scholarly journals 11-oxygenated androgens useful in the setting of discrepant conventional biomarkers in 21-hydroxylase deficiency

2020 ◽  
Author(s):  
Smita Jha ◽  
Adina F Turcu ◽  
Ninet Sinaii ◽  
Brittany Brookner ◽  
Richard J Auchus ◽  
...  
Keyword(s):  
Disease Control ◽  
Good Control ◽  
Signs And Symptoms ◽  
Bone Age ◽  
Menstrual Irregularity ◽  
Hydroxylase Deficiency ◽  
Natural History Study ◽  
Clinical Center ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency

Abstract Context Serum 17-hydroxyprogesterone (17OHP) and androstenedione (A4) are the conventional biomarkers used to assess disease control in patients with 21-hydroxylase deficiency (21OHD). However, discrepancy between the two is not uncommon, limiting interpretation. Objective To evaluate 11-oxyandrogens in discriminating good versus poor disease control in 21OHD in the setting of discrepant 17OHP and A4. Setting and Participants Retrospective analysis of 2,738 laboratory assessments obtained as part of Natural History Study of CAH at the NIH Clinical Center. Patients with discrepant 17OHP and A4 and available sera were selected. Methods A 15-steroid mass-spectrometry panel was performed in sera from patients with 21OHD and age- and sex-matched controls. Patients were categorized in “good” or “poor” control based on clinical assessment (bone age advancement, signs and symptoms of precocious puberty, menstrual irregularity, hirsutism, or hypogonadotrophic hypogonadism). Results Discrepant 17OHP and A4 was found in 469 (17%) laboratory assessments. Of these, 403 (86%) had elevated 17OHP with A4 in reference range. Of 46 patients with available sera, 30 (65%) were in good control. Median fold elevation relative to controls was higher in patients with poor versus good control for 11OHT (median [interquartile range], 2.82 [1.25-5.43] vs. 0.91 [0.49- 2.07], P= 0.003), and 11KT (3.57 [2.11-7.41] vs. 1.76 [1.24-4.00], P = 0.047). Fold elevation of 11OHT between 3.48 (sensitivity 97%, specificity 47%) and 3.88 (sensitivity 100%, specificity 40%) provided the best discrimination between poor vs. good control. Conclusion 11-oxyandrogens, especially 11OHT, may be useful in the management of CAH when conventional biomarkers are inconclusive.

Management of Congenital Adrenal Hyperplasia Using Serum Dehydroepiandrosterone Sulfate and 17-Hydroxyprogesterone Concentrations

PEDIATRICS ◽  
1978 ◽  
Vol 61 (6) ◽  
pp. 867-871
Author(s):  
Michael P. Golden ◽  
Barbara M. Lippe ◽  
Solomon A. Kaplan ◽  
Norman Lavin ◽  
John Slavin
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Good Control ◽  
Dehydroepiandrosterone Sulfate ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Exact Evaluation ◽  
Degree Of Control ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency ◽  
Urine Steroid

Simultaneous serum concentrations of dehydroepiandrosterone sulfate (DHEA-S) and 17-hydroxyprogesterone (17-OHP) were compared with urinary 17-ketosteroid (17-KS) and pregnanetriol (PT) excretion during therapy in 18 prepubertal patients with the 21-hydroxylase deficiency form of congenital adrenal hyperplasia (CAH). Patients were classified into those in good, poor, or questionable control on the basis of clinical examination, skeletal age, and 17-KS and PT excretion. During therapy, use of serum steroid concentrations was found to be nearly as accurate in judging adequacy of control as use of urine steroid concentrations. Of 34 evaluations, a definite assessment of adequacy of control could be arrived at 25 times using urinary values and 22 times using both serum DHEA-S and 17-OHP concentrations. DHEA-S concentration responded sluggishly when treatment was not adequate, being greater than 100 µg/dl only in patients significantly undertreated. It was never elevated in well-controlled patients. Mid-afternoon 17-OHP concentrations were less than 200 ng/dl in well-controlled patients but readily escaped suppression and could not be used to differentiate poor from borderline control or from temporary noncompliance. Therefore, an increased DHEA-S concentration indicated poor control and a suppressed 17-OHP concentration indicated good control. The combination of normal DHEA-S level with elevated 17-OHP level, however, did not permit exact evaluation of the degree of control. Of significance is that not all patients with CAH present with an elevated DHEA-S concentration, and only in those in whom an elevated level has been documented can DHEA-S level be used as an index of control during therapy.

scholarly journals SUN-037 Discordant Serum 17-hydroxyprogesterone and Androstenedione in the Management of Congenital Adrenal Hyperplasia: Are 11-oxygenated Androgens Useful?

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Smita Jha ◽  
Adina F Turcu ◽  
Ninet Sinaii ◽  
Brittany Brookner ◽  
Padmasree Veeraraghavan ◽  
...  
Keyword(s):  
Disease Control ◽  
Good Control ◽  
Tanner Stage ◽  
Poor Control ◽  
Serum Samples ◽  
Hydroxylase Deficiency ◽  
Monitoring Therapy ◽  
Clinical Control ◽  
Good Disease Control ◽  
21 Hydroxylase Deficiency

Abstract Background 21-hydroxylase-deficiency (21OHD) accounts for more than 95% of CAH cases. Serum 17-hydroxyprogesteron (17OHP) and androstenedione (A4) are traditional biomarkers for monitoring therapy. While generally there is good linear correlation between 17OHP and A4, physicians are likely to encounter scenarios where 17OHP is within “acceptable range” while A4 is elevated and vice versa. Mildly elevated 17OHP is considered acceptable, as normalization of 17OHP is likely to result in overtreatment. 11-ketotestosterone (11KT) is a potent agonist of the androgen receptor with androgenic activity equivalent to testosterone. We hypothesized that patients with high 17OHP would be more likely than those with high A4 to be in good disease control. We speculated that A4 would correlate more strongly with 11-oxygenated C19 steroids (11oxyandrogens) than 17OHP and that patients in poor clinical control would have higher median fold-elevation of 11oxyandrogens, especially 11-KT, compared to controls. Methods We performed retrospective analysis of patients seen at NIH from 2006 to 2019 and identified discordant 17OHP and A4 (17-OHP ≥1200 ng/dL with A4 normal for age/sex or tanner stage and vice-versa). Good or poor clinical control was based on abnormal growth, precocious puberty, irregular menses, hypogonadotrophic hypogonadism and A4/T. Quantitation of 15 steroids in stored peripheral sera was performed by LC-MS/ MS and compared to age- and sex-matched controls. Data between groups were compared using t-tests or non-parametric Wilcoxon rank sum tests. Correlation analyses utilized the Pearson and Spearman’s rho. Results We identified 122 of 789 (15%) discordant laboratory assessments among adults [84 with high 17OHP (69%)] and 347 of 1,949 (18%) among children [319 with high 17OHP (92%)]. Of these, 50 patients with available serum samples were identified (44 with high 17OHP). Twenty-five patients (50%) appeared to have good disease control. There was no difference in the frequency of patients in good or poor control between patients with high 17OHP or those with high A4 (p=0.7). Median fold elevation of 11KT relative to controls was higher in patients in poor control (2.87 fold, IQR 1.87-5.42, range 0.31-10.69) but with wide ranges and substantial overlap compared to those in good control (1.71 fold, IQR 1.06-2.92, range 0.35-16.59, p=0.068). 17OHP correlated with 21-deoxycortisol (rs=0.67, p<.001) while A4 correlated strongly with 11oxyandrogens (rs range 0.42-0.71, p<.003 for all). However, we did not find any substantial difference in the level of 11oxyandrogens between patients with high 17OHP and those with high A4. Conclusion: Discordance between 17OHP and A4 is common in the management of CAH and patients with elevation of either of these biomarkers are equally likely to have poor disease control. Limited evidence suggests a role for 11KT, as a discriminator for disease control.

scholarly journals Nonclassical 21-Hydroxylase Deficiency

2006 ◽  
Vol 91 (11) ◽  
pp. 4205-4214 ◽  
Author(s):  
Maria I. New
Keyword(s):  
Genetic Diseases ◽  
Signs And Symptoms ◽  
Bone Age ◽  
Ambiguous Genitalia ◽  
Tall Stature ◽  
Adult Males ◽  
Polycystic Ovaries ◽  
Ashkenazi Jews ◽  
Hydroxylase Deficiency ◽  
21 Hydroxylase Deficiency

Abstract Context: Nonclassical congenital adrenal hyperplasia (CAH) owing to steroid 21-hydroxylase deficiency (NC21OHD) is the most frequent of all autosomal recessive genetic diseases, occurring in one in 100 persons in the heterogeneous New York City population. NC21OHD occurs with increased frequency in certain ethnic groups, such as Ashkenazi Jews, in whom one in 27 express the disease. NC21OHD is underdiagnosed in both male and female patients with hyperandrogenic symptoms because hormonal abnormalities in NC21OHD are only mild to moderate, not severe as in the classical form of CAH. Unlike classical CAH, NC21OHD is not associated with ambiguous genitalia of the newborn female. Main Outcome Measures: The hyperandrogenic symptoms include advanced bone age, early pubic hair, precocious puberty, tall stature, and early arrest of growth in children; infertility, cystic acne, and short stature in both adult males and females; hirsutism, frontal balding, polycystic ovaries, and irregular menstrual periods in females; and testicular adrenal rest tissue in males. Conclusions: The signs and symptoms of hyperandrogenism are reversed with dexamethasone treatment.

scholarly journals Long-Term Health Outcomes of Korean Adults With Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

2021 ◽  
Vol 12 ◽  
Author(s):  
Seung Gyun Lim ◽  
Young Ah Lee ◽  
Han Na Jang ◽  
Sung Hye Kong ◽  
Chang Ho Ahn ◽  
...  
Keyword(s):  
Dehydroepiandrosterone Sulfate ◽  
Metabolic Risk ◽  
Menstrual Irregularity ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Classic Congenital Adrenal Hyperplasia ◽  
Increased Risk ◽  
21 Hydroxylase Deficiency ◽  
Age And Sex

There is a lack of studies regarding the long-term outcomes of Asian adults with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. We hypothesized that adults with CAH are at higher metabolic risk than their age-, and sex-matched controls. We further investigated the long-term health outcome-related factors in adults with CAH. We compared metabolic risk between adults with CAH (71 men, 93 women) and age-, and sex-matched controls (190 men, 261 women) from the Korean National Health and Nutrition Examination Survey data. The presence of obesity, testicular adrenal rest tumors (TARTs), and menstrual irregularity was assessed. Hormone status and treatment regimens were compared according to the presence of adverse outcomes. The median age was 27.0 y and 28.0 y for men and women, respectively. Adults with CAH had a higher waist circumference (88.0 vs. 82.3 cm in men, and 83.5 vs. 72.3 cm in women), and blood pressure (125.0 vs. 113.0 mmHg in men, and 120.0 vs. 104.0 mmHg in women) than age- and sex-matched controls (P<0.05 for all). The 2.7-fold increased risk for hypertension (men) and 2.0-fold increased risk for obesity (women) was significant in patients with CAH (P<0.05 for both). Obese adults with CAH showed significantly higher adrenal limb thicknesses (men) and 17-hydroxyprogesterone and dehydroepiandrosterone sulfate levels (women) (P<0.05 for both). TARTs occurred in 58.1% of men and did not differ by hormone or treatment regimen. Irregular menstruation was observed in 57.1% of women, with higher dehydroepiandrosterone sulfate levels in those with irregular periods. Adults with CAH had a higher metabolic risk than the general population. Poor disease control may increase their risk of metabolic morbidity and menstrual irregularity.

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.

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.

Growth curves for congenital adrenal hyperplasia from a national retrospective cohort

2016 ◽  
Vol 29 (12) ◽  
Author(s):  
Patricia Bretones ◽  
Benjamin Riche ◽  
Emmanuel Pichot ◽  
Michel David ◽  
Pascal Roy ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Adult Height ◽  
Bone Age ◽  
Strong Impact ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Bone Maturation ◽  
The Mean ◽  
Puberty Onset ◽  
21 Hydroxylase Deficiency

Abstract Background: In congenital adrenal hyperplasia (CAH), adjusting hydrocortisone dose during childhood avoids reduced adult height. However, there are currently no CAH-specific charts to monitor growth during treatment. Our objective was to elaborate growth reference charts and bone maturation data for CAH patients. Methods: We conducted a retrospective observational cohort study, in 34 French CAH centers. Patients were 496 children born 1970–1991 with genetically proven 21-hydroxylase deficiency. Their growth and bone maturation data were collected until age 18 together with adult height, puberty onset, parental height, and treatment. The mean (SD) heights were modeled from birth to adulthood. The median±1 SD and ±2 SDs model-generated curves were compared with the French references. A linear model for bone maturation and a logistic regression model for the probability of short adult height were built. Results: Growth charts were built by sex for salt wasting (SW) and simple virilizing (SV) children treated before 1 year of age. In girls and boys, growth was close to that of the general French population up to puberty onset. There was almost no pubertal spurt and the mean adult height was shorter than that of the general population in girls (−1.2 SD, 156.7 cm) and boys (−1.0 SD, 168.8 cm). Advanced bone age at 8 years had a strong impact on the risk of short adult height (OR: 4.5 per year advance). Conclusions: The 8-year bone age is a strong predictor of adult height. It will help monitoring the growth of CAH-affected children.

scholarly journals Delayed Diagnosis of Congenital Adrenal Hyperplasia with Salt Wasting Due to Type II 3β-Hydroxysteroid Dehydrogenase Deficiency

2005 ◽  
Vol 90 (4) ◽  
pp. 2076-2080 ◽  
Author(s):  
Trine H. Johannsen ◽  
Delphine Mallet ◽  
Harriet Dige-Petersen ◽  
Jørn Müller ◽  
Katharina M. Main ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Delayed Diagnosis ◽  
Bone Age ◽  
Hydroxysteroid Dehydrogenase ◽  
Type Ii ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
21 Hydroxylase Deficiency ◽  
Premature Pubarche

Abstract Classical 3β-hydroxysteroid dehydrogenase (3β-HSD) deficiency is a rare cause of congenital adrenal hyperplasia. We report two sisters presenting with delayed diagnoses of classical 3β-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 17α-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 3β-HSD deficiency because of increased dehydroepiandrosterone sulfate levels. Further hormonal studies showed markedly elevated Δ5-steroids, in particular 17α-hydroxypregnenolone greater than 100 nmol/liter (the clue to the diagnosis) and elevated Δ5-/Δ4-steroid ratios. Sequencing of the type II 3β-HSD gene documented that both girls were compound heterozygotes for T181I and 1105delA mutations. Retrospectively, elevated levels of 17α-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 3β-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.

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.

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