Keywords: Erythropoietin; Testosterone; Erythrocytosis; Polycythemia.

Introduction

Testosterone-induced polycythemia is thought to be, at least in part, due to the testosterone-induced hyper production of erythropoietin (EPO) [1]. Here, we present a case of testosterone-induced polycythemia with a low serum EPO level, suggesting that EPO is dispensable for testosterone-caused polycythemia.

Case Report

A 34-year-old previously healthy male presented as a potential allogeneic hematopoietic cell transplant donor. Routine donor eligibility tests revealed elevated hemoglobin (206 g/L) and hematocrit (0.58). He was clinically euvolemic. He reported selfadministration of testosterone enanthate, 150 mg IM weekly, for bodybuilding. Investigations were remarkable for low EPO serum level (3.5 U/L, reference range 4.0-20.0) and elevated carboxyhemoglobin (11.1%, reference range ≤3.0%) attributed to smoking. JAK2 gene was not mutated. Creatinine plasma level was normal (89 umol/L, reference range 50-120). Within 5 months of cessation of testosterone, the patient’s hemoglobin, hematocrit, and EPO level returned to normal (Table 1).Carboxyhemoglobin remained high at 10.9%, consistent with continued smoking.

Table 1: Hemoglobin and testosterone levels at baseline, immediately after a 4-month course of testosterone, and days to months after the testosterone discontinuation.

Discussion

Elevations in testosterone can lead to polycythemia through multiple mechanisms, including stimulation of the estrogen receptor alpha (ERa), the stimulation of EPO, suppression of hepcidin, and bone marrow stimulation by increasing dihydrotestosterone [2-5]. Among these, the EPO-mediated mechanism has been thought to be important [1].

EPO is produced in the kidney in response to hypoxia and is released to act on erythrocyte progenitors, especially at the Colony Forming Unit-Erythroid (CFU-E) stage, as a survival, proliferation, and differentiation factor. The concept of a modified EPO ‘set point’ has been introduced, with testosterone raising the normal homeostatic EPO level, perhaps through hepcidin suppression, leading to increased erythropoiesis and a failure of negative feedback inhibition on EPO [1,6]. However, subsequent investigations have not consistently replicated these findings, with trials showing no difference in EPO levels between testosteronesupplemented men and those receiving placebo, despite the anticipated changes in hemoglobin [7,8]. In the patient we describe, EPO levels were low at the presentation of polycythemia and returned to normal following testosterone cessation, with subsequent hemoglobin drop. Thus, feedback mechanisms were properly acting to reduce EPO in the presence of testosteronedriven polycythemia.

EPO is also stimulated by oxygen demand and thus is elevated with hypoxia [9]. Given the patient’s high carboxyhemoglobin levels attributed to smoking, we would expect EPO to be elevated to stimulate red blood cell production. Given the observed low EPO level despite the elevated carboxyhemoglobin, this further suggests that in our patient the testosterone-induced polycythemia was not driven via testosterone-induced EPO overproduction.

In conclusion, we describe a case of testosterone supplementationinduced polycythemia with reduced EPO that increased after testosterone cessation. It has been controversial whether EPO is dispensable for testosterone-induced polycythemia [1,8]. Thus, this case report is important as it suggests that for the induction of polycythemia by testosterone, EPO is dispensable.

Author Contributions: Conceptualization, N.K, R.A.K, and J.S.; data curation, N.K, R.A.K., and J.S.; writing original draft preparation, N.K.; writing – review and editing, N.K, R.A.K., and J.S.; supervision, J.S. All authors have read and agreed to the published version of the manuscript.

Funding: No funding was received to assist with the preparation of this case report.

Informed Consent Statement: The patient described herein provided written, informed consent for the publication of this case report.

Data Availability Statement: Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Conflicts of Interest: The authors declare no conflict of interest.

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