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

doi:10.1530/EJE-09-0315

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 journal › Article › peer-review

Abstract / Description of output

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 language	English
Pages (from-to)	375-80
Number of pages	6
Journal	European Journal of Endocrinology
Volume	161
Issue number	3
DOIs	https://doi.org/10.1530/EJE-09-0315
Publication status	Published - Sept 2009

Keywords / Materials (for Non-textual outputs)

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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10.1530/EJE-09-0315

Lack of regulation of 11beta-hydroxysteroid dehydrogenase type 1 during short-term manipulation of GH in patients with hypopituitarism
Copyright 2009 European Society of Endocrinology This is an Open Access article distributed under the terms of the European Journal of Endocrinology's Re-use Licence.
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@article{512025067d774f8d8d66b9fb338ed1b3,

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

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.",

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",

author = "Sigurjonsdottir, {Helga A} and Ruth Andrew and Stimson, {Roland H} and Gudmundur Johannsson and Walker, {Brian R}",

year = "2009",

month = sep,

doi = "10.1530/EJE-09-0315",

language = "English",

volume = "161",

pages = "375--80",

journal = "European Journal of Endocrinology",

issn = "0804-4643",

publisher = "BioScientifica Ltd.",

number = "3",

}

TY - JOUR

T1 - Lack of regulation of 11 beta-hydroxysteroid dehydrogenase type 1 during short-term manipulation of GH in patients with hypopituitarism

AU - Sigurjonsdottir, Helga A

AU - Andrew, Ruth

AU - Stimson, Roland H

AU - Johannsson, Gudmundur

AU - Walker, Brian R

PY - 2009/9

Y1 - 2009/9

N2 - 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.

AB - 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.

KW - 11-beta-Hydroxysteroid Dehydrogenase Type 1

KW - Adipose Tissue, White

KW - Adult

KW - Aged

KW - Drug Dosage Calculations

KW - Gene Expression Regulation, Enzymologic

KW - Glucocorticoids

KW - Hormone Replacement Therapy

KW - Human Growth Hormone

KW - Humans

KW - Hydrocortisone

KW - Hypopituitarism

KW - Male

KW - middle aged

KW - Placebos

KW - Time Factors

KW - Withholding Treatment

KW - Young Adult

U2 - 10.1530/EJE-09-0315

DO - 10.1530/EJE-09-0315

M3 - Article

C2 - 19549748

SN - 0804-4643

VL - 161

SP - 375

EP - 380

JO - European Journal of Endocrinology

JF - European Journal of Endocrinology

IS - 3

ER -

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

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