Modulation of Cortisol Metabolism during Treatment of Acromegaly Is Independent of Body Composition and Insulin Sensitivity

Abstract

Objectives: The set point of cortisol-cortisone conversion is shifted in the direction of cortisone by the inhibition of the activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) during adult GH replacement and in active acromegaly. Additionally, both fat mass and insulin may modulate 11β-HSD1 and are both influenced by changes in GH status. This study examined the relative direct contribution of GH/IGF1 in modulating cortisol metabolism. Methods: Overall cortisol/cortisone conversion (ratio of urine 11-hydroxy-/11-oxo-cortisol metabolites; Fm/Em), insulin sensitivity (homeostatic model assessment; HOMA %S) and fat mass (DXA) were examined in parallel in 6 patients (mean age 53 years, range 42–76; 4 males, 2 females) with previously untreated active acromegaly during 6 months of therapy with Sandostatin^® LAR^® (20–30 mg i.m. 4 weekly). All but 1 patient had normal ACTH reserve. Results: At baseline, Pearson correlation demonstrated an inverse relationship between serum GH (mean of a 5-point day curve) and Fm/Em (r = –0.83, p = 0.04) and a trend towards an inverse relationship between HOMA %S and Fm/Em (r = –0.79, p = 0.06) but no other patterns were evident. During the course of treatment, serum GH decreased from 9.9 ± 6.4 (mean ± SD) to 3.5 ± 3.1 ng/ml (p < 0.01) and serum IGF-1 from 785 ± 268 to 431 ± 156 ng/ml (p < 0.005). Fm/Em increased from 0.52 ± 0.1 to 0.75 ± 0.08 (p < 0.03) consistent with increased 11β-HSD1 activity. There were no significant changes in truncal fat percentage (33.0 ± 9.0 vs. 33.0 ± 8.2) or insulin sensitivity (HOMA %S: 37.1 ± 8.6 vs. 52.8 ± 33.7). Conclusions: Modulation of cortisol metabolism during treatment of active acromegaly is dependent on changes in GH/IGF-1 status and is not influenced by any individual change in body composition or insulin sensitivity.