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Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is a debilitating and progressive disease that predominantly develops in women. Over the past 15 years, cumulating evidence has pointed toward dysregulated metabolism of sex hormones in animal models and patients with PAH. 17β-estradiol (E2) is metabolized at po...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982327/ https://www.ncbi.nlm.nih.gov/pubmed/31877978 http://dx.doi.org/10.3390/ijms21010116 |
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author | Tofovic, Stevan P. Jackson, Edwin K. |
author_facet | Tofovic, Stevan P. Jackson, Edwin K. |
author_sort | Tofovic, Stevan P. |
collection | PubMed |
description | Pulmonary arterial hypertension (PAH) is a debilitating and progressive disease that predominantly develops in women. Over the past 15 years, cumulating evidence has pointed toward dysregulated metabolism of sex hormones in animal models and patients with PAH. 17β-estradiol (E2) is metabolized at positions C2, C4, and C16, which leads to the formation of metabolites with different biological/estrogenic activity. Since the first report that 2-methoxyestradiol, a major non-estrogenic metabolite of E2, attenuates the development and progression of experimental pulmonary hypertension (PH), it has become increasingly clear that E2, E2 precursors, and E2 metabolites exhibit both protective and detrimental effects in PH. Furthermore, both experimental and clinical data suggest that E2 has divergent effects in the pulmonary vasculature versus right ventricle (estrogen paradox in PAH). The estrogen paradox is of significant clinical relevance for understanding the development, progression, and prognosis of PAH. This review updates experimental and clinical findings and provides insights into: (1) the potential impacts that pathways of estradiol metabolism (EMet) may have in PAH; (2) the beneficial and adverse effects of estrogens and their precursors/metabolites in experimental PH and human PAH; (3) the co-morbidities and pathological conditions that may alter EMet and influence the development/progression of PAH; (4) the relevance of the intracrinology of sex hormones to vascular remodeling in PAH; and (5) the advantages/disadvantages of different approaches to modulate EMet in PAH. Finally, we propose the three-tier-estrogen effects in PAH concept, which may offer reconciliation of the opposing effects of E2 in PAH and may provide a better understanding of the complex mechanisms by which EMet affects the pulmonary circulation–right ventricular interaction in PAH. |
format | Online Article Text |
id | pubmed-6982327 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69823272020-02-07 Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension Tofovic, Stevan P. Jackson, Edwin K. Int J Mol Sci Review Pulmonary arterial hypertension (PAH) is a debilitating and progressive disease that predominantly develops in women. Over the past 15 years, cumulating evidence has pointed toward dysregulated metabolism of sex hormones in animal models and patients with PAH. 17β-estradiol (E2) is metabolized at positions C2, C4, and C16, which leads to the formation of metabolites with different biological/estrogenic activity. Since the first report that 2-methoxyestradiol, a major non-estrogenic metabolite of E2, attenuates the development and progression of experimental pulmonary hypertension (PH), it has become increasingly clear that E2, E2 precursors, and E2 metabolites exhibit both protective and detrimental effects in PH. Furthermore, both experimental and clinical data suggest that E2 has divergent effects in the pulmonary vasculature versus right ventricle (estrogen paradox in PAH). The estrogen paradox is of significant clinical relevance for understanding the development, progression, and prognosis of PAH. This review updates experimental and clinical findings and provides insights into: (1) the potential impacts that pathways of estradiol metabolism (EMet) may have in PAH; (2) the beneficial and adverse effects of estrogens and their precursors/metabolites in experimental PH and human PAH; (3) the co-morbidities and pathological conditions that may alter EMet and influence the development/progression of PAH; (4) the relevance of the intracrinology of sex hormones to vascular remodeling in PAH; and (5) the advantages/disadvantages of different approaches to modulate EMet in PAH. Finally, we propose the three-tier-estrogen effects in PAH concept, which may offer reconciliation of the opposing effects of E2 in PAH and may provide a better understanding of the complex mechanisms by which EMet affects the pulmonary circulation–right ventricular interaction in PAH. MDPI 2019-12-23 /pmc/articles/PMC6982327/ /pubmed/31877978 http://dx.doi.org/10.3390/ijms21010116 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Tofovic, Stevan P. Jackson, Edwin K. Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension |
title | Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension |
title_full | Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension |
title_fullStr | Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension |
title_full_unstemmed | Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension |
title_short | Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension |
title_sort | estradiol metabolism: crossroads in pulmonary arterial hypertension |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982327/ https://www.ncbi.nlm.nih.gov/pubmed/31877978 http://dx.doi.org/10.3390/ijms21010116 |
work_keys_str_mv | AT tofovicstevanp estradiolmetabolismcrossroadsinpulmonaryarterialhypertension AT jacksonedwink estradiolmetabolismcrossroadsinpulmonaryarterialhypertension |