Middle-aged and older men who are overweight, tend to have lower testosterone levels. This is associated with higher incidence of type 2 diabetes and metabolic syndrome. Obesity and medical co-morbidities contribute to the decline in testosterone levels. A review and meta-analysis of observational studies, found that men with testosterone levels ≥15.6 nmol/L had a 42% reduced risk of type 2 diabetes, compared to those with testosterone levels ≤15.5 nmol/L.

A non-randomised, observational study of men with pre-diabetes (HbA1c 5.7-6.4%) and testosterone levels ≤12.1 nmol/L receiving testosterone, compared to those who did not, associated testosterone treatment with lower risk of progressing to type 2 diabetes.

Randomised trials of testosterone in middle- and older-aged men, report reductions in fat mass, and increases in lean mass, which would be expected to reduce the risk of type 2 diabetes.

Dr Bu B. Yeap, Endocrinologist, UWA and Fiona Stanley Hospital.

A large Australian, multicentre, randomised, placebo-controlled trial (RCT) sought to test if testosterone treatment reduces the incidence of type 2 diabetes in at-risk men. Testosterone therapy to prevent type 2 diabetes mellitus in at-risk men (the T4DM) study recruited men aged 50-74 years, waist circumference ≥95 cm, baseline serum testosterone of ≤14 nmol/L, and either impaired glucose tolerance (IGT) or newly diagnosed type 2 diabetes on the basis of screening oral glucose tolerance testing (OGTT, 2-hour glucose ≥7.8 and ≤15 mmol/L).

Men were excluded if any of the following were present: hypothalamo-pituitary-gonadal (HPG) axis pathology, testosterone treatment in the past 12 months, any anabolic steroid abuse, medications affecting the HPG axis, previously diagnosed diabetes, 2-hour glucose >15 mmol/L on OGTT, haematocrit >0.50, treatment with anti-obesity drugs or planned bariatric surgery, major cardiovascular event in the past six months, or active cardiac disease, systolic BP ≥160, diastolic BP ≥100, TIA or stroke within the previous three years, or any cancer other than non-melanoma skin cancer.

All participating men received a free Weight Watchers program and were randomised to receive intramuscular testosterone undecanoate 1000mg at baseline, six weeks, and every three months thereafter, nine injections over the two-year intervention, or placebo, in double-blind fashion. Currently results are only available in abstract form.

There were 1007 men randomised and 856 underwent the end-of-study OGTT. The numbers of men with two-year OGTT two-hour glucose ≥11.1 mmol/L were 55/443 (12.4%) in the testosterone arm and 87/413 (21.1%) in placebo arm (relative risk 0.59%, P <0.001). Therefore, testosterone treatment reduced the rate of new type 2 diabetes in at-risk men by 40%, beyond the effect of a lifestyle program.

T4DM is the largest testosterone RCT completed to date, with a strongly positive result. There are caveats.

There were rigorous exclusion criteria. The effect of testosterone was studied on a background of a lifestyle program and may not be applicable to testosterone treatment given in isolation. A rise in haematocrit ≥0.54 was seen in 21.6% of men in the testosterone arm compared with 1.2% in the placebo arm (P<0.001), highlighting the need for careful medical supervision.

At time of writing the T4DM primary outcomes paper had not yet been published, which needs to be done, before the findings can be fully discussed and then translated into practice.

Meanwhile, men asking about testosterone and diabetes prevention, can be evaluated for co-morbidities such as obesity, sleep apnoea and depression, and for cardiovascular risk factors and disease. They can be encouraged to pursue healthy lifestyle behaviours. Obese men who successfully lose weight, reduce their risk of type 2 diabetes and often improve their testosterone levels.

Interest generated by T4DM provides a valuable opportunity to advance men’s health. Men can be offered individualised assessments to improve their health outcomes, while T4DM’s implications are being considered.

Key messages

  • T4DM was an Australia-wide two-year randomised controlled trial of testosterone vs placebo for men with IGT or newly diagnosed T2DM
  • Both arms had underwent a Weight Watchers program
  • Abstract results from T4DM suggest testosterone may reduce rates of new type 2 diabetes in at-risk men, beyond that achieved by a community-based lifestyle program.

References available on request.

Questions? Contact the editor.

Author competing interests: The author has received honoraria and research support from Bayer, Lilly and Lawley Pharmaceuticals, and honoraria from Besins and Ferring.

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