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Testosterone suppresses hepcidin in men: a potential mechanism for testosterone-induced erythrocytosis.

ABSTRACT: The mechanisms by which testosterone increases hemoglobin and hematocrit are unknown.The aim was to test the hypothesis that testosterone-induced increase in hematocrit is associated with suppression of the iron regulatory peptide hepcidin.Healthy younger men (ages 19-35 yr; n = 53) and older men (ages 59-75 yr; n = 56) were studied.Weekly doses of testosterone enanthate (25, 50, 125, 300, and 600 mg) were administered over 20 wk, whereas endogenous testosterone was suppressed by monthly GnRH agonist administration. Blood and serum parameters from each individual were measured at wk 0, 1, 2, 4, 8, and 20. Longitudinal analyses were performed to examine the relationship between hepcidin, hemoglobin, hematocrit, and testosterone while controlling for potential confounders.High levels of testosterone markedly suppressed serum hepcidin within 1 wk. Hepcidin suppression in response to testosterone administration was dose-dependent in older men and more pronounced than in young men, and this corresponded to a greater rise in hemoglobin in older men. Serum hepcidin levels at 4 and 8 wk were predictive of change in hematocrit from baseline to peak levels.Testosterone administration is associated with suppression of serum hepcidin. Greater increases in hematocrit in older men during testosterone therapy are related to greater suppression of hepcidin.

SUBMITTER: Bachman E

PROVIDER: S-EPMC3050108 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Testosterone suppresses hepcidin in men: a potential mechanism for testosterone-induced erythrocytosis.

Bachman Eric E Feng Rui R Travison Thomas T Li Michelle M Olbina Gordana G Ostland Vaughn V Ulloor Jagadish J Zhang Anqi A Basaria Shehzad S Ganz Tomas T Westerman Mark M Bhasin Shalender S

The Journal of clinical endocrinology and metabolism 20100721 10

<h4>Context</h4>The mechanisms by which testosterone increases hemoglobin and hematocrit are unknown.<h4>Objective</h4>The aim was to test the hypothesis that testosterone-induced increase in hematocrit is associated with suppression of the iron regulatory peptide hepcidin.<h4>Participants</h4>Healthy younger men (ages 19-35 yr; n = 53) and older men (ages 59-75 yr; n = 56) were studied.<h4>Methods</h4>Weekly doses of testosterone enanthate (25, 50, 125, 300, and 600 mg) were administered over 2 ...[more]

PMID: 20660052

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Project description:Erythrocytosis is the most common dose limiting adverse effect of testosterone therapy but the mechanisms of testosterone mediated erythropoiesis remain unclear. In this study we examine risk factors for erythrocytosis associated with testosterone therapy.A retrospective review was performed of 179 hypogonadal men on testosterone therapy at a single andrology clinic. Demographic data, testosterone therapy formulation and duration of treatment, and 5?-reductase inhibitor use were assessed. Serum dihydrotestosterone, total testosterone, free testosterone, follicle-stimulating hormone, luteinizing hormone, hematocrit and lipid levels were extracted, and changes during treatment were determined. Spearman's rank correlation was used to identify relationships between change in hematocrit and study variables.Of 179 patients 49 (27%) experienced a 10% or greater change in hematocrit and erythrocytosis (hematocrit 50% or greater) developed in 36 (20.1%) at a median followup of 7 months. Topical gels were used by 41.3% of patients, injectable testosterone by 52.5% and subcutaneous pellets by 6.1%. More men who experienced a change in hematocrit of 10% or greater used injectable testosterone than men with a change in hematocrit of less than 10% (65% vs 48%, p=0.035), and were less likely to be on a 5?-reductase inhibitor (2% vs 15%, p=0.017). Men with a change in hematocrit of 10% or greater had higher posttreatment dihydrotestosterone levels (605.0 vs 436.0 ng/dl, p=0.017) and lower luteinizing hormone and follicle-stimulating hormone levels than men with a change in hematocrit of less than 10%. Spearman's rank correlations yielded relationships between change in hematocrit and posttreatment dihydrotestosterone ?=0.258, p=0.001) and total testosterone (?=0.171, p=0.023).Dihydrotestosterone may have a role in testosterone therapy related erythrocytosis and monitoring dihydrotestosterone levels during testosterone therapy should be considered. In men in whom erythrocytosis develops, 5?-reductase inhibitors may be therapeutic.

Project description:Background The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results. Purpose To describe a coordinated set of clinical trials designed to avoid the pitfalls of prior studies and to determine definitively whether testosterone treatment of elderly men with low testosterone is efficacious in improving symptoms and objective measures of age-associated conditions. Methods We present the scientific and clinical rationale for the decisions made in the design of this set of trials. Results We designed The Testosterone Trials as a coordinated set of seven trials to determine if testosterone treatment of elderly men with low serum testosterone concentrations and symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Function Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive function (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial). The scientific advantages of this coordination were common eligibility criteria, common approaches to treatment and monitoring, and the ability to pool safety data. The logistical advantages were a single steering committee, data coordinating center and data and safety monitoring board, the same clinical trial sites, and the possibility of men participating in multiple trials. The major consideration in participant selection was setting the eligibility criterion for serum testosterone low enough to ensure that the men were unequivocally testosterone deficient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. The major considerations in choosing primary outcomes for each trial were identifying those of the highest clinical importance and identifying the minimum clinically important differences between treatment arms for sample size estimation. Potential limitations Setting the serum testosterone concentration sufficiently low to ensure that most men would be unequivocally testosterone deficient, as well as many other entry criteria, resulted in screening approximately 30 men in person to randomize one participant. Conclusion Designing The Testosterone Trials as a coordinated set of seven trials afforded many important scientific and logistical advantages but required an intensive recruitment and screening effort.

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Testosterone suppresses hepcidin in men: a potential mechanism for testosterone-induced erythrocytosis.

Publications

Testosterone suppresses hepcidin in men: a potential mechanism for testosterone-induced erythrocytosis.

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