Pulmonary arterial hypertension: basis of sex differences in incidence and treatment response

Abstract

Pulmonary arterial hypertension (PAH) is a complex disease characterized by elevated pulmonary arterial pressure, pulmonary vascular remodelling and occlusive pulmonary vascular lesions, leading to right heart failure. Evidence from recent epidemiological studies suggests the influence of gender on the development of PAH with an approximate female to male ratio of 4:1, depending on the underlying disease pathology. Overall, the therapeutic strategy for PAH remains suboptimal with poor survival rates observed in both genders. Endogenous sex hormones, in particular 17β oestradiol and its metabolites, have been implicated in the development of the disease; however, the influence of sex hormones on the underlying pathobiology remains controversial. Further understanding of the influence of sex hormones on the normal and diseased pulmonary circulation will be critical to our understanding the pathology of PAH and future therapeutic strategies. In this review, we will discuss the influence of sex hormones on the development of PAH and address recent controversies. LINKED ARTICLESThis article is part of a themed section on Biological Sex and Cardiovascular Pharmacology. To view the other articles in this section visit http://dx.doi.org/10. 1111/bph.2014.171.issue-3 Abbreviations AR, androgen receptor; BMPR2, bone morphogenetic protein receptor 2; CYP19A1, aromatase; CYP1B1, cytochrome P450 1B1; DHEA, dehydroepiandosterone; DHT, dihydrotestosterone; ER, oestrogen receptor; ERα, oestrogen receptor alpha; ERβ, oestrogen receptor beta; ET-1, endothelin-1; GPER, G protein-coupled oestrogen receptor; PAH, pulmonary arterial hypertension; PASMC, pulmonary artery smooth muscle cell; SERT, serotonin transporter; Su-Hx, SUGEN hypoxic; Tph1, tryptophan hydroxylase 1 Pulmonary arterial hypertension (PAH) is a progressive disease leading to right heart failure. Recent epidemiological data reports an increased incidence of PAH among females compared to males. For example, in the UK/Ireland and the USA, the percentage of female patients is 70 and 80% respectively (Badesch et al., 2010;Ling et al., 2012). There is mounting evidence to suggest that oestrogen and its metabolites may influence the pathogenesis of PAH. Here, we will examine the pathology, current therapies and the basis for gender differences in PAH, considering evidence gathered from both patient data and animal studies. Pulmonary arterial hypertensionPAH is defined by vascular remodelling and complex vascular lesion formation arising from the accelerated proliferation of pulmonary endothelial, smooth muscle and fibroblast cells (Rabinovitch, 2008). Clinically, the disease is defined as a mean pulmonary artery pressure of >25 mmHg at rest or >30 mmHg during exercise. Symptoms are often non-specific, including fatigue, exertional dyspnoea, oedema and syncope and as a result diagnosis is frequently delayed until the disease is well established.The main genetic defect associated with PAH is a mutation in the gene encoding bone morphogenetic protein receptor 2 (BMPR2). Ge...

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

“…Schistosomiasisinduced PH shows no sex bias (13), whereas HIV-induced PH shows a small (1.2-fold) male bias (14). The mechanisms that underlie these sexual dimorphisms in humans, especially the female bias in disease prevalence in IPAH and HPAH, are incompletely understood (8,15).…”

“…There is an opposite male bias in the typical rodent models of PH induced by chronic hypoxia or monocrotaline (MCT) (8,15,16). In these rodent models, estrogenic compounds [(estradiol-17β (E2) and 2-methoxyestradiol (2-ME)] typically inhibit PH (8,15,16).…”

“…In these rodent models, estrogenic compounds [(estradiol-17β (E2) and 2-methoxyestradiol (2-ME)] typically inhibit PH (8,15,16). Strikingly, rats or mice exposed to hypoxia plus the inhibitor SU5416 (Sugen) develop PH without any sex bias, and E2 administration has little protective effect on development of increased right ventricular systolic pressure in this model (8,17,18).…”

“…In contrast, the phrase "sex biased" refers to entities that show a quantitative phenotypic difference between the two sexes.) In converse examples, female mice overexpressing the serotonin transporter or the S100 calcium-binding protein S100A4/mts1, or administered the anorexigen dexfenfluramine (but not male mice), spontaneously develop modest PH by 5 months (15,(19)(20)(21)(22). Although only up to one-third of male mice expressing the BMPR2 R899X transgene spontaneously developed right ventricular systolic pressure >30 mmHg, this proportion increased to two-thirds when the mice were fed a high-fat diet (23); in this model, 2-ME was not protective (24).…”

“…The mechanisms underlying these disparate and contrasting sex-bias observations in different rodent models, and the differences between rodent models and the human disease, are not understood. The juxtaposition of a female bias in prevalence of human IPAH and HPAH with a male bias in disease development in the chronic hypoxia-or MCT-induced rodent models, together with the observation that administration of E2 was protective in the rodent models, led to the concept of an "estrogen paradox" to describe these observations (5,8,(15)(16)(17)(18). Any hypothesis ( Figure 1) that provides a path toward clarifying these puzzling sex-bias observations in PH in humans and rodents would be of great value.…”