Abstract Rationale Chronic obstructive pulmonary disease (COPD) coexists with World Health Organization (WHO) Group 3 pulmonary hypertension (PH; COPD-PH). In WHO Group 1 PH (pulmonary arterial hypertension: PAH), an “estrogen paradox” has been described, characterized by higher disease prevalence in females but increased mortality in males, attributed partly to pleiotropic effects of sex hormones. Similar sex-based differences have been reported in clinical studies of COPD-PH, suggesting a potential hormonal contribution to COPD-PH pathobiology. We investigated the relationships between sex hormones, vascular biomarkers, and clinical outcomes in COPD-PH. Methods We conducted a single-center observational study using data from two prospective cohorts initiated in September 2018: 1) PH with or without COPD, and 2) COPD with or without PH. Most participants underwent right heart catheterization (RHC) as part of routine clinical care where pulmonary artery blood was collected. Clinical data included mean pulmonary artery pressure (mPAP) and survival through March 2025. Sex hormones estradiol (E2), dihydroepiandrosterone sulfate (DHEAS) and testosterone and vascular biomarkers were quantified using multiplex assays. Correlation analyses were performed between sex hormones and vascular biomarkers. Bonferroni correction was applied to adjust for multiple comparisons. Associations between sex hormones and mPAP were assessed using generalized logit model, and associations with mortality were examined using multivariable logistic regression. A two-tailed p 0.05 was considered statistically significant. Results We enrolled 78 participants and stratified them into three subgroups: COPD-PH (n = 34), PAH (n = 28), and COPD without PH (n = 16). RHC was performed in 63 participants, with no significant sex difference observed in mPAP. The COPD-PH and PAH subgroups demonstrated partially overlapping correlation patterns between sex hormones and vascular biomarkers, including significant inverse correlations between testosterone and ADAMTS13 (Figure).In the PAH subgroup, log-transformed DHEAS was inversely associated with mPAP odds ratio (OR) = -6.08, standard error = 2.60, p = 0.029. In the overall cohort, higher log(DHEAS) OR = 0.39, 95% confidence interval (CI): 0.20-0.76, p = 0.006 and log(testosterone) OR = 0.44, 95% CI: 0.22-0.87, p = 0.019 were independently associated with lower mortality. In the COPD-PH subgroup, higher log(DHEAS) exhibited a similar but non-significant trend toward reduced mortality OR = 0.43, 95% CI: 0.18-1.03, p = 0.058. Conclusions Our study suggests sex hormones may play a mechanistic role in COPD-PH, paralleling the sex-differential pathobiology in PAH. The associations between sex hormones and clinical outcomes warrant validation in larger, prospective future studies. This abstract is funded by: UAB Comprehensive Cardiovascular Center
Maeda et al. (Fri,) studied this question.