Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a debilitating and progressive disease that predominantly develops in women. Over the past 15 years, cumulating evidence has pointed toward dysregulated metabolism of sex hormones in animal models and patients with PAH. 17β-estradiol (E2) is metabolized at positions C2, C4, and C16, which leads to the formation of metabolites with different biological/estrogenic activity. Since the first report that 2-methoxyestradiol, a major non-estrogenic metabolite of E2, attenuates the development and progression of experimental pulmonary hypertension (PH), it has become increasingly clear that E2, E2 precursors, and E2 metabolites exhibit both protective and detrimental effects in PH. Furthermore, both experimental and clinical data suggest that E2 has divergent effects in the pulmonary vasculature versus right ventricle (estrogen paradox in PAH). The estrogen paradox is of significant clinical relevance for understanding the development, progression, and prognosis of PAH. This review updates experimental and clinical findings and provides insights into: (1) the potential impacts that pathways of estradiol metabolism (EMet) may have in PAH; (2) the beneficial and adverse effects of estrogens and their precursors/metabolites in experimental PH and human PAH; (3) the co-morbidities and pathological conditions that may alter EMet and influence the development/progression of PAH; (4) the relevance of the intracrinology of sex hormones to vascular remodeling in PAH; and (5) the advantages/disadvantages of different approaches to modulate EMet in PAH. Finally, we propose the three-tier-estrogen effects in PAH concept, which may offer reconciliation of the opposing effects of E2 in PAH and may provide a better understanding of the complex mechanisms by which EMet affects the pulmonary circulation–right ventricular interaction in PAH.

Current and future treatments of pulmonary arterial hypertension

“…Some of the metabolites have proliferative effects (e.g., 16α‐hydroxyoestrone), while others also have anti‐proliferative and anti‐inflammatory properties (e.g., 2‐hydroxyoestradiol and 2‐methoxyoestradiol). High E2 levels were associated with PAH in male patients and reduced exercise capacity in female patients, but E2 may also have protective effects on the right ventricle (RV; recently reviewed in Tofovic & Jackson, 2019). Thus, different levels of E2 and its metabolites at different disease stages could explain sex‐dependent differences.…”

“…Moreover, genes of the Y‐chromosome are up‐regulated in PH and have protective anti‐remodelling properties in hypoxic mice (Umar et al, 2018). Decreasing circulating E2 by inhibiting conversion of androgens to E2 using the aromatase inhibitor anastrozole and inhibition of the E2 receptor with tamoxifen inhibited PH in different animal models of PH, partly in a sex‐dependent way (Tofovic & Jackson, 2019). By contrast, supplementation with E2 increased exercise capacity in male and female rats with severe PH, probably by exerting protective effects on the RV (Lahm et al, 2016).…”

17β‐estradiol reduces SARS‐CoV‐2 infection in vitro

“…Estrogens have genomic and non-genomic actions, and activate nuclear estrogen receptor alpha (ERα), nuclear estrogen receptor beta (ERβ) and membrane G-protein-coupled estrogen receptor (GPER1). These pathways have been associated with several anabolic protective actions in different organs, including lungs (for review see [Tofovic & Jackson, 2019]), cardiovascular system (for review see [Iorga et al, 2017]) and immune responses course (Di Florio et al, 2020).…”

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

“…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). However, the reason for the inconsistency remains unclear.…”