Modulation of cortisol metabolism by the growth hormone receptor antagonist pegvisomant in patients with acromegaly.
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.
Trainer
P J
PJ
Department of Endocrinology, Christie Hospital, Manchester, United Kingdom M20 4BX. peter.trainer@man.ac.uk
Drake
W M
WM
Perry
L A
LA
Taylor
N F
NF
Besser
G M
GM
Monson
J P
JP
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000172:Acromegaly / Q000188:drug therapy* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D004311:Double-Blind Method; D005260:Female; D019382:Human Growth Hormone / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism* / Q000652:urine; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008297:Male; D008875:Middle Aged; D011986:Receptors, Somatotropin / Q000037:antagonists & inhibitors*; D013760:Tetrahydrocortisol / Q000652:urine; D013761:Tetrahydrocortisone / Q000652:urine
D011986:Receptors, Somatotropin; D019382:Human Growth Hormone; D013761:Tetrahydrocortisone; D007334:Insulin-Like Growth Factor I; D013760:Tetrahydrocortisol; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; C406545:pegvisomant; D006854:Hydrocortisone