The syndrome of apparent mineralocorticoid excess: its association with 11 beta-dehydrogenase and 5 beta-reductase deficiency and some consequences for corticosteroid metabolism

J Clin Endocrinol Metab. 1986 Sep;63(3):550-7. doi: 10.1210/jcem-63-3-550.

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.

Publication types

  • Case Reports
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenases
  • Adrenal Cortex Hormones / metabolism*
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Female
  • Fibroblasts / metabolism
  • Humans
  • Hydrocortisone / analogs & derivatives
  • Hydrocortisone / metabolism
  • Hydrocortisone / urine
  • Hydroxysteroid Dehydrogenases / deficiency*
  • Male
  • Metabolism, Inborn Errors / enzymology*
  • Metabolism, Inborn Errors / metabolism
  • Oxidoreductases / deficiency*
  • Steroids / urine

Substances

  • Adrenal Cortex Hormones
  • Steroids
  • Oxidoreductases
  • Hydroxysteroid Dehydrogenases
  • 11-beta-Hydroxysteroid Dehydrogenases
  • 3-oxo-5 beta-steroid delta 4-dehydrogenase
  • Hydrocortisone