Sex Hormones and Incident Heart Failure in Men and Postmenopausal Women

The Atherosclerosis Risk in Communities Study

Di Zhao; Eliseo Guallar; Christie M. Ballantyne; Wendy S. Post; Pamela Ouyang; Dhananjay Vaidya; Xiaoming Jia; Wendy Ying; Vinita Subramanya; Chiadi E. Ndumele; Ron C. Hoogeveen; Erin D. Michos


J Clin Endocrinol Metab. 2020;105(10) 

In This Article

Abstract and Introduction


Context: Sex differences exist in heart failure (HF) phenotypes, but there is limited research on the role of sex hormones in HF and its subtypes.

Objective: To examine the associations of total testosterone, dehydroepiandrosterone sulfate (DHEA-S), and sex hormone-binding globulin (SHBG) with incident HF, HF with preserved ejection fraction (HFpEF), and HF with reduced ejection fraction (HFrEF).

Design: Atherosclerosis Risk in Communities (ARIC) study (prospective cohort study). Median follow-up is 19.2 years.

Setting: General community.

Participants: 4107 men and 4839 postmenopausal women, with mean age of 63.2 (standard deviation SD 5.7) and 62.8 (5.5) years, respectively.

Exposure: Plasma sex hormone levels were measured at visit 4 (1996-1998).

Main Outcome Measures: Incident HF events were identified through hospital discharge codes and death certificates.

Results: The Hazard Ratios for HF associated with 1 SD decrease in log-transformed total testosterone, DHEA-S, and SHBG were 1.10 (95% confidence interval 1.03, 1.17), 1.07 (1.00, 1.15), and 1.04 (0.96, 1.11) in men, and 1.05 (0.99, 1.13), 1.17 (1.09, 1.24), and 0.93 (0.85, 1.01) in women, respectively. The associations between sex hormones with subtypes of HF had similar patterns but were attenuated and became statistically insignificant.

Conclusion: In this prospective cohort, lower levels of endogenous testosterone and DHEA-S in men and DHEA-S in postmenopausal women were associated with the development of HF. Similar directions of association in both sexes and both HF subtypes suggest that sex hormones play a role in the development of HF through common pathways regardless of sex.


Clinical phenotypes of heart failure (HF) patients differ markedly by sex. Up to 60% of patients with HF with preserved ejection fraction (HFpEF) are women, in contrast to only 40% of patients with HF with reduced ejection fraction (HFrEF).[1,2] Compared with men, women develop HF at a more advanced age,[3] are more likely to have nonischemic cardiomyopathy and eccentric myocardial left ventricular (LV) remodeling, and have better prognosis and reduced mortality in response to treatment.[4]

The biological mechanisms underlying these sex differences are uncertain, but it has been hypothesized that they may be related to variations in endogenous sex hormone levels. In men, higher plasma testosterone levels are associated with lower risk of cardiovascular disease (CVD) and mortality.[5–7] In women, higher plasma testosterone levels have generally been associated with an increased risk of CVD and HF,[8,9] although the evidence has been inconsistent across studies.[10,11] Most studies, however, have evaluated the association of sex hormone levels with overall CVD, and there is a paucity of research on the role of sex hormones in HF and its subtypes. Additionally, most studies have focused on testosterone. Understanding the role of sex hormones in the etiology of HF is particularly important for HFpEF, given its high and escalating prevalence, female predominance, excessive mortality burden, and lack of effective treatment.

To address this gap, we examined the associations of sex hormones (testosterone, dehydroepiandrosterone sulfate [DHEA-S], and sex hormone binding globulin [SHBG]) with incident HF, HFrEF, and HFpEF among men and postmenopausal women in the Atherosclerosis Risk in Communities (ARIC) study, a large, community-based cohort with long-term follow-up.