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Sex, Gender, and Sex Hormones in Pulmonary Hypertension and Right Ventricular Failure

James Hester, Corey Ventetuolo, Tim Lahm

10.1002/cphy.c190011

Source: Volume 10, Issue 1, January 2020

Published online: December 2019

Full Article on Wiley Online Library



Abstract

Pulmonary hypertension (PH) encompasses a syndrome of diseases that are characterized by elevated pulmonary artery pressure and pulmonary vascular remodeling and that frequently lead to right ventricular (RV) failure and death. Several types of PH exhibit sexually dimorphic features in disease penetrance, presentation, and progression. Most sexually dimorphic features in PH have been described in pulmonary arterial hypertension (PAH), a devastating and progressive pulmonary vasculopathy with a 3‐year survival rate <60%. While patient registries show that women are more susceptible to development of PAH, female PAH patients display better RV function and increased survival compared to their male counterparts, a phenomenon referred to as the “estrogen paradox” or “estrogen puzzle” of PAH. Recent advances in the field have demonstrated that multiple sex hormones, receptors, and metabolites play a role in the estrogen puzzle and that the effects of hormone signaling may be time and compartment specific. While the underlying physiological mechanisms are complex, unraveling the estrogen puzzle may reveal novel therapeutic strategies to treat and reverse the effects of PAH/PH. In this article, we (i) review PH classification and pathophysiology; (ii) discuss sex/gender differences observed in patients and animal models; (iii) review sex hormone synthesis and metabolism; (iv) review in detail the scientific literature of sex hormone signaling in PAH/PH, particularly estrogen‐, testosterone‐, progesterone‐, and dehydroepiandrosterone (DHEA)‐mediated effects in the pulmonary vasculature and RV; (v) discuss hormone‐independent variables contributing to sexually dimorphic disease presentation; and (vi) identify knowledge gaps and pathways forward. © 2020 American Physiological Society. Compr Physiol 10:125‐170, 2020.

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Figure 1. Figure 1. Current classification of pulmonary hypertension (PH) and subtypes with evidence for sexually dimorphic features. PH classification from 6th World Symposium (Nice, 2018) according to Simonneau et al. (1351). In addition to the data presented here, one study in a large cohort of veterans with all types of PH (predominantly Group 2 and 3 PH; n = 15,464 patients) demonstrated that women with PH exhibit higher pulmonary vascular resistance and pulmonary artery pulse pressure, yet lower RAP as well as 18% greater survival compared to men with PH. *These analyses predominantly included patients with idiopathic PAH and also patients with heritable PAH and drug‐ and toxin‐associated PAH (no subgroup analyses performed). #Attenuated hypoxia‐induced PH in women not consistently found across studies. BMPR2, gene encoding bone morphogenic protein receptor 2; CYP1B1, gene encoding cytochrome P450 1B1; CYP19A1, gene encoding aromatase; ESR1, gene encoding estrogen receptor α; HFpEF, heart failure with preserved ejection fraction; HIV, human immunodeficiency virus; HT, hormone therapy; LVEF, left ventricular ejection fraction; PCH, pulmonary capillary hemangiomatosis; PVOD, pulmonary veno‐occlusive disease; PVR, pulmonary vascular resistance; RV, right ventricle; SNP, single‐nucleotide polymorphism; SSc, systemic sclerosis.
Figure 2. Figure 2. Pathophysiology of PAH. (A) Arterial cross section illustrating PAH pathology in the pulmonary arteries. Proliferation of endothelial cells (ECs), smooth muscle cells (SMCs), and fibroblasts leads to vascular remodeling with eventual occlusion of diseased vessels. Neoangiogenesis driven by apoptosis‐resistant proliferative ECs, SMCs, and other resident PA and recruited cells promotes formation of plexiform vascular lesions, which are the hallmark of PAH. Plexiform lesions may be seen within pulmonary vessels as well as extending into the adventitial tissue (not shown). Infiltration of PH vascular lesions by immune cells and bone marrow‐derived cells drives a pro‐inflammatory and pro‐proliferative state in the tissue. (B) Transverse section of the heart. High pulmonary vascular resistance in PAH produces increased afterload on the RV, resulting in adaptation and RV failure in PAH. RV hypertrophy may be adaptive and compensatory to overcome PVR and maintain cardiac output (not shown). On the other hand, RV hypertrophy may be maladaptive, marked by vessel rarefaction, metabolic dysfunction, inflammation, cell death, fibrosis, and increased RV dilatation. Maladaptive RV remodeling is associated with RV ischemia and decreased RV ejection fraction and cardiac output, resulting in RV failure.
Figure 3. Figure 3. Sex hormone synthesis and estrogen metabolism. Steroidogenic enzymes represented here are present in the lung, heart, and/or vascular tissue 148,198,315,318,480. Abundance of boxed enzymes is altered in PH/PAH 12,327,341,457,462,463,464. Compounds in red have been targeted in clinical trials of PAH therapies 194. 2‐Hydroxyestradiol and 2‐methoxyestradiol exert ER‐independent antiproliferative, anti‐inflammatory effects that appear to mitigate vascular remodeling in animal models of PAH 22,82,421. Conversely, the estrogen metabolites 4‐hydroxyestradiol, 4‐methoxyestradiol, and 16α‐hydroxyestrone signal via estrogen receptors and promote a mitogenic, inflammatory, and antiapoptotic phenotype that exacerbates PH/PAH 54,463. *Multiple CYP enzymes are capable of catalyzing estrogen hydroxylation; CYP1A1 and CYP1B1 appear to be the most relevant isoforms in PAH pathology. Factors including diet 241,276, hypoxia 107, inflammation 11, genetics 12,146, and drug exposure 71 may alter estrogen metabolism. Effects of enzymes and metabolites depicted here may be cell‐, tissue‐, and/or organ specific.
Figure 4. Figure 4. Overview of major biological effects of the most abundant sex hormones (A) and their net effects in animal studies as well as reported associations with PAH risk and outcomes in human studies (B). Note that effects of specific sex hormones on outcomes in human studies may be limited to men or pre‐ or postmenopausal women only. Human studies measured DHEA‐S (dehydroepiandrosterone sulfate). *Data based on study only. #Inconsistent associations across studies. DHEA, dehydroepiandrosterone; PA, pulmonary artery; PAEC, pulmonary artery endothelial cell; PAH, pulmonary arterial hypertension (human studies); PASMCs, pulmonary artery smooth muscle cells; PH, pulmonary hypertension; RV, right ventricle.
Figure 5. Figure 5. Simplified overview of factors contributing to sex/gender differences and sexual dimorphism in PAH and PH. Note that significant cross talk exists between the factors and mediators listed in this figure. BMPR2, gene encoding bone morphogenic protein receptor 2; CYP1B1, gene encoding cytochrome P450 1B1; CYP19A1, gene encoding aromatase; DHEA, dehydroepiandrosterone; ESR1, gene encoding estrogen receptor α; SNP, single‐nucleotide polymorphism.


Figure 1. Current classification of pulmonary hypertension (PH) and subtypes with evidence for sexually dimorphic features. PH classification from 6th World Symposium (Nice, 2018) according to Simonneau et al. (1351). In addition to the data presented here, one study in a large cohort of veterans with all types of PH (predominantly Group 2 and 3 PH; n = 15,464 patients) demonstrated that women with PH exhibit higher pulmonary vascular resistance and pulmonary artery pulse pressure, yet lower RAP as well as 18% greater survival compared to men with PH. *These analyses predominantly included patients with idiopathic PAH and also patients with heritable PAH and drug‐ and toxin‐associated PAH (no subgroup analyses performed). #Attenuated hypoxia‐induced PH in women not consistently found across studies. BMPR2, gene encoding bone morphogenic protein receptor 2; CYP1B1, gene encoding cytochrome P450 1B1; CYP19A1, gene encoding aromatase; ESR1, gene encoding estrogen receptor α; HFpEF, heart failure with preserved ejection fraction; HIV, human immunodeficiency virus; HT, hormone therapy; LVEF, left ventricular ejection fraction; PCH, pulmonary capillary hemangiomatosis; PVOD, pulmonary veno‐occlusive disease; PVR, pulmonary vascular resistance; RV, right ventricle; SNP, single‐nucleotide polymorphism; SSc, systemic sclerosis.


Figure 2. Pathophysiology of PAH. (A) Arterial cross section illustrating PAH pathology in the pulmonary arteries. Proliferation of endothelial cells (ECs), smooth muscle cells (SMCs), and fibroblasts leads to vascular remodeling with eventual occlusion of diseased vessels. Neoangiogenesis driven by apoptosis‐resistant proliferative ECs, SMCs, and other resident PA and recruited cells promotes formation of plexiform vascular lesions, which are the hallmark of PAH. Plexiform lesions may be seen within pulmonary vessels as well as extending into the adventitial tissue (not shown). Infiltration of PH vascular lesions by immune cells and bone marrow‐derived cells drives a pro‐inflammatory and pro‐proliferative state in the tissue. (B) Transverse section of the heart. High pulmonary vascular resistance in PAH produces increased afterload on the RV, resulting in adaptation and RV failure in PAH. RV hypertrophy may be adaptive and compensatory to overcome PVR and maintain cardiac output (not shown). On the other hand, RV hypertrophy may be maladaptive, marked by vessel rarefaction, metabolic dysfunction, inflammation, cell death, fibrosis, and increased RV dilatation. Maladaptive RV remodeling is associated with RV ischemia and decreased RV ejection fraction and cardiac output, resulting in RV failure.


Figure 3. Sex hormone synthesis and estrogen metabolism. Steroidogenic enzymes represented here are present in the lung, heart, and/or vascular tissue 148,198,315,318,480. Abundance of boxed enzymes is altered in PH/PAH 12,327,341,457,462,463,464. Compounds in red have been targeted in clinical trials of PAH therapies 194. 2‐Hydroxyestradiol and 2‐methoxyestradiol exert ER‐independent antiproliferative, anti‐inflammatory effects that appear to mitigate vascular remodeling in animal models of PAH 22,82,421. Conversely, the estrogen metabolites 4‐hydroxyestradiol, 4‐methoxyestradiol, and 16α‐hydroxyestrone signal via estrogen receptors and promote a mitogenic, inflammatory, and antiapoptotic phenotype that exacerbates PH/PAH 54,463. *Multiple CYP enzymes are capable of catalyzing estrogen hydroxylation; CYP1A1 and CYP1B1 appear to be the most relevant isoforms in PAH pathology. Factors including diet 241,276, hypoxia 107, inflammation 11, genetics 12,146, and drug exposure 71 may alter estrogen metabolism. Effects of enzymes and metabolites depicted here may be cell‐, tissue‐, and/or organ specific.


Figure 4. Overview of major biological effects of the most abundant sex hormones (A) and their net effects in animal studies as well as reported associations with PAH risk and outcomes in human studies (B). Note that effects of specific sex hormones on outcomes in human studies may be limited to men or pre‐ or postmenopausal women only. Human studies measured DHEA‐S (dehydroepiandrosterone sulfate). *Data based on study only. #Inconsistent associations across studies. DHEA, dehydroepiandrosterone; PA, pulmonary artery; PAEC, pulmonary artery endothelial cell; PAH, pulmonary arterial hypertension (human studies); PASMCs, pulmonary artery smooth muscle cells; PH, pulmonary hypertension; RV, right ventricle.


Figure 5. Simplified overview of factors contributing to sex/gender differences and sexual dimorphism in PAH and PH. Note that significant cross talk exists between the factors and mediators listed in this figure. BMPR2, gene encoding bone morphogenic protein receptor 2; CYP1B1, gene encoding cytochrome P450 1B1; CYP19A1, gene encoding aromatase; DHEA, dehydroepiandrosterone; ESR1, gene encoding estrogen receptor α; SNP, single‐nucleotide polymorphism.
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Teaching Material

James Hester, Corey Ventetuolo, Tim Lahm. Sex, gender, and sex hormones in pulmonary hypertension and right ventricular failure. Compr Physiol 10 : 2020, 125-170.

Didactic Synopsis

Major Teaching Points:

  • Pulmonary hypertension (PH) encompasses a heterogeneous group of diseases organized into 5 groups based on their predominant underlying pathology and clinical phenotype (Fig. 1).
  • The "estrogen puzzle" refers to two observations in PH research: 1) Many PH classes, particularly group 1 (PAH), are marked by sexually dimorphic disease presentation wherein women are at increased risk for disease development but display increased survival compared with men, and 2) Animal models demonstrated contradictory effects of estrogen signaling in PH disease progression (protective as well as detrimental).
  • Human and animal studies have shown varied effects of 17β estradiol (E2) in the pulmonary vasculature in PAH/PH, but consistently show that E2 promotes healthy RV function and adaptation. Disease-promoting effects of E2 in the pulmonary vasculature are mediated at least in part by pro-proliferative metabolites (e.g., 16α-hydroxyestrone).
  • Few studies have examined the effect of progesterone or androgen signaling in PH though these hormones possibly play a role in disease susceptibility and progression.
  • DHEA is protective in animal models of PH, and circulating DHEA levels in PAH patients correspond positively with PH endpoints and RV function in humans.

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

Figure 1. Teaching Points: Pulmonary hypertension (PH) is a syndrome of diseases, meaning that there are many unique clinical subtypes. These subtypes have been classified into 5 groups that include common features. Patients may have clinical features of more than one group and/or subtype. Gender differences are common in the diagnosis and progression of PH, particularly in Group 1 – pulmonary arterial hypertension (PAH). In general, women are more likely to develop PAH, but show increased survival and superior right heart function compared to men.

Figure 2. Teaching Points: Pulmonary arterial hypertension (PAH; Group 1 PH) affects both pulmonary blood vessels and the right ventricle (RV) of the heart. Healthy pulmonary arteries are composed of three layers (panel a) – the adventitia is the outer covering composed of extracellular matrix and containing fibroblasts, the medial layer is a thin layer of smooth muscle cells, and the intima is composed of endothelial cells which line the vessel lumen and are in direct contact with the blood and its components. In PAH, uncontrolled proliferation of all cell types of the pulmonary artery wall leads to PA remodeling and vessel occlusion. In its most severe form, this remodeling process leads to the formation of plexiform lesions, structures characterized by distorted vessel architecture and occlusion of blood flow. Note that the clear demarcation between vessel layers is no longer present in PAH. An influx of inflammatory cells and bone marrow-derived cells also contribute to PA remodeling. The PA remodeling process leads to increased pulmonary afterload and structural and functional changes of the RV (panel B). Ordinarily, the RV is a thin-walled structure that is much smaller than the left ventricle and that is exquisitely afterload sensitive. In the face of increased pulmonary vascular resistance, the RV may hypertrophy – increasing the size of the cardiomyocytes in order to generate more contractile force and move blood through the pulmonary vasculature. At a cellular level, the RV becomes fibrotic and inflamed. Angiogenesis promotes formation of new capillaries in the RV during hypertrophy, but as the RV begins to fail there are fewer vessels present in the RV wall and ischemia may be present particularly during cardiac stress. The RV's ability to compensate for changes in the pulmonary circulation varies significantly across patients and PH subtypes and little is understood about factors which predict adaptive vs. maladaptive reprograming, RV failure development, and time course.

Figure 3. Teaching points: All hormones are derived from cholesterol and can be divided into three classes based on the number of carbon atoms in their structure. Conversion between hormones requires steroidogenic enzymes, particularly of the cytochrome P450 family. These enzymes are expressed in many tissues other than traditional steroidogenic tissue and may alter hormone levels locally and in the circulation. Note that many hormones and enzymes are altered in PAH and appear to play a role in disease progression. Estrogen and its metabolites are the most studied in this regard, though DHEA also appears to be a key player in PAH. Testosterone and progesterone have received far less attention from researchers, though both hormones appear to play important roles in the cardiopulmonary system. Note that different estrogen metabolites can have very different effects on target cells and do not necessarily signal through the estrogen receptor. A shift in estrogen metabolism to promote non-proliferative non-estrogenic metabolites such as 2-ME2, rather than proliferative metabolites such as 16-OHE1, may ameliorate the progression of PAH.

Figure 4. Teaching points: The effects of sex hormones on PH are complex and sometimes contradictory. This is likely due to compartment-specific, time-dependent, dose-related and context-driven effects and/or modifiers. For instance, E2 and testosterone have been shown to display both beneficial and detrimental effect in PH. E2's beneficial effects are most clearly seen in the RV, while androgen signaling promotes RV hypertrophy and exacerbates maladaptive RV remodeling in PH. Other sex hormones (DHEA, 16-OHE1) have less contradictory findings overall, but this observation may be the result of fewer available studies. The results of animal studies and results from human subjects are also occasionally contradictory, making it difficult to draw definitive conclusions about the "gender puzzle" of PH.

Figure 5. Teaching points: The "estrogen puzzle" likely does not have a simple answer. Instead, many factors contribute to gender differences in PH prevalence and outcomes. Note in this simplified diagram that contributing factors impact not only sexually dimorphic features of PH, but also impact other disease modulators leading to extensive crosstalk. For example, genetic factors may impact expression or activity of steroidogenic enzymes, altering the hormonal milieu of the patient. Comorbidities may drive immune responses that promote inflammation, while metabolic and environmental factors may also alter inflammation or remodeling processes. Researchers are making great progress in solving the estrogen puzzle and are developing and testing new therapies based on sexually dimorphic disease presentation, however the underlying causes of the estrogen puzzle are complex and much work remains to be done.

 


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Article Title: Sex, Gender, and Sex Hormones in Pulmonary Hypertension and Right Ventricular Failure
 

How to Cite

James Hester, Corey Ventetuolo, Tim Lahm. Sex, Gender, and Sex Hormones in Pulmonary Hypertension and Right Ventricular Failure. Compr Physiol 2019, 10: 125-170. doi: 10.1002/cphy.c190011