Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency
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CONTEXT: Cortisone reductase deficiency (CRD) is characterized by a failure to regenerate cortisol from cortisone via 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), resulting in increased cortisol clearance, activation of the hypothalamic-pituitary-axis (HPA) and ACTH-mediated adrenal androgen excess. 11beta-HSD1 oxoreductase activity requires the reduced nicotinamide adenine dinucleotide phosphate-generating enzyme hexose-6-phosphate dehydrogenase (H6PDH) within the endoplasmic reticulum. CRD manifests with hyperandrogenism resulting in hirsutism, oligo-amenorrhea, and infertility in females and premature pseudopuberty in males. Recent association studies have failed to corroborate findings that polymorphisms in the genes encoding H6PDH (R453Q) and 11beta-HSD1 (Intron 3 inserted adenine) interact to cause CRD. OBJECTIVE: Our objective was to reevaluate the genetics and steroid biochemistry of patients with CRD. DESIGN: We analyzed 24-h urine collection for steroid biomarkers by gas chromatography/mass spectrometry and sequenced the HSD11B1 and H6PD genes in our CRD cohort. PATIENTS: Patients included four cases presenting with hyperandrogenism and biochemical features clearly indicative of CRD. RESULTS: Gas chromatography/mass spectrometry identified steroid biomarkers that correlated with CRD in each case. Three cases were identified as homozygous (R109AfsX3, Y316X, and G359D) and one case identified as compound heterozygous (c.960G-->A and D620fsX3) for mutations in H6PD. No mutations affecting enzyme activity were identified in the HSD11B1 gene. Expression and activity assays demonstrate loss of function for all reported H6PDH mutations. CONCLUSIONS: CRD is caused by inactivating mutations in the H6PD gene, rendering the 11beta-HSD1 enzyme unable to operate as an oxoreductase, preventing local glucocorticoid regeneration. These data highlight the importance of the redox control of cortisol metabolism and the 11beta-HSD1-H6PDH pathway in regulating hypothalamic-pituitary-adrenal axis activity.
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Mutations of H6PDH in patients or knockout of the H6PDH gene in mice appear to be both necessary and sufficient to cause this disorder.
“Mutations of H6PDH in patients (594) or knockout of the H6PDH gene in mice (595) appear to be both necessary and sufficient to cause this disorder.”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [594]
The Abstract reports that four patients with cortisone reductase deficiency had inactivating H6PD mutations and concludes that such mutations can cause the disorder. It does not establish that H6PD mutations are necessary in all patients. The mouse-knockout clause is attached to a different citation and is not judged here. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn the ER lumen, H6PDH generates cofactor NADPH that is utilised by 11β-HSD1 for the conversion of cortisone to cortisol.
“In the ER, lumen H6PDH generates cofactor NADPH that is utilised by 11β-HSD1 for the conversion of cortisone to cortisol (4) .”
From Novel H6PDH mutations in two girls with premature adrenarche: ‘apparent’ and ‘true’ CRD can be differentiated by urinary steroid profiling (2013) · cites this paper as [4]
Inactivation of H6PDH in mice and humans leads not only to loss of 11β-HSD1 oxo-reductase activity but also to gain of 11β-HSD1 dehydrogenase activity, with a profound switch to cortisol inactivation.
“Inactivation of H6PDH in mice and humans leads not only to the loss of 11β-HSD1 oxo-reductase activity but also to a gain of 11β-HSD1 dehydrogenase activity, with a profound switch to cortisol inactivation (4, 12) .”
From Novel H6PDH mutations in two girls with premature adrenarche: ‘apparent’ and ‘true’ CRD can be differentiated by urinary steroid profiling (2013) · cites this paper as [4]
ACRD is caused by mutations in the H6PD gene, which encodes the enzyme hexose-6-phosphate dehydrogenase (H6PDH).
“By contrast, ACRD is caused by mutations in the H6PD gene, which encodes the enzyme hexose-6-phosphate dehydrogenase (H6PDH).”
From Novel H6PDH mutations in two girls with premature adrenarche: ‘apparent’ and ‘true’ CRD can be differentiated by urinary steroid profiling (2013) · cites this paper as [4]
Affected patients may present with premature adrenarche in childhood including pubarche, or as adolescents and adults with androgen excess and a PCOS-like phenotype in females.
“Affected patients may present with premature adrenarche in childhood including pubarche, or as adolescents and adults with androgen excess and a PCOS-like phenotype in females (4, 5, 10) .”
From Novel H6PDH mutations in two girls with premature adrenarche: ‘apparent’ and ‘true’ CRD can be differentiated by urinary steroid profiling (2013) · cites this paper as [4]
Cortisone reductase deficiency (CRD) and apparent CRD (ACRD) are characterised by the failure to generate cortisol from inactive cortisone, resulting in HPA axis activation and excessive ACTH-mediated adrenal androgen secretion.
“Cortisone reductase deficiency (CRD) and apparent CRD (ACRD) are characterised by the failure to generate cortisol from inactive cortisone resulting in HPA axis activation and excessive ACTH-mediated adrenal androgen secretion, with ∼14 cases described clinically and biochemically in the literature (1, 2, 3, 4, 5, 6, 7, 8, 9) .”
From Novel H6PDH mutations in two girls with premature adrenarche: ‘apparent’ and ‘true’ CRD can be differentiated by urinary steroid profiling (2013) · cites this paper as [4]
ACRD results from a deficiency in H6PDH activity, which is essential for maintaining the reductive activity of HSD11B1 in vivo by provision of reduced NAD phosphate to the enzyme.
“CRD is caused by HSD11B1 deficiency (90) whereas ACRD results form a deficiency in the activity of H6PDH, which is essential for maintaining the reductive activity of HSD11B1 in vivo by the reduced form of NAD phosphate provision to the enzyme (91, 92).”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [92]
In CRD and ACRD, urinary excretion of cortisone metabolites is increased whereas cortisol metabolites are decreased, resulting in reduced ratios of cortisol over cortisone metabolites.
“Notably, the urinary excretion of cortisone metabolites is increased whereas cortisol metabolites are decreased (92) [Fig. 5A and 5B (90, 92, 95–100)], resulting in reduced ratios of cortisol over cortisone metabolites (Table 2).”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [92]
CRD and ACRD present with a similar phenotype, with affected individuals developing androgen excess in childhood, coming to clinical attention with premature adrenarche in children of both sexes or in adolescent and young adult women with a PCOS-like phenotype.
“Clinically, CRD and ACRD present with a similar phenotype, with affected individuals developing androgen excess in childhood, coming to clinical attention with premature adrenarche in children of both sexes or in adolescent and young adult women with a PCOS-like phenotype (90, 92–94).”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [92]
Urine steroid profiling in CRD and ACRD reveals distinct alterations in glucocorticoid metabolism accompanied by an overall increase of androgen excretion rates.
“Urine steroid profiling reveals distinct alterations in glucocorticoid metabolism accompanied by an overall increase of androgen excretion rates (90, 92, 95).”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [92]
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- Authors
- Lavery, G. G., Walker, E. A., Tiganescu, A., Ride, J. P., Shackleton, C. H. L., Tomlinson, J. W., Connell, J. M. C., Ray, D. W., Biason-Lauber, A., Malunowicz, E. M., Arlt, W., & Stewart, P. M.
- Affiliations
- University of Birmingham (GB)
- University of Glasgow (GB)
- University of Manchester (GB)
- University Children’s Hospital (A.B.-L.), CH-8032 Zürich, Switzerland
- Department of Laboratory Diagnostics (E.M.M.), The Children’s Memorial Health Institute, 04-736 Warsaw, Poland
- Corresponding author
- Stewart, Paul M.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2008-10-01
- Volume
- 93
- Issue
- 10
- Pages
- 3827-3832
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC2579651
- OpenAlex
- W2062311720
- Semantic Scholar
- e199ef9f84564be7a7e14668c844b6dc9431a402
- Cited by
- 95
- References
- 30
- Citations by year
- 2025: 4 · 2024: 2 · 2023: 6 · 2022: 2 · 2021: 4 · 2020: 2 · 2019: 6 · 2018: 2 · 2017: 6 · 2016: 3 · 2015: 5 · 2014: 6 · 2013: 8 · 2012: 8
- FWCI
- 7.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Wellcome Trust (066357/Z/01/Z)
- National Institutes of Health
- Medical Research Council
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 068101, R01DK068101)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- hexose-6-phosphate dehydrogenase, 11β-hydroxysteroid dehydrogenase type 1, hyperandrogenism, adrenal androgen excess, steroid biomarkers, loss-of-function mutations
- MeSH terms
- Adult, Alopecia, Carbohydrate Dehydrogenases, Child, Cortisone Reductase, DNA Mutational Analysis, Female, Hirsutism, Humans, Male, Metabolic Diseases, Middle Aged, Models, Biological, Mutation, Pedigree, Puberty, Precocious, Steroids, Biomarkers
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