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At least 19 recordsLinked to original sources
PubMed2003

Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency.

In cortisone reductase deficiency (CRD), activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS; refs. 1,2). This suggests a defect in the gene HSD11B1 encoding 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), a primary regulator of tissue-specific glucocorticoid bioavailability. We identified intronic mutations in HSD11B1 that resulted in reduced gene transcription in three individuals with CRD. In vivo, 11beta-HSD1 catalyzes the reduction of cortisone to cortisol whereas purified enzyme acts as a dehydrogenase converting cortisol to cortisone. Oxo-reductase activity can be regained using a NADPH-regeneration system and the cytosolic enzyme glucose-6-phosphate dehydrogenase. But the catalytic domain of 11beta-HSD1 faces into the lumen of the endoplasmic reticulum (ER; ref. 6). We hypothesized that endolumenal hexose-6-phosphate dehydrogenase (H6PDH) regenerates NADPH in the ER, thereby influencing directionality of 11beta-HSD1 activity. Mutations in exon 5 of H6PD in individuals with CRD attenuated or abolished H6PDH activity. These individuals have mutations in both HSD11B1 and H6PD in a triallelic digenic model of inheritance, resulting in low 11beta-HSD1 expression and ER NADPH generation with loss of 11beta-HSD1 oxo-reductase activity. CRD defines a new ER-specific redox potential and establishes H6PDH as a potential factor in the pathogenesis of PCOS.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed1974

Structural features of ring C of 20-oxo steroids and the interaction with cortisone reductase.

Kinetic measurements were made with cortisone reductase (20-dihydrocortisone-NAD(+) oxidoreductase, EC 1.1.1.53) and a series of substrates which differed in shape, size and electronic character in the region adjacent to C-11, C-14 and C-18. Structural changes at C-11 in these substrates resulted in up to 660-fold changes in the apparent K(m) value, up to 200-fold changes in the apparent V(max.) value and up to 800-fold changes in the ratio of these kinetic constants. It is suggested that interactions important for substrate function normally occur between the enzyme and the C ring in the region of C-11, that these interactions arise from so-called hydrophobic forces between the generally hydrophobic C ring portion of the substrate and a hydrophobic region of the enzyme, but that when the substrate contains a polar substituent in this portion of the molecule, then polar interactions with polar moieties of the enzyme can also be important. It is further suggested that the part of the enzyme that interacts with the region of C-11 in the substrate is flexible, and that substrate binding involves at least some degree of induced fit.

Binding Sites↗
PubMed2005

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.

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.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2006

Variants implicated in cortisone reductase deficiency do not contribute to susceptibility to common forms of polycystic ovary syndrome.

OBJECTIVE: There are close phenotypic similarities between cortisone reductase deficiency (CRD), a rare abnormality of cortisone metabolism, and polycystic ovary syndrome (PCOS). As there is evidence that CRD results from digenic mutations involving the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) and hexose-6-phosphate dehydrogenase (H6PD), we sought to establish whether CRD-associated variants in these genes, individually or in combination, influence susceptibility to PCOS. DESIGN: Case-control, family-based association and quantitative-trait analyses. PATIENTS: A UK case sample comprising 256 nuclear families ascertained from a PCOS offspring and 213 singleton PCOS cases plus 549 control subjects. MEASUREMENTS: All subjects were genotyped for CRD-related variants in HSD11B1 (rs12086634) and H6PD (rs6688832). Testosterone was measured with an in-house radioimmunoassay using ether extraction and dextran-coated charcoal separation. RESULTS: Case-control analyses revealed no differences in genotype distribution between PCOS and controls for rs12086634 or rs6688832 (both P = 0.84). Three per cent of cases and 2.4% of controls had genotype combinations (three or more variant alleles at the two sites) considered characteristic of CRD (P = 0.73). There were no departures from expectation in the family-based association studies, and no significant associations between genotypes (individually or in combination) and BMI, WHR or testosterone. CONCLUSIONS: The variants in HSD11B1 and H6PD typed, though implicated in causation of CRD, do not influence susceptibility to PCOS. It seems likely that additional variants within these genes are required for the development of CRD.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed1978

Comparison of the 3alpha-and 20beta-hydroxysteroid dehydrogenase activities of the cortisone reductase of Streptomyces hydrogenans.

The 3alpha- and 20beta-hydroxysteroid dehydrogenase (HSD) activities of cortisone reductase in Streptomyces hydrogenans have been examined to determine whether both activities are due to one enzyme. This question was raised when changes in the commercial preparations of the enzyme reduced the 3alpha-HSD activity to 5% of its original level while retaining full 20beta-HSD activity. In our experiments, the enzyme was purified to crystallinity and partially characterized. The 3alpha- and 20beta-HSD activities were both coinduced and copurified. The 3alpha- and 20beta-HSD activities were compared using the crystalline enzyme for studies of substrate competition, thermal inactivation at 52 degrees C, loss of activity with three haloacetoxysteroids, and the effects of Me2SO and temperature on the reaction rate. These studies support the conclusion that the 3alpha- and 20beta-HSD activities are due to the same enzyme molecule. In addition, it appears that the binding sites for the two activities do not act independently.

20-Hydroxysteroid Dehydrogenases↗
PubMed2003

11beta-hydroxysteroid dehydrogenase type 1 deficiency ('apparent cortisone reductase deficiency') in a 6-year-old boy.

OBJECTIVE: We present the 1st case of prepubertal hyperandrogenism because of a defect in the conversion of cortisone (E) to cortisol (F) by hepatic 11beta-hydroxysteroid dehydrogenase type 1. METHODS AND RESULTS: Clinical and anthropometric data were obtained. Serum androgens and gonadotropins with luteinizing hormone releasing hormone stimulation test, dexamethasone suppression test, and corticotropin-releasing hormone stimulation test were evaluated. Adrenal imaging and urinary steroid profiling by gas chromatography/mass spectrometry were employed. A 6.9-year-old boy presented with precocious pubarche, height (+2.6 SD), accelerated bone age (11.5 years), and Tanner stage 2 pubic hair and genitalia. Serum androgen levels were elevated and dexamethasone suppressible. Serum F was normal, but the E concentration was increased. Central precocious puberty and congenital adrenal hyperplasia were excluded. The excretion of androgen metabolites was moderately increased, but a highly increased tetrahydrocortisone (THE) and a diminished tetrahydrocortisol (THF + allo-THF) excretion was found with a [THF + allo-THF/ THE] ratio of 0.032 (normal controls 1.05 +/- 0.17). The corticotropin-releasing hormone stimulation test showed an exaggerated adrenocorticotropic hormone response, suggesting a relative deficiency of F. Two months of hydrocortisone treatment (17.5 mg daily) failed to suppress androgens adequately. Treatment with dexamethasone (0.375 mg/daily) resulted in androgen suppression. CONCLUSIONS: In the case of precocious pubarche and accelerated growth, the diagnosis of 11beta-hydroxysteroid dehydrogenase type 1 deficiency ('apparent cortisone reductase deficiency') should be considered. The diagnosis is based on determinations of urinary steroid metabolites.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed1975

The altered specificity of cortisone reductase with certain retroandrostan-3-one substrates.

The retro steroids 17beta-hydroxy-5beta,9beta,10alpha-androstan-3-one and 5beta,9beta,10alpha-androstane-3,17-dione were good substrates for cortisone reductase in the presence of NADH, and the products corresponded to the respective 3beta-hydroxy compounds, in which the 3beta-hydroxyl group is axial and the absolute configuration is 3S. The analogous natural steroids 17beta-hydroxy-5beta,9alpha,10beta-androstan-3-one and 5beta,9alpha,10beta-androstane-3,17-dione were very poor substrates, and gave the corresponding 3alpha(equatorial,3R)-hydroxy compounds, and, in the latter case, also an appreciable amount of 3beta(axial, 3S)-hydroxy-5beta,9alpha,10beta-androstan-17-one. The natural steroids 17beta-hydroxy-5alpha,9alpha,10beta-androstan-3-one and 5alpha,9alpha,10beta-androstane-3,17-dione were better substrates than the retro steroid 17beta-hydroxy-5alpha,9beta,10alpha-androstan-3-one, but were not such good substrates as the retro steroids 17beta-hydroxy-5beta,9beta,10alpha-androstan-3-one and 5beta,9beta,10alpha-androstane-3,17-dione. Unlike these retro steroid 5beta,9beta,10alpha-androstan-3-ones, the natural steroids 17beta-hydroxy-5alpha,9alpha,10beta-androstan-3-one and 5alpha,9alpha,10beta-androstane-3,17-dione gave the corresponding 3alpha(axial,3R)-hydroxy compounds. The retro steroid 17beta-hydroxy-5alpha,9beta,10alpha-androstan-3-one was not a good substrate, and the product of reaction corresponded to the 3alpha(axial,3R)-hydroxy compound. The nature of substrate recognition by this enzyme is discussed in the light of these structure-activity relationships.

Androstane-3,17-diol↗
PubMed1973

3-Hydroxy steroid dehydrogenase activities of cortisone reductase.

The behaviour of various C(19) and C(18) steroids as substrates for crystalline preparations of cortisone reductase (EC 1.1.1.53) is described. 3alpha(Axial,3R)-, 3alpha(equatorial,3R)- and 3beta(axial,3S)-hydroxy steroid-NAD oxidoreductase activities are demonstrated. Four pairs of the substrates differed only in the shape of the a/b ring junction, three pairs differed only in substitution at C-10, and four pairs differed only in substitution in ring d. The shape of the substrate molecule and certain substituents (e.g. 10beta-methyl, 17beta-hydroxy, 16-oxo or 17-oxo) altered substrate behaviour, but steroids differing considerably in shape nevertheless acted as substrates, suggesting the possibility of a large or flexible binding site. K(m) values varied about 10-fold, many being approx. 140mum. V(max.) values covered a greater range (about 200-fold) and the good substrates had high V(max.) values rather than low K(m) values.

Acetylation↗
PubMed2000

Apparent cortisone reductase deficiency: a rare cause of hyperandrogenemia and hypercortisolism.

A 55-year-old woman presented with androgenetic alopecia which had started at age 40. Her clinical history revealed that, unlike her younger sister, she was unable to conceive and was diagnosed as being sterile at age 30. At age 45, 21-hydroxylase deficiency (late-onset CAH) was assumed and glucocorticoid treatment suggested, but not initiated. There was slight hirsutism, but no other sign of virilization. Retesting of plasma steroids revealed elevated 17-OH-progesterone and free testosterone. Treatment with prednisone, cyproterone acetate, and spironolactone was started with significant clinical success. Surprisingly, the analyses of urinary steroid metabolites revealed a pattern that did not support the diagnosis of 21-hydroxylase deficiency (pregnanetriolone absent, pregnanediol, 17-OH-pregnanolone and pregnanetriol not increased). Abdominal CT showed bilateral adrenal hyperplasia and masses in both ovaries. Bilateral adnexectomy was performed, and cystic teratomas were diagnosed. Postoperative urinary steroid analyses showed a decreased tetrahydrocortisol/tetrahydrocortisone ratio (values around 0.08 as compared to age- and sex-matched controls with a ratio of about 0.5-0.8). Plasma cortisol appeared to be repeatedly elevated with exogenous sources excluded. Mass spectrometry showed that, while the tetrahydro metabolites were mainly cortisone-derived, the metabolites not reduced in A ring were mostly cortisol derivatives. This constellation clearly indicates cortisone reductase deficiency, a defect of hepatic 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD1). This enzyme catalyzes the oxidation of cortisol to cortisone and the reduction of cortisone to cortisol. In contrast to the corresponding kidney enzyme (11 beta-HSD2), its primary activity is, however, reductive. Although this is only the fifth reported case of that defect, more attention should be paid to this condition in hyperandrogenic women, even if elevated 17-OH-progesterone and testosterone suggest a more frequent cause.

Adult↗
PubMed1996

Apparent cortisone reductase deficiency: a unique form of hypercortisolism.

We describe two female siblings who had production of cortisol (F; as determined from excretion of urinary metabolites) high enough to give rise to Cushing's disease, but who had no clinical indications of the condition. The teenage patients were hirsute as a result of adrenal hyperandrogenism. A notable feature of the condition was the elevated excretion of corticosteroid metabolites with 11-carbonyl groups and very low excretion of 11 beta-hydroxylated steroids. We termed this disorder apparent cortisone (E) reductase disorder. The steroid metabolite phenotype appeared to be the opposite of that seen in the apparent mineralocorticoid excess syndrome, in which the excretion of 11-keto compounds is attenuated. As an example, the tetrahydrocortisol plus 5 alpha-tetrahydrocortisol/tetrahydrocortisone ratio was about 0.04 compared to normal values of about 1.0 and apparent mineralocorticoid excess syndrome values of 5.0-50.0. Paradoxically, among the F metabolites that had not undergone A-ring reduction, 11 beta-hydroxylated steroids dominated over 11-carbonyl compounds. The F/E ratio was about 1.8 compared to an average normal value of 0.54. Neither the father nor the mother of the patient had abnormal F metabolite/E metabolite ratios, although the father did excrete highly elevated free E and F, possibly an unrelated condition. A conclusion was not reached regarding the basis of the disorder. We considered that the most likely causes were 1) defective hepatic 11 beta-hydroxysteroid dehydrogenase-1, 2) failure to develop the adult form of F metabolism, or 3) excessive activity of A ring reduction enzymes acting on E.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1999

Apparent cortisone reductase deficiency: a functional defect in 11beta-hydroxysteroid dehydrogenase type 1.

A 36-yr-old woman was referred to the endocrine clinic for investigation of oligomenorrhea, hirsutism, and acne. She was plethoric and overweight with central fat distribution. Plasma cortisol was normal, but her adrenal glands were enlarged (CT scan). Urinary tetrahydrocortisone excretion rate was consistently high, raising the possibility of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) deficiency. In addition, 5beta- reduction of cortisol and cortisone was markedly enhanced. The levels of all cortisol metabolites were suppressed normally with dexamethasone, but conversion of oral cortisone acetate to plasma cortisol was delayed and subnormal compared with that of healthy volunteers. This was accompanied by a larger than normal increase in plasma cortisone concentration. Thus, the defect appears to be in 11beta-HSD1 activity and not in 5beta-reductase activity. Three close relatives of the subject showed no comparable abnormalities, and analysis of the coding region and exon/intron boundaries of the 11beta-HSD1 gene of the case revealed no differences from the consensus sequence. The defect may lie outside the coding region. Alternatively, some other inherited or acquired defect may lead to inhibition of this enzyme system.

11-beta-Hydroxysteroid Dehydrogenases↗