Lack of regulation of 11β-hydroxysteroid dehydrogenase type 1 during short-term manipulation of GH in patients with hypopituitarism
2009
Objective: Evidence from long-term clinical studies measuring urinary steroid ratios, and from in vitro studies, suggests that GH administered for longer than 2 months down-regulates 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1), thereby reducing cortisol regeneration in liver and adipose tissue. We aimed to measure acute effects of GH on 11b-HSD1 in liver and adipose tissue in vivo, including using a stable isotope tracer. Design: Observational studies of GH withdrawal and reintroduction in patients with hypopituitarism. Methods: Twelve men with benign pituitary disease causing GH and ACTH deficiency on stable replacement therapy for O6 months were studied after GH withdrawal for 3 weeks, and after either placebo or GH injections were reintroduced for another 3 weeks. We measured cortisol kinetics during 9,11,12,12- 2 H4-cortisol (d4-cortisol) infusion, urinary cortisol/cortisone metabolite ratios, liver 11b-HSD1 by appearance of plasma cortisol after oral cortisone, and 11b-HSD1 mRNA levels in subcutaneous adipose biopsies. Results: GH withdrawal and reintroduction had no effect on 9,12,12-[ 2 H]3-cortisol (d3-cortisol) appearance, urinary cortisol/cortisone metabolite ratios, initial appearance of cortisol after oral cortisone, or adipose 11b-HSD1 mRNA. GH withdrawal increased plasma cortisol 30‐180 min after oral cortisone, increased d4-cortisol clearance, and decreased relative excretion of 5a-reduced cortisol metabolites. Conclusions: In this setting, GH did not regulate 11b-HSD1 rapidly in vivo in humans. Altered cortisol metabolism with longer term changes in GH may reflect indirect effects on 11b-HSD1. These data do not suggest that glucocorticoid replacement doses need to be increased immediately after introducing GH therapy to compensate for reduced 11b-HSD1 activity, although dose adjustment may be required in the longer term.
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