cortodoxone and Puberty--Precocious

A nonclassic form of 11β-hydroxylase deficiency (NC11β-OHD) has been reported to cause mild androgen excess symptoms. Currently, the gold standard for biochemical diagnosis is elevated 11-deoxycortisol (11-DOC) levels after corticotropin stimulation test (ACTHstimT). However, there are no clear 11-DOC level cutoffs. One of the accepted references for 11-DOC levels for the paediatric population was published in 1991 by Lashansky et al. AIM: To determine the correlation between 11-DOC levels measured during ACTHstimT and clinical symptoms attributed to NC11β-OHD.. A retrospective study including all paediatric patients who underwent ACTHstimT at Shamir Medical Center between 2007 and 2015. Clinical data were collected from the patients' medical files. Outcome measures included the number of patients with hyperandrogenism signs and predefined elevated 11-DOC cut-off levels according to Lashansky for sex and age, and according to commercial kit cut-offs.. Data were complete at presentation for 136 patients. Long-term clinical data were documented for 98 patients, mean follow-up duration of 3.1 years (1.37-5.09). There was no statistically significant difference in the number of cases with elevated 11-DOC according to both cut-offs and early puberty, premature adrenarche nor acne. Follow-up data demonstrated no statistically significant difference in the number of cases with elevated 11-DOC levels among patients with compromised final adult height, polycystic ovarian syndrome or hyperandrogenism.. Basal and corticotropin stimulated 11-DOC levels were not significantly elevated above the 1.5 times cut-offs according to paediatric-specific norms or the commercial assay in paediatric individuals with possible clinical suspicion of NC11β-OHD.

Topics: Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Child; Cortodoxone; Female; Humans; Hyperandrogenism; Male; Mixed Function Oxygenases; Puberty, Precocious; Retrospective Studies

To explore the associations of environmental endocrine disruptors on precocious puberty in girls.. This was a case-control study in which 30 girls with precocious puberty and 46 age- and race-matched prepubertal females were enrolled. The concentrations of 10 environment endocrine disruptors (bisphenol A, bisphenol B, butylparaben, propylparaben, ethvlparaben, methylparaben, mono-butyl phthalate, mono-2-ethylhexyl phthalate, monoethyl phthalate, and monomethyl phthalate) in urine and 10 steroid hormones (dihydrotestosterone, corticosterone, hydrocortisone, 11-deoxycortisol, 17α-hydroxy progesterone, 4-androstene-3,17-dione, estrone, deoxycorticosterone, pregnenolone, and dehydroepiandrosterone) in serum were detected with the liquid chromatography-mass spectrometry (LC-MS).. According to the Mann-Whitney U test, urinary levels of bisphenol A, monobutyl phthalate, and monomethyl phthalate were significantly higher in the precocious group than in the prepubertal group, and blood levels of hydrocortisone, 11-deoxycortisol, corticosterone, deoxycorticosterone, and pregnenolone were significantly lower in the precocious group than in the prepubertal group (p<0.05, VIP>1).. Our findings confirm the association between phthalate exposure and the incidence of precocious puberty in girls. Control and reduction of children exposure to phthalate esters should be considered as a health priority.

Topics: Case-Control Studies; Child; Corticosterone; Cortodoxone; Desoxycorticosterone; Endocrine Disruptors; Environmental Exposure; Female; Humans; Hydrocortisone; Pregnenolone; Puberty, Precocious

This study investigated the prevalence and consequences of heterozygous CYP21A2 mutations in premature pubarche (PP) girls.. We investigated 36 French Mediterranean girls with isolated PP. We performed synacthen testing with 17OHP and 21-deoxycortisol evaluation, along with molecular analysis of the CYP21A2 gene in girls with abnormal elevation of one of these two adrenal steroids. Three girls (8.3%) had nonclassical adrenal hyperplasia, secondary to compound heterozygosity that associated at least one severe mutation for the three girls. A heterozygous mutation of the CYP21A2 gene was confirmed by molecular biology in eight girls (22%); a deletion of the CYP21A2 gene was found in one of them. Biological hyperandrogenism was found in the prepubertal CYP21A2 mutation carriers, whereas the four heterozygous girls who were followed long enough to have reached pubertal age presented biological and clinical hyperandrogenism.. We underline the high prevalence of heterozygous CYP21A2 mutations in girls with PP and demonstrate the usefulness of systematic screening by synacthen testing, both to improve their future clinical management and to prevent the transmission of classical adrenal hyperplasia to future offspring. Because of the severe metabolic and cardiovascular consequences of hyperandrogenism, long-term follow-up of these heterozygous patients is mandatory.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Child; Child, Preschool; Cortodoxone; Cosyntropin; Dehydroepiandrosterone Sulfate; Female; France; Heterozygote; Humans; Hyperandrogenism; Mediterranean Region; Mutation; Puberty, Precocious; Steroid 21-Hydroxylase; Testosterone

Congenital adrenal hyperplasia is a group of autosomal recessive inherited disorders of steroidogenesis. The deficiency of steroid 11-hydroxylase (CYP11B1) resulting from mutations in the CYP11B1 gene is the second most frequent cause.. We studied the functional and structural consequences of two CYP11B1 missense mutations, which were detected in a 1.8-yr-old boy with acne and precocious pseudopuberty, to prove their clinical relevance and study their impact on CYP11B1 function.. The in vitro expression studies in COS-7 cells revealed an almost complete absence of CYP11B1 activity for the P94L mutant to 0.05% for the conversion of 11-deoxycortisol to cortisol. The A368D mutant severely reduced the CYP11B1 enzymatic activity to 1.17%. Intracellular localization studies by immunofluorescence revealed that the mutants were correctly localized. Introducing these mutations in a three-dimensional model structure of the CYP11B1 protein provides a possible explanation for the effects measured in vitro. We hypothesize that the A368D mutation interferes with structures important for substrate specificity and heme iron binding, thus explaining its major functional impact. However, according to structural analysis, we would expect only a minor effect of the P94L mutant on 11-hydroxylase activity, which contrasts with the observed major effect of this mutation both in vitro and in vivo.. Analyzing the in vitro enzyme function is a complementary procedure to genotyping and a valuable tool for understanding the clinical phenotype of 11-hydroxylase deficiency. This is the basis for accurate genetic counseling, prenatal diagnosis, and treatment. Moreover, the combination of in vitro enzyme function and molecular modeling provides valuable insights in cytochrome P450 structural-functional relationships, although one must be aware of the limitations of in silico-based methods.

Topics: Acne Vulgaris; Adrenal Hyperplasia, Congenital; Animals; Base Sequence; Chlorocebus aethiops; Cortodoxone; COS Cells; Fluorescent Antibody Technique; Gene Expression; Humans; Hydrocortisone; Infant; Male; Models, Molecular; Mutagenesis, Site-Directed; Mutation, Missense; Pedigree; Puberty, Precocious; Sequence Analysis, DNA; Steroid 11-beta-Hydroxylase; Structure-Activity Relationship; Transfection

Chromosomal rearrangements are natural experiments that can provide unique insights into in vivo regulation of genes and physiological systems. We have studied a patient with congenital adrenal hyperplasia and steroid 11beta-hydroxylase deficiency who was homozygous for a deletion of the CYP11B1 and CYP11B2 genes normally required for cortisol and aldosterone synthesis, respectively. The genes were deleted by unequal recombination between the tandemly arranged CYP11B genes during a previous meiosis, leaving a single hybrid gene consisting of the promoter and exons 1-6 of CYP11B2 and exons 7-9 of CYP11B1. The hybrid gene also carried an I339T mutation formed by intracodon recombination at the chromosomal breakpoint. The mutant complementary DNA corresponding to this gene was expressed in COS-1 cells and was found to have relatively unimpaired 11beta-hydroxylase and aldosterone synthase activities. Apparently the 11beta-hydroxylase deficiency and the adrenal hyperplasia are due to the lack of expression of this gene in the adrenal zona fasciculata/reticularis resulting from replacement of the CYP11B1 promoter and regulatory sequences by those of CYP11B2.

Topics: Adrenal Hyperplasia, Congenital; Aldosterone; Androstenedione; Animals; Blotting, Southern; Child, Preschool; Cortodoxone; COS Cells; Crossing Over, Genetic; Cyproterone Acetate; Cytochrome P-450 CYP11B2; DNA, Complementary; Exons; Gene Deletion; Gene Expression; Homozygote; Humans; Male; Polymerase Chain Reaction; Promoter Regions, Genetic; Puberty, Precocious; Renin; Steroid 11-beta-Hydroxylase; Transfection

In about 5% of cases of classical congenital adrenal hyperplasia, steroid 11 beta-hydroxylase deficiency is the underlying defect. In two publications, no biochemical abnormalities have been reported in obligate heterozygotes for 11 beta-hydroxylase deficiency. We found the typical plasma steroid pattern of 11 beta-hydroxylase deficiency and identified the R448H mutation in the CYP11B1 gene in a boy presenting with pseudoprecocious puberty at age 2 yr. Both parents and an older sister were genotyped and were heterozygous carriers for the R448H mutation in CYP11B1. In contrast to the data reported in the literature, we found increased responses of plasma 11-deoxycortisol and 11-deoxycorticosterone in the short term ACTH test in the three family members heterozygous for the R448H mutation.

Topics: Adrenal Glands; Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Adult; Base Sequence; Child, Preschool; Cortodoxone; Desoxycorticosterone; Endocrine System Diseases; Exons; Female; Heterozygote; Humans; Introns; Male; Mutation; Pedigree; Puberty, Precocious; Steroid 11-beta-Hydroxylase

Biochemically adrenarche is characterized by increased production of 5-ene steroids, in particular Dehydroepiandrosterone (DHA) and its sulphate (DHA-S). It is still not clear if ACTH is responsible for this adrenal steroid production. The aim of the present study was to evaluate the effect of acute and chronic ACTH administration, without dexamethasone pretreatment, on hormonal patterns in 20 patients (5 males aged between 6 8/12 and 7 10/12 years and 15 females aged between 5 9/12 and 7 6/12 years) with idiopathic premature adrenarche. Pregnenolone (5P), DHA, DHA-S, 17-hydroxyprogesterone (17-OHP), androstenedione (A), 11-deoxycortisol (S) and cortisol (F) have been determined by Radioimmunoassay. The results of the hormonal evaluation (means +/- standard error) showed high plasma levels of DHA [329.2 +/- 41.7 ng/100 ml (dl)] and DHA-S (169.1 +/- 54 micrograms/dl) and slightly increased levels of 5P (74.4 +/- 7.1 ng/dl), of A (45.4 +/- 4.6 ng/dl) and 17-OHP (69.3 +/- 11.3 ng/dl) in comparison to those of controls, thus indicating a decrease in 3 beta-hydroxysteroid dehydrogenase activity and an increase in 17-20-lyase and 17-hydroxylase activities, characteristic for adrenarche. Acute and chronic ACTH stimulation did not amplify the characteristic basal hormonal pattern, but they induced a shift of adrenal steroid metabolism to 4-ene pathway, suggesting that the basal hormonal pattern in premature adrenarche may be independent or, at least, not exclusively dependent on ACTH control.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Cortex; Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Androstenedione; Child; Cortodoxone; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Female; Humans; Hydrocortisone; Hydroxyprogesterones; Male; Pregnenolone; Puberty, Precocious

In search for a biochemical marker to differentiate between adrenocortical carcinoma (AC) and adenoma (AA), plasma levels of the following steroids were studied preoperatively and postoperatively: 11-deoxycorticosterone (DOC), corticosterone (B), 11-deoxycortisol (S), and cortisol (F). Levels were measured by Sephadex LH-20 chromatography and specific radioimmunoassays. The subjects included eight children ages 2 years, 5 months to 9 years, 10 months. There were three girls and 5 boys with pseudoprecocious puberty due to adrenocortical tumors (histologically, four were AC and four, AA). The preoperative showed that DOC and S levels were elevated in all patients, F levels were elevated in four of eight children when compared with age-matched controls, whereas B was normal. Postoperatively, all levels returned to normal. The ratios of B/DOC and F/S as an index of adrenal 11 beta-hydroxylase activity were calculated. The preoperative ratios of B/DOC were markedly decreased in all patients with AC compared to controls (7.7,4.1,5.9,1.9 versus 23.5, median), but normal in three of four patients with AA (16.2, 29.6, 16.1). The F/S ratios were significantly lower in AC and AA when compared with controls. The data indicate a deficiency in 11 beta-hydroxylation in cases of adrenocortical tumors. Despite a still limited number of patients, the decreased B/DOC ratios may possibly indicate malignancy and could be helpful in distinguishing by biochemical means between benign and malignant adrenocortical tumors.

Topics: Adenoma; Adrenal Cortex Neoplasms; Adrenal Hyperplasia, Congenital; Carcinoma; Child; Child, Preschool; Chromatography, Gel; Corticosterone; Cortodoxone; Desoxycorticosterone; Female; Humans; Hydrocortisone; Male; Puberty, Precocious; Radioimmunoassay; Steroid Hydroxylases

Seven children with central precocious puberty and either neurofibromatosis and/or optic gliomas were referred to the National Institutes of Health, Bethesda, Md, for evaluation and treatment with the long-acting luteinizing hormone releasing hormone analogue (LHRHa) D-Trp6-Pro9-NEt-LHRH. Only six of the seven children chose to receive treatment. Four children presented with neurofibromatosis, three of whom also had optic gliomas; the remaining three children had isolated optic gliomas, without other neurocutaneous stigmas. All had central precocious puberty mediated by activation of the hypothalamic-pituitary-gonadal axis. Six months of LHRHa therapy caused suppression of gonadotropin and sex steroid levels, stabilization or regression of secondary sexual characteristics, and decreases in growth velocity and the rate of bone age maturation. We conclude that LHRHa therapy is effective in the treatment of central precocious puberty secondary to neurofibromatosis and/or optic gliomas.

Topics: 17-alpha-Hydroxyprogesterone; Child; Child, Preschool; Chorionic Gonadotropin; Cortodoxone; Cranial Nerve Neoplasms; Estradiol; Female; Follicle Stimulating Hormone; Glioma; Gonadotropin-Releasing Hormone; Growth; Humans; Hydroxyprogesterones; Luteinizing Hormone; Male; Neurofibromatosis 1; Optic Nerve Diseases; Puberty, Precocious; Skin Neoplasms; Testosterone; Triptorelin Pamoate