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

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.

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.

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.