17-Beta Estradiol Attenuates Hypoxic PH via Estrogen Receptor-Mediated Effects
The question: How does 17β-estradiol (E2) exert its protective effects in hypoxia-induced pulmonary hypertension? Does E2 work indirectly by being converted to certain metabolites or directly by activating the estrogen receptor?
Why is this important? Even though women are more frequently affected by pulmonary arterial hypertension (PAH), they exhibit better right ventricular function and higher survival rates than men. Women also appear to be protected from hypoxia-induced pulmonary hypertension (HPH), a type of PH that is distinct from PAH and that is associated with prolonged exposure to low oxygen concentrations from chronic lung disease, sleep-disordered breathing or residence at high altitude. A better understanding of the effects of sex hormones on the pulmonary vasculature and right ventricle is therefore needed, since this 1) may help explain the reason for the observed gender differences in PH and 2) may facilitate the development of novel, hormone-derived therapies for PAH and/or HPH.
Past studies: Several investigators have demonstrated protective effects of E2 in animal studies of HPH or other types of PH. It has also been demonstrated that the phase of the menstrual cycle affects the ability of pulmonary arteries to contract: pulmonary arteries from female rats with high endogenous E2 levels contract less than arteries from female rats with lower E2 levels or than arteries from male rats. However, while these studies revealed mechanisms of how E2 affects modulators of pulmonary artery contraction, it remains unknown how E2 affects the uncontrolled growth of cells of the pulmonary artery wall that contributes to the narrowing of the pulmonary vasculature. In addition, it remains unknown how E2 improves the function of the right ventricle (a critical determinant of survival in all forms of PH). Lastly, since E2 may work indirectly by being converted to certain metabolites or directly by activating the estrogen receptor, it is important to decipher which of these pathways mediates E2 protection in HPH. This pathway may then be targeted therapeutically.
This study: Male rats with HPH were treated with E2 and co-treated with either inhibitors of the E2 conversion process or with an agent that blocks the estrogen receptor. While the conversion inhibitors did not affect E2-mediated protection, blockade of the estrogen receptor significantly attenuated E2’s protective effects. This indicates that E2-metabolite conversion is not necessary for E2 protection in HPH. Rather, it is E2’s effect on the estrogen receptor that mediates its protection.
Further experiments revealed that both of the two estrogen receptor subtypes (estrogen receptor–α and –β) mediate E2’s actions. E2 exerted beneficial receptor-mediated effects on both the pulmonary vasculature and right ventricle, which were associated with inhibition of signaling pathways that drive cellular growth and with augmentation of pathways that inhibit cell growth. In isolated pulmonary artery endothelial cells (cells that make up the lining of lung blood vessels), E2 again inhibited cell growth. However, this effect was only seen in cells exposed to low oxygen concentrations, suggesting that E2 exerts specific protective effects when oxygen levels are low. Taken together, these results suggest that E2 exerts hypoxia-specific and receptor-mediated inhibitory effects on the growth of cells of the pulmonary vasculature and right ventricle.
Who may benefit from these findings: Patients with HPH or PAH, healthcare providers and researchers.
The bottom line: While it is premature to make recommendations on the use of estrogens for HPH, this study indicates that in an environment characterized by low oxygen concentrations, E2 may exert beneficial effects on the pulmonary artery and right ventricle. Further exploration of the pathways affected by E2 may, therefore, allow for the development of targeted, non-hormonal therapies for both men and women with HPH. This is of importance since no specific pharmacologic therapy for HPH exists. In fact, the drugs that are used for PAH may worsen symptoms in HPH since they may decrease patients’ oxygen saturations. While we cannot extrapolate the current results to patients with PAH, this study, viewed in the context of previous investigations, raises the possibility that protective estrogen receptor signaling may be distorted in PAH, thereby making women more prone to the development of the disease.
Where to find this article: Am J Respir Crit Care Med. 2012 Mar 1 (Epub ahead of print). PMID: 22383500.
List of authors: Lahm T, Albrecht M, Fisher AJ, Selej M, Patel NG, Brown JA, Justice MJ, Brown MB, Van Demark M, Trulock KM, Dieudonne D, Reddy JG, Presson RG, Petrache I. Departments of Medicine and Anesthesiology, Richard L. Roudebush VA Medical Center and Indiana University School of Medicine, Indianapolis, Ind.
Funding: This article was funded in part by an American Thoracic Society/Pulmonary Hypertension Association/Pfizer Fellowship in Pulmonary Arterial Hypertension Research to Tim Lahm. Please see the article for a complete list of the investigators’ research support.
Article provided for Pathlight by Tim Lahm, MD, Division of Pulmonary, Allergy, Critical Care, Occupational and Sleep Medicine, Richard L. Roudebush VA Medical Center; Department of Medicine, Indiana University School of Medicine, Indianapolis, Ind.
This article was first published in Pathlight Summer 2012.