Estrogen: Friend or Foe in Monge's Disease?

Rationale: Chronic mountain sickness (CMS), or Monge's disease, is a progressive debilitating syndrome caused by chronic (years) exposure to high altitude hypoxia, as experienced by people living in the Andean region. 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 (brain and heart), often resulting in myocardial infarction or stroke in young adults. Within the population of Cerro de Pasco in the Andes, CMS prevalence is vastly different between males and females, being rare in females. Of interest is that there is a sharp increase in CMS incidence in females after menopause. This suggests the role of gender and sex hormones in altering disease manifestation.

Methods: In order to understand the molecular basis for polycythemia of high altitude, we have generated a disease in-the dish-model by re-programming fibroblasts and native CD34+ve cells from CMS and non-CMS subjects and converting them to RBC. Using this in-vitro platform, we are now studying the interactions between genetic factors and sex hormones (Testosterone, Estrogen and Progesterone) and their effect on RBC production in the CMS and non-CMS subjects at high altitude.

Results: While we found that testosterone increased RBC production mildly (insignificantly), estrogen in physiologic concentrations (10nM), in sharp contrast, reduced the CD235a (Glycophorin A- marker of mature RBC) remarkably (from 56% in the untreated CMS sample to 10% in the treated CMS) and eliminated the CMS EE phenotype. There is also stage-specificity and dose response effects for estrogen. This strongly suggests that estrogen has a protective role against the polycythemia phenotype. To probe further, we studied the effect of estrogen (10nM) on GATA1, a critical link with erythropoiesis. There was a sharp 5 fold decrease in GATA1 (p<0.01) and its target genes such as Alas2 (p<0.001) in erythroid cells. This decreased expression resulted in marked reduction (>50%) in RBC production, demonstrating that estrogen constrains RBC production in females.

Conclusion: Our results demonstrate that estrogen inhibits GATA1 expression and prevents excessive erythropoiesis and Monge's disease in females at high altitude. We believe that these studies not only shed light on the role of sex hormones on hypoxia-induced excessive erythropoiesis but have a broader application in their regulation of erythropoiesis and related blood disorders.