Recent findings from testosterone studies

Meta-analysis supports association between metabolic syndrome and hypogonadism; testosterone replacement therapy may improve metabolic control and reduce central obesity

Image: analyzing blood glucose

Testosterone and metabolic syndrome: a meta-analysis study. Corona G, Monami M, Rastrelli G, et al. J Sex Med 2011;8(1):272-283.

A systematic review and meta-analysis of available prospective and cross-sectional studies comparing androgen levels in men with or without metabolic syndrome (MetS) was performed to analyse the relationship between androgen levels and MetS.1 Additionally, a separate meta-analysis of available randomized controlled trials reporting the metabolic effects of testosterone replacement therapy was performed. Overall, 21 quality studies were included; 13 cross-sectional, 3 longitudinal and 4 randomized controlled published trials, and 1 unpublished randomized controlled trial. Data for 2,254 men with and 6,407 men without MetS were included.

Key Points

  • Men with MetS had significantly lower levels of total plasma testosterone compared with healthy subjects1
  • This was also true when men with or without erectile dysfunction were analysed separately and when different definitions of MetS were used1
  • The presence of type 2 diabetes mellitus (T2DM) further enhanced the MetS-related decline in testosterone levels1
  • Adjusted for age and body mass index, both T2DM and MetS independently predicted low testosterone (p<0.001 and p<0.05, respectively)1
  • Data from longitudinal studies showed that baseline testosterone was significantly lower among patients with MetS than in controls (mean -2.17 nmol/L; p<0.0001)1
  • Testosterone replacement therapy significantly reduced metabolic risk factors, including fasting plasma glucose, homeostasis model assessment index of insulin resistance (HOMA-IR), triglycerides and waist circumference, and increased HDL-cholesterol.1

What is known

A group of interrelated factors, including abdominal obesity, insulin resistance, impaired glucose tolerance, dyslipidaemia and hypertension have become known as the metabolic syndrome (MetS).2 Although various diagnostic definitions have been proposed and there has been controversy over whether the MetS should be considered an independent syndrome, there is evidence that MetS is associated with a doubling of the 5- to 10-year risk of cardiovascular diseases and a 5-fold increase in the risk of T2DM.2 In addition, there is a large body of evidence that erectile dysfunction (ED) and male hypogonadism are often related to MetS,3-5 and that ED may be predictive of the presence of MetS.6 There also is emerging evidence that hypogonadism and ED are surrogate markers predicting metabolic and cardiovascular events.7-11

The presence of hypogonadism and ED in men with MetS may therefore signal to healthcare professionals that specific lifestyle changes (weight loss, physical exercise) or pharmacological interventions (testosterone replacement) may be beneficial to delay progression to a higher cardiovascular and metabolic risk category. Furthermore, testosterone replacement therapy has been shown to improve insulin resistance, glycaemic control, central obesity, lean body mass, hypercholesterolaemia and pro-inflammatory cytokines associated with diabetes, atherosclerosis and MetS.12-15 However, there have been few randomised, controlled studies specifically evaluating whether testosterone replacement therapy benefits MetS in hypogonadal men.

What this study adds

This meta-analysis of available randomised controlled trials comparing testosterone levels in subjects with or without MetS confirmed that testosterone replacement therapy is able to improve central obesity and other factors related to insulin resistance in subjects with MetS. In particular, the meta-analysis provided evidence of a reduction in visceral adiposity and HOMA-IR, as well as fasting glycaemia and triglyceride levels. Although confirmation through large placebo-controlled trials is required, it is hypothesized that testosterone replacement therapy might contribute to an improvement in the efficacy of treatments for MetS by reducing visceral adiposity. However, the relatively short duration of the available randomised controlled trials and the limited number of patients enrolled means that these findings should be treated with caution.

The evaluation of available cross-sectional and longitudinal studies also provided additional support for an independent relationship between MetS and hypogonadism, regardless of the way MetS is defined. MetS is significantly associated with an overall lower total testosterone level of over 2 nmol/L, with the difference more apparent in men with, rather than without, erectile dysfunction. The findings suggest that testosterone level may be a useful indicator of metabolic status in men with erectile dysfunction.

References

1. Corona G, Monami M, Rastrelli G, et al. Testosterone and metabolic syndrome: a meta-analysis study. J Sex Med 2011;8(1):272-283.
2. 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.
3. 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.
4. Borges R, Temido P, Sousa L, et al. Metabolic syndrome and sexual (dys)function. J Sex Med 2009;6(11):2958-2975.
5. Somani B, Khan S, Donat R. Screening for metabolic syndrome and testosterone deficiency in patients with erectile dysfunction: results from the first UK prospective study. BJU Int 2010;106(5):688-690.
6. Kupelian V, Shabsigh R, Araujo AB, et al. Erectile dysfunction as a predictor of the metabolic syndrome in aging men: results from the Massachusetts Male Aging Study. J Urol 2006;176(1):222-226.
7. Rodriguez A, Muller DC, Metter EJ, et al. Aging, androgens, and the metabolic syndrome in a longitudinal study of aging. J Clin Endocrinol Metab 2007;92(9):3568-3572.
8. Haring R, Volzke H, Felix SB, et al. Prediction of metabolic syndrome by low serum testosterone levels in men: results from the study of health in Pomerania. Diabetes 2009;58(9):2027-2031.
9. Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 2004;27(5):1036-1041.
10. Corona G, Monami M, Boddi V, et al. Male sexuality and cardiovascular risk. A cohort study in patients with erectile dysfunction. J Sex Med 2010;7(5):1918-1927.
11. Corona G, Monami M, Boddi V, et al. Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction. J Sex Med 2010;7(4 Pt 1):1557-1564.
12. 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.
13. Kapoor D, Goodwin E, Channer KS, et al. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006;154(6):899-906.
14. 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.
15. Kalinchenko SY, Tishova YA, Mskhalaya GJ, et al. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study. Clin Endocrinol (Oxf) 2010;73(5):602-612.

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Last updated: 2018
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