Inhibiting oestrogen signalling in pulmonary arterial hypertension: sex, drugs and research

Abstract

@ERSpublicationsInhibition of oestrogen signalling in PAH is currently being studied clinically but several questions remain http://ow.ly/G7xK30cPN5MCite this article as: Lahm T, Kawut SM. Inhibiting oestrogen signalling in pulmonary arterial hypertension: sex, drugs and research. Eur Respir J 2017; 50: 1700983 [https://doi.org/10.1183/ 13993003.00983-2017.Pulmonary arterial hypertension (PAH) is a sexually dimorphic disease that affects women more than men. Several pre-clinical and clinical studies identified 17β-oestradiol (E2), the most abundant female sex hormone, and/or its metabolite 16α-hydroxyoestrone as disease mediators in PAH (reviewed by LAHM et al. E2 is mostly synthesised through aromatisation of androgens by the enzyme aromatase (encoded by the CYP19A1 gene). In females, this process primarily occurs in the ovaries, though later in life, extragonadal E2 production (e.g. in adipocytes) becomes the predominant source (as it is in males throughout life). Classical E2 signalling is characterised by activation of the oestrogen receptors ERα and/or ERβ, which translocate to the nucleus and act as transcription factors by binding to oestrogen response elements of target genes (reviewed by MURPHY [4]). However, several variations of this pathway exist, including nongenomic signalling and signalling through an orphan G-protein coupled receptor [1,4]. Aromatase and oestrogen receptors are found in both sexes and in every major organ system (including the lung and the right ventricle [5-8]), implying that oestrogens can have biologically relevant effects throughout the body.Preclinical and clinical studies implicate aromatase as a potential contributor to PAH pathogenesis [6,9]. Similarly, oestrogen receptor-mediated signalling has been linked to PAH development [8]. These studies have led to a recently published, small phase II randomised clinical trial (RCT) of aromatase inhibition with anastrozole in postmenopausal women and men with PAH [10]. This study demonstrated that anastrozole decreased serum E2 levels by 40% and increased 6-min walk distance, leading the authors to conclude that anastrozole therapy appeared safe and warranted further evaluation. Based on these results, a

Exogenous Estrogen Preserves Distal Pulmonary Arterial Mechanics and Prevents Pulmonary Hypertension in Rats

“…Importantly, continuous exogenous E2 was superior to both physiologically cyclical endogenous estrogen (intact females) and little to no estrogen (ovariectomized females) in limiting PH development. Although several recent studies from our group and others demonstrated a protective effect of E2 on RV function (1,3,4), we now identify a novel and direct protective effect of E2 on distal PA structure and function. In particular, exogenous, continuous E2 repletion attenuated the distal PA remodeling, increase in Z 0 , increase in TPG, and decrease in distensibility induced by SuHx in intact and OVX female rats.…”

Clinical and hemodynamic phenotype of BMPR2 variation carriers with pulmonary arterial hypertension: A systematic review and a call to action

“…Previous evidence showed limited penetrance of BMPR2 mutations (~20%) with variable risk development during follow-up (14% males and 42% females), suggesting additional hormonal, environmental, and other genetic variations contributing to the development and progression of the disease (Amano et al, 2004;Frost et al, 2019;Ghigna et al, 2016;Southgate et al, 2020;White et al, 2013). For example, 17β-estradiol and its metabolite, 16α-hydroxy estrone, were identified as penetrance mediators in female BMPR2/PAH+ (Lahm & Kawut, 2017). In a Chinese cohort, male BMPR2/PAH+ were significantly associated with an increased risk of death after adjustment for age at diagnosis (hazard ratio, 3.7; 95% CI, 1.4-9.7; p=0.008 vs. hazard ratio, 1.3; 95% CI, 0.6-2.9; p=0.446) (Liu et al, 2012).…”

Sex Differences in Pulmonary Hypertension

“…A detailed description of sex hormone metabolism and signaling, published elsewhere (Austin et al, 2013;Lahm et al, 2014;Lahm and Kawut, 2017;Tofovic and Jackson, 2019;Tofovic and Jackson, 2020), is beyond the scope of this review. Briefly, the three main estrogenic steroids are 17-β estradiol (estradiol or E2), the primary active sex hormone in the female, estrone (E1) and estriol (E3).…”