Genotypes at 11beta-hydroxysteroid dehydrogenase type 11B1 and hexose-6-phosphate dehydrogenase loci are not risk factors for apparent cortisone reductase deficiency in a large population-based sample

J Clin Endocrinol Metab. 2005 Oct;90(10):5880-3. doi: 10.1210/jc.2005-0942. Epub 2005 Aug 9.


Context: Apparent cortisone reductase deficiency (ACRD) is a rarely ascertained condition characterized by signs of androgen excess in women or children and decreased urinary excretion of cortisol metabolites compared with cortisone metabolites. These findings suggest a deficiency of 11beta-hydroxysteroid dehydrogenase type 1 (11-HSD1; encoded by the HSD11B1 gene), which normally converts cortisone to cortisol. Common polymorphisms in both HSD11B1 and the hexose-6-phosphate dehydrogenase (H6PD) gene encoding hexose-6-phosphate dehydrogenase have been found together in ACRD patients, who carry three of a possible four minor alleles at the two loci.

Objective: The objective of this study was to confirm the postulated digenic inheritance mechanism for ACRD.

Design: This was a population-based association study (Dallas Heart Study). Subjects were genotyped for the 1971T>G polymorphism in intron 3 of HSD11B1 and the R453Q polymorphism in H6PD.

Subjects: The study comprised 3551 individuals in a population-based sample (50% black, 35% white, and 15% Hispanic).

Main outcome measure: The main outcome measure was association between genotypes and risk for polycystic ovarian syndrome.

Results: Both polymorphisms occurred more frequently than previously reported. Thus, ACRD genotypes (at least three of four minor alleles) occurred in 7.0% of subjects. There were no associations between genotype and body mass index; waist/hip ratio; visceral adiposity; measures of insulin sensitivity; levels of testosterone, FSH, or LH (in females); or risk of polycystic ovarian syndrome. There was no genotype effect on urinary free cortisol/cortisone or corticosteroid metabolite ratios, which were measured in 10 subjects, each carrying zero, three, or four minor alleles.

Conclusions: Previously reported associations of ACRD with HSD11B1 and H6PD alleles represent ascertainment bias. However, rare severe mutations in these genes cannot be ruled out.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenases / genetics*
  • Adolescent
  • Adult
  • Aged
  • Alleles
  • Carbohydrate Dehydrogenases / genetics*
  • Cortisone Reductase / deficiency*
  • Female
  • Gene Frequency
  • Genetic Testing
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Polycystic Ovary Syndrome / genetics
  • Polycystic Ovary Syndrome / urine
  • Population
  • Risk Factors
  • Steroids / urine
  • Texas / epidemiology


  • Steroids
  • Carbohydrate Dehydrogenases
  • galactose-6-phosphate dehydrogenase
  • 11-beta-Hydroxysteroid Dehydrogenases
  • Cortisone Reductase