Context and Objective: Women use less carbohydrate during endurance exercise, as compared with men. In rodents, 17␤-estradiol (E2) supplementation robustly increases lipid use and lowers muscle and liver glycogen use during exercise. E2 supplementation has been found to influence substrate selection by decreasing glucose rate of appearance (Ra), disappearance (Rd), and metabolic clearance rate during exercise in humans; however, neither a change in total carbohydrate use nor a sparing of muscle

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... glycogen was demonstrated. Subjects and Methods: We investigated the effect of 8 d of E2 (2 mg/d) supplementation on glucose turnover and net muscle glycogen use in 11 men using a randomized, double-blind, placebo-controlled, crossover design. Subjects underwent primed constant infusion of [6,6-2 H]glucose, and muscle biopsies were taken before and after 90 min of cycling at 65% maximal oxygen uptake. Results: E2 supplementation decreased the respiratory exchange ratio (P ϭ 0.03) and glucose Ra and Rd (both P ϭ 0.04) during exercise, as compared with placebo. E2 supplementation lowered proglycogen (P Ͻ 0.05) and total glycogen (P ϭ 0.04) concentration, as compared with placebo; however, there was no effect of E2 on net muscle glycogen use during exercise. Conclusions: These findings show that E2 supplementation alters fuel selection in exercising men by increasing lipid use and reducing carbohydrate use, glucose Ra (primarily liver glucose production), and Rd (primarily muscle glucose uptake). Furthermore, E2 reduces the basal level of total muscle glycogen, particularly the proglycogen form. (J Clin Endocrinol Metab 90: 6218 -6225, 2005)