Furthermore, testosterone fails to directly activate EPO transcription in Hep3B cells, an EPO-secreting cell line that is highly sensitive to hypoxic induction ( 11), thus suggesting that any putative EPO-dependent mechanism for testosterone-induced erythrocytosis may be indirect, of modest magnitude, and/or transient. Erythrocytosis in some other testosterone trials also was not associated with increased EPO levels, although these studies were likely underpowered to detect an effect given the interindividual variability in EPO levels ( 8–10). For example, administration of graded doses of testosterone to healthy young and older men, whose endogenous testosterone production was suppressed by administration of a long-acting gonadotropin releasing hormone agonist, dose dependently increased hemoglobin and hematocrit but did not change EPO levels consistently after 20 weeks even at supraphysiologic doses of testosterone ( 4). However, human studies have not provided clear evidence that testosterone stimulates EPO secretion. In retrospect, this erythropoiesis-stimulating activity of plasma from testosterone-treated animals may not only have reflected the activity of erythropoietin (EPO) but may also have reflected other circulating factors that are regulated by testosterone and which modulate erythropoiesis or systemic iron bioavailability ( 5–7). Historical studies in preclinical models had suggested that testosterone induces an erythropoiesis-stimulating factor, which was measured in these early studies by a bioassay using a polycythemic mouse model ( 5). Thus, understanding the mechanism of testosterone-induced erythrocytosis is important within the context of its safety, especially in older men, who experience greater increments in hemoglobin and hematocrit in response to testosterone administration than young men ( 4).
Increased red blood cell mass (erythrocytosis) is the most common adverse event associated with testosterone therapy in clinical practice and in testosterone trials ( 2, 3). T estosterone use in men has increased markedly over the past 15 years-reaching nearly $1.7 billion in prescription sales in 2012-due to numerous factors, including the increased awareness of androgen deficiency syndromes in men and the growing off-label use of testosterone for age-related decline in testosterone levels ( 1).
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