Modulation of 11 beta-hydroxysteroid dehydrogenase isozymes by growth hormone and insulin-like growth factor: In vivo and in vitro studies

The interconversion of hormonally active cortisol (F) and inactive cortison e (E) is catalyzed by two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD), an oxo-reductase converting E to F (11 beta HSD1) and a dehy drogenase (11 beta HSD2) converting F to E. 11 beta HSD1 is important in me diating glucocorticoid-regulated glucose homeostasis and regional adipocyte differentiation. Earlier studies conducted with GH-deficient subjects trea ted with replacement GH suggested that GH may modulate 11 beta HSD1 activit y. In 7 acromegalic subjects withdrawing from medical therapy (Sandostatin-LAR ; 20-40 mg/month for at least 12 months), GH rose from 7.1 +/- 1.5 to 17.5 +/- 4.3 mU/L (mean +/- SE), and insulin-like growth factor I (IGF-I) rose f rom 43.0 +/- 8.8 to 82.1 +/- 13.7 nmol/L (both P < 0.05) 4 months after tre atment. There was a significant alteration in the normal set-point off to E interconversion toward E. The fall in the urinary tetrahydrocortisols/tetr ahydocortisone ratio (THF+allo-THF/THE; 0.82 +/- 0.06 to 0.60 +/- 0.06;P < 0.02) but unaltered urinary free F/urinary free E ratio (a marker for 11 be ta HSD2 activity) suggested that this was due to inhibition of 11 beta HSD1 activity. An inverse correlation between GH and the THF+allo-THF/THE ratio was observed (r = -0.422; P < 0.05). Conversely, in 12 acromegalic patient s treated by transsphenoidal surgery (GH falling from 124 +/- 49.2 to 29.3 +/- 15.4 mU/L; P < 0.01), the THF+aIlo-THF/THE ratio rose from 0.53 +/- 0.0 6 to 0.63 +/- 0.07 (P < 0.05). Patients from either group who failed to dem onstrate a change in GH levels showed no change in the THF+allo-THF/THE rat io. In vitro studies conducted on cells stably transfected with either the huma n 11 beta HSD1 or 11 beta HSD2 complementary DNA and primary cultures of hu man omental adipose stromal cells expressing only the 11 beta HSD1 isozyme indicated a dose-dependent inhibition of 11 beta HSD1 oxo-reductase activit y with IGF-I, but not GH. Neither IGF-I nor GH: had any effect on 11 beta H SD2 activity. GH, through an IGF-I-mediated effect, inhibits 11 beta HSD1 activity. This reduction in E to F conversion will increase the MCR of F, and care should be taken to monitor the adequacy of function of the hypothalamo-pituitary-a drenal axis in acromegalic subjects and in GH-deficient, hypopituitary pati ents commencing replacement GH therapy. Conversely, enhanced E to F convers ion occurs with a reduction in GH levels; in Liver and adipose tissue this would result in increased hepatic glucose output and visceral adiposity, su ggesting that part of the phenotype currently attributable to adult GH defi ciency may be an indirect consequence of its effect on tissue F metabolism via 11 beta HSD1 expression.