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

1. Saad F, Aversa A, Isidori AM, et al. Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Curr Diabetes Rev 2012;8(2):131-143.
2. Stanworth RD, Kapoor D, Channer KS, et al. Statin therapy is associated with lower total but not bioavailable or free testosterone in men with type 2 diabetes. Diabetes Care 2009;32(4):541-546.
3. Traish AM, Guay A, Feeley R, et al. The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction. J Androl 2009;30(1):10-22.
4. Traish AM, Saad F, Guay A. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J Androl 2009;30(1):23-32.
5. Yeap BB, Hyde Z, Almeida OP, et al. Lower testosterone levels predict incident stroke and transient ischemic attack in older men. J Clin Endocrinol Metab 2009;94(7):2353-2359.
6. Cattabiani C, Basaria S, Ceda GP, et al. Relationship between testosterone deficiency and cardiovascular risk and mortality in adult men. J Endocrinol Invest 2012;35(1):104-120.
7. Stellato RK, Feldman HA, Hamdy O, et al. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care 2000;23(4):490-494.
8. Hamilton EJ, Gianatti E, Strauss BJ, et al. Increase in visceral and subcutaneous abdominal fat in men with prostate cancer treated with androgen deprivation therapy. Clin Endocrinol (Oxf) 2011;74(3):377-383.
9. Levine GN, D'Amico AV, Berger P, et al. Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. Circulation 2010;121(6):833-840.
10. Heufelder AE, Saad F, Bunck MC, et al. Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl 2009;30(6):726-733.
11. Jones TH, Saad F. The effects of testosterone on risk factors for, and the mediators of, the atherosclerotic process. Atherosclerosis 2009;207(2):318-327.
12. Allan CA, Strauss BJ, Burger HG, et al. Testosterone therapy prevents gain in visceral adipose tissue and loss of skeletal muscle in nonobese aging men. J Clin Endocrinol Metab 2008;93(1):139-146.
13. Boyanov MA, Boneva Z, Christov VG. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male 2003;6(1):1-7.
14. Casaburi R, Bhasin S, Cosentino L, et al. Effects of testosterone and resistance training in men with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;170(8):870-878.
15. Crawford BA, Liu PY, Kean MT, et al. Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment. J Clin Endocrinol Metab 2003;88(7):3167-3176.
16. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA 2008;299(1):39-52.
17. Ferrando AA, Sheffield-Moore M, Yeckel CW, et al. Testosterone administration to older men improves muscle function: molecular and physiological mechanisms. Am J Physiol Endocrinol Metab 2002;282(3):E601-607.
18. Jones TH, Arver S, Behre HM, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 2011;34(4):828-837.
19. Kapoor D, Clarke S, Stanworth R, et al. The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2007;156(5):595-602.
20. Kapoor D, Goodwin E, Channer KS, et al. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006;154(6):899-906.
21. Kenny AM, Fabregas G, Song C, et al. Effects of testosterone on behavior, depression, and cognitive function in older men with mild cognitive loss. J Gerontol A Biol Sci Med Sci 2004;59(1):75-78.
22. Kenny AM, Prestwood KM, Gruman CA, et al. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci 2001;56(5):M266-272.
23. Marin P, Holmang S, Gustafsson C, et al. Androgen treatment of abdominally obese men. Obes Res 1993;1(4):245-251.
24. Page ST, Amory JK, Bowman FD, et al. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab 2005;90(3):1502-1510.
25. Sheffield-Moore M, Dillon EL, Casperson SL, et al. A randomized pilot study of monthly cycled testosterone replacement or continuous testosterone replacement versus placebo in older men. J Clin Endocrinol Metab 2011;96(11):E1831-1837.
26. Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab 1999;84(8):2647-2653.
27. Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 2010;95(2):639-650.
28. Steidle C, Schwartz S, Jacoby K, et al. AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J Clin Endocrinol Metab 2003;88(6):2673-2681.
29. Svartberg J, Agledahl I, Figenschau Y, et al. Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip. Int J Impot Res 2008;20(4):378-387.
30. Wittert GA, Chapman IM, Haren MT, et al. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A Biol Sci Med Sci 2003;58(7):618-625.
31. Kalinchenko SY, Tishova YA, Mskhalaya GJ, et al. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study. Clin Endocrinol (Oxf) 2010;73(5):602-612.
32. Saad F, Haider A, Giltay EJ, et al. Age, obesity and inflammation at baseline predict the effects of testosterone administration on the metabolic syndrome. Horm Mol Biol Clin Invest 2011;6:193-199.
33. Witham MD, Avenell A. Interventions to achieve long-term weight loss in obese older people: a systematic review and meta-analysis. Age Ageing 2010;39(2):176-184.
34. Chomentowski P, Dube JJ, Amati F, et al. Moderate exercise attenuates the loss of skeletal muscle mass that occurs with intentional caloric restriction-induced weight loss in older, overweight to obese adults. J Gerontol A Biol Sci Med Sci 2009;64(5):575-580.
35. Solomon TP, Sistrun SN, Krishnan RK, et al. Exercise and diet enhance fat oxidation and reduce insulin resistance in older obese adults. J Appl Physiol 2008;104(5):1313-1319.
36. Morgentaler A, Lipshultz LI, Bennett R, et al. Testosterone therapy in men with untreated prostate cancer. J Urol 2011;185(4):1256-1260.
37. Morgentaler A, Schulman C. Testosterone and prostate safety. Front Horm Res 2009;37:197-203.
38. Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci 2005;60(11):1451-1457.
39. Fernandez-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2010;95(6):2560-2575.
40. Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. Eur Urol 2009;55(1):121-130.

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