Testosterone replacement therapy and its withdrawal in hypogonadal men with severe obesity

Big guy sweating on the bike

Effects of testosterone undecanoate replacement and withdrawal on cardio-metabolic, hormonal and body composition outcomes in severely obese hypogonadal men: a pilot study. Francomano D, Bruzziches R, Barbaro G, et al. J Endocrinol Invest 2014; 33(4): 401-411.

Obesity is a chronic, worldwide health problem that has serious economic and social consequences. This summary discusses the results of an observational, open-label, parallel-arm study that investigated the cardiometabolic effects of diet and physical exercise (DPE) with or without testosterone undecanoate (TU) 1,000 mg/12 weeks for 54 weeks in 24 hypogonadal men with severe obesity (mean age, 54 ± 8 years; total testosterone level, <12 nmol/L; mean BMI, 42 kg/m2).1 A 24-week extension period of DPE alone investigated the effects of withdrawal of TU from treatment. The DPE program consisted of a personalized hypocaloric diet and requirement to complete ≥150 min/week of aerobic exercise of moderate intensity and/or ≥90 min/week of vigorous exercise.

Key Points

  • Treatment with DPE + TU for 54 weeks improved hormonal and cardiometabolic parameters in 24 hypogonadal men with severe obesity (BMI 42 kg/m2) versus DPE alone, but following withdrawal of TU for 24 weeks returned to baseline levels1

    • Total and free testosterone were significantly improved at 54 weeks in the DPE + TU group only (both p<0.0001); however, testosterone levels returned to hypogonadal levels after withdrawal of TU
    • DPE + TU significantly improved circumferential myocardial shortening, ejection fraction, and E/A ratio at 54 weeks (all p<0.01)
  • Following an earlier study by Heufelder et al.2 in 2009, this controlled study is the second to show the added benefit of testosterone in combination with DPE1
  • This is the second study to show that treatment with DPE + testosterone resulted in significant and persistent improvements in body composition, weight loss, and all metabolic syndrome parameters1,3

    • Improvements in lean mass (p<0.0001; Figure) and fat mass (p<0.01) were seen only in the DPE + TU group at 54 weeks, but were lost after withdrawal of TU for lean mass only
    • Glycemia, basal and peak insulin serum levels, and total and LDL cholesterol improved only with DPE + TU treatment, and maintained significance after 24 weeks of withdrawal of TU (all p<0.01)
    • DPE + TU resulted in greater improvements in HOMA-I than DPE alone (p<0.01 and p<0.05, respectively) and were maintained following withdrawal of TU
    • DPE + TU significantly improved both systolic and diastolic blood pressure, and improvements were maintained following withdrawal of TU (both p<0.01)
  • This study was the first to measure epicardial fat (EF), a measure of cardiovascular performance, which was significantly reduced only in the DPE + TU group (p<0.01); however, improvements were not maintained following withdrawal of TU1
  • This is the first published report to show that DPE + TU improved surrogate markers of endothelial function, measured using the Endopat2000 device, although such improvements were lost following withdrawal of TU1

    • Significant improvements in T/B ratio and CIMT were achieved only in the DPE + TU group (both p<0.01) at 54 weeks
    • In the DPE + TU group only, a direct relationship was seen between testosterone levels and endothelial function (r2 = 0.43; p<0.005)
    • An inverse relationship was observed between EF versus endothelial function (r2 = –0.46; p<0.001) and testosterone levels (r2 = –0.56; p<0.0005)
    • Patients treated with DPE + TU only showed a significant reduction of overall cardiovascular risk (p<0.01)

What is known

The association between male obesity and hypogonadism has previously been demonstrated,4 and low testosterone levels themselves are predictive of visceral obesity.5 Approximately 80% and 40% of obese adults suffer from at least one and two or more obesity-related comorbidities, respectively,6 suggesting that the pathogenetic mechanisms between hypogonadism, obesity, type 2 diabetes, and metabolic syndrome (MS) are complex and multidirectional.7 EF, a metabolically active fat depot, is strongly associated with obesity, type 2 diabetes, MS, and coronary artery disease (CAD),8,9 and is an independent predictor of impaired diastolic function in healthy overweight patients even after adjustment for the MS, CAD, and hypertension.10 This group of comorbidities is associated with an increased risk of cardiovascular disease, which has significant consequences on quality of life and life expectancy.

What this study adds

This controlled study clearly demonstrated the beneficial effects of TU on hormonal, cardiovascular, and metabolic parameters versus DPE alone in severely obese hypogonadal men. Of note, withdrawal of TU for 24 weeks led to maintenance of metabolic and blood pressure parameters, but had a negative impact on hormonal (including testosterone levels) and cardiovascular parameters, which returned to baseline levels.

In addition, the present study is the first to demonstrate consistent evidence that TU improves endothelial dysfunction, measured using the Endopat2000 device. This improvement may be the result of a reduction in EF thickness, which is associated with increased atherosclerotic plaque and myocardial ischemia.11,12 For the first time, an inverse relationship was demonstrated for EF versus endothelial function or testosterone levels, and a direct relationship between testosterone levels and endothelial function. Whilst the exact mechanisms of action of testosterone are unknown, the effects of TU on total versus EF percentage decrease suggest that they may be directly mediated by androgen receptor activation.1 These findings demonstrate that improvement of testosterone levels may reduce cardiovascular risk markers such as EF and CIMT, and may reduce overall cardiovascular risk in hypogonadal men with severe obesity. Furthermore, these results complement findings that showed that testosterone replacement therapy improved myocardial ischemia and cardiac symptoms in patients with proven cardiovascular disease13 and chronic heart failure.14,15

The findings from this controlled study suggest that testosterone as an adjunctive therapy is beneficial to cardiac function in severely obese hypogonadal men in whom DPE alone may not result in a decrease in cardiovascular risk. These outcomes were not maintained after the withdrawal of TU, suggesting that TU should be continued in hypogonadal men with severe obesity who already have an increased cardiovascular risk.

Figure: Improvements in lean mass

References

1. Francomano D, Bruzziches R, Barbaro G, 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(4): 401-411.
2. 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.
3. Francomano D, Ilacqua A, Bruzziches R, et al. Effects of 5-year treatment with testosterone undecanoate on lower urinary tract symptoms in obese men with hypogonadism and metabolic syndrome. Urology 2014;83(1):167-173.
4. Saad F, Gooren LJ. The role of testosterone in the etiology and treatment of obesity, the metabolic syndrome, and diabetes mellitus type 2. J Obes 2011;2011:471554.
5. Tsai EC, Boyko EJ, Leonetti DL, et al. Low serum testosterone level as a predictor of increased visceral fat in Japanese-American men. Int J Obes 2000;24(4):485-491.
6. Janssen I, Mark AE. Elevated body mass index and mortality risk in the elderly. Obes Rev 2007;8(1):41-59.
7. Mammi C, Calanchini M, Antelmi A, et al. Androgens and adipose tissue in males: a complex and reciprocal interplay. Int J Endocrinol 2012;2012:789653.
8. Rosito GA, Massaro JM, Hoffmann U, et al. Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community-based sample: the Framingham Heart Study. Circulation 2008;117(5):605-613.
9. Mookadam F, Goel R, Alharthi MS, et al. Epicardial fat and its association with cardiovascular risk: a cross-sectional observational study. Heart Views 2010;11(3):103-108.
10. Cavalcante JL, Tamarappoo BK, Hachamovitch R, et al. Association of epicardial fat, hypertension, subclinical coronary artery disease, and metabolic syndrome with left ventricular diastolic dysfunction. Am J Cardiol 2012;110(12):1793-1798.
11. Tamarappoo B, Dey D, Shmilovich H, et al. Increased pericardial fat volume measured from noncontrast CT predicts myocardial ischemia by SPECT. JACC Cardiovasc Imaging 2010;3(11):1104-1112.
12. Cheng VY, Dey D, Tamarappoo B, et al. Pericardial fat burden on ECG-gated noncontrast CT in asymptomatic patients who subsequently experience adverse cardiovascular events. JACC Cardiovasc Imaging 2010;3(4):352-360.
13. Tirabassi G, Gioia A, Giovannini L, et al. Testosterone and cardiovascular risk. Intern Emerg Med 2013;8 Suppl 1:S65-69.
14. Iellamo F, Rosano G, Volterrani M. Testosterone deficiency and exercise intolerance in heart failure: treatment implications. Curr Heart Fail Rep 2010;7(2):59-65.
15. Volterrani M, Rosano G, Iellamo F. Testosterone and heart failure. Endocrine 2012;42(2):272-277.

Last updated: 2018
G.MKT.GM.MH.01.2018.0500