By Monica Mollica Iron Mag
Testosterone, historically believed to be important only for male reproduction and sexuality, has over the past decades transformed from niche hormone to multi-system player. A rapidly accumulating body of research is showing that testosterone is an important metabolic hormone with marked effects on energy metabolism and body composition.
In USA, 36% of the adult population are obese (BMI >30), (affecting a similar proportion of men and women) , and obesity prevalence is escalating worldwide. According to the McKinsey Global Institute (MGI) report “Overcoming obesity: An initial economic analysis”, obesity is “one of the top three preventable social burdens (along with smoking and violence/war/terrorism) generated by human beings” imposing an estimated annual global direct economic burden amounting to 2 trillion USD.
Obesity treatments with comprehensive lifestyle modification and/or drugs are notorious for their poor long-term efficacy and inability to achieve long-term weight loss maintenance.[5-9] Even with continued lifestyle treatment, significant weight regain occurs.[7, 9, 10] And obesity drugs have side effects which limit their long-term and widespread use. [11, 12] Therefore, new interventions are urgently needed to combat this alarming preventable threat to society.
Here I summarize a recent study that investigated the effects of long-term testosterone treatment – up to 8 years – on weight loss and waist size in 411 testosterone deficient men with obesity classes I-III.
• Testosterone therapy for up to 8 years results in progressive, continuous and sustained reduction in body weight, waist circumference and BMI, regardless of obesity grade and age.
• Improvements in obesity parameters are accompanied by significant improvements in glycemic control (fasting glucose and HbA1c), lipids (total cholesterol, LDL, HDL, triglycerides and total cholesterol:HDL ratio), liver transaminases, inflammation, blood pressure (both systolic and diastolic) and quality of life, regardless of obesity grade and age.
• Treating obese hypogonadal men with testosterone for 8 years is safe. Elevations in PSA and hematocrit stayed within normal ranges, and the incidence of prostate cancer is lower than expected from the prostate cancer incidence reported in the general population of men not treated with testosterone.
• Using testosterone therapy as a mode of obesity treatment may result in greater beneficial effects on body composition than diet and/or drug induced weight loss.
What is known
Obesity is the underlying driver of many chronic diseases and weight loss improves health, particularly cardio-metabolic risk factors  and reduces healthcare costs. Although lifestyle changes with diet and exercise are considered the first step in obesity treatment, by themselves lifestyle changes are inadequate for obesity treatment and successful long-term maintenance of weight loss.[5-9]
Obesity is a risk factor for incident testosterone deficiency and its consequences ; an excessive amount of body fat suppresses the HPT (hypothalamic-pituitary-gonadal) axis and thereby reduces testosterone production by multiple mechanisms; via increased insulin resistance, metabolic syndrome and diabetes [17, 18], and elevation in estradiol and cortisol levels.[19, 20] In line with this, cross-sectional analyses show that obese men have lower testosterone levels than age-matched non-obese men.[21, 22] Strikingly, the prevalence of testosterone deficiency in severely obese men may be as high as almost 80%. In the prospective Massachusetts Male Aging Study (MMAS), non-obese men who became obese had a decline of testosterone levels comparable to that of 10 years of aging. Another prospective study confirmed that weight gain results in a proportional decrease in testosterone levels at follow-up.
Many intervention studies show that testosterone therapy in obese men with testosterone deficiency reduces fat mass and increases lean body mass with concomitant weight loss and reductions in waist circumference and body mass index (BMI).[26-30] Notably, long-term testosterone therapy for up to 6 years in obese men with testosterone deficiency results in a significant and marked weight loss, and reduced waist circumference and BMI.[27, 31-34] Importantly, testosterone therapy results in sustained weight loss without recidivism and weight regain.[32-34]
Thus, it is possible that testosterone therapy in obese men with testosterone deficiency may prove useful in treatment of the underlying pathophysiological conditions of obesity. Support for this comes from experimental studies demonstrating that testosterone is an important metabolic hormone  that increases fat oxidation.[35-37] Accordingly, testosterone therapy in hypogonadal obese men has been suggested as a novel approach for the treatment of obesity.[38, 39]
What this study adds
The study by Saad et al. investigated effects of long-term testosterone therapy on anthropometric as well as metabolic parameters for up to 8 years (mean 6 years) in hypogonadal men with different degrees of obesity; class I (BMI 30–34.9; mean age: 58 years), class II (BMI 35–39.9; mean age: 60 years) and class III (BMI ⩾ 40 kgm−2; mean age: 60 years).
All 411 obese, hypogonadal men received testosterone therapy in urological clinics, which comprised two independent observational registries. All men received long-acting injections of testosterone undecanoate in 3-monthly intervals. Figure 1 illustrates how the treatment elevated testosterone levels, which are also given numerically in table 1.
Figure 1: Trough levels of total testosterone in hypogonadal men in obesity classes I, II, and III receiving long-term testosterone treatment.
Figure from Saad et al. 2015 
In all three classes of obesity, testosterone therapy resulted in significant weight loss and decrease in waist circumference and BMI, as outlined in the table 1 and figure 2a to 2d below.
Table 1: Changes in obesity parameters and total testosterone levels for up to 8 years (mean 6 years).
* Note: When interpreting the elevations in testosterone levels (total and free), one has to bear in mind that these reported levels are trough levels, i.e. the lowest level measured immediately before the next injection. Pharmacokinetic data show that after one injection of testosterone undecanoate it takes 9 days to reach Cmax (concentration maximum, i.e. the peak level) at 923 ng/dL (32 nmol/L), and 70.2 days for half of the injected testosterone dose to be eliminated from the body (i.e. t½ = elimination half-life, is 70.2 days). Mean levels in the lower normal range – but significantly higher compared with baseline values – can be maintained until approximately 12 weeks after one injection. While these pharmacokinetic data were derived in non-obese men – and will likely differ in obese men – it does give a rough guideline when interpreting testosterone levels during testosterone treatment.
The figures below illustrate graphically the reductions in waist circumference, weight, BMI and percent weight loss.
Figure 2a to 2d: Reductions of waist circumference (a), body weight (b), BMI (c) and body weight (d) in hypogonadal men receiving long-term testosterone treatment.
All obesity groups also experienced significant improvements in metabolic parameters; glycemic control (fasting glucose and HbA1c), lipids (total cholesterol, LDL, HDL, triglycerides and total cholesterol:HDL ratio), liver transaminases, inflammation and blood pressure (both systolic and diastolic) all improved. This was accompanied by a marked and significantly increased quality of life, regardless of obesity class.
Subgroup analyses to assess the effectiveness of testosterone therapy in patients ⩽ 65 years old (n = 323) and in patients >65 years old (n = 88) showed that testosterone therapy is equally effective in improving obesity and metabolic parameters, as well as quality of life, irrespective of age.
Testosterone therapy in obese men increased hemoglobin and hematocrit but the levels remained within physiological ranges. There were no major adverse cardiovascular events. Prostate volume increased in all men regardless of obesity grade, but there were no cases of urination problems. In fact, lower urinary tract symptoms (assessed by the IPSS scale) decreased. As expected, PSA levels increased in all men (regardless of obesity grade) but the increase stayed within normal range and was not clinically significant. 8 patients were diagnosed with low-grade prostate cancer while on testosterone treatment. Notably, this represented only 1.9% of treated men, and is far less than the prostate cancer incidence reported in the general population of men not treated with testosterone. For more information, see my previous article “Incidence of Prostate Cancer after Testosterone Therapy for up to 17 years”.
It was concluded in this study that testosterone therapy is a safe and effective treatment to achieve sustained and lasting weight loss in obese hypogonadal men irrespective of the severity of obesity.
Comparison to traditional obesity treatments
The improvements in obesity parameters in this study markedly outperform those seen with traditional obesity treatments. For example, a comprehensive program of lifestyle modification can produce a 7% to 10% reduction of body weight. The weight loss achieved in the study by Saad et al. amounted to 16.8% to 23.6%.
A systematic review of long-term weight loss studies in obese adults found that diet/lifestyle treatment produces <5 kg weight loss after 2-4 years, pharmacologic treatment 5-10 kg weight loss after 1-2 years, and surgical treatment 25-75 kg weight loss after 2-4 years. As demonstrated in the study by Saad et al., testosterone therapy results in weight loss far exceeding that of both diet/lifestyle therapy and traditional drug therapy. Only surgical treatment results in greater weight loss, but it is not without risks.
Obesity medications approved for long-term use, when prescribed with lifestyle interventions, produce additional weight loss relative to placebo ranging from approximately 3% of initial weight for orlistat and lorcaserin to 9% for top-dose (15/92 mg) phentermine plus topiramate-extended release at 1 year. While a weight loss of 9% after 1 year may seem large, the long-term safety and efficacy of phentermine + topiramate is unknown.
The Look AHEAD trial, which investigated the long-term effects of a lifestyle intervention on weight found a weight loss of -6.15% after 4 years. In the study by Saad et al. weight loss at the 4 year mark ranged from -10% to -15%, depending on obesity grade. Notably, an 8 year analysis of The Look AHEAD trial – with subjects having a baseline BMI of 35 (the same as in the study by Saad et al.) – reported a weight loss of 17.4, 8.1, and 8.8 kg for years 1, 4, and 8, respectively. The corresponding weight loss in men on testosterone therapy in the study by Saad et al. was 6.6, 23.6 and 38.4 kg in class I obese men, 8.4, 36.6, and 55.8 kg in class II obese men, and 7.7, 40.8, and 67.2 kg in class III obese men, as outlined in table 2.
Table 2: Weight loss with testosterone therapy compared with traditional lifestyle intervention (diet and exercise).
When looking at the Look AHEAD data, note the marked weight regain after the first year. As the comparison data clearly show, while a comprehensive lifestyle intervention can result in a large 1 year weight loss, in the long run testosterone therapy results in a 4 to 8-fold greater weight loss, with no signs of weight regain.
Further, in sex-specific analysis of the Look AHEAD data, differences in fat mass in men in the lifestyle intervention and control groups were not significant at year 8. In stark contrast, testosterone therapy results in a progressively continuous weight loss, as well as waist loss, as evidenced by the study by Saad et al. The large reduction in waist circumference suggests that the weight loss was due mostly to a reduction in fat mass, and not lean body mass. Loss of lean body mass is the main drawback with calorie restricted diets, as shown in The Look AHEAD trial.
As testosterone therapy is well-documented to increase lean body mass , testosterone therapy in obese hypogonadal men can serve as a novel form of obesity treatment that may confer greater beneficial effects on body composition than diet/exercise and/or drug induced weight loss. This, coupled with the correction of testosterone deficiency and its detrimental health consequences per se, will in turn further enhance the health benefits.
1. Saad, F., The emancipation of testosterone from niche hormone to multi-system player. Asian J Androl, 2015. 17(1): p. 58-60.
2. Kelly, D.M. and T.H. Jones, Testosterone: a metabolic hormone in health and disease. J Endocrinol, 2013. 217(3): p. R25-45.
3. Yanovski, S.Z. and J.A. Yanovski, Long-term drug treatment for obesity: a systematic and clinical review. JAMA, 2014. 311(1): p. 74-86.
4. Dobbs, R., et al., Overcoming obesity: An initial economic analysis http://www.mckinsey.com/insights/economic_studies/how_the_world_could_better_fight_obesity Accessed December 1, 2014.
5. Jeffery, R.W., et al., Long-term maintenance of weight loss: current status. Health Psychol, 2000. 19(1 Suppl): p. 5-16.
6. Douketis, J.D., et al., Systematic review of long-term weight loss studies in obese adults: clinical significance and applicability to clinical practice. Int J Obes (Lond), 2005. 29(10): p. 1153-67.
7. Pekkarinen, T., J. Kaukua, and P. Mustajoki, Long-term weight maintenance after a 17-week weight loss intervention with or without a one-year maintenance program: a randomized controlled trial. J Obes, 2015. 2015: p. 651460.
8. Johansson, K., M. Neovius, and E. Hemmingsson, Effects of anti-obesity drugs, diet, and exercise on weight-loss maintenance after a very-low-calorie diet or low-calorie diet: a systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr, 2014. 99(1): p. 14-23.
9. Pownall, H.J., et al., Changes in body composition over 8 years in a randomized trial of a lifestyle intervention: the look AHEAD study. Obesity (Silver Spring), 2015. 23(3): p. 565-72.
10. Middleton, K.M., S.M. Patidar, and M.G. Perri, The impact of extended care on the long-term maintenance of weight loss: a systematic review and meta-analysis. Obes Rev, 2012. 13(6): p. 509-17.
11. Rueda-Clausen, C.F., R.S. Padwal, and A.M. Sharma, New pharmacological approaches for obesity management. Nat Rev Endocrinol, 2013. 9(8): p. 467-78.
12. Patham, B., D. Mukherjee, and Z.T. San Juan, Contemporary review of drugs used to treat obesity. Cardiovasc Hematol Agents Med Chem, 2013. 11(4): p. 272-80.
13. Saad, F., et al., Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity Classes I-III: Observational data from two registry studies. Int J Obes (Lond), 2015. Jul 29 [Epub ahead of print].
14. American College of Cardiology/American Heart Association Task Force on Practice Guidelines, O.E.P., Expert Panel Report: Guidelines (2013) for the management of overweight and obesity in adults. Obesity (Silver Spring), 2014. 22 Suppl 2: p. S41-410.
15. Finkelstein, E.A., et al., The lifetime medical cost burden of overweight and obesity: implications for obesity prevention. Obesity (Silver Spring), 2008. 16(8): p. 1843-8.
16. Haring, R., et al., Prevalence, incidence and risk factors of testosterone deficiency in a population-based cohort of men: results from the study of health in Pomerania. Aging Male, 2010. 13(4): p. 247-57.
17. Grossmann, M., Low testosterone in men with type 2 diabetes: significance and treatment. J Clin Endocrinol Metab, 2011. 96(8): p. 2341-53.
18. Pitteloud, N., et al., Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. J Clin Endocrinol Metab, 2005. 90(5): p. 2636-41.
19. Mah, P.M. and G.A. Wittert, Obesity and testicular function. Mol Cell Endocrinol, 2010. 316(2): p. 180-6.
20. Cohen, P.G., The hypogonadal-obesity cycle: role of aromatase in modulating the testosterone-estradiol shunt–a major factor in the genesis of morbid obesity. Med Hypotheses, 1999. 52(1): p. 49-51.
21. Yeap, B.B., et al., Lower serum testosterone is independently associated with insulin resistance in non-diabetic older men: the Health In Men Study. Eur J Endocrinol, 2009. 161(4): p. 591-8.
22. Tajar, A., et al., Characteristics of androgen deficiency in late-onset hypogonadism: results from the European Male Aging Study (EMAS). J Clin Endocrinol Metab, 2012. 97(5): p. 1508-16.
23. Pellitero, S., et al., Hypogonadotropic hypogonadism in morbidly obese males is reversed after bariatric surgery. Obes Surg, 2012. 22(12): p. 1835-42.
24. Travison, T.G., et al., The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men. J Clin Endocrinol Metab, 2007. 92(2): p. 549-55.
25. Camacho, E.M., et al., Age-associated changes in hypothalamic-pituitary-testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study. Eur J Endocrinol, 2013. 168(3): p. 445-55.
26. Francomano, D., et al., Effects of testosterone undecanoate replacement and withdrawal on cardio-metabolic, hormonal and body composition outcomes in severely obese hypogonadal men: a pilot study. J Endocrinol Invest, 2014. 37: p. 401-411.
27. Francomano, D., A. Lenzi, and A. Aversa, Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in ageing men with metabolic syndrome. Int J Endocrinol, 2014. 2014: p. 527470.
28. Behre, H.M., et al., A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up. Aging Male, 2012. 15(4): p. 198-207.
29. Kapoor, D., 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): p. 899-906.
30. Bhattacharya, R.K., et al., Effect of 12 months of testosterone replacement therapy on metabolic syndrome components in hypogonadal men: data from the Testim Registry in the US (TRiUS). BMC Endocr Disord, 2011. 11: p. 18.
31. Haider, A., et al., Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: An observational study. Obes Res Clin Pract, 2014. 8(4): p. e339-49.
32. Haider, A., et al., Effects of long-term testosterone therapy on patients with “diabesity”: results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. Int J Endocrinol, 2014. 2014: p. 683515.
33. Saad, F., et al., Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity (Silver Spring), 2013. 21(10): p. 1975-81.
34. Yassin, A. and G. Doros, Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Clin Obes, 2013. 3(3-4): p. 73-83.
35. Frederiksen, L., et al., Testosterone therapy increased muscle mass and lipid oxidation in aging men. Age (Dordr), 2012. 34(1): p. 145-56.
36. Birzniece, V., et al., Testosterone stimulates extra-hepatic but not hepatic fat oxidation (Fox): comparison of oral and transdermal testosterone administration in hypopituitary men. Clin Endocrinol (Oxf), 2009. 71(5): p. 715-21.
37. Host, C., et al., Independent effects of testosterone on lipid oxidation and VLDL-TG production: a randomized, double-blind, placebo-controlled, crossover study. Diabetes, 2013. 62(5): p. 1409-16.
38. Saad, F., et al., Testosterone as potential effective therapy in treatment of obesity in men with testosterone deficiency: a review. Curr Diabetes Rev, 2012. 8(2): p. 131-43.
39. Allan, C.A. and R.I. McLachlan, Androgens and obesity. Curr Opin Endocrinol Diabetes Obes, 2010. 17(3): p. 224-32.
40. von Eckardstein, S. and E. Nieschlag, Treatment of male hypogonadism with testosterone undecanoate injected at extended intervals of 12 weeks: a phase II study. J Androl, 2002. 23(3): p. 419-25.
41. Wadden, T.A., et al., Lifestyle modification for obesity: new developments in diet, physical activity, and behavior therapy. Circulation, 2012. 125(9): p. 1157-70.
42. Look, A.R.G. and R.R. Wing, Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial. Arch Intern Med, 2010. 170(17): p. 1566-75.
43. Neto, W.K., et al., Effects of testosterone on lean mass gain in elderly men: systematic review with meta-analysis of controlled and randomized studies. Age (Dordr), 2015. 37(1): p. 9742.