title: The syndrome of apparent mineralocorticoid excess: its association with 11 beta-dehydrogenase and 5 beta-reductase deficiency and some consequences for corticosteroid metabolism.
abstract: We describe the metabolism of cortisol (F) in three children, two of them siblings, with apparent mineralocorticoid excess (AME). As with prior patients with AME, oxidation of F to cortisone (E) was impaired, but reduction of E to F was not. We propose that this metabolic defect is caused by deficient 11-dehydrogenase associated with unimpaired 11-reductase. The following supporting observations were made: urinary C21 11-hydroxy metabolites exceeded C21 11-oxo metabolites: ratio of urinary cortols to cortolones, 6.6 +/- 2.8 (+/- SD; normal, 0.47); tetrahydrocortisol (THF) and alloTHF to tetrahydrocortisone, 14.6 +/- 5.6 (normal, approximately 1); normal subjects oxidized [11 alpha-3H]F with transfer of 3H to water; the patients did not; 11-hydroxy, but not 11-oxo, C19 steroids were excreted into the urine; and fibroblasts from patients had 5 times more 11-reductase activity than normal subjects, though fibroblasts from neither group had 11-dehydrogenase activity. Other defects of cortisol metabolism not directly associated with 11-dehydrogenase deficiency were found: impaired conversion of tetrahydro to hexahydro neutral steroids, indicating defective reductive metabolism of the side chain; depressed F production rate and increased half-life of circulating F, resulting in normal blood levels of F; increased excretion of unconjugated F metabolites; and decreased excretion of THF relative to alloTHF, consistent with a 5 beta-reductase defect. Excretion of acidic metabolites of F (cortoic acids) was within the normal range. However, little or no 20 beta-hydroxy acids were excreted, while the level of urinary 20 alpha-hydroxy acids was increased. The 11-hydroxy to 11-oxo ratio of acid metabolites was similar to values in normal subjects. The proportion of cortoic acids relative to neutral hexahydro metabolites was increased (0.37 to 1.27 in patients; 22 in normal subjects). We conclude that children with AME have multiple defects in the conversion of F to neutral metabolites, while metabolism to cortoic acids was less extensively affected. How the defects in cortisol metabolism and the symptoms of AME are related remains to be determined.
authors.forename: C
authors.initials: C
authors.lastname: Monder
authors.forename: C H
authors.initials: CH
authors.lastname: Shackleton
authors.forename: H L
authors.initials: HL
authors.lastname: Bradlow
authors.forename: M I
authors.initials: MI
authors.lastname: New
authors.forename: E
authors.initials: E
authors.lastname: Stoner
authors.forename: F
authors.initials: F
authors.lastname: Iohan
authors.forename: V
authors.initials: V
authors.lastname: Lakshmi
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases; D000305:Adrenal Cortex Hormones / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000378:metabolism / Q000652:urine; D006913:Hydroxysteroid Dehydrogenases / Q000172:deficiency*; D008297:Male; D008661:Metabolism, Inborn Errors / Q000201:enzymology* / Q000378:metabolism; D010088:Oxidoreductases / Q000172:deficiency*; D013256:Steroids / Q000652:urine
chemical_list: D000305:Adrenal Cortex Hormones; D013256:Steroids; D010088:Oxidoreductases; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; C021936:3-oxo-5 beta-steroid delta 4-dehydrogenase; D006854:Hydrocortisone