Modulatory Effect of Raloxifene and Estrogen on the Metabolic Action of Growth Hormone in Hypopituitary Women

Context: The metabolic action of GH is attenuated by estrogens administered via the oral route. Selective estrogen receptor modulators lower IGF-I to a lesser degree than 17 beta-estradiol in GH-deficient women, and their effect on fat and protein metabolism is unknown. Objective: The aim of the study was to compare the modulatory effects of 17 beta-estradiol and raloxifene, a selective estrogen receptor modulator, on the metabolic action of GH. Design: We conducted an open-label, two-group, randomized, two-period crossover study. Patients and Intervention: Ten hypopituitary women received GH therapy alone (0.5 mg/d) and GH plus 17 beta-estradiol (E(2); 2mg/d). Eleven hypopituitary women received GH therapy alone and GH plus raloxifene (R; 60 mg/d). The treatment duration was 1 month, with a 4-wk washout period. Main Outcome Measures: IGF-I, IGFBP-3, resting energy expenditure, and fat oxidation were quantified by indirect calorimetry. We measured whole body leucine turnover from which leucine rate of appearance and leucine incorporation into protein were estimated. Results: GH significantly stimulated all outcome measures. During GH treatment, addition of R significantly reduced mean IGF-I but not IGFBP-3, whereas E(2) reduced both IGF-I and IGFBP-3 levels. Cotreatment with R but not E(2) significantly attenuated the stimulatory effects of GH on fat oxidation. There was a strong trend (P = 0.08) toward a greater reduction in leucine incorporation into protein after R compared to E(2) cotreatment. Conclusions: The modulatory effects of E(2) and R at therapeutic doses on GH action are different. R during GH therapy exerts a greater inhibitory effect on lipid oxidation and protein anabolism compared to E(2). (J Clin Endocrinol Metab 95: 2099-2106, 2010)