Authors Grossmann M, Hoermann R, Wittert G, Yeap BB.
Review Date January 2015
Citation Clinical Endocrinology (Oxf) 2014; doi: 10.1111/cen.12664
Low serum testosterone is known to be associated with insulin resistance and the associated conditions, type 2 diabetes (T2D) and the metabolic syndrome from many cross-sectional studies. A longitudinal association between low testosterone and incident T2D has been seen in some but not all studies. The association is thought to be mediated partly by changes in body composition, particularly visceral fat mass. A number of intervention studies have tested the hypothesis that testosterone treatment improves glucose metabolism but results are inconclusive
To perform a systematic review and meta-analysis of placebo-controlled double-blind randomized controlled clinical trials (RCT) of testosterone (T) treatment in men with T2D and/or the metabolic syndrome.
The authors followed the PRISMA statement for reporting systematic reviews and meta-analyses. Eligible studies included double-blind RCTs that assessed the effects of testosterone therapy on glucose therapy in men with a diagnosis of metabolic syndrome and/or T2D. Medline, Embase and Cochrane databases were searched from inception to July 2014. Reference lists of potentially eligible articles and relevant reviews were manually searched. Two authors selected the studies and disagreements were resolved by consensus and third party adjudication. Study quality was assessed by two reviewers using the CONSORT checklist.
The primary outcomes of interest were the mean differences in insulin resistance, measured by the homeostatic model of insulin resistance (HOMA-IR), and glycaemic control, measured by HbA1c between treatment and control groups. Secondary outcomes included the effects of testosterone on symptoms, cardiovascular risk markers and adverse effects. These were reported descriptively due to heterogeneity between studies.
From the original 112 studies identified, seven RCTs were eligible for the meta-analysis including 833 men 449 treated and 384 placebo). 531 men had T2D (+/- metabolic syndrome) and 302 had metabolic syndrome alone. Studies were of moderate to high quality but there was large between-trial heterogeneity. In the 5 studies using a simple linear equation to calculate the homeostatic model assessment of insulin resistance (HOMA1), testosterone treatment modestly improved insulin resistance, compared to placebo: pooled mean difference = -1.58 (-2.25, -0.91), P < 0.001. However, the treatment effect was non-significant in the 3 RCTs using a more stringent computer-based equation (HOMA2): mean difference = -0.19 (-0.86, 0.49), P = 0.58. Testosterone treatment did not improve HbA1c: mean difference = -0.15 (-0.39, 0.10), P = 0.25, or constitutional symptoms, Aging Male Symptom score: mean difference = -2.49 (-5.81, 0.83), P = 0.14.
Three studies reported modest reductions in total cholesterol with T treatment, LDL-cholesterol was reduced in one study and modest decreases in HDL-cholesterol were reported in two studies. None showed effects on triglycerides or blood pressure and findings for sexual function were inconsistent. Serious adverse events were few.
The authors concluded that the results of the meta-analysis do not support the routine use of testosterone treatment in men with relatively well-controlled T2D and/or the metabolic syndrome without classical hypogonadism, to improve glucose metabolism or constitutional symptoms. Additional studies are needed to determine whether hormonal interventions are warranted in selected men with T2D and/or the metabolic syndrome.
Points to Note
- These results differ from previous meta-analyses that have shown more favourable effects of T treatment on glucose metabolism. The authors suggest this is most likely due to more stringent inclusion criteria, i.e. only placebo-controlled double-blind RCTs, and the inclusion of 2 recent trials using the HOMA2 measure of insulin resistance.
- It appears that T treatments may be more effective in improving glycaemic outcomes in men with the metabolic syndrome compared to men with established T2D.
- Most trials include men with relatively well controlled T2D so the effects of T treatment in men with poorly controlled T2D are unknown.
- Only one RCT reported changes in body composition. Although T treatment increased muscle mass and decreased fat mass there, was no improvement in insulin resistance. Studies are needed to see if T acts selectively on subcutaneous fat compared to visceral fat.
- Limitations of this review include: only 7 studies of modest size were reviewed, authors did not have access to individual level data; not all studies complied with the CONSORT reporting criteria; HOMA-IR is a proxy measure of insulin resistance (although it has been shown to correlate well with clamp-based techniques).