Pulmonary arterial hypertension: sex-specific differences and outcomes

Abstract

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening vascular disease characterized by increased pulmonary vascular resistance, leading to right ventricular failure and death. It has a higher prevalence in women than men, yet notable sex-based differences influence disease presentation, treatment response, and outcomes. This narrative review explores the distinct sex differences in PAH and their significant impact on prognosis. Data from major PAH clinical trials indicate that nearly 78.4% of participants are women. According to the REVEAL registry, the most common causes of PAH in women are connective tissue disease-associated PAH (CTD-PAH), idiopathic PAH (IPAH), and congenital heart disease-associated PAH (CHD-PAH). Women are often found to have better baseline right ventricular (RV) function and hemodynamics before treatment, as well as more favorable RV adaptation post-therapy. They also demonstrate a stronger response to endothelin receptor antagonists (ERA) and prostacyclins. Most notably, these factors contribute to better survival outcomes in women compared to men. In conclusion, significant sex-based differences exist in PAH, underscoring the need for personalized treatment approaches that consider sex-related factors. Future research should focus on optimizing therapeutic strategies to improve outcomes for both sexes.

Introduction

PAH is a progressive, life-threatening vascular disease characterized by increased pulmonary vascular resistance, ultimately leading to right ventricular failure and death. While PAH affects both men and women, it is significantly more prevalent in women. ¹ However, important sex-based differences influence disease presentation, treatment response, and prognosis. Understanding these differences is essential for optimizing patient management and improving outcomes.

This narrative review explores the impact of sex on PAH epidemiology, pathophysiology, treatment response, and clinical outcomes, highlighting the need for personalized therapeutic strategies based on sex-specific factors.

Epidemiology of PAH by sex

Most PAH registries have documented a higher prevalence among women, with proportions ranging from 62% to 80%.^{2 –6} Notably, major clinical trials investigating PAH therapies consistently report a high proportion of women participants. In 2024, Moutchia et al. conducted an individual participant data network meta-analysis of 6811 PAH patients from 20 phase III randomized clinical trials, revealing that 78.4% were women. ⁷ Similarly, in the United States, Badlam et al. analyzed data from the United States Pulmonary Hypertension Scientific Registry, where 79% of the 499 enrolled patients were women. ⁸ Shapiro et al. further corroborated these findings in the REVEAL Registry, which included 2318 women out of 2969 total participants (78%). ⁹

Beyond differences in prevalence, the underlying etiology of PAH also varies between sexes. According to the REVEAL Registry, the most common causes of PAH in women are CTD-PAH, IPAH, and CHD-PAH. By contrast, portopulmonary hypertension, HIV-associated PAH, and drug- and toxin-induced PAH are more frequently observed in men. ⁹ However, regional variations exist in PAH etiology. For instance, in Saudi Arabia, CHD-PAH is more prevalent in men than in women. ¹⁰

Pathophysiology of PAH by sex

PAH presents remarkable sex-based differences in pathophysiology, shaped by both hormonal and non-hormonal factors. Women are more susceptible to developing PAH than men, largely due to hormonal influences, particularly estrogen. Interestingly, despite this heightened susceptibility, women generally demonstrate better RV function and prognosis, a paradox often referred to as the “estrogen paradox.”^11,12

Estrogen plays a complex dual role in PAH. On one hand, it enhances RV function and improves survival in women, yet on the other hand, it contributes to pulmonary arterial remodeling, a central feature of PAH pathology.^11,12 Multiple studies have demonstrated the association between elevated plasma estradiol and increased severity of idiopathic PAH in both men and postmenopausal women, suggesting that estradiol may originate from peripheral, non-ovarian sources. Aromatase, the enzyme catalyzing the conversion of androgens to estrogens, is upregulated in the remodeled pulmonary arteries of PAH patients and in human pulmonary artery smooth muscle cells.^{13 –16} This local overexpression implies that abnormalities in estrogen synthesis and metabolism—rather than systemic estrogen levels alone—may significantly influence disease susceptibility and progression, particularly in women.^{13 –16} Supporting this notion, studies have shown that human pulmonary artery smooth muscle cells (PASMCs) exhibit higher aromatase expression in women compared to men. ¹³ Moreover, experimental models of PAH have demonstrated that treatment with the aromatase inhibitor anastrozole can mitigate disease severity—an effect observed predominantly in women. ¹³

Research by Tello and colleagues has shown that women with PAH exhibit higher contractility and better RV-pulmonary artery coupling compared to men, as evidenced by pressure–volume loop parameters and cardiac magnetic resonance imaging (MRI). ¹⁷ Similarly, the Multi-Ethnic Study of Atherosclerosis, which conducted cardiac MRI on 5098 participants, found that while men had approximately 8% greater RV mass and larger RV volumes than women, they also exhibited a 4% lower right ventricular ejection fraction (RVEF) in absolute terms (p < 0.001), likely influenced by testosterone. ¹⁸ In fact, in male mice, testosterone increased RV hypertrophy and fibrosis after pulmonary artery banding, and survival improved after castration, which removed the testosterone influence. ¹⁹

Beyond hormones, non-hormonal factors also play a crucial role in the sex differences observed in PAH. These include sex chromosome-linked mechanisms and epigenetic regulation, such as the upregulation of the long noncoding RNA X-inactive-specific transcript (lncRNA-Xist) in women, potentially altering the expression of X-linked genes associated with PAH and contributing to its higher incidence in women. ²⁰ Moreover, BMPR2 mutations are present in ~80% of familial and up to 20% of sporadic PAH cases, causing impaired BMPR-II signaling critical for vascular homeostasis. This leads to PASMCs’ proliferation and reduced apoptosis, driving vascular remodeling and elevated pulmonary vascular resistance. Estrogen and its metabolites, notably 16α-hydroxyestrone, further suppress BMPR-II signaling in PASMCs, contributing to women’s heightened PAH risk. ²¹

In addition, Hewes and colleagues, using rat models, identified significant sex-based differences in PAH progression, such as variations in hemodynamics, vascular morphology, and chemokine/cytokine profiles. Their research suggests that PAH in men is largely driven by macrophage-mediated pathology, while women may benefit from T-cell-mediated protection against vascular damage. ²² Moreover, men are more prone to developing severe vascular lesions and exhibit higher levels of inflammatory markers, such as HMGB1, which may further increase their susceptibility to progressive PAH. ²³

Risk stratification of PAH by sex

Current guidelines stress the importance of comprehensive risk stratification at diagnosis, using validated scoring systems to categorize patients into low-, intermediate-, and high-risk groups.^24,25 Risk stratification is a key component in evaluating the severity of PAH prior to initiating therapy. The European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines recommend a three-strata model at diagnosis, incorporating a variety of parameters, including clinical, imaging, and biomarker data. Echocardiography is one of the imaging modalities commonly used to assess risk in PAH patients at the time of diagnosis. The guidelines employ fixed cutoff values to categorize patients into low-, intermediate-, and high-risk groups based on measures such as right atrial (RA) area and the Tricuspid Annular Plane Systolic Excursion to Systolic Pulmonary Arterial Pressure (TAPSE/sPAP) ratio. ²⁴

In a study by Benjamin et al., men were found to have significantly larger right heart dimensions—including RA and RV areas—compared to women. These differences remained consistent across NYHA functional classes and cardiac index risk groups, with the exception of RA area in patients with high-risk cardiac index and NYHA class IV. When indexed to body surface area (BSA), RA area demonstrated better age-adjusted survival discrimination than the fixed ESC/ERS thresholds. Notably, the TAPSE/sPAP ratio showed no significant sex differences, reinforcing its utility as a reliable prognostic marker. ²⁶

Treatment decisions are guided by these risk assessments and standardized protocols, irrespective of sex. However, emerging evidence suggests that sex-based differences may influence risk stratification and treatment response, potentially leading to revisions in future risk assessment strategies and treatment guidelines.^{27 –29}

Interestingly, most major clinical trials evaluating pulmonary vasodilator therapies have enrolled more women participants than men, prompting questions about whether treatment responses are truly comparable between the sexes.^{30 –33}

Treatment response and prognosis of PAH by sex

Before the introduction of targeted therapies for PAH, data from the NIH registry painted a bleak picture for patients with PAH, with a median survival of just 2.8 years. Survival rates were alarmingly low, with only 68% of patients surviving 1 year, 48% at 3 years, and just 34% at 5 years. ³⁴ However, the landscape shifted dramatically with the findings from the REVEAL registry, which included 2635 patients with various PAH subtypes enrolled between 2006 and 2009. The survival rates following diagnostic right heart catheterization (RHC) were notably higher: 85% at 1 year, 68% at 3 years, 57% at 5 years, and 49% at 7 years. ³⁵ This shift underscores the significant progress in the management of WHO Group I PAH, which has evolved considerably in recent years, fueled by advancements in the development of targeted therapeutic options since the 1990s. ³² Historically, PAH treatment has focused on three key pathways: endothelin-1, nitric oxide, and prostacyclin. ²⁴ More recently, the introduction of a fourth pathway targeting the activin/TGF-β signaling axis has represented a breakthrough by addressing the proliferative mechanisms driving PAH pathology. ³³

Sex-based differences in treatment efficacy have been observed across various drug classes. For instance, research suggests that women generally have lower levels of endothelin-1 than men.^36,37 A study by Gabler et al. in 2012 evaluated gender-specific responses to endothelin receptor antagonists (ERAs) and found that women experienced greater improvements in the 6-minute walk test (6MWT) than men. The placebo-adjusted treatment response for women was 44.1 m, compared to 16.7 m for men. In addition, women on placebo showed a greater decline in 6MWT performance, a trend that was mitigated when treated with ERAs. ²⁸ In parenteral prostacyclin therapy, the PROSPECT trial in 2015 evaluated hospitalizations and survival outcomes in PAH patients receiving IV epoprostenol. The study revealed that women had a significantly higher 1-year freedom from hospitalization after treatment initiation (54.6%) compared to men (38.3%, p < 0.015). Furthermore, women had a significantly higher 1-year survival rate (88.0%) compared to men (71.0%, p < 0.001). ³⁸ Conversely, PDE5 inhibitors like sildenafil appear to be more effective in men. ³⁹ Mathai et al. demonstrated that men receiving PDE5 inhibitors were more likely to achieve clinically meaningful improvements in 6MWD and health-related quality of life compared to women. ⁴⁰ However, other studies found no significant sex-based differences in response to riociguat or selexipag. ²⁷ Sotatercept is a novel PAH therapy targeting the BMPR2 pathway. In the PULSAR trial, it significantly improved PVR and 6MWT, with similar efficacy across sexes. ⁴¹

Overall, survival rates for PAH have significantly improved over time, but sex-related differences in outcomes remain, influenced by a complex interplay of factors. Women, in particular, tend to exhibit more favorable hemodynamics, including lower right atrial pressure and mean pulmonary artery pressure, as well as a higher cardiac index. ⁴² Although both sexes experience similar reductions in PVR with therapy, with no significant difference in hemodynamic changes based on RHC, women show marked improvements in RVEF, while men do not. This disparity may help explain some of the differences in treatment response and survival outcomes. ⁴³

Registry data further highlight these sex-based survival differences. The Pulmonary Hypertension Association Registry (PHAR) reports that women have a 48% lower risk of death compared to men (p < 0.001). ⁴⁴ Similarly, the REVEAL Registry shows better 2-year and 5-year survival estimates for women than for men. ³⁵ A study using the Veterans Affairs-Clinical Assessment Reporting and Tracking (VA-CART) Database revealed that women had higher PVR but lower right atrial pressure and pulmonary artery wedge pressure than their male counterparts (all p < 0.001). ⁴⁵ Furthermore, veteran women with PAH had an 18% higher survival rate than men (p = 0.02). ⁴⁵ These findings consistently indicate that, in general, women have better survival rates than men. However, these outcomes may vary significantly across regions, such as between developed and developing countries, where factors beyond sex—like genetic predisposition, access to care, and delays in diagnosis and treatment—play a pivotal role. These factors require further investigation to better understand their impact on survival and treatment outcomes. ⁴⁶

Conclusion

PAH is not a one-size-fits-all disease—sex-based differences significantly impact its prevalence, pathophysiology, treatment response, and survival outcomes (Figure 1). While women generally demonstrate better RV function and prognosis, men tend to experience more severe disease progression. These distinctions highlight the need for personalized, sex-specific risk assessment and treatment strategies. Advancing research in this area is essential to optimizing care and improving outcomes for both men and women.

Figure 1.

Key differences between women and men with PAH.

Source: Created in https://BioRender.com

CTD-PAH, connective tissue disease-associated pulmonary arterial hypertension; ERA, endothelin receptor antagonist; HIV, human immunodeficiency virus; PAH, pulmonary arterial hypertension; PDE5, phosphodiesterase type 5; PDE5i, phosphodiesterase type 5 inhibitor; PGI₂, prostacyclin (Prostaglandin I₂); RV, right ventricular; TTT, Testosterone.