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Review
. 2025 Sep 1;31(5):411-428.
doi: 10.1097/MCP.0000000000001197. Epub 2025 Jul 23.

Sex differences in pulmonary (arterial) hypertension: does it matter?

Corey E Ventetuolo  1   2   3 , Alexis E Sherman-Roe  1
Affiliations
Review

Sex differences in pulmonary (arterial) hypertension: does it matter?

Corey E Ventetuolo et al. Curr Opin Pulm Med. .

Abstract

Purpose of review: This review synthesizes the current prevailing theories behind the 'sex paradox' or 'sex puzzle' in pulmonary arterial hypertension (PAH), a disease marked by sexual dimorphism. To a lesser extent, we also review sex differences in other forms of pulmonary hypertension.

Recent findings: Although more females than males develop PAH worldwide, female sex is associated with improved right ventricular (RV) function and survival. We review the role of sex chromosomes and sex hormones and their relationships to genomic and epigenetic regulation, immune function, and RV function, sex-based differences in therapeutic response and social determinants of health and intersectionality with gender in PAH pathobiology, prevalence and outcomes. We include experimental studies and observational human data that have led to the study of sex hormone modulation as a treatment strategy in PAH, with recently completed clinical trials. In addition, we explore potential future directions to help understand the mechanisms that underpin sex biases in pulmonary vascular disease, as well as those that may inform potential therapeutic targets.

Summary: Survival in PAH depends on RV function, and females have improved survival despite increased prevalence for reasons that remain unclear. While knowledge gaps remain, recent advancements offer promise and many future directions.

Keywords: pulmonary arterial hypertension; right ventricle; sex chromosomes; sex differences in pulmonary arterial hypertension; sex hormones.

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References

    1. Shapiro S, Traiger GL, Turner M, et al. Sex differences in the diagnosis, treatment, and outcome of patients with pulmonary arterial hypertension enrolled in the registry to evaluate early and long-term pulmonary arterial hypertension disease management. Chest. 2012. Feb;141(2):363–73. - PubMed

    1. DesJardin JT, Kime N, Kolaitis NA, et al. Investigating the "sex paradox" in pulmonary arterial hypertension: Results from the Pulmonary Hypertension Association Registry (PHAR). J Heart Lung Transplant. 2024;43(6):901–910.

      Sex-based analysis of the Pulmonary Hypertension Association Registry. Despite less favorable hemodynamic and metrics, females had a 48% lower risk of death compared to males. After adjustments for covariates, authors raise the possibility of collider-stratification bias or another unmeasured factor to account for the observed increased mortality risk among males with PAH.

    1. Hoeper MM, Huscher D, Ghofrani HA, et al. Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: Results from the COMPERA registry. Int J Cardiol. 2013. Sep 30;168(2):871–80. - PubMed

    1. Pagnesi M, Riccardi M, Savonitto G, et al. Sex differences in pulmonary arterial hypertension: Insights from the FOCUS-PAH registry. Int J Cardiol. 2025. Jul 1;430:133180.

      Real-world registry from seven European PH centers (six in Italy, one in the UK) spanning two-decades with ~66% of patients female. Female sex was independently associated with a lower risk mortality compared with male sex.

    1. Shelburne NJ, Nian H, Beck GJ, et al. Male Sex Is Associated With Worse Right Ventricular Function and Survival in Pulmonary Hypertension in the Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics Cohort. CHEST Pulm. 2024. Sep;100046.

      PVDOMICs study in the US across seven PH centers. Patients with PAH and PH were enrolled and underwent hemodynamics, cardiac MRI, and echocardiography to further evaluate the relationship between sex and pulmonary vascular resistance (PVR) and RV ejection fraction. Male sex was associated with worse RV function, decreased transplant-free survival, and elevation in PVR.

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