High testosterone levels in older men associated with greater risk of atrial fibrillation

By Pooja Toshniwal PahariaReviewed by Lily Ramsey, LLMMay 2 2024

In a recent study published in eClinicalMedicine, researchers investigated whether higher endogenous testosterone levels increase atrial fibrillation (AF) risk among healthy older males.

Study: Testosterone and the risk of incident atrial fibrillation in older men: further analysis of the ASPREE study. Image Credit: Orawan Pattarawimonchai/Shutterstock.com

Background

Testosterone levels in older males fall due to testicular Leydig cellular dysfunction, aggravated by medical conditions such as obesity. Males with androgen deficits caused by pituitary, hypothalamic, or testicular disorders are frequently prescribed testosterone replacement therapy.

However, worries about the safety of testosterone therapy have led to a rise in testosterone prescriptions, mainly for older men who do not have organic illnesses.

The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial reported no differences in major adverse cardiovascular event (MACE) or mortality incidences; however, testosterone-treated men had more AF episodes.

The effect of serum testosterone levels on AF risk is unclear, as previous research has yielded conflicting results.

About the study

The present study examined the link between serum testosterone and atrial fibrillation incidence.

The study comprised 4,570 male participants from the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Participants were 70 years of age or older and did not have any preexisting medical illnesses such as cardiovascular, prostate, dementia, thyroid, or potentially fatal disorders.

The researchers excluded individuals prescribed medications interfering with hypothalamic-pituitary axis (HPA) functions and men with thyroid malignancies or thyroid-related drugs to eliminate confounding factors such as thyroxine overdose and hyperthyroidism associated with elevated testosterone levels. 
The researchers obtained laboratory and anthropometric data at baseline, and participants filled out questionnaires about their comorbidities, medical and social history, lifestyle, and physical function.

Yearly in-person follow-ups and six-monthly phone conversations enabled evaluation and data collection. The researchers collected blood and urine samples from the individuals.

The team used chemiluminescence immunoassays to assess serum testosterone and thyroid-stimulating hormone (TSH) levels.

They ascertained AF as an incident in the case of a new diagnosis mentioned in yearly reviews and self-reports and less frequently in the case of an abnormal heart rate or self-report documented with anticoagulant or antiarrhythmic drug prescriptions.

The researchers used Cox proportional hazard regressions to model AF risk, adjusting for age, body mass index (BMI), smoking status, alcohol consumption, diabetes mellitus, hypertension, dyslipidemia, aspirin allocation, and thyroid hormone levels.

They performed sensitivity analyses, eliminating individuals with TSH levels below 0.30 mU/ml and limiting the analysis to individuals with serum testosterone levels within the clinically normal range. The researchers followed the participants until June 2017 and examined the data between June and September 2023.

Results and discussion

The median participant age, follow-up time, total serum testosterone, and BMI were 74 years, 4.40 years, 15.80 nmol/L, and 27.60 kg/m2, respectively. Among the participants, 12% were diabetic, and 76% were hypertensive. In total, 286 males had atrial fibrillation (15 per 1,000 participant-years).

Males with new-onset atrial fibrillation showed a higher likelihood of being older, current, or former cigarette smokers with elevated BMI at study initiation.
Males with new-onset AF had higher baseline testosterone levels compared to those without (17 versus 15.7 nmol/L). The researchers found non-linear relationships between baseline testosterone levels and AF incidence, with a significant increase at higher serum total testosterone levels.

The study found that every 1.0 nmol/L rise in serum testosterone raised the incidence of atrial fibrillation by 18%.

Males with serum testosterone in the fourth and fifth quintiles (Q) had a higher incidence of atrial fibrillation (Q4:Q3 quintiles, hazard ratio 1.9; and Q5:Q3 quintiles, hazard ratio 2.0). 

Similar findings were observed after excluding males with heart failure or MACE and those with TSH concentrations below 0.30 mU/L, limiting the study to individuals with serum testosterone within normal ranges.

Shorter telomeres and higher serum testosterone levels increase AF risk among middle- to elderly males. Higher testosterone conversion to estradiol increases aromatase expression in epicardial adipose tissues, predisposing to arrhythmia.

In-vitro investigations indicate that testosterone administration may increase β1-adrenergic receptors and spontaneous-type action potentials within pulmonary veins, potentially leading to AF. Sex-related hormones may potentially affect cardiovascular tissues by modifying ion channel activity.

The study findings revealed that higher testosterone concentrations in healthy older males increase AF risk. Men in the top two quintiles had a two-fold higher chance of developing AF than those in the middle quartile.

The findings support the TRAVERSE study, indicating atrial fibrillation as an unintended consequence of serum testosterone in high-normal concentrations, and clinicians must evaluate AF risk when assessing the risk-benefit ratio of testosterone treatment.

Future research should consider non-observational study designs to determine causality and circadian fluctuations in testosterone levels.