Protective role of estrogen against excessive erythrocytosis in Monge’s disease

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.

The interaction effect between hemoglobin and hypoxemia on COVID-19 mortality in a sample from Bogotá, Colombia: An exploratory study

“…Estrogens regulate EPO, HIF1A, GATA1, VEGF , genes related to erythropoiesis and erythroid apoptosis mechanisms. [48] These findings suggest that sex hormones moderate the erythropoietic response of chronic exposure to hypoxia and may contribute to the mortality excess in male patients with COVID-19.…”

Sub‐maximal aerobic exercise training reduces haematocrit and ameliorates symptoms in Andean highlanders with chronic mountain sickness

“…The inclusion of male highlanders only is an additional limitation of our study. CMS has a very low prevalence in pre‐menopausal women (Azad et al., 2021 ; Leon‐Velarde et al., 1997 ; Leon‐Velarde et al., 2001 ), and therefore forming comparable groups covering the same age range to avoid any confounding effects of age, and of menopause itself, would have been difficult. For these and cultural reasons, women were not included in the study and therefore our findings cannot be extrapolated to female CMS highlanders.…”

Role of Nuclear Receptors in Controlling Erythropoiesis

“…These experiments were confirmed in vivo, where high dosage of estrogens causes anemia in humans and animal models [ 54 , 56 ]. Interestingly, it has been observed that in people living at high altitudes, females are more protected than males against chronic mountain sickness erythrocytosis (CMS or Monge’s disease); of note, the incidence of CMS clearly increases after menopause, confirming the link with estrogen levels [ 57 ]. The same study reported that ER acts by repressing GATA1, with subsequent erythroid progenitor apoptosis, as originally observed by G. Blobel and colleagues [ 58 , 59 ].…”