) is more controversial than in men with more profound reductions in testosterone, or indeed with organic hypogonadism. While TT may reflect adaptation to obesity-associated lowering of SHBG, it is important to emphasize that 97 % of our study population had a baseline free testosterone (calculated from LCMS/MS total testosterone) of less than 243 pmol/L, the lower limit reported for healthy young men [4], and 89 % a level of less than 220 pmol/L, the cut-off for late onset hypogonadism [35]. While we did not find an added effect of testosterone treatment on diet-induced loss of body weight in this 56-week study, it is possible that the duration of our study was insufficient, given that a recent meta-analysis of observational studies has suggested that testosterone treatment may be associated with time-dependent weight loss that may only be evident after 2 years of treatment [36]. Finally, our study was not designed to examine cardio-metabolic outcomes.