Testosterone therapy can improve components of metabolic syndrome

20 December 2013

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 therapy in males with TD and MetS. Furthermore, there is a lack of data investigating the potential side effects of long-term testosterone therapy on both the prostate and bladder in this patient population. In addressing this gap, two recently-published studies investigated the use of testosterone therapy 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 testosterone therapy 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.

KEY POINTS

  • Long-term testosterone therapy significantly increased levels of total testosterone by approximately 9 nmol/L in men with TD and MetS over a treatment period of 5 years (p<0.0001)1,2
  • Testosterone therapy in hypogonadal men achieved improvements in anthropometric parameters associated with MetS, including weight, BMI, and waist circumference
    1. Testosterone therapy was associated with long-term reductions in waist circumference of -8.5 ± 0.17 cm and body weight of -15.35 ± 0.43 kg (both p<0.0001)3
    2. TU 1,000 mg significantly reduced waist circumference and BMI by -9.6 ± 3.8 cm and -2.9 ± 14, respectively, compared with controls (both p<0.0001)2
  • Testosterone therapy in hypogonadal men has demonstrated gradual and consistent long-term improvements in lipid profiles, a key component of MetS (Figure)
    1. Treatment with TU 1,000 mg resulted in significant reductions in levels of total cholesterol (TC), LDL cholesterol, and triglycerides (TG) at 12 (p<0.0001 vs. baseline) and 24 months (p<0.0001 vs. 12 months); furthermore, all reductions in lipid profile levels were maintained throughout the 5-year treatment period1
    2. In the same study, TU 1,000 mg slightly, but significantly, increased levels of HDL cholesterol at 12 months (p<0.0001 vs. baseline), which remained elevated for 5 years of treatment1
    3. Similar results were observed for TC (-66 ± 19 mg/dL), LDL cholesterol (-51 ± 16 mg/dL), TG (-41 ± 19 mg/gL), and HDL cholesterol (+21 ± 11 mg/dL) in the second controlled study (all p<0.0001 vs. control group)2
  • Testosterone therapy was associated with rapid improvements in cardiovascular risk factors, such as blood pressure and levels of fibrinogen, which were sustained over 5 years of treatment
    1. TU 1,000 mg reduced systolic (from 153.55 ± 17.6 to 137.72 ± 10.9 mmHg) and diastolic blood pressure (from 93.49 ± 11.32 to 79.59 ± 7.36 mmHg) over 2 years, and blood pressure remained at this level until study end (both p<0.0001 vs. baseline)1
    2. Francomano et al. observed similar reductions in systolic (-23 ± 10 mmHg) and diastolic (-17 ± 10 mmHg) blood pressure over 5 years of treatment (both p<0.0001 vs. control group)2
    3. In the same study, TU 1,000 mg was associated with a decrease in levels of fibrinogen (-268 ± 46 mg/dL, p<0.0001), an inflammatory and pro-coagulatory marker2
  • Testosterone therapy in men with TD and MetS improved measures of insulin resistance over 5 years

    1. TU 1,000 mg significantly decreased fasting blood glucose after 12 (p<0.0001 vs. baseline) and 24 months (p=0.012 vs. 12 months), at which point levels reached a plateau1

    2. TU 1,000 mg was associated with significant reductions in levels of HbA1c at 12 (p<0.0001 vs. baseline) and 24 months (p<0.0001 vs. 12 months),1 and at 60 months (p<0.001)2

    3. Insulin sensitivity, as measured by homeostatic measurement assessment-insulin resistance (HOMA-IR), was also significantly reduced by testosterone therapy after 5 years of treatment (-1.6 ± 0.6, p<0.001)2

  • Inflammatory response, an important component of MetS and cardiovascular disease, was reduced by testosterone therapy in males with MetS and TD

    1. Testosterone therapy significantly reduced levels of C-reactive protein (CRP), an inflammatory marker, in long-term observational (from 6.29 ± 7.96 to 1.03 ± 1.89 U/L, p<0.0001)1 and controlled studies (-1.13 ± 1.3 mg/mL, p<0.001)2 over 5 years of treatment

  • Testosterone therapy reduced levels of liver enzymes, suggesting an improvement in liver function

    1. Treatment with TU 1,000 mg for 5 years reduced levels of aspartate transaminase (from 43.05 ± 17.29 to 20.18 ± 3.22 U/L, p<0.0001 with a plateau after 24 months) and alanine transaminase (from 43.89 ± 18.11 to 20.55 ± 3.92 U/L, p<0.0001 with a plateau after 36 months)1

  • These improvements in cardiometabolic risk factors suggest that testosterone therapy may have a role in improving components of MetS,1whilst the reduction in inflammatory response may contribute to maintenance of unaltered urinary function and protection of the prostate gland in men with TD2

What is known

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

What these studies add

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 testosterone therapy 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 findings11-14 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 testosterone therapy may improve hypertension have been limited, but these 5-year studies show important and consistent findings with regard to the role of testosterone therapy in improving MetS components.

For the first time, findings from Francomano et al.report that testosterone therapy 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, testosterone therapy 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 testosterone therapy improves many elements attributed to MetS, and may provide a protective effect on the prostate gland in men with TD.

Changes in concentration of lipid parameters at 5 years post treatment from two long-term studies (Traish1 and Francomano2) investigating the effects of testosterone therapy in men with testosterone deficiency and metabolic syndrome

Figure. Changes in concentration of lipid parameters at 5 years post treatment from two long-term studies (Traish1 and Francomano2) investigating the effects of testosterone therapy in men with testosterone deficiency and metabolic syndrome. Baseline levels in the two studies were 282 mg/dL1 and 237 mg/dL2 for total cholesterol; 164 mg/dL1 and 161 mg/dL2 for LDL cholesterol, respectively.

References

  • Traish AM, Haider A, Doros G, et al. Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int J Clin Pract 2014; 68(3): 314-329. Return to content
  • 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): 167-174. Return to content
  • Saad F, Haider A, Doros G, et al. Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity (Silver Spring) 2013;21(10):1975-1981. Return to content
  • Muraleedharan V, Jones TH. Testosterone and the metabolic syndrome. Ther Adv Endocrinol Metab 2010;1(5):207-223. Return to content
  • Li C, Ford ES, Li B, et al. Association of testosterone and sex hormone-binding globulin with metabolic syndrome and insulin resistance in men. Diabetes Care 2010;33(7):1618-1624. Return to content
  • Corona G, Mannucci E, Ricca V, et al. The age-related decline of testosterone is associated with different specific symptoms and signs in patients with sexual dysfunction. Int J Androl 2009;32(6):720-728. Return to content
  • Corona G, Rastrelli G, Monami M, et al. Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. Eur J Endocrinol 2013;168(6):829-843. Return to content
  • Camacho EM, Huhtaniemi IT, O'Neill TW, 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):445-455. Return to content
  • Schatzl G, Madersbacher S, Temml C, et al. Serum androgen levels in men: impact of health status and age. Urology 2003;61(3):629-633. Return to content
  • Trifiro MD, Parsons JK, Palazzi-Churas K, et al. Serum sex hormones and the 20-year risk of lower urinary tract symptoms in community-dwelling older men. BJU Int 2010;105(11):1554-1559. Return to content
  • Zitzmann M, Nieschlag E. Androgen receptor gene CAG repeat length and body mass index modulate the safety of long-term intramuscular testosterone undecanoate therapy in hypogonadal men. J Clin Endocrinol Metab 2007;92(10):3844-3853. Return to content
  • Page ST, Herbst KL, Amory JK, et al. Testosterone administration suppresses adiponectin levels in men. J Androl 2005;26(1):85-92. Return to content
  • Khaw K, Dowsett M, Folkerd E, et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation 2007;116(23):2694-2701. Return to content
  • Malkin CJ, Pugh PJ, Jones RD, et al. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab 2004;89(7):3313-3318. Return to content
  • Traish AM, Abdou R, Kypreos KE. Androgen deficiency and atherosclerosis: The lipid link. Vascul Pharmacol 2009;51(5-6):303-313. Return to content