scholarly journals Salivary profiles of 11-oxygenated androgens follow a diurnal rhythm in patients with congenital adrenal hyperplasia

2021 ◽  
Author(s):  
Hanna Nowotny ◽  
Matthias K. Auer ◽  
Christian Lottspeich ◽  
Heinrich Schmidt ◽  
Ilja Dubinski ◽  
...  
Keyword(s):  
Diurnal Rhythm ◽  
Area Under The Curve ◽  
Early Morning ◽  
Hydroxylase Deficiency ◽  
Cross Sectional ◽  
Female Patients ◽  
Male Patients ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency ◽  
Monitoring Treatment

AbstractContextSeveral studies have highlighted the importance of the 11-oxygenated 19-carbon (11oxC19) adrenal-derived steroids as potential biomarkers for monitoring patients with 21-hydroxylase deficiency (21OHD).ObjectiveTo analyze circadian rhythmicity of 11oxC19 steroids in saliva profiles and evaluate their relevance as potential monitoring parameters in 21OHD.Design, Setting, and ParticipantsCross-sectional single center study including 34 patients with classic 21OHD (men=14; women=20) and 32 BMI- and age-matched controls (men=15; women=17).Outcome MeasuresSalivary concentrations of the following steroids were analyzed by LC-MS/MS: 17-hydroxyprogesterone (17OHP), androstenedione (A4), testosterone (T), 11β-hydroxyandrostenedione (11OHA4) and 11-ketotestosterone (11KT).ResultsSimilar to the previously described rhythmicity of 17OHP, 11OHA4 and 11KT concentrations followed a distinct diurnal rhythm in both patients and controls with highest concentrations in the early morning and declining throughout the day (11-OHA4: male patients Δmean = 79 %; male controls Δmean = 81%; female patients Δmean = 33 %; female controls Δmean = 91 %; 11KT: male patients Δmean = 64 %; male controls Δmean = 60 %; female patients Δmean = 49 %; female controls Δmean = 81 %). Significant correlations between the area under the curve (AUC) for 17OHP and 11KT (r(p)male = 0.741**; r(p)female = 0.842****), and 11OHA4 (r(p)male = 0.385n.s.; r(p)female = 0.527*) were observed in patients but not in controls.ConclusionsAdrenal 11oxC19 androgens are secreted following a diurnal pattern. This should be considered when evaluating their utility for monitoring treatment control.

scholarly journals Salivary profiles of 11-oxygenated androgens follow a diurnal rhythm in patients with congenital adrenal hyperplasia

2021 ◽  
Author(s):  
Hanna Franziska Nowotny ◽  
Matthias K Auer ◽  
Christian Lottspeich ◽  
Heinrich Schmidt ◽  
Ilja Dubinski ◽  
...  
Keyword(s):  
Diurnal Rhythm ◽  
Area Under The Curve ◽  
Early Morning ◽  
Adrenal Hyperplasia ◽  
Treatment Control ◽  
Cross Sectional ◽  
Female Patients ◽  
Single Center Study ◽  
Male Patients ◽  
Monitoring Treatment

Abstract Context Several studies have highlighted the importance of the 11oxygenated 19carbon (11oxC19) adrenalderived steroids as potential biomarkers for monitoring patients with 21hydroxylase deficiency (21OHD). Objective To analyze circadian rhythmicity of 11oxC19 steroids in saliva profiles and evaluate their relevance as potential monitoring parameters in 21OHD. Design, Setting, and Participants Cross-sectional single center study including 59 patients with classic 21OHD (men=30; women=29) and 49 BMI- and agematched controls (men=19; women=30). Outcome Measures Salivary concentrations of the following steroids were analyzed by LCMS/MS: 17hydroxyprogesterone (17OHP), androstenedione (A4), testosterone (T), 11βhydroxyandrostenedione (11OHA4) and 11ketotestosterone (11KT). Results Similar to the previously described rhythmicity of 17OHP, 11OHA4 and 11KT concentrations followed a distinct diurnal rhythm in both patients and controls with highest concentrations in the early morning and declining throughout the day (11-OHA4: mean reduction of hormone concentrations between timepoint one and five (Δmean) in male patients = 66 %; male controls Δmean = 83 %; female patients Δmean = 47 %; female controls Δmean = 86 %; 11KT: male patients Δmean = 57 %; male controls Δmean = 63 %; female patients Δmean = 50 %; female controls Δmean = 76 %). Significant correlations between the area under the curve (AUC) for 17OHP and 11KT (r pmale = 0.773 <0.0001; r pfemale = 0.737 <0.0001), and 11OHA4 (r pmale = 0.633 0.0002; r pfemale = 0.564 0.0014) were observed in patients but not present or reduced in controls. Conclusions Adrenal 11oxC19 androgens are secreted following a diurnal pattern. This should be considered when evaluating their utility for monitoring treatment control.

scholarly journals Measurement of Salivary Adrenal-Specific Androgens as Biomarkers of Therapy Control in 21-Hydroxylase Deficiency

2019 ◽  
Vol 104 (12) ◽  
pp. 6417-6429 ◽  
Author(s):  
Irina Bacila ◽  
Jo Adaway ◽  
James Hawley ◽  
Sundus Mahdi ◽  
Ruth Krone ◽  
...  
Keyword(s):  
Cross Sectional Study ◽  
Hormonal Control ◽  
Hydroxylase Deficiency ◽  
Cross Sectional ◽  
Monitoring Strategies ◽  
Liquid Chromatography Tandem Mass ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency ◽  
Monitoring Treatment ◽  
Patient Subgroups

Abstract Background Monitoring of hormonal control represents a key part of the management of congenital adrenal hyperplasia (CAH). Monitoring strategies remain suboptimal because they rely on frequent blood tests and are not specific for adrenal-derived hormones. Recent evidence suggests the crucial role of adrenal-specific 11-oxygenated-C19 androgens in the pathogenesis of CAH. Objective To establish a correlation between plasma and salivary adrenal-specific androgens in CAH as a noninvasive monitoring strategy. Design This prospective cross-sectional study recruited patients between 2015 and 2018. Setting Multicenter study including 13 tertiary centers in the United Kingdom. Participants Seventy-eight children with CAH and 62 matched healthy controls. Methods Using liquid chromatography–tandem mass spectrometry, plasma and salivary concentrations of five steroids were measured: 17-hydroxyprogesterone (17OHP), androstenedione (A4), testosterone (T), 11-hydroxyandrostenedione (11OHA4), and 11-ketotestosterone (11KT). The correlation between plasma and salivary steroids was analyzed to assess their use in clinical practice. Results Strong correlations between plasma and salivary steroid concentrations in patients with CAH were detected: 17OHP (rs = 0.871; P < 0.001), A4 (rs = 0.931; P < 0.001), T (rs = 0.867; P < 0.001), 11OH4A (rs = 0.876; P < 0.001), and 11KT (rs = 0.944; P < 0.001). These results were consistent for patient subgroups based on sex and age. Analysis of patient subgroups based on 17OHP concentrations established clear correlations between plasma and salivary concentrations of the adrenal-specific androgen 11KT. Conclusions The current study identified tight correlations between plasma and saliva for the adrenal-derived 11-oxygenated C19 androgen 11KT, as well as 17OHP and A4, which are widely used for monitoring treatment in CAH. This combination of steroid hormones will serve as an improved noninvasive salivary test for disease monitoring in patients with CAH.

scholarly journals Molecular diagnosis of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Tania Mayvel Espinosa Reyes ◽  
Teresa Collazo Mesa ◽  
Paulina Arasely Lantigua Cruz ◽  
Adriana Agramonte Machado ◽  
Emma Domínguez Alonso ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Point Mutations ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Cross Sectional ◽  
Salt Wasting ◽  
Frequent Mutations ◽  
Detection Of Mutations ◽  
21 Hydroxylase Deficiency ◽  
Intron 2

Abstract Background Congenital adrenal hyperplasia (CAH) is an autosomal recessive group of diseases. 21-Hydroxylase deficiency (21OHD) accounts for between 95 and 99% of all CAH cases. Objectives To characterize the genotype of patients clinically diagnosed with 21OHD and to identify the most frequent mutations in the Cuban population. Methods Cross-sectional descriptive study that included all patients diagnosed with 21OHD from January 2000 to December 2018. For the molecular analysis of the CYP21A2 gene, a protocol was used that used the polymerase chain reaction in 2 stages; in the first stage genomic DNA was amplified and 5 point mutations were detected in the second stage (Intron 2, Deletion of 8 bp, G318X, I172N and P30L). Results The 5 point mutations were identified in 31 of the 55 (56%) studied patients, 16/21 (76%) in the salt-wasting, 12/18 (67%) in the simple virilizing and 3/16 (19%) in the nonclassical form. The Intron 2 mutation was the most frequent, followed by G318X and 8 bp deletion. Compound heterozygotes were found in 10 patients, all corresponded to classic forms of the disease. Conclusions The causal CYP21A2 gene mutation was detected in 56% (72% in classic CAH), which makes the method encouraging. The most frequent mutations observed were Intron 2 and G318X. The detection of mutations offers confirmation of diagnosis, prediction of phenotype and genetic counseling.

scholarly journals Ovarian intratumoral 21-hydroxylase deficiency in a postmenopausal hirsute woman

2012 ◽  
Vol 56 (9) ◽  
pp. 672-676 ◽  
Author(s):  
Selma B. Souto ◽  
Pedro V. Baptista ◽  
Filomena Barreto ◽  
Pedro F. Sousa ◽  
Daniel C. Braga ◽  
...  
Keyword(s):  
Histopathological Examination ◽  
Serum Testosterone ◽  
Serum Levels ◽  
Left Ovary ◽  
Serum Testosterone Level ◽  
Hydroxylase Deficiency ◽  
Postoperative Serum ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency ◽  
Hormone Analysis

Virilising ovarian tumours are a rare cause of hyperandrogenism in women, accounting for less than 5% of all ovarian neoplasms. It occurs most often in - and postmenopausal women. We report a case of a 64 year-old woman with signs of virilisation that had started 3 years before. Blood hormone analysis revealed increased levels of testosterone, and 17-hydroxyprogesterone. The tetracosactin test revealed 21-hydroxylase deficiency. Radiological imaging demonstrated a nodule in her left ovary. The patient was submitted to bilateral laparoscopic oophorectomy, and histopathological examination revealed a luteoma of the left ovary. Postoperative serum testosterone level and 17-hydroxyprogesterone returned to normal levels in one month. Virilism regressed within six months. Our patient also showed an elevation in 17-OHP serum levels. Normalization of 17-OHP after oophorectomy suggests a case of intratumoral 21-hydroxylase deficiency. To our knowledge, this is the first description of ovarian intratumoral 21-hydroxylase deficiency in a postmenopausal woman. Arq Bras Endocrinol Metab. 2012;56(9):672-6

scholarly journals Hormonal evaluation and mutation screening for steroid 21-hydroxylase deficiency in patients with unilateral and bilateral adrenal incidentalomas

2002 ◽  
pp. 349-355 ◽  
Author(s):  
A Patocs ◽  
M Toth ◽  
C Barta ◽  
M Sasvari-Szekely ◽  
I Varga ◽  
...  
Keyword(s):  
Mutation Screening ◽  
Tumor Formation ◽  
Adrenal Incidentalomas ◽  
Hydroxylase Deficiency ◽  
Similar Frequency ◽  
Specific Pcr ◽  
Large Gene ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency ◽  
Hormonal Evaluation

OBJECTIVE: The aims of the present study were (a) to examine the occurrence of 21-hydroxylase gene (CYP21) mutations in patients with unilateral and bilateral adrenal incidentalomas and (b) to correlate the results of mutation screening with hormonal parameters of 21-hydroxylase deficiency. DESIGN: The frequency of the eight commonly occurring CYP21 mutations in blood DNA samples of 19 patients with bilateral, as well as in blood and tumoral tissue DNA samples of 31 patients with unilateral adrenal incidentalomas, was determined. In all patients, hormonal evaluation for 21-hydroxylase deficiency was performed using measurements of basal and ACTH-stimulated plasma 17-hydroxyprogesterone (17-OHP) concentrations. METHODS: Blood and tumoral DNA samples were analyzed by allele-specific PCR for the detection of the eight commonly occurring CYP21 mutations (deletion/large gene conversion, intron 2 splicing, Ile172Asn, exon 6 cluster, Val281Leu, Leu307insT, Gln318Stop and Arg356Trp mutations). Plasma 17-OHP concentrations were measured by radioimmunoassay. RESULTS: Of the 19 patients with bilateral adrenal incidentalomas, one patient had homozygous (Val281Leu) and three patients had heterozygous germline CYP21 mutations (Val281Leu in two cases and Arg356Trp in one case). Heterozygous germline CYP21 mutations were also detected in five of the 31 patients with unilateral adrenal incidentalomas (Ile172Asn in three cases and Val281Leu in two cases). Mutation screening of tumoral DNA in unilateral incidentalomas showed the presence of corresponding germline mutations but no additional somatic mutations were found. ACTH-stimulated plasma 17-OHP concentrations were above 1500 ng/dl in all patients with bilateral incidentalomas who had homozygous and heterozygous CYP21 mutations, but heterozygous carriers with unilateral incidentalomas had highly variable ACTH-stimulated plasma 17-OHP levels (between 111 and 1705 ng/dl). CONCLUSIONS: These results suggest a similar frequency of germline CYP21 mutations in patients with bilateral and unilateral adrenal incidentalomas (21.1% and 16.1% respectively). Therefore, it cannot be ruled out that, in at least some patients, CYP21 mutations may play a role in the pathomechanism of bilateral and unilateral adrenal incidentalomas. However, the lack of clear association of CYP21 mutations with increased ACTH-stimulated plasma l7-OHP response, especially in patients with unilateral incidentalomas, suggests that the effect of CYP21 mutations on adrenocortical tumor formation may also involve mechanism(s) independent of ACTH-induced changes in 17-OHP secretion.

Classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency: a cross-sectional study of factors involved in bone mineral density

2003 ◽  
Vol 21 (6) ◽  
pp. 396-401 ◽  
Author(s):  
Patr�cia Oliveira de Almeida Freire ◽  
Sofia Helena Valente de Lemos-Marini ◽  
Andr�a Trevas Maciel-Guerra ◽  
Andr� Moreno Morcillo ◽  
Maria Tereza Matias Baptista ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Congenital Adrenal Hyperplasia ◽  
Bone Mineral ◽  
Cross Sectional Study ◽  
Sectional Study ◽  
Adrenal Hyperplasia ◽  
Mineral Density ◽  
Hydroxylase Deficiency ◽  
Cross Sectional ◽  
21 Hydroxylase Deficiency

The prevalence of the non-classical form of congenital adrenal hyperplasia as exemplified (by the population of the Moscow region)

2013 ◽  
Vol 59 (4) ◽  
pp. 18-22
Author(s):  
T A Ionova ◽  
A N Tiul'pakov ◽  
S G Kalinenkova
Keyword(s):  
Neonatal Screening ◽  
Moscow Region ◽  
Hydroxylase Deficiency ◽  
Classical Form ◽  
True Incidence ◽  
Monogenic Diseases ◽  
Frequent Mutations ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency ◽  
Autosomal Recessive Pattern

The non-classical form of 21-hydroxylase deficiency (NC21OH) is one of the most common monogenic diseases inherited in the autosomal-recessive pattern. The incidence of this condition in the Russian population, unlike that of its classical variant, remains to be elucidated. Aim. The objective of the present study was to estimate the true incidence of NC21OH based on the prevalence of the two most frequent mutations associated with this disease. A total of 998 randomly selected blood spots were obtained in the course of neonatal screening of the children born within one calendar year at the territory of the Moscow region. The incidence of the disease was calculated with the use of Hardi-Weinberg equation. The minimal prevalence rate of NC21OH in the population of the Moscow region was estimated to be 1:2206. The level of 17-hydroxyprogesterone (17-OHP) calculated based on the results of the screening studies can not be used to identify the carriers of the pathology of interest whereas neonatal screening allows to diagnose no more than 90% of the cases of NC21OH.

Development of a Direct Fluoroimmunoassay for Serum Levels of 17-Hydroxyprogesterone

1988 ◽  
Vol 25 (1) ◽  
pp. 35-41 ◽  
Author(s):  
B A El-Gamal ◽  
S A Eremin ◽  
D S Smith ◽  
J Landon
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Sodium Salicylate ◽  
Serum Levels ◽  
Adrenal Hyperplasia ◽  
Initial Sample ◽  
Hydroxylase Deficiency ◽  
Sample Extraction ◽  
Analytical Recovery ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency

A direct, rapid and highly specific fluoroimmunoassay for determining serum levels of 17-hydroxyprogesterone has been developed. It is based on the use of a sheep antiserum covalently coupled to magnetisable particles and fluorescein-labelled steroid. Sodium salicylate is employed to eliminate interference from endogenous binding proteins in serum. The sensitivity of 0·5 nmol/L is adequate for clinical purposes. Analytical recovery, linearity and precision are satisfactory and the results obtained correlate closely with those of an established radioimmunoassay using 3H-labelled steroid and the same antiserum after initial sample extraction and chromatography. The values found for serum from normal adult subjects ranged from 1·0 to 12·6 nmol/L while those from treated and untreated patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency were 1·5 to 190 and 28·0 to 655 nmol/L, respectively.

scholarly journals Relationship of CYP21A2 genotype and serum 17-hydroxyprogesterone and cortisol levels in a large cohort of Italian children with premature pubarche

2011 ◽  
Vol 165 (2) ◽  
pp. 307-314 ◽  
Author(s):  
Lucia Ghizzoni ◽  
Marco Cappa ◽  
Alessandra Vottero ◽  
Graziamaria Ubertini ◽  
Daniela Carta ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Serum Levels ◽  
Cortisol Response ◽  
Operating Characteristics ◽  
Acth Stimulation ◽  
Hydroxylase Deficiency ◽  
17 Hydroxyprogesterone ◽  
Italian Children ◽  
21 Hydroxylase Deficiency ◽  
Premature Pubarche

ObjectivePremature pubarche (PP) is the most frequent sign of nonclassic congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency in childhood. The aim of this study was to assess the relationship between the CYP21A2 genotype and baseline and ACTH-stimulated 17-hydroxyprogesterone (17-OHP) and cortisol serum levels in patients presenting with PP.Patients and methodsA total of 152 Italian children with PP were studied. Baseline and ACTH-stimulated 17-OHP and cortisol serum levels were measured and CYP21A2 gene was genotyped in all subjects.ResultsBaseline and ACTH-stimulated serum 17-OHP levels were significantly higher in NCCAH patients than in both heterozygotes and children with idiopathic PP (IPP). Of the patient population, four NCCAH patients (7.3%) exhibited baseline 17-OHP values <2 ng/ml (6 nmol/l). An ACTH-stimulated 17-OHP cutoff level of 14 ng/ml (42 nmol/l) identified by the receiver-operating characteristics curves showed the best sensitivity (90.9%) and specificity (100%) in distinguishing NCCAH patients. This value, while correctly identifying all unaffected children, missed 9% of affected individuals. Cortisol response to ACTH stimulation was <18.2 μg/dl (500 nmol/l) in 14 NCCAH patients (28%) and none of the heterozygotes or IPP children. Among the 55 NCCAH patients, 54.5% were homozygous for mild CYP21A2 mutations, 41.8% were compound heterozygotes for one mild and one severe CYP21A2 gene mutations, and 3.6% had two severe CYP21A2 gene mutations.ConclusionIn children with PP, baseline 17-OHP levels are not useful to rule out the diagnosis of NCCAH, which is accomplished by means of ACTH testing only. The different percentages of severe and mild CYP21A2 gene mutations found in PP children compared with adult NCCAH patients is an indirect evidence that the enzyme defect is under-diagnosed in childhood, and it might not lead to the development of hyperandrogenic symptoms in adulthood. Stress-dose glucocorticoids should be considered in patients with suboptimal cortisol response to ACTH stimulation.

scholarly journals The Application of a New Highly-Sensitive Radioimmunoassay for Plasma 21-Deoxycortisol to the Detection of Steroid-21-Hydroxylase Deficiency

1994 ◽  
Vol 31 (1) ◽  
pp. 56-64 ◽  
Author(s):  
Jean Fiet ◽  
Jean-Marie Villette ◽  
Hervé Galons ◽  
Philippe Boudou ◽  
Jean-Michel Burthier ◽  
...  
Keyword(s):  
Metabolic Pathway ◽  
Late Onset ◽  
Plasma Concentrations ◽  
Normal Subjects ◽  
Hydroxylase Deficiency ◽  
Classical Form ◽  
Standard Curve ◽  
Basal Plasma ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency

21-deoxycortisol (21-DF) is a steroid of strictly adrenal origin formed by the 11-hydroxylation of 17-hydroxyprogesterone. This metabolic pathway is minor in normal subjects, in whom basal plasma concentrations range from 0·03 to 0·63 nmol/L and from 0·865 to 1·50 nmol/L after adrenocorticotropic hormone (ACTH; Synacthène Immédiat, Ciba/Geigy, France). However, this metabolic pathway becomes major in 21-hydroxylase-deficient patients: in those who have the classical form of congenital adrenal hyperplasia (CAH) basal plasma 21-DF levels can attain more than 144 nmol/L. The synthesis of two isomers, E and Z, of the 21-deoxycortisol-3-carboxymethyloxime (CMO) hapten enabled us to prepare the corresponding E and Z immunogens by coupling them to bovine serum albumin (BSA), as well as the corresponding iodinated E and Z 21-DF-3-CMO-histamine tracers. We developed a very sensitive radioimmunoassay for 21-DF in plasma by associating an anti-21-DF-3-CMO-BSA-E isomer antibody to an iodinated 21-DF histamine-Z isomer (standard curve IC 50 = 8 pg/tube). This plasma 21-DF radioimmunoassay allowed diagnosis of the classical form of CAH in untreated newborn (basal 21-DF levels greater than 144 nmol/L), as well as the late-onset form (post-ACTH 21-DF levels greater than 11 · 54 nmol/L), and also permitted detection of 21-hydroxylase-deficient heterozygotes of both forms of CAH among the general population (post-ACTH 21-DF levels between 2·02 and 9·52 nmol/L).

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