Physicians' Academy for Cardiovascular Education

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.

Literature - Koeverden ID, de Bakker M, Haitjema S et al. - Cardiovasc Res 2018. cvy188,

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).

Main results

Patient characteristics

Blood levels and plaque characteristics

Clinical outcome


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.


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