Gender, sex hormones and pulmonary hypertension

Abstract

Most subtypes of pulmonary arterial hypertension (PAH) are characterized by a greater susceptibility to disease among females, although females with PAH appear to live longer after diagnosis. While this "estrogen paradoxȍ of enhanced female survival despite increased female susceptibility remains a mystery, recent progress has begun to shed light upon the interplay of sex hormones, the pathogenesis of pulmonary hypertension, and the right ventricular response to stress. For example, emerging data in humans and experimental models suggest that estrogens or differential sex hormone metabolism may modify disease risk among susceptible subjects, and that estrogens may interact with additional local factors such as serotonin to enhance the potentially damaging chronic effects of estrogens on the pulmonary vasculature. Regardless, it remains unclear why not all estrogenic compounds behave equally, nor why estrogens appear to be protective in certain settings but detrimental in others. The contribution of androgens and other compounds, such as dehydroepiandrosterone, to pathogenesis and possibly treatment must be considered as well. In this review, we will discuss the recent understandings on how estrogens, estrogen metabolism, dehydroepiandrosterone, and additional susceptibility factors may all contribute to the pathogenesis or potentially to the treatment of pulmonary hypertension, by evaluating current human, cell-based, and experimental model data.

Keywords: bone morphogenetic protein receptor type II; dehydroepiandrosterone; estrogen; pulmonary hypertension; serotonin.

Figure 1

Simplified schematic of estrogen metabolism. Parent compound estrogens are metabolized via oxidative metabolism to hydroxestradiol forms in the initial step of metabolism. Hydroxylation may occur at position C2, C4, or C16. This step of oxidative metabolism determines the nature of the biologic effects of the metabolites of 17β-estradiol (E2). These products are most commonly cleared from circulation via methylation, as demonstrated in (Figure 5.

Figure 2

Major estrogen receptor (ER)-mediated signaling pathways engaged by 17β-estradiol (E2). (A) and (B) E2 diffuses through the cell membrane and interacts with ER-α or –β, followed by formation of E2-ER homo- or heterodimers. The E2-ER complexes then translocate into the nucleus to interact with estrogen response elements (ERE; A) or with other transcription factors (TF; B). (C) ERs are directly phosphorylated by growth factors (GF). (D) E2 can interact with membrane-bound classical ERs or GPR30, leading to rapid changes in protein function without immediately altering genomic pathways.

Figure 3

BMPR2 mutant PMVEC show dysregulation of ERα trafficking. Immunohistochemistry studies demonstrate abnormal movement of ERα in BMPR2 mutant cells. While in control PMVEC (left) the ERα moves to the nucleus with E2 stimulation, ERα appears to move to the cell surface in BMPR2 mutant PMVEC cells (right) stimulated by E2 exposure.

Figure 4

The BMP pathway and estrogen have multiple avenues of mutual regulation.

Figure 5

Crossroads of estradiol metabolism in PAH: Activities of 2-hydroxylation, 16alpha-hydroxylation, and 17beta-HSD pathways may determine the overall biological effects of estradiol in PAH.

Figure 6

The influence of serotonin and estrogen in the development of PAH. Estrogens can increase the expression of TPH1, the 5-HT1B receptor and SERT. Serotonin, shear stress, hypoxia, SUGEN + hypoxia and estrogen all increase the expression of CYP1B1 (and perhaps other CYP enzymes) which can metabolize estrogen to both pro- and anti-proliferative metabolites, some via COMT. Changes in this system that favour accumulation of pro-proliferative metabolites in the face of decreased protective metabolites would favour proliferation of PASMCs and contribute to pulmonary vascular remodeling.

Figure 7

Synthesis and metabolism of dehydroepiandrosterone (DHEA).