Abstract
Pulmonary arterial hypertension (PAH) is a complex and devastating disease with a poor long-term prognosis. While women are at increased risk for developing PAH, they exhibit superior right heart function and higher survival rates than men. Susceptibility to disease risk in PAH has been attributed, in part, to estrogen signaling. In contrast to potential pathological influences of estrogen in patients, studies of animal models reveal estrogen demonstrates protective effects in PAH. Consistent with this latter observation, an ovariectomy in female rats appears to aggravate the condition. This discrepancy between observations from patients and animal models is often called the “estrogen paradox.” Further, the tissue-specific interactions between estrogen, its metabolites and receptors in PAH and right heart function remain complex; nonetheless, these relationships are essential to characterize to better understand PAH pathophysiology and to potentially develop novel therapeutic and curative targets. In this review, we explore estrogen-mediated mechanisms that may further explain this paradox by summarizing published literature related to: (1) the synthesis and catabolism of estrogen; (2) activity and functions of the various estrogen receptors; (3) the multiple modalities of estrogen signaling in cells; and (4) the role of estrogen and its diverse metabolites on the susceptibility to, and progression of, PAH as well as their impact on right heart function.
Highlights
Pulmonary arterial hypertension (PAH) is a complex and devastating disease characterized by a progressive increase in pulmonary vascular resistance (PVR) and subsequent, right heart failure, considered the most common cause of death in patients [1]
Significant progress has been made in our understanding of estrogen synthesis and catabolism, earlier research efforts primarily focused on circulating levels of estrogen and/or its metabolism in the liver
A better understanding of the local concentrations of estrogen and its metabolites in the heart and lungs, enzymes involved in estrogen metabolism, and their activity, is required to further clarify the role of estrogen in PAH
Summary
Pulmonary arterial hypertension (PAH) is a complex and devastating disease characterized by a progressive increase in pulmonary vascular resistance (PVR) and subsequent, right heart failure, considered the most common cause of death in patients [1]. In order to better understand the estrogen paradox, this review will summarize available evidence and discuss the following: [1] potential origins of sex differences; [2] mechanisms involving estrogen anabolism and catabolism; [3] the diverse cellular roles of ERs; [4] multiple modes of estrogen signaling; [5] direct and indirect effects of estrogen hormone and its metabolites. These discussions will shed insight into the impact of both the presence and severity of PAH on estrogen anabolism and catabolism, ERs, and estrogen metabolites. Hoeper et al re-analyzed the results of the Comparative Prospective Registry of Newly Initiated Therapies
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