European Journal of Endocrinology (2006) 154 899–906 ISSN 0804-4643 CLINICAL STUDY Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes D Kapoor1,3, E Goodwin1, K S Channer2 and T H Jones1,3 1Centre for Diabetes and Endocrinology, Barnsley NHS Foundation Trust Hospital, Gawber Road, Barnsley S75 2EP, UK and 2Department of Cardiology, Royal Hallamshire Hospital, Sheffield, UK and 3Academic Unit of Endocrinology, Division of Genomic Medicine, University of Sheffield, UK (Correspondence should be addressed to T H Jones; Email: [email protected]) Abstract Objective: Low levels of testosterone in men have been shown to be associated with type 2 diabetes, visceral adiposity, dyslipidaemia and metabolic syndrome. We investigated the effect of testosterone treatment on insulin resistance and glycaemic control in hypogonadal men with type 2 diabetes. Design: This was a double-blind placebo-controlled crossover study in 24 hypogonadal men (10 treated with insulin) over the age of 30 years with type 2 diabetes. Methods: Patients were treated with i.m. testosterone 200 mg every 2 weeks or placebo for 3 months in random order, followed by a washout period of 1 month before the alternate treatment phase. The primary outcomes were changes in fasting insulin sensitivity (as measured by homeostatic model index (HOMA) in those not on insulin), fasting blood glucose and glycated haemoglobin. The secondary outcomes were changes in body composition, fasting lipids and blood pressure. Statistical analysis was performed on the delta values, with the treatment effect of placebo compared against the treatment effect of testosterone. Results: Testosterone therapy reduced the HOMA index (K1.73G0.67, PZ0.02, nZ14), indicating an improved fasting insulin sensitivity. Glycated haemoglobin was also reduced (K0.37G0.17%, PZ0.03), as was the fasting blood glucose (K1.58G0.68 mmol/l, PZ0.03). Testosterone treatment resulted in a reduction in visceral adiposity as assessed by waist circumference (K1.63G0.71 cm, PZ0.03) and waist/hip ratio (K0.03G0.01, PZ0.01). Total cholesterol decreased with testosterone therapy (K0.4G0.17 mmol/l, PZ0.03) but no effect on blood pressure was observed. Conclusions: Testosterone replacement therapy reduces insulin resistance and improves glycaemic control in hypogonadal men with type 2 diabetes. Improvements in glycaemic control, insulin resistance, cholesterol and visceral adiposity together represent an overall reduction in cardiovascular risk. European Journal of Endocrinology 154 899–906 Introduction Furthermore, in diabetic men observational studies have reported a higher prevalence of hypogonadism Hyperinsulinaemia and insulin resistance are antece- when compared with non-diabetics (7–10). Dhindsa dents to clinically established type 2 diabetes. Insulin and colleagues found the prevalence of hypogonadism resistance is also an essential component of the metabolic in type 2 diabetic men to be as high as 33% using free syndrome, which is defined as the presence of three or testosterone measurement by the equilibrium dialysis more of the following factors: central obesity, hyper- method (10). triglyceridaemia, low high-density lipoprotein (HDL), Visceral obesity is an important cause of insulin hypertension and a raised fasting blood glucose (1). This resistance and is strongly linked to the development of syndrome is associated with an increased risk of the impaired glucose tolerance. Studies have shown that free premature development of coronary artery disease. testosterone levels are low in obese men and inversely Studies in healthy men have shown an inverse correlated with the degree of obesity (11, 12). There is an relationship between total testosterone levels and increase in deposition of abdominal adipose tissue in insulin concentrations (2, 3). Low testosterone levels hypogonadal subjects, which in turn leads to a further in men have been found to predict insulin resistance and decrease in testosterone concentrations, through the future development of type 2 diabetes (4–6). conversion to oestradiol by aromatase, hence facilitating q 2006 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.02166 Online version via www.eje-online.org Downloaded from Bioscientifica.com at 10/02/2021 03:31:47AM via free access 900 D Kapoor and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 154 fat deposition and a greater degree of hypogonadism washout period of 1 month in between. Each patient (12). In addition, leptin levels increase with obesity and was randomised to receive either placebo or testoster- this hormone causes a further reduction in androgen one therapy first and after the washout period patients levels in men (12, 13). crossed over to the alternate therapy. Further evidence for the association between hypo- Subjects were men aged over 30 years with type 2 gonadism and insulin levels in men has been reported in diabetes and with hypogonadism. All patients gave written studies on patients undergoing treatment for prostate informed consent and the local research ethics committee carcinoma where androgen ablation is the main approved the protocol. Inclusion criteria were type 2 treatment. Two studies have shown an increase in diabetic men with HbA1c up to 9.5% showing no insulin levels in patients treated with gonadotrophin- significant symptoms of hyperglycaemia. Hypogonadism releasing hormone (GnRH) agonists (14, 15). Another wasdefinedastotaltestosteronelevel!12 nmol/l (on two study reported an increase in insulin and glucose levels separate occasions) and symptoms of hypogonadism after surgical castration for prostate carcinoma (16). (positive ADAM score) (26). Patients were excluded if These observations suggest that an inverse relationship they had any inflammatory disease or infection with exists between serum androgens and insulin sensitivity. elevation of C-reactive protein O10 mg/l, were already on Low testosterone levels have also been found to be hormone therapy or had any contraindication to testoster- associated with dyslipidaemia and hypertension (17). one therapy such as elevation of prostate-specific antigen Furthermore, Laaksonen and colleagues have shown (PSA) beyond the age-adjusted normal range. HOMA was that hypotestosteronaemia is associated not only with not measured in those patients treated with insulin. components of the metabolic syndrome but also with the metabolic syndrome itself, independent of body mass index (BMI) (18). Randomisation and drug treatment Interventional studies have been limited. A study in male castrated rats demonstrated impaired insulin Patients were randomised to ‘testosterone first’ or sensitivity that was corrected with physiological testos- ‘placebo first’ using a computer-generated random terone replacement treatment but not with supraphysio- number. Treatment was with Sustanon 200 mg logical therapy (19). Similarly, a study in healthy men (testosterone propionate 30 mg, testosterone phenyl- with low total testosterone levels (! 11.8 nmol/l), propionate 60 mg, testosterone isocaproate 60 mg, and reported an improvement in insulin sensitivity and a testosterone decanoate 100 mg/ml, Organon Labora- decrease in insulin levels using testosterone or dihydro- tories, Cambridge, UK), a depot preparation of testos- testosterone treatment (20). Testosterone treatment has terone given by deep i.m. injection. Intramuscular also been shown to reduce insulin resistance in obese men injections were given once every 2 weeks, with patients (21, 22) and to decrease total cholesterol in hypogonadal receiving a total of six injections in each phase. The final men with coronary artery disease, even in those taking assessment in each treatment phase was 12–14 days statins (23). A study of type 2 diabetic men using oral after the previous injection. This regimen is commonly testosterone showed an improvement in glycaemic used as standard physiological testosterone replacement control (24) although Corrales et al. have reported a therapy in men with androgen deficiency and neutral effect using i.m. testosterone treatment (25). represents 3 months of testosterone treatment. Placebo To our knowledge, this is the first study to assess the was given as 0.9% normal saline. Drugs were drawn in effect of testosterone treatment on insulin resistance identical syringes by a research nurse in a separate and glycaemic control in hypogonadal men with type 2 clinical room away from the patient and the doctor diabetes. assessing the patient. Subjects and methods Assessment This was a double-blind placebo-controlled crossover Patients were screened initially with a questionnaire study performed at the Centre for Diabetes and detailing their medical history and their concomitant Endocrinology, Barnsley NHS Foundation Trust Hospi- medications were noted. Assessments were always made tal, Barnsley, UK. The primary outcomes were changes between 0800 and 1000 h after an overnight fast. All in the homeostasis model assessment (HOMA) index of concomitant oral hypoglycaemic, anti-hypertensive and insulin resistance, fasting blood glucose and glycated lipid-lowering medications were permitted and contin- haemoglobin. The secondary outcomes were changes in ued throughout the study without dose adjustment. fasting lipids, blood pressure and anthropometric However, those patients who were on insulin were measurements including waist circumference, waist/ permitted to make insulin dose