Sex differences in the pulmonary circulation: implications for pulmonary hypertension

Abstract

Pulmonary arterial hypertension (PAH), a form of pulmonary hypertension, is a complex disease of multifactorial origin. While new developments regarding pathophysiological features and therapeutic options in PAH are being reported, one important fact has emerged over the years: there is a sex difference in the incidence of this disease such that while there is a higher incidence in females, disease outcomes are much worse in males. Accordingly, recent attention has been focused on understanding the features of sex differences in the pulmonary circulation and the contributory mechanisms, particularly sex hormones and their role in the pathological and pathophysiological features of PAH. However, to date, there is no clear consensus whether sex hormones (particularly female sex steroids) are beneficial or detrimental in PAH. In this review, we highlight some of the most recent evidence regarding the influence of sex hormones (estrogen, testosterone, progesterone, dehydroepiandrosterone) and estrogen metabolites on key pathophysiological features of PAH such as proliferation, vascular remodeling, vasodilation/constriction, and inflammation, thus setting the stage for research avenues to identify novel therapeutic target for PAH as well as potentially other forms of pulmonary hypertension.

Keywords: estrogen; pulmonary artery; pulmonary hypertension; sex hormones.

Fig. 1.

Overview of the metabolism of sex hormones. ER, estrogen receptor; 3β-HSD, 3-β-hydroxysteroid dehydrogenase; GPR, G protein-coupled receptor; CYP1A1, cytochrome P-450, family 19, subfamily A, polypeptide 1 gene; COMT, catechol-O-methyltransferase.

Fig. 2.

Schematic summarizing the effects of sex hormones on pulmonary arterial endothelial cells (PAECs) and smooth muscle cells. While the effects of sex hormones on the pulmonary endothelium alleviate pulmonary arterial hypertension, the effects on the smooth muscle are mixed. NO, nitric oxide; DHEA, dehydroepiandrosterone; VDCC, voltage-dependent calcium channel; TRPC, transient receptor potential channel; CaSR, calcium sensing receptor; PASMCs, pulmonary artery smooth muscle cells; [Ca²⁺]_i, intracellular Ca²⁺ concentration.