DHEA treatment in pulmonary arterial hypertension significantly decreased plasma nitrite in females (p=0.023) and nitrate in males (p<0.001) compared to placebo.
RCT (n=26)
placebo-controlled
randomized
Does Dehydroepiandrosterone (DHEA) treatment alter plasma nitrate and nitrite levels in participants with pulmonary arterial hypertension?
DHEA treatment in PAH alters nitric oxide signaling biomarkers differently based on biological sex and menopausal status, which correlates with right ventricular function.
Abstract Rationale Dehydroepiandrosterone-sulfate (DHEA-S) levels are reduced in pulmonary arterial hypertension (PAH), which may alter nitric oxide signaling. DHEA treatment had mixed results in the EDIPHY trial, which may have been due to imbalances in sex and menopausal status despite randomization. We hypothesized that DHEA treatment would alter plasma nitrate and nitrite levels, and that this relationship would be modified by biological sex and menopausal status. Methods We performed a post-hoc analysis of the EDIPHY trial, a randomized, placebo-controlled, 18-week crossover study of DHEA in PAH. Plasma nitrite and nitrate levels were measured in LI-Hep tubes by tri-iodide (nitrite) and vanadium chloride (nitrate) based reductive chemiluminescence (Sievers 280i nitric oxide analyzer; GE Analytical Instruments). Outcomes were modeled over time with generalized linear mixed models using normal or lognormal distributions as appropriate. Results Twenty-six participants were enrolled (20 females, 8 premenopausal, 12 postmenopausal; 6 males). Females on active DHEA treatment had a significant decrease in nitrite on DHEA (0.1648 μm 95% CI 0.0950, 0.2859 to 0.0837 95% CI 0.0481, 0.1455) vs placebo (0.2024 95% CI 0.1074, 0.3814 to 0.2155 95% CI 0.1014, 0.4580) (p = 0.023), an effect seen only in premenopausal females (0.1546 μm 95% CI 0.0738, 0.3241 to 0.0533 95% CI 0.0289, 0.0981) compared to placebo (0.1183 μm 95% CI 0.0703, 0.1989 to 0.1016 95% CI 0.0471, 0.2192)(p = 0.043) in the first treatment period. Males on active DHEA had a significant reduction in nitrate on DHEA (57.0287 μm 95% CI 43.1563, 75.3603 to 38.2100 μm 95% CI 30.1012, 48.5032) versus placebo (73.0241 95% CI 61.4871, 86.7257 to 91.1200 95% CI 68.6200, 120.9977) (p 0.001) during the second treatment period. In all participants, there were significant interactions between active treatment and nitrate levels and the relationships with right ventricular end diastolic volume (RVEDV) (p for interaction, 0.001), RV end systolic volume (RVESV)(p for interaction, 0.01), and RV stroke volume (RVSV)(p for interaction, 0.01), such that active treatment and higher nitrate levels were associated with lower RVEDV and RVESV, but also lower RVSV. Nitrite levels modified the relationship between active treatment and six-minute walk distance (6MWD), such that higher levels of nitrite were associated with longer 6MWD (p for interaction, 0.10). Conclusions These preliminary findings indicate the relationship between DHEA treatment and RV function in PAH may be moderated by effects on oxidative stress and nitric oxide signaling and may vary by biologic sex and menopausal status. This abstract is funded by: National Heart, Lung, and Blood Institute
Varga et al. (2026) conducted an RCT in pulmonary arterial hypertension (n=26). Dehydroepiandrosterone (DHEA) vs. placebo was evaluated on Plasma nitrite and nitrate levels. DHEA treatment in pulmonary arterial hypertension significantly decreased plasma nitrite in females (p=0.023) and nitrate in males (p<0.001) compared to placebo.