Sex and gender in pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a rare disease characterised by pulmonary vascular remodelling and elevated pulmonary pressure, which eventually leads to right heart failure and death. Registries worldwide have noted a female predominance of the disease, spurring particular interest in hormonal involvement in the disease pathobiology. Several experimental models have shown both protective and deleterious effects of oestrogens, suggesting that complex mechanisms participate in PAH pathogenesis. In fact, oestrogen metabolites as well as receptors and enzymes implicated in oestrogen signalling pathways and associated conditions such as BMPR2 mutation contribute to PAH penetrance more specifically in women. Conversely, females have better right ventricular function, translating to a better prognosis. Along with right ventricular adaptation, women tend to respond to PAH treatment differently from men. As some young women suffer from PAH, contraception is of particular importance, considering that pregnancy in patients with PAH is strongly discouraged due to high risk of death. When contraception measures fail, pregnant women need a multidisciplinary team-based approach. This article aims to review epidemiology, mechanisms underlying the higher female predominance, but better prognosis and the intricacies in management of women affected by PAH.

Gender differences in genotypic distribution of endothelin-1 gene and endothelin receptor A gene in pulmonary hypertension associated with rheumatic mitral valve disease

“…The female subjects are more prone to develop pulmonary arterial hypertension. 2 A greater percentage of PAH patients in several registries are females thus suggesting that female gender may be a risk factor for PAH. 2 Also, connective tissue disorder associated pulmonary hypertension has a 9:1 female to male ratio.…”

“…Right ventricular dimensions and function were determined by measuring RV basal and mid-cavity diameters and tricuspid annular plane systolic excursion (TAPSE). RVSP was calculated from peak tricuspid regurgitation (TR) jet obtained under color flow imaging guidance using formula, RVSP = 4(V TR ) 2 + RAP, where V TR is peak velocity of TR jet and RAP is estimated right atrial pressure. The pulmonary artery end-diastolic pressure (PADP) was calculated from pulmonary regurgitation jet continuous wave Doppler trace.…”

“… 1 The female gender is a risk factor for idiopathic pulmonary arterial hypertension (PAH)[World Health Organization (WHO) group I PH] with greater proportion of female patients (56–86%) reported in several registries. 2 In the European Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), the higher female to male ratio 2.3:1 was especially evident in younger patients (median age 54 years) compared to older patients (1.2:1, median age 75 years) highlighting the role of gender. 2 Also, connective tissue disease associated pulmonary hypertension has a 9:1 female to male ratio.…”

“… 2 In the European Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), the higher female to male ratio 2.3:1 was especially evident in younger patients (median age 54 years) compared to older patients (1.2:1, median age 75 years) highlighting the role of gender. 2 Also, connective tissue disease associated pulmonary hypertension has a 9:1 female to male ratio. 3 Further, females with liver disease have a higher risk of developing porto-pulmonary hypertension.…”

“… 4 Multiple mechanisms might be responsible for the gender differences in the incidence of PH including sex hormones, immunologic triggers and genetic factors. 2 The genetic predisposition in concurrence with environmental factors probably plays a major role in the disease expression.…”