Higher androgen bioactivity is associated with excessive erythrocytosis and chronic mountain sickness in Andean Highlanders: a review

Abstract

Populations living at high altitudes (HA), particularly in the Peruvian Central Andes, are characterised by presenting subjects with erythrocytosis and others with excessive erythrocytosis (EE)(Hb>21 g dl(-1) ). EE is associated with chronic mountain sickness (CMS), or lack of adaptation to HA. Testosterone is an erythropoietic hormone and it may play a role on EE at HA. The objective of the present review was to summarise findings on role of serum T levels on adaptation at HA and genes acting on this process. Men at HA without EE have higher androstenedione levels and low ratio androstenedione/testosterone than men with EE, suggesting low activity of 17beta-hydroxysteroid dehydrogenase (17beta-HSD), and this could be a mechanism of adaptation to HA. Higher conversion of dehydroepiandrosterone to testosterone in men with EE suggests nigher 17beta-HSD activity. Men with CMS at Peruvian Central Andes have two genes SENP1, and ANP32D with higher transcriptional response to hypoxia relative to those without. SUMO-specific protease 1 (SENP1) is an erythropoiesis regulator, which is essential for the stability and activity of hypoxia-inducible factor 1 (HIF-1α) under hypoxia. SENP1 reverses the hormone-augmented SUMOylation of androgen receptor (AR) increasing the transcription activity of AR.In conclusion, increased androgen activity is related with CMS.

Aromatase Inhibitor-Induced Erythrocytosis in a Patient Undergoing Hormonal Treatment for Breast Cancer

“…Androgens have been known to have a stimulatory role in red blood cell production, which is one of the reasons why men have a higher red cell count. This effect of androgens on erythrocytosis is also seen at higher altitudes as reported by Gonzales et al [ 4 , 5 ]. The complete mechanisms by which testosterone induces erythrocytosis are still largely unknown.…”

A Case of Anastrozole-Induced Erythrocytosis

“…Androgens have been associated with increased red blood cell production [2]. Gonzales and Chaupis [3] has described that testosterone causes erythrocytosis by increasing the serum EPO levels, but in our case serum EPO levels were normal, which indicates that AI induced erythrocytosis by EPO independent mechanism.…”

SENP1, but not fetal hemoglobin, differentiates Andean highlanders with chronic mountain sickness from healthy individuals among Andean highlanders

“…SENP1 belongs to a family of proteases that are present in the nucleus and cytoplasm, and it reverses the posttranslational modification of small ubiquitin-like modifiers (SUMOs). Higher SENP1 expression has been hypothesized to be associated with higher androgen activity in Andean highlanders with EE [34]. Higher expression of SENP1 has been documented to induce HIF-1α and reduce apoptosis, thus promoting the development or progression of prostate [35] and other cancer [36,37] cells.…”