Modulation of cortisol metabolism by the growth hormone receptor antagonist pegvisomant in patients with acromegaly.

2.50
Hdl Handle:
http://hdl.handle.net/10541/84114
Title:
Modulation of cortisol metabolism by the growth hormone receptor antagonist pegvisomant in patients with acromegaly.
Authors:
Trainer, Peter J; Drake, William M; Perry, Lesley A; Taylor, N F; Besser, G M; Monson, John
Abstract:
Pegvisomant is a GH receptor antagonist and highly efficacious new treatment for acromegaly. The two isoenzymes of 11beta-hydroxysteroid dehydrogenase are responsible for the interconversion of cortisol and its inactive metabolite cortisone. We demonstrated previously that the type I isoform, which is principally responsible for conversion of cortisone to cortisol, is partially inhibited by GH. The net activity of the enzyme can be measured by analysis of the urinary ratio of 11-hydroxy/11-oxo cortisol metabolites or of the urinary ratio of tetrahydrocortisol/tetrahydrocortisone [(tetrahydrocortisol + 5alpha-tetrahydrocortisol)/tetrahydrocortisone]. We studied the influence of pegvisomant on cortisol metabolism in patients with active acromegaly. Seven patients (four women and three men; median age, 58 yr; range, 39-72) were studied at baseline and again after a mean of 46 weeks of treatment. The mean insulin-like growth factor I (IGF-I) level at baseline fell from 939.7 +/- 271.1 to 346.9 +/- 379.0 ng/mL on 20 mg/day pegvisomant. The 11-hydroxy/11-oxo ratio increased from a pretreatment mean value of 0.61 +/- 0.18 to 0.88 +/- 0.20 (P < 0.02) and when the six patients in whom serum IGF-I normalized were considered separately, the change was from 0.62 +/- 0.19 to 0.90 +/- 0.21 (P < 0.04). The tetrahydrocortisols/tetrahydrocortisone ratio increased from a pretreatment mean value of 0.64 +/- 0.21 to 0.98 +/- 0.26 (P < 0.02) and in the six patients in whom serum IGF-I normalized, the ratio rose from 0.66 +/- 0.23 to 1.01 +/- 0.26 (P < 0.04). These data 1) indicate that blockade of GH action with pegvisomant in patients with acromegaly is associated with reversal of the inhibition of 11beta-hydroxysteroid dehydrogenase and correction of cortisol metabolism, and 2) suggest that in active acromegaly, cortisol clearance is accelerated and that this is reversed by successful treatment. This is further evidence of the efficacy of pegvisomant in the management of acromegaly and has important implications for determining optimum glucocorticoid replacement.
Affiliation:
Department of Endocrinology, Christie Hospital, Manchester, United Kingdom M20 4BX. peter.trainer@man.ac.uk
Citation:
Modulation of cortisol metabolism by the growth hormone receptor antagonist pegvisomant in patients with acromegaly. 2001, 86 (7):2989-92 J. Clin. Endocrinol. Metab.
Journal:
The Journal of Clinical Endocrinology and Metabolism
Issue Date:
Jul-2001
URI:
http://hdl.handle.net/10541/84114
PubMed ID:
11443156
Type:
Article
Language:
en
ISSN:
0021-972X
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorTrainer, Peter Jen
dc.contributor.authorDrake, William Men
dc.contributor.authorPerry, Lesley Aen
dc.contributor.authorTaylor, N Fen
dc.contributor.authorBesser, G Men
dc.contributor.authorMonson, Johnen
dc.date.accessioned2009-10-13T08:19:47Z-
dc.date.available2009-10-13T08:19:47Z-
dc.date.issued2001-07-
dc.identifier.citationModulation of cortisol metabolism by the growth hormone receptor antagonist pegvisomant in patients with acromegaly. 2001, 86 (7):2989-92 J. Clin. Endocrinol. Metab.en
dc.identifier.issn0021-972X-
dc.identifier.pmid11443156-
dc.identifier.urihttp://hdl.handle.net/10541/84114-
dc.description.abstractPegvisomant is a GH receptor antagonist and highly efficacious new treatment for acromegaly. The two isoenzymes of 11beta-hydroxysteroid dehydrogenase are responsible for the interconversion of cortisol and its inactive metabolite cortisone. We demonstrated previously that the type I isoform, which is principally responsible for conversion of cortisone to cortisol, is partially inhibited by GH. The net activity of the enzyme can be measured by analysis of the urinary ratio of 11-hydroxy/11-oxo cortisol metabolites or of the urinary ratio of tetrahydrocortisol/tetrahydrocortisone [(tetrahydrocortisol + 5alpha-tetrahydrocortisol)/tetrahydrocortisone]. We studied the influence of pegvisomant on cortisol metabolism in patients with active acromegaly. Seven patients (four women and three men; median age, 58 yr; range, 39-72) were studied at baseline and again after a mean of 46 weeks of treatment. The mean insulin-like growth factor I (IGF-I) level at baseline fell from 939.7 +/- 271.1 to 346.9 +/- 379.0 ng/mL on 20 mg/day pegvisomant. The 11-hydroxy/11-oxo ratio increased from a pretreatment mean value of 0.61 +/- 0.18 to 0.88 +/- 0.20 (P < 0.02) and when the six patients in whom serum IGF-I normalized were considered separately, the change was from 0.62 +/- 0.19 to 0.90 +/- 0.21 (P < 0.04). The tetrahydrocortisols/tetrahydrocortisone ratio increased from a pretreatment mean value of 0.64 +/- 0.21 to 0.98 +/- 0.26 (P < 0.02) and in the six patients in whom serum IGF-I normalized, the ratio rose from 0.66 +/- 0.23 to 1.01 +/- 0.26 (P < 0.04). These data 1) indicate that blockade of GH action with pegvisomant in patients with acromegaly is associated with reversal of the inhibition of 11beta-hydroxysteroid dehydrogenase and correction of cortisol metabolism, and 2) suggest that in active acromegaly, cortisol clearance is accelerated and that this is reversed by successful treatment. This is further evidence of the efficacy of pegvisomant in the management of acromegaly and has important implications for determining optimum glucocorticoid replacement.en
dc.language.isoenen
dc.subject.mesh11-beta-Hydroxysteroid Dehydrogenases-
dc.subject.meshAcromegaly-
dc.subject.meshAdult-
dc.subject.meshAged-
dc.subject.meshDouble-Blind Method-
dc.subject.meshFemale-
dc.subject.meshHuman Growth Hormone-
dc.subject.meshHumans-
dc.subject.meshHydrocortisone-
dc.subject.meshHydroxysteroid Dehydrogenases-
dc.subject.meshInsulin-Like Growth Factor I-
dc.subject.meshMale-
dc.subject.meshMiddle Aged-
dc.subject.meshReceptors, Somatotropin-
dc.subject.meshTetrahydrocortisol-
dc.subject.meshTetrahydrocortisone-
dc.titleModulation of cortisol metabolism by the growth hormone receptor antagonist pegvisomant in patients with acromegaly.en
dc.typeArticleen
dc.contributor.departmentDepartment of Endocrinology, Christie Hospital, Manchester, United Kingdom M20 4BX. peter.trainer@man.ac.uken
dc.identifier.journalThe Journal of Clinical Endocrinology and Metabolismen

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