The estrogen puzzle in pulmonary arterial hypertension.

The biology of pulmonary arterial hypertension (PAH) is full of mysteries, and one of its longer-standing ones has also intrigued and inspired both scientists and artists throughout history: the female sex. Although affecting patients of all ages and both sexes, PAH preferentially affects young women, suggesting that the female sex is a risk factor for PAH. Even in heritable PAH associated with autosomal dominant mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2), women after puberty are 2.5 times more likely to develop PAH than males.1 In idiopathic PAH the female/male ratio ranges from 1.7:1 or 1.9:1 to 4.1:1 in 3 published PAH registries (the National Institutes of Health registry in the 80s,2 the French registry,3 and the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL),4 respectively). On the other hand, the disease can be more severe in men. Female animals with PAH tend to have lower pulmonary artery pressures and better outcomes compared with males,5 and similarly, male PAH patients have higher mortality than females.6 The basis for this apparent paradox remains unknown.