Low testosterone/estradiol ratio associated with higher CV risk in men with atherosclerotic disease
Testosterone to estradiol ratio reflects systemic and plaque inflammation and predicts future cardiovascular events in men with severe atherosclerosis.
Introduction and methods
Low testosterone levels are associated with an increased risk of atherosclerotic manifestations in men [1,2], and studies have shown that an imbalanced testosterone/estradiol (T/E2) ratio can contribute to CVD progression in men [3,4]. However, these findings have been obtained in small studies or animal models and remain to be established in larger cohort studies focusing on the effect of these sex hormones on CVD in patients.
This sub-analysis of the Athero-Express Biobank Study investigated the effect of the sex hormones testosterone and estradiol on atherosclerotic plaques and cardiovascular (CV) events in 611 men with carotid endarterectomy (CEA), by calculating T/E2 ratios around time of surgery, and by analyzing histologic plaque characteristics (n=500) and inflammatory biomarkers in the blood (n=611) during a follow-up of three years.
The T/E2 was calculated by the formula: testosterone/(10*estradiol) and patients were classified based on low and high ratios. Atherosclerotic plaque samples (n=500) and patient characteristics (from the Utrecht Patient-Oriented Database (UPOD)) were collected between 2002 and 2016. CV events and/or hospitalization were addressed by questionnaires and validated by using hospital data systems. Major adverse cardiovascular event (MACE) was defined as myocardial infarction (MI), stroke or CV death (fatal MI, fatal stroke, fatal ruptured abdominal aneurysma, fata heart failure or sudden death).
- Low T/E2 ratio was defined as Q1: <0.9878 (n=152) and Q2; 0.9878 – 1.4191 (n=153), and high T/E2 ratio was defined as Q3; 1.4192 – 1.8916 (n=153) and Q4; >1.8916 (n=153).
- Mean testosterone and estradiol concentrations were 12.3 nmol/L (SD±5.56) and 92.8 pmol/L (SD±38.44), respectively.
- Low T/E2 ratio was significantly associated with BMI ≥25 (P<0.001).
Blood levels and plaque characteristics
- Lower T/E2 ratio was significantly associated with higher C-reactive protein levels (2.81 μg/mL vs. 1.22 μg/mL p<0.001) and leucocytes (8.98*109/L vs. 7.75*109/L , p=0.001) in blood.
- A negative association was found between T/E2 ratio and the amount of neutrophils (B=-0.366; p=0.012), plaque calcification (OR: 0.816; p=0.044), interleukine-6 (IL-6) (B=-0.15 p=0.009) and IL-6 receptor (B=-0.13; p=0.024) in the atherosclerotic plaque.
- 72 patients (11.8%) experienced a major CV endpoint during a mean follow-up of 2.7 years.
- 6.5% suffered from stroke, 2.9% endured a MI and in total 3.9% died due to CV causes.
- After adjustments T/E2 ratio was an independent predictor for major CV events (HR low T/E2 ratio: 1.67, 95%CI: 1.02-2.76, p=0.043).
- Low T/E2 ratio was associated with increased stroke incidence during follow-up (HR: 2.09, 95%CI: 1.06-4.14, p=0.034).
- BMI showed a significant interaction with the association between T/E2 ratio and MACE. HR of T/E2 ratio for MACE was higher in those with BMI ≥25 (HR: 2.42, 95%CI: 1.09-5.38, p=0.030), compared to BMI <25 (no longer statistically significantly elevated HR).
In men with atherosclerotic disease, low T/E2 ratio was associated with increased systemic inflammation, inflammatory proteins in the plaque, and a higher risk of major CV events in future, compared to high T/E2 ratio. The effects are largest in men with higher BMI. These findings expand the evidence on how hormonal dysbalance is associated with inflammation and vascular function, and ultimately poor outcomes. Normalizing T/E2 may play a role in secondary prevention of CVD in men.