Context: The R453Q variant in the hexose-6-phosphate dehydrogenase gene (H6PD) and 83557insA mutations in 11beta-hydroxysteroid dehydrogenase (11betaHSD) type 1 gene (HSD11B1) interact, resulting in cortisone reductase deficiency (CRD), a rare disorder characterized by a polycystic ovary syndrome (PCOS)-like phenotype.
Objective: The objective was to study these mutations in PCOS.
Design: The design was a case-control study.
Setting: The study was conducted in an academic hospital.
Participants: A total of 116 PCOS patients and 76 nonhyperandrogenic controls participated.
Main outcome measures: Genotype distributions and influence of genotypes on clinical and biochemical variables and, in 28 patients and 12 controls, estimates of 11betaHSD oxoreductase activity were the main outcome measures.
Results: Four controls and five patients presented three of four mutant alleles in H6PD R453Q and HSD11B1 83557insA, which is the genotype observed in some subjects with CRD. Estimates of 11betaHSD oxoreductase activity were measured in six of these nine women, ruling out CRD. Moreover, H6PD R453Q and HSD11B1 83557insA genotypes, either separately or in combination, did not influence 11betaHSD oxoreductase activity. The distribution of H6PD R453Q genotypes (R/R, R/Q, and Q/Q) was different in patients and controls (42% of controls and 63% of PCOS patients were R/R; 53% of controls and 31% of PCOS patients were R/Q; and 5% of controls and 6% of PCOS patients were Q/Q; chi(2) = 9.1; P = 0.011). Patients homozygous for R453 alleles presented with increased cortisol and 17-hydroxyprogesterone levels, compared with carriers of Q453 alleles, but these differences were not observed in controls. On the contrary, HSD11B1 83557insA genotypes were not associated with PCOS and did not influence any phenotypic variable.
Conclusions: Digenic triallelic genotypes of the H6PD R453Q variant and HSD11B1 83557insA mutation do not always cause CRD. On the contrary, the H6PD R453Q variant is associated with PCOS and might influence its phenotype by influencing adrenal activity.