Excess Cortisol Can Lead to Lasting Changes to Blood Stem Cells
People with active Cushing’s disease show increased production of red blood cells due to the presence of a type of altered blood stem cell that show abnormal activation of glucocorticoid receptor (GR) signaling, a study shows.
The GR is the receptor protein activated by glucocorticoids, or steroid hormones, including cortisol, which is found at excess levels in patients living with Cushing’s.
While patients in remission showed lower cortisol levels and normal red blood cell counts, their blood stem cells maintained altered properties generated in response to previous exposure to excess cortisol.
The study, “Hypercortisolemic Cushing’s patients possess a distinct class of hematopoietic progenitor cells leading to erythrocytosis,” was published in the journal Haematologica.
Cushing’s disease is caused by benign tumors that lead to the overproduction of cortisol, which is involved in the regulation of various bodily processes, such as blood pressure, inflammation, and food conversion into energy.
People diagnosed with Cushing’s also are unable to respond to external glucocorticoid treatment, which in normal conditions would suppress cortisol production to avoid excess levels.
Research in lab-grown human blood stem cells suggests that exposure to dexamethasone (DEX) — a lab-made glucocorticoid almost identical to cortisol — triggers the production of red blood cells.
Blood stem cells, also called hematopoietic stem cells, have the ability to make unlimited copies of themselves and mature into all types of blood cells in the body.
However, whether body exposure to glucocorticoids promotes red blood cell production remains poorly understood. Furthermore, given that glucocorticoids are widely used as anti-inflammatory treatments, understanding their effects on the body has clinical relevance.
What did the study find?
To find out, researchers in the U.S. and Italy analyzed blood samples from 13 Cushing’s patients with active disease, 13 patients in remission after surgical removal of their tumor, and eight healthy people (used as controls). Four of the 13 patients had their blood drawn before and after surgical remission.
Patients with active disease had significantly higher mean blood cortisol levels and a higher hematocrit, or the percentage of red blood cells in the blood, compared with those in remission and with controls.
The levels of platelets and hemoglobin, the protein in red blood cells that carries oxygen throughout the body, were also significantly higher in patients with active disease than in those in remission.
However, the team detected no significant association between hematocrit values and cortisol levels in the blood or urine in patients with active disease and those in remission.
“This lack of correlation may in part be due to the wide intra-patient variability in cortisol values,” the researchers wrote.
White blood, or immune, cell counts were also higher in active patients than in those in remission and in controls.
Analysis of different types of immune cells revealed higher counts of neutrophils in patients with active disease, but lower numbers of pro-inflammatory immune cells, which was expected due to glucocorticoids’ anti-inflammatory effects.
Although the overall frequency of immune monocytes was similar across the groups, active disease patients had more monocytes with the CD163 receptor protein, which is induced by GR activation.
High numbers of CD163-positive monocytes were also retained in remission patients, suggesting that “monocytes maintain a memory of their activation state upon clinical remission,” the researchers wrote.
The team then looked at participants’ circulating cells containing the CD34 receptor protein, which is a marker of hematopoietic stem cells and other blood progenitor cells. They found that only the CD34-positive cells from patients with active disease had markers consistent with a stress response.
What do the findings suggest?
“These results suggest that the circulating progenitor cells from active Cushing’s patients are a unique population likely generated from the hematopoietic stem cells in response to the high cortisol levels,” the scientists wrote.
When these abnormal CD34-positive cells were grown in the lab, they produced similarly high numbers of red blood cells in the presence and absence of DEX. They also showed increased GR signaling activation, regardless of dexamethasone exposure.
In contrast, cells from controls generated higher numbers of red blood cells when grown in the presence of DEX, but not without glucocorticoid treatment.
While a similar response would be expected from patients in remission, their CD34-positive cells were also unresponsive to DEX, generating similarly low red blood cell numbers with or without the glucocorticoid.
This suggested that “the apparently normal progenitor cells observed in these patients retain some memory of altered response to GR activation,” the researchers wrote.
Further analysis suggested that blood progenitor cells from people with active Cushing’s have constantly active GR signaling, while those from patients in remission “are unable to activate GR signaling,” the researchers wrote.
This hypothesis “is consistent with the clinical observation that long-term [simultaneous health conditions] are seen in patients with Cushing’s despite remission, including persistent obesity, increased cardiovascular risk, evidence of abnormal systemic inflammation …, as a memory of their previously [excess cortisol-related] features,” they added.
These findings highlight that chronic exposure to excess glucocorticoids such as cortisol leads to overproduction of red blood cells by generating a unique and stressed blood progenitor cell population with a constantly active GR that does not respond to DEX, the researchers noted.
“Although remission rescues the [red blood cell overproduction] and the [characteristics] of the circulating [CD34-positive cells], a memory of other prior changes is maintained in remission,” and these cells show “an abnormal response to exogenous DEX,” the team wrote.
About the Author
