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Testosterone with diet and exercise reverses Metabolic Syndrome and improves glycemic control in hypogonadal men with newly diagnosed Type 2 Diabetes

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Fifty-two week treatment with diet and exercise plus transdermal testosterone reverses the Metabolic Syndrome (MetS) and improves glycemic control in men with newly diagnosed Type 2 Diabetes and subnormal plasma testosterone. AE Heufelder, F Saad, M Bunck, and L Gooren. November/December 2009. Journal of Andrology;30:(6);726-733.

In a single blind 52-week randomized clinical trial, 32 hypogonadal men (morning plasma testosterone concentration lower than 12 nmol/L, reference range >14 nmo/l) with recently diagnosed Type 2 Diabetes (T2D) and with Metabolic Syndrome (MetS) underwent supervised diet and exercise (D&E). Half of this group received D&E with testosterone administered as a relatively low dose (50 mg) gel (Testogel®) once daily. No glucose-lowering agents were administered prior to or during the study period.1

Key Points

  • Serum testosterone, glycosylated haemoglobin (HbA1c), fasting plasma glucose, high-density lipoprotein cholesterol, triglyceride concentrations, and waist circumference improved in both groups after 52 weeks of treatment1
  • The addition of testosterone significantly further improved these measures compared with D&E alone1
  • All D&E and testosterone treated patients reached the HbA1c glycemic control goal of less than 7.0%, and 87.5% achieved HbA1c of less than 6.5%. In comparison, only 40.4% of the D&E alone participants reached HbA1c less than 7.0%, and none reached less than 6.5%1
  • Based on Adult Treatment Panel III criteria, 81.3% of the D&E with testosterone patients no longer met the criteria of MetS compared with 31.3% of those receiving D&E alone1
  • Testosterone treatment improved insulin sensitivity (HOMA model), adiponectin, and high-sensitivity C-reactive protein1
  • Serum PSA concentrations did not differ between the two treatment groups indicating that 52 weeks of testosterone replacement does not appear to increase risks of prostate problems.1

What is known

Men with T2D have lower serum testosterone concentrations than men without diabetes and there is an inverse association between testosterone levels and HbA1c concentrations.2,3

In men with low plasma testosterone, the risk of T2D appears to be greater4 and a meta-analysis shows that testosterone levels are significantly lower in men with T2D.5

In hypogonadal men, the effect of testosterone supplementation on glycemic control has been mixed. Two studies found no effect,6,7 whereas Kapoor et al (2006)8 found that testosterone replacement therapy improved glycemic control.

Individuals with T2D often have disturbances consistent with the Metabolic Syndrome,9 and individuals with the MetS have increased risk of developing T2D.10

Treatment with exogenous testosterone in those with low testosterone levels has been shown to improve metabolic features of MetS8 and produce beneficial effects on circulating high-sensitive C-reactive protein (hsCRP) levels in individuals with T2D. Some consider low testosterone to be a significant contributor in the development of insulin resistance and MetS in some men.9

Few clinical studies have evaluated the effect of normalization of serum testosterone concentrations on glucose homeostasis6,7 and results from such studies have showed limited beneficial effects of testosterone administration.8

What this study adds

In this study, insulin sensitivity, measured by HOMA, improved in two groups of men receiving supervised D&E. This effect was significantly greater when testosterone was added.1

Testosterone treatment also significantly improved circulating levels of adiponectin and hsCRP, key serum markers respectively of insulin sensitivity and hepatic steatosis.1

The changes in both adiponectin and hsCRP were significantly correlated with the therapy induced changes in bio-available testosterone.1These findings are not in line with a previous placebo controlled, randomized study in hypogonadal T2D patients. In these studies, adiponectin levels decreased after 3 to 6 months of treatment with intramuscular mixed testosterone esters.11 (These opposing findings in the circulating adiopnectin concentrations could be a result of the different routes of testosterone administration used with widely variable testosterone levels.)

This study found a decline in serum levels of hsCRP upon D&E plus testosterone, a finding not reported by Kapoor et al (2007)12, but replicated in a study by Haider et al (2009)13.

References

1. AE Heufelder, F Saad, M Bunck, and L Gooren. 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. November/December 2009. J Andro;30:(6);726-733.
2. Svartberg J. Epidemiology: testosterone and the metabolic syndrome. Int J Impot Res. 2007;19:124–128.
3.Stanworth RD, Jones TH. Testosterone in obesity, metabolic syndrome and type 2 diabetes. Front Horm Res. 2009;37:74–90.
4. Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab. 2006;91:4335–4343.
5. Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2006;295:1288–1299.
6. Lee CH, Kuo SW, Hung YJ, Hsieh CH, He CT, Yang TC, Lian WC, Chyi-Fan S, Pei D. The effect of testosterone supplement on insulin sensitivity, glucose effectiveness, and acute insulin response after glucose load in male type 2 diabetics. Endocr Res. 2005;31:139–148.
7. Basu R, Dalla Man C, Campioni M, Basu A, Nair KS, Jensen MD, Khosla S, Klee G, Toffolo G, Cobelli C, Rizza RA. Effects of two years of testosterone replacement on insulin secretion, insulin action, glucose effectiveness, hepatic insulin clearance and postprandial glucose turnover in elderly men. Diabetes Care.2007;30:1972–1978.
8. Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control,visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006;154:899–906.
9. Haffner SM. The metabolic syndrome: inflammation, diabetes mellitus, and cardiovascular disease. Am J Cardiol. 2006;97:3A–11A.
10. Hanley AJ, Karter AJ, Williams K, Festa A, D’Agostino RB Jr, Wagenknecht LE, Haffner SM. Prediction of type 2 diabetes mellitus with alternative definitions of the metabolic syndrome: the Insulin Resistance Atherosclerosis Study. Circulation. 2005;112:3713–3721.
11. Lanfranco F, Zitzmann M, Simoni M, Nieschlag E. Serum adiponectin levels in hypogonadal males: influence of testosterone replacement therapy. Clin Endocrinol (Oxf). 2004;60:500–507.
12. Kapoor D, Clarke S, Stanworth R, Channer KS, Jones TH. The effect of testosterone replacement therapy on adipocytokines and Creactive protein in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2007;156:595–602.
13. Haider A, Gooren LJ, Padungtod P, Saad F. Concurrent improvement of the metabolic syndrome and lower urinary tract symptoms upon normalisation of plasma testosterone levels in hypogonadal elderly men. Andrologia. 2009;41:7–13.

 

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