Lack of regulation of 11 beta-hydroxysteroid dehydrogenase type 1 during short-term manipulation of GH in patients with hypopituitarism

Helga A Sigurjonsdottir, Ruth Andrew, Roland H Stimson, Gudmundur Johannsson, Brian R Walker

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)375-80
Number of pages6
JournalEuropean Journal of Endocrinology
Volume161
Issue number3
DOIs
Publication statusPublished - Sep 2009

Keywords

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • Adipose Tissue, White
  • Adult
  • Aged
  • Drug Dosage Calculations
  • Gene Expression Regulation, Enzymologic
  • Glucocorticoids
  • Hormone Replacement Therapy
  • Human Growth Hormone
  • Humans
  • Hydrocortisone
  • Hypopituitarism
  • Male
  • middle aged
  • Placebos
  • Time Factors
  • Withholding Treatment
  • Young Adult

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