Testosterone : of importance in patients with dysglycemia and cardiovascular disease?

Abstract

Background: Testosterone has been associated with cardiovascular (CV) health in men and women with or without diabetes. There are however conflicting results which warrant further investigations to understand if testosterone is important for prognosis, in particular in relation to diabetes and cardiovascular disease (CVD). To gain further insight, several aspects such as when and which testosterone fraction to assess as well as genetic variations in the androgen receptor are of interest to study.

Aims: To study the role of testosterone in men and women with different levels of dysglycemia and CVD by investigating: 1. the dynamics of testosterone levels up to a year following an acute myocardial infarction (AMI) in men with and without dysglycemia 2. the relation between the androgen receptor gene CAG repeat length, testosterone levels and prognosis 3. the prognostic implications of total testosterone, free testosterone and the binding protein sex hormone-binding globulin (SHBG) in patients with AMI compared to healthy controls as well as in men and women with dysglycemia and high CV risk.

Methods: Studies I and II were based on data from the GAMI study, a prospective cohort study of patients with AMI providing blood samples at four time points up to a year post-infarction, and healthy, age-matched controls. Study participants were classified as having normal (NGT) or abnormal glucose tolerance (AGT) based on oral glucose tolerance tests and followed for about 11 years for CV events, and CV and all-cause mortality; Study I comprised male patients (n=123) and controls (n=124), Study II comprised male patients (n=121) with blood samples available for DNA analyses. Studies III and IV were based on a biomarker substudy of ORIGIN which was a large, multicenter randomized controlled trial following patients with dysglycemia and high CV risk for about six years for CV events and all-cause mortality. Study III comprised all male patients (n=5 553) and Study IV all female patients (n=2 848) in the biomarker substudy.

Results: In Study I, median testosterone levels were lower immediately after an AMI compared to controls at baseline (243 ng/dl vs. 380 ng/dl; p<0.01) but increased at discharge, three months and 12 months to 311, 345 and 357 ng/dl respectively. Patients with AGT had the lowest levels at the first timepoint (230 ng/dl). Total and free testosterone did not predict CV events or all-cause mortality in men with AMI but CV and all-cause mortality in controls. In Study II, contrary to the hypothesis, there was no correlation between CAG repeat length and testosterone and moreover CAG repeat length did not predict CV events or all-cause mortality. In Study III, total and free testosterone did not predict prognosis in Cox regression analyses by one standard deviation increment but low free testosterone (≤7 ng/dl) was associated with increased allcause mortality. Additionally, increasing SHBG was related to a higher risk of CV events (HR 1.07; 95% CI 1.00–1.14; p<0.03) and all-cause mortality (HR 1.13; 95% CI 1.06–1.21; p<0.01). Finally, in Study IV, total and free testosterone did not predict any outcomes in women but SHBG was related to increased all-cause mortality (HR 1.14; 95% CI 1.05-1.24; p<0.01).

Conclusions: Low testosterone was common in patients hospitalized with AMI, in particular in those with AGT, but increased over time indicating that samples taken in close proximity to AMI should be interpreted with caution. In contrast to healthy controls where low total and free testosterone was predictive of prognosis, only free testosterone ≤7 ng/dl was associated with all-cause mortality in patients. This suggests that testosterone may be a mediator in CVD and prognosis rather than a traditional risk factor. The potential importance of CAG repeat length in this context was not confirmed. Interestingly, SHBG was an independent predictor for CV events and all-cause mortality in men and for all-cause mortality in women with dysglycemia. This warrants further study to clarify whether the actions of SHBG are mediated through an impact on the distribution of testosterone or if SHBG is a direct prognostic marker.