Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042755 (masculinization)
 2,562 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Slices of an adreno-cortical adenoma which had been obtained at operation from an 11-year-old girl with clinical signs of virilism were incubated with each of the following steroids: [1,2-3H]progesterone, [4-14C]pregnenolone, [1,2-3H]testosterone, [4-14C]androstenedione and [7-3H]dehydroepiandrosterone, respectively. Isolation and identification of the free radioactive metabolites were achieved by gel column chromatography on Sephadex LH-20, thin-layer chromatography, radio gas chromatography and isotope dilution. After incubation of progesterone, the following metabolites were identified: 11beta-hydroxyprogesterone, 16alpha-hydroxyprogesterone, 17alpha-hydroxyprogesterone, 21-deoxycortisol, corticosterone and cortisol. Pregnenolone was metabolized to 17alpha-hydroxypregnenolone, progesterone, dehydroepiandrosterone, androstenedione and 11beta-hydroxyandrostenedione. When testosterone was used as substrate, 11beta-hydroxytestosterone, androstenedione and 11beta-hydroxyandrostenedione were found as metabolites, whereas androstenedione was metabolized to testosterone and 11beta-hydroxyandrostenedione. After incubation of dehydroepiandrosterone, only androstenedione and 11beta-hydroxyandrostenedione were isolated and identified. From these results, it appears that cortisol was formed in the adenoma tissue via 21-deoxycortisol and corticosterone. Delta4-3oxo steroids of the C19-series arose exclusively from pregnenolone via 17alpha-hydroxypregnenolone and dehydroepiandrosterone, and not from progesterone and 17alpha-hydroxyprogesterone. Calculated on the amounts of metabolites formed, the highest enzyme activities were those of the 11beta-hydroxylase and the 17alpha-hydroxylase. It is interesting to note that only traces of testosterone were detected after incubation of androstenedione, whereas testosterone yielded large amounts of androstenedione.
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PMID:Studies on the metabolism of steroid hormones in a virilizing adrenal cortex adenoma. 21 78

The 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4)isomerase (3beta-HSD) isoenzymes are responsible for the oxidation and isomerization of Delta(5)-3beta-hydroxysteroid precursors into Delta(4)-ketosteroids, thus catalyzing an essential step in the formation of all classes of active steroid hormones. The 3beta-HSD gene family should have evolved to facilitate differential patterns of tissue- and cell-specific expression and regulation involving multiple signal transduction pathways, which are activated by several growth factors, steroids, and cytokines. In humans, there are two 3beta-HSD isoenzymes, which were chronologically designated type I and II encoded by HSD3B1 and HSD3B2 gene, respectively. HSD3B1 gene encodes the almost exclusive 3beta-HSD isoenzyme expressed in the placenta and peripheral tissues, whereas HSD3B2 gene encodes the predominant 3beta-HSD isoenzyme expressed in the adrenal gland, ovary, and testis and its deficiency is responsible for a rare form of congenital adrenal hyperplasia causing various degrees of salt-wasting in both sexes and incomplete masculinization of the external genitalia in genetic males. Although an elevated ratio of Delta(5)-Delta(4)-steroids was considered to be the best biological parameter for the diagnosis of this autosomal recessive disorder, the most accurate criteria now appears to be the plasma levels of 17-OH-pregnenolone greater than 100 nmol/L following ACTH stimulation. To date a total of 34 mutations (including 5 frameshift, 4 nonsense, 1 in-frame deletion, 1 splicing, and 23 missense mutations) have been identified in the HSD3B2 gene in 56 individuals from 44 families suffering from classical 3beta-HSD deficiency. In almost all the cases, the functional characterization of HSD3B2 mutations has provided a molecular explanation for the heterogeneous clinical presentation of this disorder. Indeed these experiments confirm that no functional 3betaHSD type II isoenzyme is expressed in the adrenals and gonads of the patients suffering from a severe salt-wasting form, whereas the non-salt-losing form results from specific missense mutation(s) in the HSD3B2 gene, which causes an incomplete loss of enzymatic activity thus leaving sufficient enzymatic activity to prevent salt wasting. Moreover, various mutations appear to have a drastic effect upon stability of the protein, therefore providing molecular evidence of a new mechanism involved in classical 3beta-HSD deficiency. Thus, the elucidation of the molecular basis of 3beta-HSD deficiency has highlighted the fact that mutations in the HSD3B2 gene can result in a wide spectrum of molecular repercussions, which are associated with the different phenotypic manifestations of classical 3beta-HSD deficiency and also provide valuable information concerning the structure-function relationships of the 3beta-HSD superfamily.
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PMID:Congenital adrenal hyperplasia due to 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4) isomerase deficiency. 1242 6

Classical 3beta-hydroxysteroid dehydrogenase (3beta-HSD) deficiency is a rare cause of congenital adrenal hyperplasia. We report two sisters presenting with delayed diagnoses of classical 3beta-HSD, despite salt wasting (SW) episodes in infancy. Sibling 1 was referred for premature pubarche, slight growth acceleration, and advanced bone age, whereas sibling 2 had no signs of virilization. At referral, increased 17alpha-hydroxyprogesterone associated with premature pubarche at first suggested a nonclassical 21-hydroxylase deficiency. Sequencing of the CYP21 gene showed both girls only heterozygotes (V281L mutation). This result, combined with SW in infancy, suggested a 3beta-HSD deficiency because of increased dehydroepiandrosterone sulfate levels. Further hormonal studies showed markedly elevated Delta5-steroids, in particular 17alpha-hydroxypregnenolone greater than 100 nmol/liter (the clue to the diagnosis) and elevated Delta5-/Delta4-steroid ratios. Sequencing of the type II 3beta-HSD gene documented that both girls were compound heterozygotes for T181I and 1105delA mutations. Retrospectively, elevated levels of 17alpha-hydroxyprogesterone were found on blood spots from Guthrie's test. There is no previous report of the combination of SW and premature pubarche due to mutations in the type II 3beta-HSD gene. Because neonatal diagnosis could have prevented life-threatening crises in these girls, this report further supports the benefits for neonatal screening for congenital adrenal hyperplasia whatever the etiology.
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PMID:Delayed diagnosis of congenital adrenal hyperplasia with salt wasting due to type II 3beta-hydroxysteroid dehydrogenase deficiency. 1567 Nov 4