The Role of Sex in the Pathophysiology of Pulmonary Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease characterised by increased pulmonary vascular resistance and pulmonary artery remodelling as result of increased vascular tone and vascular cell proliferation, respectively. Eventually, this leads to right heart failure. Heritable PAH is caused by a mutation in the bone morphogenetic protein receptor-II (BMPR-II). Female susceptibility to PAH has been known for some time, and most recent figures show a female-to-male ratio of 4:1. Variations in the female sex hormone estrogen and estrogen metabolism modify FPAH risk, and penetrance of the disease in BMPR-II mutation carriers is increased in females. Several lines of evidence point towards estrogen being pathogenic in the pulmonary circulation, and thus increasing the risk of females developing PAH. Recent studies have also suggested that estrogen metabolism may be crucial in the development and progression of PAH with studies indicating that downstream metabolites such as 16α-hydroxyestrone are upregulated in several forms of experimental pulmonary hypertension (PH) and can cause pulmonary artery smooth muscle cell proliferation and subsequent vascular remodelling. Conversely, other estrogen metabolites such as 2-methoxyestradiol have been shown to be protective in the context of PAH. Estrogen may also upregulate the signalling pathways of other key mediators of PAH such as serotonin.

Gender differences in pulmonary arterial hypertension patients with BMPR2 mutation: a meta-analysis

“…Given that BMP ligands and their receptors play important roles in disease progression, the regulation of this signal could function as a therapeutic target. As mentioned earlier, there is a "sex paradox" in PH that it has long been known females have a higher susceptibility than males to PAH, in which the most recent figures show that the female-to-male ratio is 4:1 [28]. In a large cohort of individuals with BMPR2 receptor mutations (including those with IPAH or HPAH or drug-and toxin-induced PAH), approximately 70% of the patients were women [6].…”

“…At low doses, oestrogen acts as a pro-oxidant, whereas at higher doses, it acts to suppress oxidative stress. In addition to its dose-effect, studies have demonstrated that some oestrogen metabolites (such as 17-β oestradiol and 2-OH-estradiol) can also promote antiproliferative and proapoptotic signals, inhibit oxidative stress and collagen deposition, and protect right ventricular function in PAH, while other metabolites (such as 16-α-OHoestradiol) have the opposite effects [28]. The effects of key enzymes in the lungs (such as CYP1B1 and catechol-O-methyl-transferase (COMT)) have also been explored.…”

Prognostic Value of Gamma-Glutamyltransferase in Male Patients With Idiopathic Pulmonary Arterial Hypertension

“…More severe oxidative stress in male patients with BMPR2 mutation might be the reason for increased GGT activity (36). Another explanation was that BMPR2 mutation contributed to poor RV function more directly in males, whereas it weakened in females (2). However, little is known about sex-specific differences in BMPR2 expression and its potential effects in RV function in PAH (2).…”

“…Patients with pulmonary arterial hypertension (PAH) have a poor prognosis due to progressive pulmonary vascular remodeling, which leads to right ventricular (RV) overload and right heart failure without effective treatment (1). There is a famous sex paradox in PAH: females have more predominance in developing PAH than males, yet have better survival than males (2). Complex sex hormone signaling or processing pathways in the pathology of idiopathic PAH (IPAH) have been observed, such as impacts of different sex hormones in the RV function, bone morphogenetic protein receptor type 2 (BMPR2) mutation, oxidative stress and autoimmunity (3)(4)(5)(6).…”

Novel SLCO2A1 mutations cause gender-differentiated pachydermoperiostosis

“…This difference of hormone levels was responsible for the gender difference of asthma ( 51 , 52 ), rhinitis ( 52 ) and depression ( 53 ) among other conditions. Estrogen has been shown to increase the risk of pulmonary hypertension ( 54 ) but promoted fat metabolism and protected against obesity ( 55 ). High androgen-to-estrogen ratio was shown to be associated with higher risk of esophageal adenocarcinoma ( 56 ) but androgen could block estrogen-induced proliferation of breast cancer cells ( 57 ).…”