Ventetuolo Corey E, Sherman-Roe Alexis E
Department of Medicine, The Warren Alpert Medical School of Brown University.
Center for Advanced Lung Care, Brown University Health.
Curr Opin Pulm Med. 2025 Sep 1;31(5):411-428. doi: 10.1097/MCP.0000000000001197. Epub 2025 Jul 23.
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.
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.
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.
本综述综合了肺动脉高压（PAH）中“性别悖论”或“性别谜题”背后当前流行的理论，PAH是一种具有性别二态性的疾病。在较小程度上，我们还综述了其他形式肺动脉高压中的性别差异。
尽管全球范围内患PAH的女性比男性多，但女性性别与右心室（RV）功能改善及生存率提高相关。我们综述了性染色体和性激素的作用及其与基因组和表观遗传调控、免疫功能和RV功能的关系，PAH病理生物学中治疗反应的性别差异、健康的社会决定因素以及与性别的交叉性、患病率和结局。我们纳入了导致将性激素调节作为PAH治疗策略进行研究的实验研究和观察性人体数据，以及最近完成的临床试验。此外，我们探索了潜在的未来方向，以帮助理解肺动脉疾病中性别偏见背后的机制，以及那些可能为潜在治疗靶点提供信息的机制。
PAH患者的生存取决于RV功能，尽管患病率增加，但女性的生存率有所提高，原因尚不清楚。虽然仍存在知识空白，但最近的进展带来了希望和许多未来方向。
