Progress in solving the sex hormone paradox in pulmonary hypertension

Am J Physiol Lung Cell Mol Physiol. 2014 Jul 1;307(1):L7-26. doi: 10.1152/ajplung.00337.2013. Epub 2014 May 9.


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.

Keywords: dehydroepiandrosterone; estrogen; progesterone; right ventricle; sex differences; testosterone.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Dehydroepiandrosterone / metabolism
  • Dehydroepiandrosterone / pharmacology
  • Estrogens / metabolism*
  • Estrogens / pharmacology
  • Familial Primary Pulmonary Hypertension
  • Female
  • Heart Ventricles / drug effects
  • Heart Ventricles / metabolism
  • Heart Ventricles / physiopathology
  • Humans
  • Hypertension, Pulmonary / metabolism*
  • Hypertension, Pulmonary / physiopathology
  • Lung / blood supply*
  • Male
  • Mice
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / metabolism
  • Pulmonary Artery / physiopathology
  • Rats
  • Receptors, Estrogen / metabolism*
  • Risk Factors
  • Sex Factors
  • Testosterone / metabolism
  • Testosterone / pharmacology


  • Estrogens
  • Receptors, Estrogen
  • Testosterone
  • Dehydroepiandrosterone