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Endocrinology. 2015 May; 156(5): 1623–1629.
Published online 2015 Mar 16. doi: 10.1210/en.2014-1784
PMCID: PMC4398764
PMID: 25774550
The Effects of Short-Term and Long-Term Testosterone Supplementation on Blood Viscosity and Erythrocyte Deformability in Healthy Adult Mice
Wen Guo,corresponding author Eric Bachman,* Johannes Vogel,* Michelle Li, Liming Peng, Karol Pencina, Carlo Serra, Nicolae L. Sandor, Ravi Jasuja, Monty Montano, Shehzad Basaria, Max Gassmann, and Shalender Bhasin
Abstract
Testosterone treatment induces erythrocytosis that could potentially affect blood viscosity and cardiovascular risk. We thus investigated the effects of testosterone administration on blood viscosity and erythrocyte deformability using mouse models. Blood viscosity, erythrocyte deformability, and hematocrits were measured in normal male and female mice, as well as in females and castrated males after short-term (2 wk) and long-term (5–7 mo) testosterone intervention (50 mg/kg, weekly). Castrated males for long-term intervention were studied in parallel with the normal males to assess the effect of long-term testosterone deprivation. An additional short-term intervention study was conducted in females with a lower testosterone dose (5 mg/kg). Our results indicate no rheological difference among normal males, females, and castrated males at steady-state. Short-term high-dose testosterone increased hematocrit and whole-blood viscosity in both females and castrated males. This effect diminished after long-term treatment, in association with increased erythrocyte deformability in the testosterone-treated mice, suggesting the presence of adaptive mechanism. Considering that cardiovascular events in human trials are seen early after intervention, rheological changes as potential mediator of vascular events warrant further investigation.
The use of testosterone as a prescription drug has increased dramatically in recent years. Several studies raised concerns about the cardiovascular risk of testosterone therapy (1,–3). Epidemiologic studies suggested that both very low and very high testosterone levels are linked to cardiovascular and cerebral risk (4, 5), but the mechanism remains unclear. Elevated blood viscosity is associated with cardiovascular and cerebral risk, especially in the context of therapeutic administration of erythropoiesis-stimulating agents (6,–9). Likewise, testosterone administration consistently increases hematocrits in men (10, 11). Because erythrocyte mass is a major contributor to blood viscosity, testosterone administration might thus increase blood viscosity. However, relevant literature is scant and inconclusive (12,–14). On the other hand, increased erythrocyte deformability has been reported in erythropoietin-transgenic mice, which allows the mice to offset their whole-blood viscosity to a much lower level than that predicted from their exceptionally high hematocrits (15). It is unclear whether men or animals acquire similar adaptations to testosterone-induced erythrocytosis. Here, we report the effects of testosterone on blood viscosity and erythrocyte deformability in mice after short-term and long-term interventions.
Published online 2015 Mar 16. doi: 10.1210/en.2014-1784
PMCID: PMC4398764
PMID: 25774550
The Effects of Short-Term and Long-Term Testosterone Supplementation on Blood Viscosity and Erythrocyte Deformability in Healthy Adult Mice
Wen Guo,corresponding author Eric Bachman,* Johannes Vogel,* Michelle Li, Liming Peng, Karol Pencina, Carlo Serra, Nicolae L. Sandor, Ravi Jasuja, Monty Montano, Shehzad Basaria, Max Gassmann, and Shalender Bhasin
Abstract
Testosterone treatment induces erythrocytosis that could potentially affect blood viscosity and cardiovascular risk. We thus investigated the effects of testosterone administration on blood viscosity and erythrocyte deformability using mouse models. Blood viscosity, erythrocyte deformability, and hematocrits were measured in normal male and female mice, as well as in females and castrated males after short-term (2 wk) and long-term (5–7 mo) testosterone intervention (50 mg/kg, weekly). Castrated males for long-term intervention were studied in parallel with the normal males to assess the effect of long-term testosterone deprivation. An additional short-term intervention study was conducted in females with a lower testosterone dose (5 mg/kg). Our results indicate no rheological difference among normal males, females, and castrated males at steady-state. Short-term high-dose testosterone increased hematocrit and whole-blood viscosity in both females and castrated males. This effect diminished after long-term treatment, in association with increased erythrocyte deformability in the testosterone-treated mice, suggesting the presence of adaptive mechanism. Considering that cardiovascular events in human trials are seen early after intervention, rheological changes as potential mediator of vascular events warrant further investigation.
The use of testosterone as a prescription drug has increased dramatically in recent years. Several studies raised concerns about the cardiovascular risk of testosterone therapy (1,–3). Epidemiologic studies suggested that both very low and very high testosterone levels are linked to cardiovascular and cerebral risk (4, 5), but the mechanism remains unclear. Elevated blood viscosity is associated with cardiovascular and cerebral risk, especially in the context of therapeutic administration of erythropoiesis-stimulating agents (6,–9). Likewise, testosterone administration consistently increases hematocrits in men (10, 11). Because erythrocyte mass is a major contributor to blood viscosity, testosterone administration might thus increase blood viscosity. However, relevant literature is scant and inconclusive (12,–14). On the other hand, increased erythrocyte deformability has been reported in erythropoietin-transgenic mice, which allows the mice to offset their whole-blood viscosity to a much lower level than that predicted from their exceptionally high hematocrits (15). It is unclear whether men or animals acquire similar adaptations to testosterone-induced erythrocytosis. Here, we report the effects of testosterone on blood viscosity and erythrocyte deformability in mice after short-term and long-term interventions.
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