Mechanisms responsible for reduced erythropoiesis during androgen deprivation therapy in men with prostate cancer

Abstract

Androgen deprivation therapy (ADT) is a mainstay of treatment for prostate cancer (PCa). As androgens stimulate erythropoiesis, ADT is associated with a reduction in hematocrit, which in turn contributes to fatigue and related morbidity. However, the mechanisms involved in ADT-induced reduction in erythropoiesis remain unclear. We conducted a 6-mo prospective cohort study and enrolled men with PCa about to undergo ADT (ADT-Group) and a control group of men who had previously undergone prostatectomy for localized PCa and were in remission (Non-ADT Group). All participants had normal testosterone levels at baseline. Fasting blood samples were collected at baseline, 12 wk, and 24 wk after initiation of ADT; samples were obtained at the same intervals from enrollment in the Non-ADT group. Blood count, iron studies, erythropoietin, erythroferrone, and hepcidin levels were measured. Seventy participants formed the analytical sample (31 ADT, 39 Non-ADT). ADT was associated with a significant reduction in erythrocyte count (estimated mean difference = −0.2×106cells/µl, 95%CI = −0.3 to −0.1×106cells/µl, P < 0.001), hematocrit (−1.9%, 95%CI = −2.7 to −1.1%, P < 0.001), and hemoglobin (−0.6 g/dl, 95%CI = −0.8 to −0.3 g/dl, P < 0.001). Serum hepcidin concentration increased in the ADT-group (18 ng/ml, P < 0.001); however, iron concentrations did not change (−1.1 µg/dl, P = 0.837). Ferritin levels increased in men on ADT (60 ng/ml, P < 0.001). Iron binding capacity, transferrin saturation, erythroferrone, and erythropoietin did not change. Nine men undergoing ADT developed new-onset anemia. In conclusion, reduced proliferation of marrow erythroid progenitors leads to ADT-induced reduction in erythropoiesis. Future studies should evaluate the role of selective androgen receptor modulators in the treatment of ADT-induced anemia.

Hepcidin Therapeutics

“…Similar effects were observed in clinical trials with healthy or anemic men [150,151,152] and men with type 2 diabetes and concurrent hypogonadotropic hypogonadism [153]. Conversely, androgen deprivation therapy reduced erythropoiesis and increased hepcidin in men with prostate cancer [154]. These findings suggest that testosterone could be valuable for the treatment of AI; however, cardiovascular adverse effects associated with testosterone administration limit its clinical applications [155].…”

Differential effects of testosterone on circulating neutrophils, monocytes, and platelets in men: Findings from two trials

“…androgen deprivation therapy for prostate cancer has recently been shown to be associated with a decrease in leukocyte count. 14 However, there are no randomized trial data on the effects of exogenous testosterone on circulating leukocytes and platelets. Because of the known association of increased leukocyte [15][16][17][18] and platelet counts [19][20][21] with cardiovascular and thromboembolic risk, these findings, if confirmed in human studies, could affect the safety of testosterone treatment.…”

Increased prostaglandin-D2 in male STAT3-deficient hearts shifts cardiac progenitor cells from endothelial to white adipocyte differentiation

“…The present study found that EPO reduced ZFP423 expression and adipocyte formation from CKO-CPC, suggesting that lower EPO levels in CKO hearts may further promote the shift from endothelial to adipocyte differentiation in CKO-CPC. So far, there is no evidence for a sex-specific regulation of EPO since EPO blood levels in patients undergoing androgen deprivation therapy remained unchanged [ 51 ].…”