Sex Differences, Estrogen Metabolism and Signaling in the Development of Pulmonary Arterial Hypertension

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.

The Role of Thyroid Disorders, Obesity, Diabetes Mellitus and Estrogen Exposure as Potential Modifiers for Pulmonary Hypertension

“…In addition, Sweeney et al showed that 80% of the female PAH patients reported prior use of exogenous estrogen therapy, either in the form of oral contraceptive pills (premenopausal women) or as hormone replacement therapy (postmenopausal women) [52]. On the other hand, female PAH patients demonstrate superior right heart function and survival rates than their male counterparts [66]. Additionally, several studies using animal models have suggested that estrogens may have a protective role in the PAH setting; however, we must be cautious when extrapolating these findings to humans [66].…”

“…On the other hand, female PAH patients demonstrate superior right heart function and survival rates than their male counterparts [66]. Additionally, several studies using animal models have suggested that estrogens may have a protective role in the PAH setting; however, we must be cautious when extrapolating these findings to humans [66]. This controversy has been often referred to as the "estrogen paradox".…”

“…They can also inhibit myocardial fibrosis and right-heart hypertrophy, thus exhibiting beneficial effects in PAH [67]. The worse mortality rates and right heart function of the male PAH patients could be explained by the fact that sex hormones might influence the adaptation of the right ventricle to the increased afterload differently in males than in females [66]. On the other hand, the detrimental effects of estrogen could be attributed to data showing that estrogen reduces wild-type BMPR2 expression in pulmonary artery smooth muscle cells and lymphocytes [68].…”

SOX17 Deficiency Mediates Pulmonary Hypertension: At the Crossroads of Sex, Metabolism, and Genetics

“…PAH is a sexually dimorphic disease with female predominance ( 6 ). Sex differences are attributed, in major part, to the role of sex hormones and, importantly, estrogen metabolites in PAH pathophysiology ( 6 , 7 ). From work in patients with PAH, estrogenic activity is associated with the penetrance of PAH ( 8 , 9 ).…”

“…Cumulatively, discrepancies between patients and animal models of PAH are commonly referred to as the “estrogen paradox” ( 7 ). The estrogen paradox is explained partly by the complexity of 17β-estradiol (E2) metabolism and the potential tissue-specific roles of the diverse estrogen metabolites ( 6 ). For example, the most abundant circulating estrogen, E2, appears to exert protective effects in the right ventricle in a variety of rodent models of PH ( 7 ).…”