Associations between blood testosterone and DHEA and risk of ischaemic cardiovascular events in healthy older women; a prospective cohort sub-study of the ASPREE trial

Associations between blood testosterone and DHEA and risk of ischaemic cardiovascular events in healthy older women; a prospective cohort sub-study of the ASPREE trial

Background

Blood testosterone concentrations in women decline during the reproductive years and reach a nadir in the seventh decade, after which concentrations increase and are restored to those of reproductive aged women early in the eighth decade. Whether having higher testosterone blood levels is favourable or disadvantageous for ischaemic cardiovascular disease (CVD) risk and all-cause mortality in older women is unknown.

Methods

The Sex Hormones in Older Women (SHOW) study is a sub-study of the longitudinal ASPREE (ASPirin in Reducing Events in the Elderly) randomised trial which recruited 9180 Australian women, aged at least 70 years, with no prior CVD events, between 2010 and 2014. Sex hormones were measured by liquid chromatography and tandem mass spectrometry and sex hormone binding globulin (SHBG) by immunoassay in 6358 of the 6392 participants with baseline biobank samples. Major adverse cardiovascular events (MACE) comprised fatal coronary heart disease (excluding heart failure), nonfatal myocardial infarction, and fatal or nonfatal ischaemic stroke. Women were excluded from the analysis if they were taking sex hormones, anti-oestrogens, anti-androgens or systemic glucocorticoids. Associations between hormones and MACE and all-cause mortality were examined using Cox proportional hazards regression that included age, body mass index (BMI), smoking status, alcohol consumption, diabetes, hypertension, dyslipidaemia, impaired renal function and treatment allocation (aspirin or placebo).

Findings

The median age of the 5535 women included in the analysis was 74.0 (IQR:71.7-77.7) years at baseline. During a median 4.4 years of follow-up (24,553 person-years) 144 women experienced a MACE; incidence rate of 5.9/1000 person-years. There were 200 deaths. In the fully adjusted models, higher testosterone (3rd and 4th quartiles) and DHEA (three highest quartiles) were associated with a lower risk of MACE (hazard ratios for the 4th (highest) quartile versus the 1st (lowest) quartile were 0.57 [95% CI, 0.36 to 0.91, p=0.02] and 0.61 [95%CI, 0.38 to0.97, p=0.04, respectively). MACE risk in only the second quartile of oestrone was significantly different to the lowest quartile (p=0.02). Divergence of the cumulative hazard curves for MACE for the lowest quartiles of testosterone and DHEA emerged early and were statistically significantly different from the higher quartiles by year 3. No association was seen between SHBG and MACE, or between any hormone or SHBG and all-cause mortality.

Interpretation

Testosterone and DHEA concentrations above the lowest quartile in older women are associated with a reduced risk of a first ever MACE. As the physiological effects of DHEA are mediated through its steroid metabolites, should these findings be replicated, primary prevention trials of testosterone for the prevention of ischaemic cardiovascular events in older women would be warranted.