title: Progress in solving the sex hormone paradox in pulmonary hypertension.
abstract: Pulmonary arterial hypertension (PAH) is a devastating and progressive disease with marked morbidity and mortality. Even though being female represents one of the most powerful risk factors for PAH, multiple questions about the underlying mechanisms remain, and two "estrogen paradoxes" in PAH exist. First, it is puzzling why estrogens have been found to be protective in various animal models of PAH, whereas PAH registries uniformly demonstrate a female susceptibility to the disease. Second, despite the pronounced tendency for the disease to develop in women, female PAH patients exhibit better survival than men. Recent mechanistic studies in classical and in novel animal models of PAH, as well as recent studies in PAH patients, have significantly advanced the field. In particular, it is now accepted that estrogen metabolism and receptor signaling, as well as estrogen interactions with key pathways in PAH development, appear to be potent disease modifiers. A better understanding of these interactions may lead to novel PAH therapies. It is the purpose of this review to 1) review sex hormone synthesis, metabolism, and receptor physiology; 2) assess the context in which sex hormones affect PAH pathogenesis; 3) provide a potential explanation for the observed estrogen paradoxes and gender differences in PAH; and 4) identify knowledge gaps and future research opportunities. Because the majority of published studies investigated 17β-estradiol and/or its metabolites, this review will primarily focus on pulmonary vascular and right ventricular effects of estrogens. Data for other sex hormones will be discussed very briefly.
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine, and Richard L. Roudebush VA Medical Center; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; and tlahm@iu.edu.
authors.forename: Tim
authors.initials: T
authors.lastname: Lahm
authors.affiliation: Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, School of Medicine, Denver, Colorado.
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine, and Richard L. Roudebush VA Medical Center; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
mesh_terms: D000818:Animals; D003687:Dehydroepiandrosterone / Q000378:metabolism / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology; D008168:Lung / Q000098:blood supply*; D008297:Male; D051379:Mice; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D012307:Risk Factors; D012737:Sex Factors; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology
chemical_list: D004967:Estrogens; D011960:Receptors, Estrogen; D013739:Testosterone; D003687:Dehydroepiandrosterone
keywords: dehydroepiandrosterone; estrogen; progesterone; right ventricle; sex differences; testosterone