Aromatase Inhibitor and Growth in the Pubertal Male with GHD

Mauras and colleagues conducted a 12-month pilot study of 20 adolescent males with clinical and biochemical evidence of growth hormone deficiency (GHD) who were treated with GH (mean dose ~0.3/mg/kg/wk) for at least 6 months (range: 6 months–9 years) prior to the study. The investigation sought to determine whether treatment over a period of 12 months with the aromatase inhibitor anastrozole can achieve sustained suppression of estrogen production and delay epiphyseal fusion in adolescent males with GHD. Physical examination, genital Tanner staging, bone age, DEXA scan, and an early morning blood sample were obtained at baseline and throughout the duration of the study. Ten boys were maintained on GH only and 10 were started on anastrozole (1 mg orally daily) in addition to GH.

Results showed a 60% drop in estradiol concentrations in the anastrozole group and a 50% increase in concentrations in the control group (GH only; Figure 1).

Figure 1. Percentage change in plasma estradiol concentrations.

Figure 2. Absolute change from baseline in serum testosterone concentration. * refers to the difference within each group at 12 mo vs baseline; ** refers to the difference between groups: * p =0.001; ** p =0.03.

The reciprocal increase in testosterone and free testosterone concentrations in the anastrozole group was substantially greater than the rise in testosterone during spontaneous puberty in the control group (Figure 2). IGF-I and IGFBP-3 did not change significantly in the anastrozole group, whereas IGF-I rose significantly at 12 months in the control group. There were no significant differences between the anastrozole and control groups with regard to lipid concentrations, body composition, or bone density, nor any differences in growth velocity rates, height SD scores, bone age advancement, or predicted adult height.

The authors concluded that compared to GH-deficient boys treated with only GH, 12-month treatment with an aromatase inhibitor in combination with GH results in a significant and sustained suppression of circulating estrogen concentrations and reciprocal increases in testosterone concentrations. Anastrozole treatment was not associated with detectable detrimental effects on body composition, tempo of puberty or bone mineralization, and was well tolerated and safe over the period studied. The lack of effect of anastrozole on growth velocity, bone age advancement, or predicted adult height was interpreted by the investigators to be due to the limited duration of use (ie, 12 months).

Editor’s Comment: It is reasonable to predict that there will be more studies examining the growth-promoting benefits of aromatase inhibitors. They offer the promise of prolonged growth without the metabolic and psychological drawbacks of arresting pubertal development. This controlled pilot study opens the way to a larger and longer duration study of the synergistic benefits of GH and anastrozole on adult height. Because of the role that sex hormones play in brain development and function, 1 it would be prudent to include neuropsychological endpoints in any study that alters the typical ratios observed between testosterone and estradiol in adolescent males.

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Table of Contents 21-4 Aromatase Inhibitor and Growth in the Pubertal Male with GHD
Volume 21, Issue 4, December 2005 © 2005 Prime Health Consultants, Inc.

Mauras and colleagues conducted a 12-month pilot study of 20 adolescent males with clinical and biochemical evidence of growth hormone deficiency (GHD) who were treated with GH (mean dose ~0.3/mg/kg/wk) for at least 6 months (range: 6 months–9 years) prior to the study. The investigation sought to determine whether treatment over a period of 12 months with the aromatase inhibitor anastrozole can achieve sustained suppression of estrogen production and delay epiphyseal fusion in adolescent males with GHD. Physical examination, genital Tanner staging, bone age, DEXA scan, and an early morning blood sample were obtained at baseline and throughout the duration of the study. Ten boys were maintained on GH only and 10 were started on anastrozole (1 mg orally daily) in addition to GH. Results showed a 60% drop in estradiol concentrations in the anastrozole group and a 50% increase in concentrations in the control group (GH only; Figure 1). Figure 1. Percentage change in plasma estradiol concentrations. Figure 2. Absolute change from baseline in serum testosterone concentration. * refers to the difference within each group at 12 mo vs baseline; ** refers to the difference between groups: * p =0.001; ** p =0.03. Adapted from Mauras N, et al. J Pediatr Endocrinol Metab. 2004;17:1597-1606. Copyright © 2004. JPEM. The reciprocal increase in testosterone and free testosterone concentrations in the anastrozole group was substantially greater than the rise in testosterone during spontaneous puberty in the control group (Figure 2). IGF-I and IGFBP-3 did not change significantly in the anastrozole group, whereas IGF-I rose significantly at 12 months in the control group. There were no significant differences between the anastrozole and control groups with regard to lipid concentrations, body composition, or bone density, nor any differences in growth velocity rates, height SD scores, bone age advancement, or predicted adult height. The authors concluded that compared to GH-deficient boys treated with only GH, 12-month treatment with an aromatase inhibitor in combination with GH results in a significant and sustained suppression of circulating estrogen concentrations and reciprocal increases in testosterone concentrations. Anastrozole treatment was not associated with detectable detrimental effects on body composition, tempo of puberty or bone mineralization, and was well tolerated and safe over the period studied. The lack of effect of anastrozole on growth velocity, bone age advancement, or predicted adult height was interpreted by the investigators to be due to the limited duration of use (ie, 12 months). Mauras N, Welch S, Rini A, Klein KO. An open label 12-month pilot trial on the effects of the aromatase inhibitor anastrozole in growth hormone (GH)-treated GH deficient adolescent boys. J Pediatr Endocrinol Metab. 2004;17:1597–1606. Editor’s Comment: It is reasonable to predict that there will be more studies examining the growth-promoting benefits of aromatase inhibitors. They offer the promise of prolonged growth without the metabolic and psychological drawbacks of arresting pubertal development. This controlled pilot study opens the way to a larger and longer duration study of the synergistic benefits of GH and anastrozole on adult height. Because of the role that sex hormones play in brain development and function, 1 it would be prudent to include neuropsychological endpoints in any study that alters the typical ratios observed between testosterone and estradiol in adolescent males. David E. Sandberg, PhD Reference - (linked to ) McEwen BS. J Clin Endocrinol Metab. 1999;84:1790–1797.