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 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1), thereby reducing cortisol regeneration in liver and adipose tissue. We aimed to measure acute effects of GH on 11 beta-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 > 6 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-H-2(4)-cortisol (d4-cortisol) infusion, urinary cortisol/cortisone metabolite ratios, liver 11 beta-HSD1 by appearance of plasma cortisol after oral cortisone, and 11 beta-HSD1 mRNA levels in subcutaneous adipose biopsies.
Results: GH withdrawal and reintroduction had no effect on 9.12,12-[H-2](3)-cortisol (d3-cortisol) appearance, urinary cortisol/cortisone metabolite ratios, initial appearance of cortisol after oral cortisone, or adipose 11 beta-HSD1 mRNA. GH withdrawal increased plasma cortisol 30-180 min after oral cortisone, increased d4-cortisol clearance. and decreased relative excretion of 5 alpha-reduced cortisol metabolites.
Conclusions: In this setting GH did not regulate 11 beta-HSD1 rapidly in vivo in humans. Altered cortisol metabolism with longer term changes in GH may reflect indirect effects on 11 beta-HSD1. These data do not suggest that glucocorticoid replacement doses need to be increased immediately after introducing GH therapy to compensate for reduced 11 beta-HSD1 activity, although dose adjustment may be required in the longer term.
- 11-beta-Hydroxysteroid Dehydrogenase Type 1
- Adipose Tissue, White
- Drug Dosage Calculations
- Gene Expression Regulation, Enzymologic
- Hormone Replacement Therapy
- Human Growth Hormone
- middle aged
- Time Factors
- Withholding Treatment
- Young Adult