Cortisone reductase deficiency

Cortisone reductase deficiency is caused by dysregulation of the 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1), otherwise known as cortisone reductase, a bi-directional enzyme, which catalyzes the interconversion of cortisone to cortisol in the presence of NADH as a co-factor. If levels of NADH are low, the enzyme catalyses the reverse reaction, from cortisol to cortisone, using NAD+ as a co-factor.
Cortisol is a glucocorticoid that plays a variety of roles in many different biochemical pathways, including, but not limited to: gluconeogenesis, suppressing immune system responses and carbohydrate metabolism.
One of the symptoms of cortisone reductase deficiency is hyperandrogenism, resulting from activation of the Hypothalamic–pituitary–adrenal axis. The deficiency has been known to exhibit symptoms of other disorders such as Polycystic Ovary Syndrome in women. Cortisone Reductase Deficiency alone has been reported in fewer than ten cases in total, all but one case were women.[2] Elevated activity of 11β-HSD1 can lead to obesity or Type II Diabetes, because of the role of cortisol in carbohydrate metabolism and gluconeogenesis.[3]

Cortisone reductase deficiency
Other namesHSD 11b1 deficiency [1]
11β-hydroxysteroid dehydrogenase type 1
SpecialtyMedical genetics

Signs and symptoms

Cortisol inhibition, and as a result, excess androgen release can lead to a variety of symptoms. Other symptoms come about as a result of increased levels of circulating androgen. Androgen is a steroid hormone, generally associated with development of male sex organs and secondary male sex characteristics The symptoms associated with Cortisone Reductase Deficiency are often linked with Polycystic Ovary Syndrome (PCOS) in females. The symptoms of PCOS include excessive hair growth, oligomenorrhea, amenorrhea, and infertility. In men, cortisone reductase deficiency results in premature pseudopuberty, or sexual development before the age of nine.[4]

Genetics

Inactivating mutations in the H6PD gene lead to a lowered supply of NADH, causing cortisone reductase to catalyze the reaction from cortisol to cortisone.[5] This is the most common manifestation of CRD. It has been shown that CRD can be caused by mutations in the HSD11B1 gene as well, specifically mutations caused by K187N and R137C, affecting active site residue and disruption of salt bridges at the subunit interface of the dimer, respectively. In the K187N mutant, activity is abolished, and in the R137C mutant activity is greatly reduced, but not completely abolished.[6]

Pathophysiology
An overview of how cortisone reductase is driven by NADH production by hexose-6-phosphate and how it affects the HPA Axis in a healthy body.
Cortisone Reductase Deficiency effects on HPA and body in presence of deficient H6PD

In a healthy body, blood cortisone and cortisol levels are roughly equimolar.[7] Cortisone reductase deficiency leads to an elevated level of inert cortisone to active cortisol in adipose tissue. Cortisone reductase deficiency is caused by dysregulation of the 11β-hydroxysteroid dehydrogenase type 1 enzyme, otherwise known as cortisone reductase. The 11β-HSD1 enzyme is responsible for catalyzing the interconversion of circulating cortisone to cortisol, using NADH as a co-factor. The oxidative or reductive capacity of the enzyme is regulated by NADH produced by hexose-6-phosphate dehydrogenase (H6PD).[8] H6PD is distinct from its isozyme, glucose-6-phosphate dehydrogenase (G6PDH) in that G6PDH is a cytolytic enzyme and draws from a separate pool of NAD+. H6PD is also capable of catalyzing the oxidation of several phosphorylated hexoses, while G6PDH shows affinity for glucose, specifically.[9] The enzyme cortisone reductase exists in a tightly controlled reaction space, facing the lumen of the endoplasmic reticulum of cells in the liver and lungs. NADH produced by hexose-6-phosphate is delivered directly to the catalytic site of cortisone reductase.[10] If NADH production is limited, then cortisone reductase is also capable of catalysing the reverse reaction taking circulating cortisol and reducing it to cortisone.[11] Dysregulation of hexose-6-phosphate dehydrogenase occurs as a result of gene mutation.[12] Cortisol is important in signalling inhibition of adrenocorticotropic hormone release from the pituitary. Reduced cortisol in circulation activates the H-P-A Axis to produce and release more cortisol, and therefore androgen.

Effect on HPA Axis

The Hypothalamic-Pituitary-Adrenal axis relies on blood levels of cortisol to act as negative feedback. Low levels of blood cortisol leads to release of Corticotrope Releasing Hormone (CRH) activating the anterior pituitary and signalling the release of Adrenocorticotropic Hormone (ACTH), stimulating the adrenal gland to make more cortisol.[13] In addition to cortisol, the adrenal gland also releases androgen, leading to hyperandrogenism, which gives rise to the symptoms commonly associated with Cortisone Reductase Deficiency.

Diagnosis

Diagnosis of cortisone reductase deficiency is done through analysis of cortisol to cortisone metabolite levels in blood samples.[14]

Treatment

There is no treatment for cortisone reductase deficiency. Shots of cortisol are quickly metabolised into cortisone by the dysregulated 11β-HSD1 enzyme; however, symptoms can be treated. Treatment of hyperandroginism can be done through prescription of antiandrogens.[15] They do so by inhibiting the release of gonadotropin and luteinizing hormone, both hormones in the pituitary, responsible for the production of testosterone.

References
  1. "Cortisone reductase deficiency | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 5 October 2019.
  2. Stewart, P. M. (2003). "Tissue-specific Cushing's syndrome, 11beta-hydroxysteroid dehydrogenases and the redefinition of corticosteroid hormone action" (PDF). European Journal of Endocrinology. 149 (3): 163–8. doi:10.1530/eje.0.1490163. PMID 12943516.
  3. Pereira, C. D.; Azevedo, I; Monteiro, R; Martins, M. J. (2012). "11β-Hydroxysteroid dehydrogenase type 1: Relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus". Diabetes, Obesity and Metabolism. 14 (10): 869–81. doi:10.1111/j.1463-1326.2012.01582.x. PMID 22321826.
  4. Lavery, G. G.; Walker, E. A.; Tiganescu, A; Ride, J. P.; Shackleton, C. H.; Tomlinson, J. W.; Connell, J. M.; Ray, D. W.; Biason-Lauber, A; Malunowicz, E. M.; Arlt, W; Stewart, P. M. (2008). "Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency". The Journal of Clinical Endocrinology & Metabolism. 93 (10): 3827–32. doi:10.1210/jc.2008-0743. PMC 2579651. PMID 18628520.
  5. Draper, N; Walker, E. A.; Bujalska, I. J.; Tomlinson, J. W.; Chalder, S. M.; Arlt, W; Lavery, G. G.; Bedendo, O; Ray, D. W.; Laing, I; Malunowicz, E; White, P. C.; Hewison, M; Mason, P. J.; Connell, J. M.; Shackleton, C. H.; Stewart, P. M. (2003). "Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency". Nature Genetics. 34 (4): 434–9. doi:10.1038/ng1214. PMID 12858176.
  6. Lawson, A. J.; Walker, E. A.; Lavery, G. G.; Bujalska, I. J.; Hughes, B; Arlt, W; Stewart, P. M.; Ride, J. P. (2011). "Cortisone-reductase deficiency associated with heterozygous mutations in 11beta-hydroxysteroid dehydrogenase type 1". Proceedings of the National Academy of Sciences. 108 (10): 4111–6. Bibcode:2011PNAS..108.4111L. doi:10.1073/pnas.1014934108. PMC 3054023. PMID 21325058.
  7. Tomlinson, J. W.; Stewart, P. M. (2001). "Cortisol metabolism and the role of 11beta-hydroxysteroid dehydrogenase". Best Practice & Research Clinical Endocrinology & Metabolism. 15 (1): 61–78. doi:10.1053/beem.2000.0119. PMID 11469811.
  8. Draper, N; Walker, E. A.; Bujalska, I. J.; Tomlinson, J. W.; Chalder, S. M.; Arlt, W; Lavery, G. G.; Bedendo, O; Ray, D. W.; Laing, I; Malunowicz, E; White, P. C.; Hewison, M; Mason, P. J.; Connell, J. M.; Shackleton, C. H.; Stewart, P. M. (2003). "Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency". Nature Genetics. 34 (4): 434–9. doi:10.1038/ng1214. PMID 12858176.
  9. Hewitt, K. N.; Walker, E. A.; Stewart, P. M. (2005). "Minireview: Hexose-6-phosphate dehydrogenase and redox control of 11{beta}-hydroxysteroid dehydrogenase type 1 activity". Endocrinology. 146 (6): 2539–43. doi:10.1210/en.2005-0117. PMID 15774558.
  10. Senesi, S; Csala, M; Marcolongo, P; Fulceri, R; Mandl, J; Banhegyi, G; Benedetti, A (2010). "Hexose-6-phosphate dehydrogenase in the endoplasmic reticulum". Biological Chemistry. 391 (1): 1–8. doi:10.1515/BC.2009.146. PMID 19804362.
  11. Hughes, K. A.; Manolopoulos, K. N.; Iqbal, J; Cruden, N. L.; Stimson, R. H.; Reynolds, R. M.; Newby, D. E.; Andrew, R; Karpe, F; Walker, B. R. (2012). "Recycling between cortisol and cortisone in human splanchnic, subcutaneous adipose, and skeletal muscle tissues in vivo". Diabetes. 61 (6): 1357–64. doi:10.2337/db11-1345. PMC 3357308. PMID 22511204.
  12. Qin, K; Rosenfield, R. L. (2011). "Mutations of the hexose-6-phosphate dehydrogenase gene rarely cause hyperandrogenemic polycystic ovary syndrome". Steroids. 76 (1–2): 135–9. doi:10.1016/j.steroids.2010.10.001. PMC 3023921. PMID 21050867.
  13. Tomlinson, J. W.; Stewart, P. M. (2001). "Cortisol metabolism and the role of 11beta-hydroxysteroid dehydrogenase". Best Practice & Research Clinical Endocrinology & Metabolism. 15 (1): 61–78. doi:10.1053/beem.2000.0119. PMID 11469811.
  14. Stewart, P. M. (2003). "Tissue-specific Cushing's syndrome, 11beta-hydroxysteroid dehydrogenases and the redefinition of corticosteroid hormone action" (PDF). European Journal of Endocrinology. 149 (3): 163–8. doi:10.1530/eje.0.1490163. PMID 12943516.
  15. Charitidou, C; Farmakiotis, D; Zournatzi, V; Pidonia, I; Pegiou, T; Karamanis, N; Hatzistilianou, M; Katsikis, I; Panidis, D (2008). "The administration of estrogens, combined with anti-androgens, has beneficial effects on the hormonal features and asymmetric dimethyl-arginine levels, in women with the polycystic ovary syndrome". Atherosclerosis. 196 (2): 958–65. doi:10.1016/j.atherosclerosis.2007.03.002. PMID 17418849.
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