Oral low-dose testosterone administration induces whole-body protein anabolism in postmenopausal women: a novel liver-targeted therapy

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In hypopituitary men, oral delivery of unesterified testosterone in doses that result in a solely hepatic androgen effect enhances protein anabolism during GH treatment. In this study, we aimed to determine whether liver-targeted androgen supplementation induces protein anabolism in GH-replete normal women. Eight healthy postmenopausal women received 2-week treatment with oral testosterone at a dose of 40 mg/day (crystalline testosterone USP). This dose increases portal concentrations of testosterone, exerting androgenic effects on the liver without a spillover into the systemic circulation. The outcome measures were whole-body leucine turnover, from which leucine rate of appearance (LRa, an index of protein breakdown) and leucine oxidation (Lox, a measure of irreversible protein loss) were estimated, energy expenditure and substrate utilization. We measured the concentration of liver transaminases as well as of testosterone, SHBG and IGF1. Testosterone treatment significantly reduced LRa by 7.1 ± 2.5% and Lox by 14.6 ± 4.5% (P<0.05). The concentration of liver transaminases did not change significantly, while that of serum SHBG fell within the normal range by 16.8 ± 4.0% and that of IGF1 increased by 18.4 ± 7.7% (P<0.05). The concentration of peripheral testosterone increased from 0.4 ± 0.1 to 1.1 ± 0.2 nmol/l (P<0.05), without exceeding the upper normal limit. There was no change in energy expenditure and fat and carbohydrate utilization. Hepatic exposure to unesterified testosterone by oral delivery stimulates protein anabolism by reducing protein breakdown and oxidation without inducing systemic androgen excess in women. We conclude that a small oral dose of unesterified testosterone holds promise as a simple novel treatment of protein catabolism and muscle wasting.