Cardiopulmonary function fluctuates during menstrual cycle in premenopausal women with PAH

During the menstrual cycle, premenopausal women with pulmonary arterial hypertension experience fluctuations in markers of cardiopulmonary function that may be driven by estradiol and dehydroepiandrosterone sulfate.

“Although we and others have previously linked higher circulating estradiol levels to the risk and severity of PAH in both men and postmenopausal women, these relationships have not been robustly studied in young women who are still menstruating,” Grayson L. Baird, PhD, assistant professor of diagnostic imaging at the Warren Alpert Medical School of Brown University and Lifespan Hospital System, Providence, and colleagues wrote in the Annals of the American Thoracic Society.

Researchers conducted a prospective, observational study to evaluate eight women with stable PAH (mean age, 37 years; 63% white) and 20 women without PAH (mean age, 28 years; 75% white). Most women had idiopathic PAH and were well controlled on PAH therapy. Participants completed four study visits 1 week apart, starting on the first day of menstruation.

Women with PAH had higher, but less variable, estradiol levels during the menstrual cycle compared with controls (P < .001). Levels of estradiol were higher among women with PAH in the follicular phase and at the end of the luteal phase (P < .001). Levels of dehydroepiandrosterone sulfate (DHEA-S) were lower among women with PAH throughout the menstrual cycle (P < .001), according to the results.

Women with PAH had shorter 6-minute walk distance and higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels compared with controls. The researchers reported a significant but inverse association between estradiol and 6-minute walk distance (P < .001) and between estradiol and NT-proBNP (P = .03) during the cycle. According to the researchers, each 1 pg/mL increase in estradiol was associated with a 28-m decrease in 6-minute walk distance during the follicular phase and a 34-m increase during the luteal phase among women with PAH. With increasing estradiol levels during the follicular phase, the researchers observed an increase in NT-proBNP levels; however, this relationship was reversed during the luteal phase, they wrote. The researchers reported no relationship between estradiol and 6-minute walk distance or NT-proBNP in women without PAH.

Women with PAH had lower levels of DHEA-S. Each 100 µg/dL increase in DHEA-S was associated with a 127 m increase in 6-minute walk distance, which the researchers noted was moderated by cardioprotective estradiol metabolite 2-methoxyestrone (P < .001 for all). As DHEA-S levels increased, NT-proBNP decreased (P = .001), according to the results.

In other findings, expression of extracellular vesicle miRNA-21, miRNA-29c and miRNA-376a was higher among women with PAH compared with controls and fluctuated more during the menstrual cycle. The relationship between miRNA expression, PAH status and menstrual phase was moderated by DHEA-S levels for miRNA-29c (P < .001), miRNA-376a (P = .001) and perhaps miRNA-21 (P = .06), according to the researchers.

“This is the first study to characterize the menstrual cycle in women with PAH, to document cyclical fluctuations in PAH clinical metrics that are associated with major hormones of biological import and to identify potential mechanistic mediators in the relationship between sex hormones and PAH disease activity,” the researchers wrote.

The data suggest “a critical role for these hormones in PAH pathogenesis,” they wrote.

The researchers noted several limitations of the study, including its start on the first day of menstruation, lack of confirmation of ovulation, and no recording of activity levels or environmental or dietary exposures.