Background Pulmonary arterial hypertension (PAH) is a devastating disease that affects women more often than men; recent U.S. cohorts demonstrate a female:male ratio of 3 to 4:1. Paradoxically, males have worse survival. The differential effects of sex hormones, particularly estrogen, on the pulmonary vasculature and right ventricle likely account for some of these differences. The role of female-specific risk factors, such as reproductive exposures, are poorly understood in the pathophysiology of PAH.

Research Question To investigate the role of reproductive factors and exogenous estrogen exposures in PAH onset and severity in women enrolled in the United States Pulmonary Hypertension Scientific Registry (USPHSR).

Study Design and Methods Using questionnaires from 390 women with PAH, enrolled in both the PAH Biobank and USPHSR, we conducted linear regression analyses to assess the association between patient reported reproductive variables and PAH disease severity variables, as well as REVEAL Lite 2.0 scores. We adjusted for potential confounders including age, race, BMI, and PAH sub-group (idiopathic, heritable, associated).

Results Younger menopause age (< 40 years) associates with a lower cardiac index (CI) at diagnosis, even when controlling for use of hormone replacement therapy (HRT). There was a trend toward lower CI in women with menopause age of 41-50 years. Women who had ever used HRT were diagnosed with PAH an average of 13.4 years later and “ever use” of HRT associates with higher pulmonary vascular resistance and lower CI at diagnosis.

Interpretation Premature menopause (age < 40 years) and ever use of HRT associate with worse hemodynamics, including lower CI, at diagnosis in women with PAH. Further investigations into reproductive history and estrogen exposures may offer an opportunity for more comprehensive risk factor screening and modification by physicians treating patients with PAH.

R. D. Stapleton has NIH grants; royalties from Elsevier; DSMB honoraria and travel. D. B. Badesch has contracts with Acceleron/Merck, United Therapeutics, Liquidia, AI Therapeutics, Altavant, and Pfizer. H. W. Farber is a non-commercial speaker for Bayer; participates on DSMB or advisory board for Acceleron, Actelion, Aerovate, Aerami, United Therapeutics, Altavant, and Keros. A. E. Frost is on study monitoring committees for Actelion, Gossamer Bio, and United Therapeutics. W. C. Nichols has NIH grants. C. G. Elliott participates on DSMB for Gossamer Bio, Insmed, and Respira. E. D. Austin has NIH grants; participates on advisory board for Merck and adjudication committee for ACI, Inc. The remaining authors have no potential conflicts of interest to disclose.

The PAH Biobank study was funded from HL105333 (W.C.N.) and is presently supported by HL160941 (W.C.N.). Financial support for statistical analysis was provided by the University of Vermont Larner College of Medicine, Department of Medicine Pilot Grant Award (IRB 00002284).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Institutional Review Board of the University of Vermont waived ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors.