Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry.Traish AM, Haider A, Doros G, et al. Int J Clin Pract 2014; 68(3): 314-329.

Effects of 5-year treatment with testosterone undecanoate on lower urinary tract symptoms in obese men with hypogonadism and metabolic syndrome. Francomano D, Ilacqua A, Bruzziches R, et al. J Urol 2014; 83(1): 167-174.

Recent evidence suggests that a relationship exists between testosterone deficiency (TD) and metabolic syndrome (MetS) and, indeed, TD could itself be considered an additional clinical feature of MetS. However, this relationship has yet to be explored in long-term studies, and only limited, short-term data in small populations exist for testosterone replacement therapy (TRT) in males with TD and MetS. Furthermore, there is a lack of data investigating the potential side effects of long-term TRT on both the prostate and bladder in this patient population. In addressing this gap, two recently-published studies investigated the use of TRT in men with TD and MetS over a 5-year period.

An observational study by Traish et al. investigated the long-term effects of testosterone undecanoate (TU) 1,000 mg on components of MetS in 255 mainly elderly men (mean age 58.02 ± 6.30 years) with hypogonadism (total testosterone <12.1 nmol/L) from a cumulative registry.¹ A second study by Francomano et al. investigated the long-term effects of TRT on urinary function. Twenty men (mean age 57 years) with TD (<11 nmol/L) and MetS were treated with TU 1,000 mg over a 5-year period and compared with 20 male controls.² This summary discusses the key findings from these two studies.

It is established that MetS, a disease characterized by a group of cardiovascular risk factors, and TD are closely linked.⁴ Both diseases are also known to be independently associated with increased cardiovascular and all-cause mortality.¹ In a study of 1226 males, reduced levels of total, free, and bioavailable testosterone, and sex hormone-binding globulin, were associated with a higher prevalence of MetS.⁵ Additional research has shown that a higher prevalence of MetS, as well as further cardiovascular risk factors (waist circumference and TGs), were associated with reduced levels of testosterone and age in males with sexual dysfunction.⁶ This relationship implies that restoring levels of testosterone in hypogonadal males may relieve components of MetS. Recent studies have investigated this hypothesis, and it is further supported by recent publications.^7,8

MetS and lower urinary tract symptoms (LUTS) have many similar metabolic abnormalities, and studies suggest that TD may be the common link between MetS and LUTS. A cross-sectional study demonstrated that approximately 20% of men with LUTS are also affected by TD,⁹ and an increasing number of men with MetS are affected by LUTS.² In addition, a prospective study observed an inverse relationship between dihydrotestosterone and the prevalence of LUTS, and suggested that men with higher levels of bioavailable testosterone had a 56% decreased risk of LUTS.¹⁰

The findings from these two publications are novel and differ from previous studies. Traish et al.¹ investigated the effects of treatment with TU on MetS over a period of 5 years, the longest treatment duration to date, and concluded that TRT improves many components of MetS, which may otherwise contribute to progression to CVD. Importantly, this study is the first to report the effects of TU on levels of TC over a 5-year period. During this follow-up, treatment with TU significantly reduced levels of TC by 25–40% compared with baseline; supporting data from previous studies that suggested that the synthesis and disposal of TC is affected by TU.^11-13 Data from Francomano et al. back these initial findings.²

Improvements in lipid profiles were observed in both studies following treatment with TU for 5 years, with increases and decreases in levels of HDL and LDL cholesterol, respectively (Figure).^1,2 These results complement previous findings^11-14 and have important implications in attenuating the risk of cardiovascular disease in men with TD. Further important improvements in components of MetS reported by both long-term studies include reductions in insulin sensitivity and blood pressure, although the mechanism for the latter is still not completely clear. Previous results showing that TRT may improve hypertension have been limited, but these 5-year studies show important and consistent findings with regard to the role of TRT in improving MetS components.

For the first time, findings from Francomano et al.² report that TRT for 5 years does not affect urinary function in men with TD and MetS. Chronic inflammation is a common factor in both MetS and LUTS. In both studies, TRT significantly reduced levels of CRP,^1,2 a non-specific marker of inflammation, in men with TD over a 5-year treatment period. This suggests that increasing levels of testosterone to physiological levels may play an important role in reducing inflammatory response in men with TD, and may contribute to maintaining unaltered urinary function and protecting the prostate gland from inflammation. Whilst no single treatment improves all components of MetS, these long-term studies show that TRT improves many elements attributed to MetS, and may provide a protective effect on the prostate gland in men with TD.