Insights from the menstrual cycle in pulmonary arterial hypertension

Grayson L. Baird, Thomas Walsh, Jason Aliotta, Melissa Allahua, Ruth Andrew, Ghada Bourjeily, Alexander S. Brodsky, Nina Denver, Mark Dooner, Elizabeth O. Harrington, James R. Klinger, Margaret R. MacLean, Christopher J. Mullin, Mandy Pereira, Athena Poppas, Mary Whittenhall, Corey E. Ventetuolo

Research output: Contribution to journalArticle

Abstract

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.
Original languageEnglish
JournalAnnals of the American Thoracic Society
Early online date4 Sep 2020
DOIs
Publication statusE-pub ahead of print - 4 Sep 2020

Keywords

  • estradiol
  • DHEA
  • menstrual cycle
  • pulmonary hypertension
  • microRNA

Cite this

Baird, G. L., Walsh, T., Aliotta, J., Allahua, M., Andrew, R., Bourjeily, G., Brodsky, A. S., Denver, N., Dooner, M., Harrington, E. O., Klinger, J. R., MacLean, M. R., Mullin, C. J., Pereira, M., Poppas, A., Whittenhall, M., & Ventetuolo, C. E. (2020). Insights from the menstrual cycle in pulmonary arterial hypertension. Annals of the American Thoracic Society. https://doi.org/10.1513/AnnalsATS.202006-671OC