Recent findings from testosterone studies

Testosterone replacement therapy improves body composition, insulin resistance and markers of atherosclerosis in men with low testosterone and metabolic syndrome

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Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study. Aversa A, Bruzziches R, Francomano D, et al. J Sex Med 2010;7(10):3495-3503.

The aim of this study was to evaluate whether long-term testosterone replacement therapy could modify cardiovascular risk factors and atherosclerosis progression in a population of hypogonadal men with metabolic syndrome (MetS) and/or type 2 diabetes mellitus (T2DM). The randomized, double-blind, double-dummy, placebo-controlled, parallel group study enrolled 50 men (mean age 57 years) to receive intramuscular (IM) testosterone undecanoate (TU) 1000 mg every 12 weeks (n=40) or placebo transdermal gel (3-6 g daily; n=10) for 24 months. Hypogonadism was defined as total testosterone ≤11 nmol/L or free testosterone ≤250 pmol/L; MetS and T2DM were defined according to National Cholesterol Education Program-Third Adult Treatment Panel (NCEP-ATPIII) and International Diabetes Federation (IDF) criteria.1

Key Points

  • After 12 months, there was a significant difference in homeostasis model assessment index of insulin resistance (HOMA-IR), carotid intima media thickness (CIMT) and high-sensitivity C-reactive protein (hsCRP) between the TU and placebo groups (p<0.01)1
  • No modification of metabolic factors occurred during treatment with placebo1)
  • Consequently, all patients received TU for the remaining 12 months of the study1
  • TU markedly improved insulin sensitivity from baseline to 12 months (p<0.0001), and maintained the improvement after 24 months1
  • HOMA-IR significantly improved in patients shifted from placebo to testosterone undecanoate (p<0.001) due to a reduction in fasting glucose and fasting insulin levels1
  • TU also significantly reduced hsCRP levels (p<0.0001) and CIMT values (p<0.001)1
  • Overall at 24 months, only 35% and 58% of patients still met NCEP-ATPIII and IDF criteria, respectively, for a diagnosis of MetS1
  • The main determinants of improvement in MetS were reduction in waist circumference (p<0.0001), visceral fat mass (p<0.0001) and improvement in HOMA-IR (Figure 1).1

What is known

Late-onset hypogonadism represents the progressive decline in serum testosterone associated with advancing age and characterized by a deficiency in serum testosterone levels below the young healthy adult male reference range of approximately 10–35 nmol/L (300–1000 ng/dL).2-4 Beyond the association of hypogonadism with erectile dysfunction,5there is growing recognition that low testosterone is an independent risk factor for a range of cardiovascular and metabolic conditions, including MetS, obesity, T2DM, and cardiovascular disease (CVD) including atherosclerosis and myocardial infarction.6-12 MetS is characterised by a group of interrelated risk factors, including central abdominal obesity, elevated triglycerides, reduced high-density lipoprotein cholesterol (HDL-C), insulin resistance, impaired glucose tolerance, and hypertension.13 Therefore, ameliorating MetS may help to prevent cardiovascular events and delay the progression of CVD.

This is the first controlled study to investigate whether long-term testosterone replacement therapy can counter cardiovascular risk factors and atherosclerosis progression in men with low testosterone and MetS.

What this study adds

Dr. Antonio Aversa, lead author of the study, commented that this controlled study demonstrated that prolonged testosterone replacement therapy with TU improved body composition, insulin resistance and plasma surrogate markers of endothelial function and atherosclerosis, while markedly reducing the percentage of patients reporting three or more components of the MetS. Furthermore, although the sample size was not large, the striking results suggest that testosterone supplementation may have an important role in MetS patients to delay the progression of CVD. He noted that these findings are in contrast to a controversial study, which found an increased risk of cardiovascular adverse events in a population of older men with limitations in mobility and a high prevalence of chronic disease, despite similar plasma testosterone levels in the two studies.14 However, the present study “was more exhaustive in terms of investigation of plasma markers of atherosclerosis and thrombosis, and the intramuscular long-acting formulation was not associated with increased circulating estrogen levels.” In conclusion, TU should be considered as an adjunctive therapy for the treatment of those men affected by hypogonadism and MetS, in whom the correction of lifestyle factors alone may not be sufficient to decrease cardiovascular risk factors and the progression of artherosclerosis.

Figure 1: Change from baseline values of body composition and HOMA-IR after 12 and 24 months treatment with testosterone undecanoate (TU) or placebo. Note: from month 12, both the TU and placebo groups received TU 1000 mg every 12 weeks.
Figure 1: Change from baseline values of body composition and HOMA-IR after 12 and 24 months treatment with testosterone undecanoate (TU) or placebo.  Note: from month 12, both the TU and placebo groups received TU 1000 mg every 12 weeks.

 

References

1. Aversa A, Bruzziches R, Francomano D, et al. Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study. J Sex Med 2010;7(10):3495-3503.
2. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2006;91(6):1995-2010.
3. Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. Eur Urol 2009;55(1):121-130.
4. Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 2002;87(2):589-598.
5. Borges R, Temido P, Sousa L, et al. Metabolic syndrome and sexual (dys)function. J Sex Med 2009;6(11):2958-2975.
6. Corona G, Mannucci E, Fisher AD, et al. Low levels of androgens in men with erectile dysfunction and obesity. J Sex Med 2008;5(10):2454-2463.
7. Corona G, Mannucci E, Petrone L, et al. NCEP-ATPIII-defined metabolic syndrome, type 2 diabetes mellitus, and prevalence of hypogonadism in male patients with sexual dysfunction. J Sex Med 2007;4(4 Pt 1):1038-1045.
8. Fukui M, Kitagawa Y, Ose H, et al. Role of endogenous androgen against insulin resistance and atherosclerosis in men with type 2 diabetes. Curr Diabetes Rev 2007;3(1):25-31.
9. Oh JY, Barrett-Connor E, Wedick NM, et al. Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study. Diabetes Care 2002;25(1):55-60.
10. Traish AM, Guay A, Feeley R, et al. The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction. J Androl 2009;30(1):10-22.
11. Traish AM, Saad F, Feeley RJ, et al. The dark side of testosterone deficiency: III. Cardiovascular disease. J Androl 2009;30(5):477-494.
12. Traish AM, Saad F, Guay A. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J Androl 2009;30(1):23-32.
13. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120(16):1640-1645.
14. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med 2010;363(2):109-122.

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Last updated: 2018
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