scholarly journals Tildacerfont in Adults with Classic Congenital Adrenal Hyperplasia: Results from Two Phase 2 Studies

2021 ◽  
Author(s):  
Kyriakie Sarafoglou ◽  
Chris N Barnes ◽  
Michael Huang ◽  
Erik A Imel ◽  
Ivy-Joan Madu ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Upper Respiratory Tract ◽  
Phase 2 ◽  
Adrenal Hyperplasia ◽  
Open Label ◽  
Hydroxylase Deficiency ◽  
Two Phase ◽  
Clear Dose Response ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency

Abstract Context Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is typically treated with lifelong supraphysiologic doses of glucocorticoids (GCs). Tildacerfont, a corticotropin-releasing factor type-1 receptor antagonist, may reduce excess androgen production, allowing for GC dose reduction. Objective Assess tildacerfont safety and efficacy. Design and Setting Two Phase 2 open-label studies. Patients Adults with 21OHD. Intervention Oral tildacerfont 200-1000 mg once daily (QD) (n=10) or 100-200 mg twice daily (n=9 and 7) for 2 weeks (Study 1) and 400 mg QD (n=11) for 12 weeks (Study 2). Main outcome measure Efficacy was evaluated by changes from baseline at 8 am in adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), and androstenedione (A4) according to baseline A4 ≤2x upper limit of normal (ULN) or A4 >2x ULN. Safety was evaluated using adverse events (AEs) and laboratory assessments. Results In Study 1, evaluable participants with baseline A4 >2x ULN (n=11; 19-67 years, 55% female) had reductions from baseline in ACTH (-59.4% to -28.4%), 17-OHP (-38.3% to 0.3%), and A4 (-24.2% to -18.1%), with no clear dose response. In Study 2, participants with baseline A4 >2x ULN (n=5; 26-63 years, 40% female) had ~80% maximum mean reductions in biomarker levels. ACTH and A4 were normalized for 60% and 40%, respectively. In both studies, participants with baseline A4 ≤2x ULN maintained biomarker levels. AEs (in 53.6% of patients overall) included headache (7.1%) and upper respiratory tract infection (7.1%). Conclusions For patients with 21OHD, up to 12 weeks of oral tildacerfont reduced or maintained key hormone biomarkers toward normal.

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.

17-HYDROXYPROGESTERONE IN THE COSYNTROPIN TEST: RESULTS IN NORMAL AND HIRSUTE WOMEN AND IN MILD CONGENITAL ADRENAL HYPERPLASIA

1979 ◽  
Vol 90 (3) ◽  
pp. 481-489 ◽  
Author(s):  
M. Gourmelen ◽  
M. T. Pham-Huu-Trung ◽  
M. G. Bredon ◽  
F. Girard
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Adrenal Hyperplasia ◽  
Acth Stimulation ◽  
Hydroxylase Deficiency ◽  
Individual Values ◽  
Minimum Concentration ◽  
The Mean ◽  
17 Hydroxyprogesterone ◽  
The Individual ◽  
21 Hydroxylase Deficiency

ABSTRACT The variations in plasma cortisol, testosterone and 17-hydroxyprogesterone (17-OHP) induced by an im injection of 0.25 mg cosyntrophin were studied in three groups of subjects: 16 healthy women, 16 hirsute women (HW) and 10 mild cases of congenital adrenal hyperplasia (CAH). The basal values of cortisol and testosterone were comparable between the three groups. In the patients with mild CAH, the mean 17-OHP concentration was increased: 483.9 ng/100 ml (113-1200 ng), but it should be noted that the individual values could overlap with the normal concentrations found in the controls and the HW during the luteal phase of the cycle. One hour after the injection of cosyntropin, a massive response of 17-OHP was observed in the mild cases of CAH, the mean basal concentration was multiplied by ten: 4843 ng/100 ml. The minimum concentration reached was 1740 ng/100 ml which is still 3-fold the highest level seen either in normal women (400 ng/ml) or in hirsute women (550 ng/100 ml). Determination of 17-OHP following a short-term ACTH stimulation, therefore provides evidence of partial 21-hydroxylase deficiency.

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.

Influence of different genotypes on 17-hydroxyprogesterone levels in patients with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency

2000 ◽  
Vol 52 (5) ◽  
pp. 601-607 ◽  
Author(s):  
Tânia A. S. S. Bachega ◽  
Ana E. C. Billerbeck ◽  
José A. M. Marcondes ◽  
Guiomar Madureira ◽  
Ivo J. P. Arnhold ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency

Serum 3α-androstanediol glucuronide measurements in children with congenital adrenal hyperplasia

1994 ◽  
Vol 131 (5) ◽  
pp. 504-508 ◽  
Author(s):  
Sükrü Hatun ◽  
Nurşen Yordam ◽  
Ali Süha Çalikoǧlu
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Control Group ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Female Children ◽  
The Mean ◽  
Simple Virilizing ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency ◽  
Androstanediol Glucuronide

Hatun Ş, Yordam N, Çalikoǧlu AS. Serum 3α-androstandiol glucuronide measurements in children with congenital adrenal hyperplasia. Eur J Endocrinol 1994;131:504–8. ISSN 0804–4643 To determine the value of 3α-androstanediol glucuronide (3-AG) measurements in children with congenital adrenal hyperplasia, we compared serum 3AG, 17-hydroxyprogesterone (17-OHP), androstenedione (A), testosterone (T) and dihydrotestosterone (DHT) levels and 24-h urinary 17-ketosteroid (17-KS) excretion in 42 female children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, including 27 with the simple virilizing and 15 with the salt-losing form. Their mean age was 74.5 ±48.5 months (range, 6–194 months). Twenty-four-hour urinary 17-KS excretion and serum 3-AG, A, T, DHT and 17-OHP levels were measured in the patients. The values were less than the mean + 2 sd of the control group in 63%, 74%, 67%, 69%, 60% and 31% of the patients, respectively. Serum 3-AG levels correlated with 24-h urinary 17-KS excretion (r = 0.66) and plasma A (r = 0.80), 17-OHP (r = 0.56), T (r = 0.79) and DHT (r = 0.62) levels. We conclude that serum 3-AG is a useful metabolic index in the management of children with congenital adrenal hyperplasia. Şükrü Hatun, Türk-İş Blk, 274/7, Aydinlikevler, Ankara, Turkey

scholarly journals Mass spectrometry: an essential tool to be used in discrimination between causes of congenital adrenal hyperplasia, and its benefits versus radioimmunoassay

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Heba Asfour ◽  
Heba Baz ◽  
Hend Soliman ◽  
Yasmine Elshiwy ◽  
Marwa Elsharkawy ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Tandem Mass Spectrometry ◽  
Congenital Adrenal Hyperplasia ◽  
Predictive Accuracy ◽  
Cost Effective ◽  
Tandem Mass ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency

Abstract Background Measurement of multiple steroids, 17 hydroxyprogesterone, 11 deoxycortisol, and 21 deoxycortisol, is required to discriminate between congenital adrenal hyperplasia due to 21 hydroxylase deficiency and that due to 11 beta hydroxylase deficiency. This work aims at the selection of the more appropriate, cost-effective method among either mass spectrometry or radioimmunoassay for the quantitation of the previous steroids. In this study, blood samples were collected from 31 patients that were newly diagnosed with congenital adrenal hyperplasia; 17 hydroxyprogesterone and 21 deoxycortisol were assayed using tandem mass spectrometry. Eleven deoxycortisol was assayed using 2 methods: radioimmunoassay and tandem mass spectrometry. Results Measuring 11 deoxycortisol using tandem mass spectrometry could significantly discriminate patients with 11 beta hydroxylase deficiency from those with 21 hydroxylase deficiency (p = 0.002), whereas radioimmunoassay failed (p = 0.095). Moreover, the former was highly predictive of 11 beta hydroxylase deficiency at a cutoff ≥ 11 ng/ml with 100% sensitivity and 92.3% specificity. Simultaneous measurement of 21 deoxycortisol and 11 deoxycortisol and their enrollment in an equation yielded an overall predictive accuracy 96.8% for diagnosis of CAH due to both enzymatic deficiencies. Conclusions Measurement of 11 deoxycortisol using mass spectrometric approach is mandated as a part of work up to differentiate types of congenital adrenal hyperplasia.

scholarly journals Fertility recovery in patients with non-classical congenital adrenal hyperplasia caused by 21-hydroxylase deficiency

2018 ◽  
Vol 64 (2) ◽  
pp. 79-84
Author(s):  
Elena L. Soboleva ◽  
Natalia S. Osinovskaya ◽  
Natalia N. Tkachenko ◽  
Vladislav S. Baranov ◽  
Marina A. Tarasova
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Fertility Restoration ◽  
Glucocorticoid Therapy ◽  
Total Testosterone ◽  
Adrenal Hyperplasia ◽  
Miscarriage Rate ◽  
Hydroxylase Deficiency ◽  
Cyp21a2 Gene ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency

Background. Very little research has been devoted to the studying fertility problem in nonclassical congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency. It is difficult to draw definitive conclusions regarding the need for glucocorticoid therapy in NCAH women based on limited data. Therefore, evaluating fertility in patients with NCAH and exploring the possibility of correcting its disturbances seemed to us to be a matter of importance. Aims — to evaluate the reproductive function of patients with NCAH and explore potential treatments for this disorder. Materials and methods. The study group included 60 patients with NCAH aged between 18 and 33 years old. NCAH was diagnosed based on early-morning serum 17-hydroxyprogesterone (17-OHP) levels above 30 nmol/l or 17-hydroxyprogesterone levels after ACTH stimulation above 26 nmol/l and/or characterized by molecular analysis of the CYP21A2 gene. Ultrasonography of the uterus and ovaries were performed in the cycle’s follicular phase. Total testosterone, dehydroepiandrosterone sulfate (DHEAS), Androstenedione, 17-OHP and Progesterone was measured. Results. Overall, the patients complained of menstrual cycle disorders (60%), infertility — (28%), hirsutism — (63%). Prior to being diagnosed with NCAH, Thirty-four women sought care because of infertility or recurrent miscarriages. Seventeen women (50%) had miscarriages; later on, five of them developed secondary infertility. Two patients became pregnant without treatment being already diagnosed and progressed to delivery. Once the diagnosis of NCAH was made, 58 women started receiving glucocorticoid therapy, Thirty nine (67%) women became pregnant while on glucocorticoid therapy. Thus glucocorticoid therapy reduced the miscarriage rate from 50 to 10.3%; р<0.001. There was no difference in the miscarriage rate between patients who received or quit glucocorticoid therapy during pregnancy. Conclusions. Glucocorticoid therapy is a highly efficacious method of fertility restoration in NCAH patients. Use of glucocorticoids during pregnancy planning significantly reduced the miscarriage rate. No difference in pregnancy outcome between the patients who received glucocorticoid therapy during pregnancy as opposed to those who did not indicates the advisability of treatment discontinuation once pregnancy is determined.

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