Abstract
Monge’s disease (chronic mountain sickness (CMS)) is a maladaptive condition caused by chronic (years) exposure to high-altitude hypoxia. One of the defining features of CMS is excessive erythrocytosis with extremely high hematocrit levels. In the Andean population, CMS prevalence is vastly different between males and females, being rare in females. Furthermore, there is a sharp increase in CMS incidence in females after menopause. In this study, we assessed the role of sex hormones (testosterone, progesterone, and estrogen) in CMS and non-CMS cells using a well-characterized in vitro erythroid platform. While we found that there was a mild (nonsignificant) increase in RBC production with testosterone, we observed that estrogen, in physiologic concentrations, reduced sharply CD235a+ cells (glycophorin A; a marker of RBC), from 56% in the untreated CMS cells to 10% in the treated CMS cells, in a stage-specific and dose-responsive manner. At the molecular level, we determined that estrogen has a direct effect on GATA1, remarkably decreasing the messenger RNA (mRNA) and protein levels of GATA1 (p < 0.01) and its target genes (Alas2, BclxL, and Epor, p < 0.001). These changes result in a significant increase in apoptosis of erythroid cells. We also demonstrate that estrogen regulates erythropoiesis in CMS patients through estrogen beta signaling and that its inhibition can diminish the effects of estrogen by significantly increasing HIF1, VEGF, and GATA1 mRNA levels. Taken altogether, our results indicate that estrogen has a major impact on the regulation of erythropoiesis, particularly under chronic hypoxic conditions, and has the potential to treat blood diseases, such as high altitude severe erythrocytosis.
Highlights
Chronic mountain sickness (CMS), or Monge’s disease, is a progressive and debilitating syndrome caused by chronic exposure to high-altitude hypoxia[1,2,3,4,5,6,7,8,9]
These results suggest that the exaggerated response to hypoxia in CMS cells is governed genetically in CMS females and by the hormonal milieu, as the effect of hypoxia on RBC production is blunted by estrogen
Previous studies have shown a correlation of testosterone and progesterone with hemoglobin levels in CMS patients[24,27,28,29,47], but the effect of estrogen on RBC production is still unclear in CMS patients at high altitude
Summary
Chronic mountain sickness (CMS), or Monge’s disease, is a progressive and debilitating syndrome caused by chronic (years or lifetime) exposure to high-altitude hypoxia[1,2,3,4,5,6,7,8,9]. We take advantage of an “experiment in nature” in which human populations at high altitude in the Andes have adapted to chronic hypoxia, whereas other Andean individuals at the same high altitude do not seem to have adapted. These nonadapted individuals have CMS or Monge’s disease. Excessive erythrocytosis (EE) is one of the critical traits of CMS, and this excessive pathobiologic response has deleterious effects since a high hematocrit would increase blood viscosity and reduce blood flow to hypoxia-sensitive organs (e.g., brain and heart), often resulting in myocardial infarction or stroke in young adults. Among all the signs and symptoms, the hematocrit remains a clearly defined quantitative trait and has been
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