Testosterone for the treatment of obesity in hypogonadal men

Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Saad F, Aversa A, Isidori AM, et al. Curr Diabetes Rev 2012;8(2):131-143.

A recent review of the PubMed literature evaluated studies reporting data on the role of testosterone in counteracting obesity and its associated complications in men with testosterone deficiency (hypogonadism).1 The role of testosterone in this regard was summarized from three perspectives: i) evidence from epidemiological and observational studies; ii) evidence from androgen deprivation therapy (ADT), mainly in men undergoing treatment for prostate cancer (PCa); and iii) evidence from testosterone treatment of men with testosterone deficiency.

The aim of the present review was not to advocate testosterone in the anti-obesity treatment armamentarium but to define more precisely its role in the treatment of obesity and its associated complications in hypogonadal men, while balancing the potential benefits against its (long-term) risks. Until now, testosterone treatment in this patient population has not been seriously considered.
Key Points


Low testosterone levels are associated with decreased lean body mass and, more importantly, epidemiological evidence shows that low testosterone is an independent risk factor for the metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM)2-4 and cardiovascular disease (CVD)5
The relationship between testosterone and obesity is complex6


A vicious circle exists whereby MetS suppresses testosterone biosynthesis; conversely, reduced testosterone predisposes and contributes to MetS onset7 and, in turn, obesity
The role of testosterone in MetS onset is demonstrated in men with PCa undergoing ADT and in men with T2DM. Testosterone treatment in these men decreased total lean body mass, increased total fat mass and, longer term, led to the development of MetS8,9
Testosterone and other sex steroid hormones play a fundamental role in regulating cellular metabolism plus accumulation and distribution of adipose tissues


In the DIMALITE (Diabetes Management by Lifestyle and Testosterone) study, 12 months of testosterone treatment combined with diet plus exercise reduced the waist circumference (a reliable indicator of visceral obesity) of men with newly diagnosed T2DM to a significantly greater extent than diet plus exercise alone (p<0.05), therefore reversing MetS and improving glycemic control10
Evidence suggests that testosterone levels decline with age and lifestyle changes may partially prevent or redress this decline10
An increasing body of evidence indicates a beneficial effect of testosterone on visceral fat,11 with changes in visceral fat correlating with changes in serum total testosterone.12 Furthermore, data from a number of randomized controlled trials confirm the beneficial effects of testosterone on body composition (i.e., increased lean body mass, decreased fat mass) and MetS parameters.13-30 An example of this benefit in elderly men is shown in Figure 1.29
Specific characteristics of obese individuals such as waist circumference and body mass index (BMI) also act as predictors of the effect of testosterone administration


In the double-blind, placebo-controlled Moscow study, changes in BMI and waist circumference demonstrated a progressive improvement in hypogonadal men treated with testosterone versus placebo recipients (p<0.001)31,32
Current interventions to reduce long-term weight loss in obese men, namely diet and exercise, are often unsuccessful,33 achieving only a transient effect following physicians’ advice to improve lifestyle


However, a systematic review of the literature concluded that exercise is an effective weight loss tool in men aged ≥50 years, with a BMI >25 kg/m2 to preserve fat-free mass and combat sarcopenic obesity following moderate weight loss induced by energy restriction34
While restoring testosterone to physiological values in hypogonadal men reduces fat mass and increases lean body mass, the net result can sometimes be a quantitatively less impressive loss of body weight35


Yet, the effect of testosterone administration on metabolism is biphasic: a rapid and acute improvement in insulin sensitivity is evident prior to loss of body fat, followed by a significant loss of total and visceral body fat over the long term
Since testosterone replacement is likely to promote a more active lifestyle, and given the rapid effects of its administration, patients should prepare for greater energy expenditure. However, physicians treating obesity should be cautious and aware of the risks of recommending exercise to obese hypogonadal men
Studies evaluating the long-term safety of testosterone have not been conducted
Physicians often hesitate to prescribe testosterone to men aged >50 years, fearing it will induce prostate cancer, yet there is no convincing evidence to implicate testosterone as the main factor in the development/progression of the disease36,37
While elevated hematocrit may be associated with stroke and coronary heart disease, data from large meta-analyses of placebo-controlled trials of testosterone administration to (elderly) hypogonadal men have not shown a link per se between increased hematocrit due to androgen supplementation, nor has an increased risk of stroke/any cardiovascular event in general been demonstrated38,39

What is known
Obesity is a growing worldwide problem, impacting health and quality of life and which, if it continues to grow, will become an even greater healthcare and economic burden. Any imbalance between food intake and energy utilization may result in the risk of obesity and related comorbidities including MetS, CVD, T2DM and testosterone deficiency (hypogonadism).

While limiting food intake, combined with moderate exercise, produces significant weight loss, maintains lean body mass and improves insulin sensitivity, it appears a difficult regimen to adhere to. Bariatric surgery is clinically effective for severely obese individuals compared with non-surgical interventions, but has limitations, e.g., patient reluctance to undergo such dramatic surgery and the risk of short- and long-term complications such as infection and nutritional deficiencies. Therefore, interest in testosterone has grown following data obtained from clinical and pre-clinical studies which have implicated a role for this agent in the pathophysiology of obesity.
What this study adds
Physicians managing obesity and its associated comorbidities may be unfamiliar or unaware of the physiology and pathophysiology of hypogonadism and its impact on body composition, therefore they may not consider seriously the potential of testosterone treatment in men with MetS, T2DM and CVD. Nevertheless, despite a lack of comparison studies, the extent of changes observed with testosterone therapy appear superior to (or at least as effective as) the majority of available drugs used to reduce excess fat mass. Furthermore, the mood-elevating action of testosterone in men with MetS may boost their motivation to lose weight by adhering to a regimen of diet and exercise, and reinforcing a more active lifestyle. However, physicians should be aware of and counsel their patients with hypogonadism about the risks of exercise for weight reduction.

There is a consensus of expert opinion that testosterone treatment in elderly men might be viewed as a responsible practice, provided certain guidelines are followed.40 Therefore, testosterone therapy may represent a useful agent in obesity management in hypogonadal men when combined with diet and exercise. Nonetheless, long-term safety studies in this patient population are urgently needed to provide convincing evidence that abdominal obesity and MetS are ameliorated by normalizing testosterone levels in hypogonadal men.

Figure 1: Parenteral testosterone undecanoate for 1 year improves body composition in elderly men
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References

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