Anemia under Androgen Deprivation: Influence of Flutamide, Cyproteroneacetate and Orchiectomy on the Erythropoietin System

Abstract

Objective: There is a high incidence of anemia in patients with advanced prostate cancer (PC) under androgen deprivation. Pathophysiology of this anemia remains unclear. Erythropoietin (EPO) is the main growth factor inducing erythropoesis in response to hypoxia. In this study, function of the EPO-system following androgen deprivation was tested in standardized animal model. Methods: Animals were pretreated by either orchiectomy, injection of cyproteroneacetate or flutamide. After hypoxic stimulation, EPO mRNA expression and EPO serum levels were studied. Results: In all animals, EPO mRNA expression and EPO serum levels were increased following hypoxic stimulation. Compared to the control group, this increase was even more pronounced after androgen deprivation. None of the different forms of androgen deprivation had a negative stimulating effect on EPO expression. Conclusion: Unexpectedly, androgen deprivation did not suppress EPO mRNA expression and EPO serum concentrations. Instead, stimulation of the EPO system was even more pronounced after androgen deprivation. A deficient EPO system does not appear to contribute to the clinically observed anemia in patients treated by androgen deprivation.

Prostate carcinoma · Anemia · Androgen deprivation · Erythropoietin · Animal model

References

• 1 Henry D H. Recombinant human erythropoietin in the treatment of anemia associated with solid tumors. In: Bauer C, Koch KM, Scigalla P, Wieczorek L (eds) Erythropoietin: Molecular Physiology and clinical application. New York; Marcel Dekker 1993: 293-298
• 2 Reimers H J, Sundermann G. Anemia and the rehabilitation of the cancer patient.  Onkologie. 1999;  22 356-357
• 3 Asbell S O, Leon S A, Tester W J, Brereton H D, Ago C T, Rotman M. Development of anemia and recovery in prostate cancer patients treated with combined androgen blockade and radiotherapy.  Prostate. 1996;  29 243-248
• 4 Hamilton J B. The role of testosterone secretion as indicated by the effects of castration in man and by studies of pathological conditions and the short lifespan associated with maleness.  Recent Prog Horm Res. 1948;  3 257-289
• 5 Strum S B, McDermed J E, Scholz M C, Johnson H, Tisman G. Anemia associated with androgen deprivation in patients with prostate cancer receiving combined hormone blockade.  Br J Urol. 1997;  79 933-941
• 6 Weber J P, Walsh P C, Peters C A, Spivak J L. Effect of reversible androgen deprivation on hemoglobin and serum reactive erythropoietin in men.  Am J Hemat. 1991;  36 90-194
• 7 Eri L M, Tveter K J. Safety, side effects and patients acceptance of luteinizing hormone releasing agonist leuprolide in the treatment of benign prostatic hyperplasia.  J Urol. 1994;  152 448-452
• 8 Strum S B, McDermed J E, Scholz M C, Johnson H, Tisman G. Anemia associated with androgen deprivation in patients with prostate cancer receiving combined hormone blockade.  Br J Urol. 1997;  79 933-941
• 9 Prout G R, Keating M A, Griffin P P. Long term experience with flutamide in patients with prostate carcinoma.  Urology. 1989;  34 37-45
• 10 Beshara S, Letocha H, Torbjörn L, Wikström B, Sandhagen B, Nilsson S, Danielson B G. Anemia associated with advanced prostatic adenocarcinoma: effects of recombinant human erythropoietin.  Prostate. 1997;  31 53-160
• 11 Decensi A, Torrisi R, Fontana V. Stimulation of erythropoiesis by non-steroidal anti-androgen nilutamide in men with prostate cancer: evidence for a agonistic effect.  Br J Cancer. 1994;  69 617-619
• 12 Fisher J W, Langston J W. Effects of testosterone, cobalt and hypoxia on erythropoietin production in the isolated perfused dog kidney.  Ann NY Acad Sci. 1968;  149 75-87
• 13 Ratcliffe P J, Jones R W, Phillips R E, Nicholls L G, Bell J I. Oxygen dependent modulation of mRNA levels in isolated rat kidneys studied by RNAase protection.  J Exp Med. 1990;  172 657-660
• 14 Blanchard K L, Fandrey J, Goldberg M A, Bunn H F. Regulation of the erythropoietin gene.  Stem Cells Dayt Suppl.. 1993;  1 1-7
• 15 Schofield C J, Ratcliffe P J. Oxygen sensing by HIF hydroxylases.  Nature reviews/Molecular Cell Biology. 2004;  5 343-354
• 16 Habenicht U F, El Etreby M F. Selective inhibtion of androstenedione-induced prostate growth in intact beagle dogs by a combined treatment with the antiandrogen cyproterone acetate and the aromatase inhibitor 1-methyl-androsta-1,4-diene-3,17-dione (1-methyl-ADD).  The prostate. 1989;  14 309-322
• 17 Ballal S H, Domoto D T, Polack D C, Marciulonis P, Martin J K. Androgenes potentiate the effects of erythropoietin in the treatment of anemia of end stage renal disease.  Am J Kidney Dis. 1991;  17 29-33
• 18 Gascon A, Belvis J J, Berisa F, Iglesias E. Nandrolone decanoate may be an adjuvant therapy to augment hemoglobin response today. Nephrology Dialysis.  Transplantation. 1999;  14 2257-2258