The role of androgen receptor CAG repeat polymorphism and other factors which affect the clinical response to testosterone replacement in metabolic syndrome and type 2 diabetes: TIMES2 sub-study

R D Stanworth, S Akhtar, K S Channer, T H Jones
European Journal of Endocrinology 2014, 170 (2): 193-200

CONTEXT: The TIMES2 (testosterone replacement in hypogonadal men with either metabolic syndrome or type 2 diabetes) study reported beneficial effects of testosterone replacement therapy (TRT) on insulin resistance and other variables in men with diabetes or metabolic syndrome. The androgen receptor CAG repeat polymorphism (AR CAG) is known to affect stimulated AR activity and has been linked to various clinically relevant variables.

OBJECTIVE: To assess the role of AR CAG in the alteration of clinical response to TRT in the TIMES2 study.

DESIGN: Subgroup analysis from a multicentre, randomised, double-blind, placebo-controlled and parallel group study.

SETTING: Outpatient study recruiting from secondary and primary care.

PATIENTS: A total of 139 men with hypogonadism and type 2 diabetes or metabolic syndrome, of which 73 received testosterone during the TIMES2 study.

INTERVENTION: Testosterone 2% transdermal gel vs placebo.

MAIN OUTCOME MEASURE: Regression coefficient of AR CAG from linear regression models for each variable.

RESULTS: AR CAG was independently positively associated with change in fasting insulin, triglycerides and diastolic blood pressure during TRT with a trend to association with HOMA-IR - the primary outcome variable. There was a trend to negative association between AR CAG and change in PSA. There was no association of AR CAG with change in other glycaemic variables, other lipid variables or obesity.

CONCLUSION: AR CAG affected the response of some variables to TRT in the TIMES2 study, although the association with HOMA-IR did not reach significance. Various factors may have limited the power of our study to detect the significant associations between AR CAG, testosterone levels and change in variables with testosterone treatment. Analysis of similar data sets from other clinical trials is warranted.

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