Insights from the menstrual cycle in pulmonary arterial hypertension

Baird, Grayson L. and Walsh, Thomas and Aliotta, Jason and Allahua, Melissa and Andrew, Ruth and Bourjeily, Ghada and Brodsky, Alexander S. and Denver, Nina and Dooner, Mark and Harrington, Elizabeth O. and Klinger, James R. and MacLean, Margaret R. and Mullin, Christopher J. and Pereira, Mandy and Poppas, Athena and Whittenhall, Mary and Ventetuolo, Corey E. (2020) Insights from the menstrual cycle in pulmonary arterial hypertension. Annals of the American Thoracic Society. ISSN 2325-6621

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    Rationale: Sex hormones play a role in pulmonary arterial hypertension (PAH), but the menstrual cycle has never been studied. Objectives: We conducted a prospective observational study of eight women with stable PAH and 20 healthy controls over one cycle. Methods: Participants completed four study visits one week apart starting on the first day of menstruation. Relationships between sex hormones, hormone metabolites, and extracellular vesicle microRNA (miRNA) expression and clinical markers were compared with generalized linear mixed modeling. Results: Women with PAH had higher but less variable estradiol (E2) levels (p < 0.001) that tracked with six-minute walk distance (6MWD) (p < 0.001), N-terminal prohormone of brain natriuretic peptide (NT-proBNP) (p = 0.03) levels, and tricuspid annular plane systolic excursion (p < 0.01); the direction of these associations depended on menstrual phase. Dehydroepiandrosterone-sulfate (DHEA-S) levels were lower in women with PAH (all visits, p < 0.001). In PAH, each 100 g/dL increase in DHEA-S was associated with a 127-meter increase in 6MWD (p < 0.001) and was moderated by the cardioprotective E2 metabolite 2- methoxyestrone (p < 0.001). As DHEA-S increased, NT-proBNP levels decreased (p = 0.001). Expression of extracellular vesicle miRNAs-21, -29c, and -376a was higher in PAH, moderated by E2 and DHEA-S levels, and tracked with hormone associated changes in clinical measures. Conclusions: Women with PAH have fluctuations in cardiopulmonary function during menstruation driven by E2 and DHEA-S. These hormones in turn influence transcription of extracellular vesicle miRNAs implicated in the pathobiology of pulmonary vascular disease and cancer.