Gender, sex hormones and pulmonary hypertension


July  8, 2013

Source: Pulmonary Circulation - Official Journal of the Pulmonary Vascular Research Institute


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 paradox" 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.

Pulmonary hypertension (PH) is the inappropriate elevation of pulmonary artery pressure which can ultimately result in right ventricular (RV) dysfunction and failure. PH may occur due to a wide variety of clinical conditions, the majority of which are manifested histopathologically by medial hypertrophy of the pulmonary arterioles with intimal proliferation. [1],[2] In the current classification scheme for PH, PAH is considered Category 1, and is divided into multiple disease subgroups including idiopathic PAH (IPAH), heritable PAH (HPAH), and PAH-associated (APAH) with a variety of other systemic diseases or drug/toxin exposures. [3] Nearly all subtypes of PAH share a common feature: A higher female than male prevalence among adult patients. [4],[5],[6] However, the precise mechanisms of this gender disparity remain elusive, as does the impact of gender upon RV response to PH and, ultimately, survival.

Long recognized, [7] the skewed gender ratio was confirmed in 1987 by a large National Institutes of Health (NIH) registry, which reported a female to male ratio of 1.7:1. [8] However, the precise prevalence and incidence rates of PAH substratified according to gender, as well as clinical outcomes, remain incompletely understood in the current era. Recent epidemiologic studies, such as the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), have begun to shed light on the gender inequity and suggest differences between disease initiation and progression. REVEAL, an observational cohort study of PAH cases in North America, [9] recently reported that 79.5% of prevalent adult PAH patients were females, with a female predominance across virtually all subtypes of PAH. [4],[10] Investigating incident cases, UK and Ireland investigators recently reported that 69.9% of incident PAH patients from 2001-2009 were females. [11] However, while data from France support the high prevalence of female cases (65.3%) for most subtypes of PAH, among incident cases, the percentage of females was only 57.0%. [6] 
The potential difference in prevalence and incidence according to gender, at least in the French cohort, suggests that females live longer than males after diagnosis of PAH. Initial prospectively collected data from France support this conclusion, with improved survival at three years for females compared to males. [12],[13] Similarly, REVEAL investigators retrospectively found that men over 60 years of age had poorer survival compared with younger males and compared to all females. [10] While comprehensive prospective data will emerge over the coming years to address specifics with regard to the gender epidemiology of PH, the suggestion that females get disease more frequently but survive longer underscores the complexity of gender in the pathogenesis and course of PH; and, it highlights the need to more precisely understand the pathologic (and potentially protective) consequences of gender. The prospect that gender-associated factors, which promote disease onset may differentially impact disease outcome is particularly interesting given the prevailing opinion that while PAH is a pulmonary vascular disease, survival is dictated by RV adaptation to load stress. This incongruous finding has been termed the "estrogen paradox in PH." [14] 

The epidemiology of PH with regard to gender is but one component of the evolving story around gender in this devastating disease. The issue has attracted renewed focus in the past few years, providing fertile ground for the intersection of in vitro, animal model, and human studies to ultimately improve our understanding of not only the factors which promote disease, but also those which modify survival. While chromosomal differences (XX versus XY) certainly exist between the genders, an obvious source of variation is the production, metabolism, and response to sex hormones, which will be the particular focus of this review.

Sex Hormones and Human PAH Top

The impact of sex hormones on the pulmonary vasculature and right heart is complex and incompletely understood. For example, while acutely vasodilatory, estrogens may have deleterious consequences upon the pulmonary vasculature with chronic excess exposure. Thus, differential exposure to sex hormones is an active area of investigation, particularly in PAH research.
Estrogens and androgens are vasoactive compounds in the pulmonary vasculature with variable effects on cell proliferation and apoptosis. Several previous reports described an association between pharmacologically (and natural increase via pregnancy) enhanced estrogen exposure and PAH. [15],[16],[17],[18] More recently, Sweeney and colleagues determined that 81% of women with PAH reported prior use of any female hormone therapy, including 70% reporting exogenous hormone use for greater than 10 years. [19] Meanwhile, in a select cohort of portal hypertension patients, Roberts and colleagues found that both elevated plasma 17β-estradiol (estradiol, E2) levels and genetic variations in estrogen signaling are associated with portopulmonary PAH (PPHTN). [20] However, comprehensive measures of parent compound estrogen and androgen levels in incident and prevalent PH cases are lacking.

While both female and male sex hormones may contribute to pathogenesis (or protection), the metabolic products of sex hormone metabolism are biologically active and may also contribute. As with parent compound sex hormones, the complete effect of the various sex hormone metabolites on the pulmonary vasculature and right ventricle has yet to be determined, but may be highly relevant. For example, variability in metabolism may account for the apparent contradictory influences of estrogens discussed below, perhaps via differential sex hormone receptor activation and signaling.

The majority of estrogen and androgen metabolism occurs via the Cytochrome P450 (CYP) system, although there may be organ-specific differences. [21] CYPs constitute a gene superfamily that plays an essential role in the metabolism of exogenous chemicals present in the diet and environment, as well as endogenous substances such as parent compound estrogens and androgens. [22],[23] For the metabolism of estrogens, the initial step is typically an oxidative process, via CYP1B1 and other CYP enzymes [Figure 1]. CYP1B1 and several other CYPs are highly expressed in the lung. CYPs oxidize estrogens to 2-hydroxy (2-OHE 1/2 ) and 4-hydroxy (4-OHE 1/2 ) estrogens in the initial metabolic step [24] to produce "2-estrogens" and "4-estrogens," or, oxidation of estrogens by hydroxylation can occur at the C-16 position, predominantly resulting in 16α-hydroxyestrone (16α-OHE 1 ) for the ultimate generation of "16-estrogens." [25],[26] While full details on the molecular consequences of exposure to the various estrogen metabolites on the pulmonary vasculature are needed, it appears that "2-estrogens" are typically anti-mitogenic, while "16-estrogens" stimulate cellular proliferation by constitutively activating the estrogen receptors. In addition to being more mitogenic, "16-estrogens" may also be more detrimental due to a genotoxic effect via the formation of unstable DNA adducts. [27],[28] As a result, one might ultimately hypothesize that individuals who produce more "16-estrogens" are at increased risk of diseases that result from both the mitogenic and genotoxic effects of estrogens. [29],[30],[31],[32],[33],[34] 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.

The detection of a germline mutation in the gene bone morphogenetic protein receptor type 2 (BMPR2) gene confers the greatest risk of PAH, although the factors modifying this risk are unclear. Penetrance of PAH among BMPR2 mutation carriers is incomplete and differs according to gender: Female penetrance is ~42%, while male penetrance is ~14%. [35] In an effort to determine genetic modifiers of BMPR2-associated PAH, West et al. studied expression array data, verified by quantitative PCR, in BMPR2 mutation carriers' EBV-immortalized lymphocytes, and found that CYP1B1 gene expression was reduced 10-fold among female BMPR2 mutation carriers with PAH compared to healthy females. [36] This finding prompted the hypothesis that among female BMPR2 mutation carriers, those with PAH were more likely to possess genetic variants associated with altered CYP1B1 activity, as well as measurable alterations in estrogen metabolites, compared to those without PAH.

To test this hypothesis, targeted functional variants in CYP1B1 were evaluated in a cohort of 140 BMPR2 mutation carriers (86 females, 54 males). Genetic polymorphisms were chosen based upon previous association with alterations in protein function, including CYP1B1 Asn453Ser (N453S). [37] As hypothesized, among females there was a four-fold higher penetrance of PAH (P = 0.005) among subjects homozygous for the wild-type genotype (N/N) of CYP1B1 Asn453Ser (N453S); no difference was detected among males. This genotype had previously been associated with alterations in in vitro CYP1B1 activity and with differences in breast cancer risk in humans. [38] A nested study of a small number of those BMPR2 mutation carriers supported this finding. Specifically, female BMPR2 mutation carriers with PAH had a significantly lower ratio of 2-hydroxyestrogens (2-OHE 1/2 ): 16α-hydroxyestrone (16α-OHE 1 ) compared to unaffected BMPR2 mutation carriers (P = 0.006) carriers. [39] In an effort to explore the biology of this association, it was subsequently demonstrated that parent compound estrogens, and "16-estrogens," directly reduce BMPR2 gene expression; additionally, this effect occurred at least in part via direct estrogen receptor alpha (ERα) binding to the BMPR2 gene promoter. [40] Taken together, these results support the hypothesis that variations in estrogen metabolism may contribute to the development of PAH among humans at heightened genetic risk (BMPR2 gene mutation), although the precise molecular mechanisms and relevance to variations in estrogen receptor signaling need to be clarified.

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