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

We describe the metabolism of cortisol (F) in three children, two of them siblings, with apparent mineralocorticoidexcess (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: 1) 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, ∼1); 2) normal subjects oxidized [11α -³H]F with transfer of 3H to water; the patients did not; 3) 11-hydroxy, but not 11-oxo, C₁₉ steroids were excreted into the urine; and 4) 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: 1) impaired conversion of tetrahydro to hexahydro neutralsteroids, indicating defective reductive metabolism of theside chain; 2) depressed F production rate and increased halflife of circulating F, resulting in normal blood levels of F; 3) increased excretion of unconjugated F metabolites; and 4) decreased excretion of THF relative to alloTHF, consistent with a 5β-reductase defect. Excretion of acidic metabolites of F (cortoicacids) was within the normal range. However, little or no 20β - hydroxy acids were excreted, while the level of urinary 20α ahydroxy 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.