scholarly journals OR25-02 A Phase 3 Study of a Modified-Release Hydrocortisone in the Treatment of Congenital Adrenal Hyperplasia

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Deborah P Merke ◽  
Ashwini Mallappa ◽  
Wiebke Arlt ◽  
Aude Brac de la Perriere ◽  
Angelica Linden Hirschberg ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Disease Control ◽  
Hormonal Control ◽  
Dose Titration ◽  
Modified Release ◽  
Adrenal Hyperplasia ◽  
Diurnal Cortisol ◽  
Classic Cah ◽  
The Mean ◽  
21 Hydroxylase Deficiency

Abstract Background: Patients with congenital adrenal hyperplasia (CAH) due to classic 21-hydroxylase deficiency have poor health outcomes related to inadequate glucocorticoid (GC) replacement. We compared disease control of adults with classic CAH treated with a modified release hydrocortisone (MRHC), which replicates physiological diurnal cortisol secretion, versus standard GC therapy. Methods: 6 month, open label, study in 122 patients randomised either to treatment with MRHC (Chronocort®, Diurnal Ltd, Cardiff, UK) twice daily at ~ 0700h & ~2300h, or to remain on their standard GC regimen (hydrocortisone, prednisolone, prednisone, dexamethasone). Patients had 24-hr profiling of serum 17-hydroxyprogesterone (17-OHP) at baseline and for dose titration at 4 and 12 weeks. The primary efficacy endpoint was the change from baseline to 24 weeks in the natural logarithm of the mean of the 24-hr standard deviation score (SDS) profile for 17-OHP. Results: Both groups achieved improved hormonal control at 24 weeks. The mean 24-hour 17-OHP SDS was significantly lower on MRHC compared to standard GC at 4 weeks (p = 0.0074) and 12 weeks (p = 0.019), but not at 24 weeks. In post-hoc analyses at 24 weeks, MRHC treatment showed a greater reduction in 17-OHP SDS compared to standard GC in the morning, 0700-1500h (p = 0.0442) and a greater reduction in log transformed 17-OHP 24 hour AUC (p=0.0251). Defining a morning 17-OHP <1200ng/dl (<36 nmol/L) as good control, for patients not controlled at baseline 85% were well controlled at 24 weeks with MHRC versus 50% on standard GC. For patients controlled at baseline 100% were controlled at 24 weeks on MHRC versus 84% with standard GC (p = 0.0018). The variability of 17-OHP over 24 hours was significantly reduced in the MRHC group compared to standard GC: the ratio of amplitude at 24 weeks divided by amplitude at baseline was for MRHC, 0.361 [95% CI: 0.235, 0.651], and standard GC, 0.917 [0.773, 1.366]; (p = 0.0001).There were no adrenal crises on MRHC and fewer stress doses despite similar incidence of inter-current illness to the standard GC group which had 3 adrenal crises. MRHC was associated with patient reported benefit including restoration of menstruation in 4 patients on MRHC and 1 on standard GC and two partner pregnancies in patients on MRHC and none on standard GC. Discussion: This is the largest randomised controlled trial of GC treatment in CAH and showed that intensification of therapy could improve control of the androgen-precursor, 17-OHP, and that this hormonal control was superior in the morning with MRHC. MRHC reduced the fluctuations in 17-OHP such that in the majority of patients the 17-OHP profile was within the reference range throughout 24 hours, providing consistent and optimal disease control. Conclusion: Diurnal cortisol replacement with a MRHC improves the biochemical control of classic CAH with a twice-daily therapeutic regimen.

scholarly journals MANAGEMENT OF ENDOCRINE DISEASE: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: update on the management of adult patients and prenatal treatment

2017 ◽  
Vol 176 (4) ◽  
pp. R167-R181 ◽  
Author(s):  
Anne Bachelot ◽  
Virginie Grouthier ◽  
Carine Courtillot ◽  
Jérôme Dulon ◽  
Philippe Touraine
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Management Strategies ◽  
The United States ◽  
Fertility Treatment ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Androgen Excess ◽  
Classic Cah ◽  
21 Hydroxylase Deficiency ◽  
And Control

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by cortisol and in some cases aldosterone deficiency associated with androgen excess. Goals of treatment are to replace deficient hormones and control androgen excess, while avoiding the adverse effects of exogenous glucocorticoid. Over the last 5 years, cohorts of adults with CAH due to 21-hydroxylase deficiency from Europe and the United States have been described, allowing us to have a better knowledge of long-term complications of the disease and its treatment. Patients with CAH have increased mortality, morbidity and risk for infertility and metabolic disorders. These comorbidities are due in part to the drawbacks of the currently available glucocorticoid therapy. Consequently, novel therapies are being developed and studied in an attempt to improve patient outcomes. New management strategies in the care of pregnancies at risk for congenital adrenal hyperplasia using fetal sex determination and dexamethasone have also been described, but remain a subject of debate. We focused the present overview on the data published in the last 5 years, concentrating on studies dealing with cardiovascular risk, fertility, treatment and prenatal management in adults with classic CAH to provide the reader with an updated review on this rapidly evolving field of knowledge.

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.

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.

scholarly journals Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia

2021 ◽  
Author(s):  
Deborah P Merke ◽  
Ashwini Mallappa ◽  
Wiebke Arlt ◽  
Aude Brac de la Perriere ◽  
Angelica Lindén Hirschberg ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Disease Control ◽  
Standard Therapy ◽  
Extension Study ◽  
Modified Release ◽  
Adrenal Hyperplasia ◽  
Androgen Excess ◽  
Phase 3 ◽  
Patient Reported ◽  
17 Hydroxyprogesterone

Abstract Context Standard glucocorticoid therapy in congenital adrenal hyperplasia (CAH) regularly fails to control androgen excess, causing glucocorticoid overexposure and poor health outcomes. Objective We investigated whether modified-release hydrocortisone (MR-HC), which mimics physiologic cortisol secretion, could improve disease control. Methods A 6-month, randomized, phase 3 study was conducted of MR-HC vs standard glucocorticoid, followed by a single-arm MR-HC extension study. Primary outcomes were change in 24-hour SD score (SDS) of androgen precursor 17-hydroxyprogesterone (17OHP) for phase 3, and efficacy, safety and tolerability of MR-HC for the extension study. Results The phase 3 study recruited 122 adult CAH patients. Although the study failed its primary outcome at 6 months, there was evidence of better biochemical control on MR-HC, with lower 17OHP SDS at 4 (P = .007) and 12 (P = .019) weeks, and between 07:00h to 15:00h (P = .044) at 6 months. The percentage of patients with controlled 09:00h serum 17OHP (< 1200 ng/dL) was 52% at baseline, at 6 months 91% for MR-HC and 71% for standard therapy (P = .002), and 80% for MR-HC at 18 months’ extension. The median daily hydrocortisone dose was 25 mg at baseline, at 6 months 31 mg for standard therapy, and 30 mg for MR-HC, and after 18 months 20 mg MR-HC. Three adrenal crises occurred in phase 3, none on MR-HC and 4 in the extension study. MR-HC resulted in patient-reported benefit including menses restoration in 8 patients (1 on standard therapy), and 3 patient and 4 partner pregnancies (none on standard therapy). Conclusion MR-HC improved biochemical disease control in adults with reduction in steroid dose over time and patient-reported benefit.

scholarly journals Children with classic congenital adrenal hyperplasia experience salt loss and hypoglycemia: evaluation of adrenal crises during the first 6 years of life

2016 ◽  
Vol 174 (2) ◽  
pp. 177-186 ◽  
Author(s):  
Brigitte Odenwald ◽  
Uta Nennstiel-Ratzel ◽  
Helmuth-Günther Dörr ◽  
Heinrich Schmidt ◽  
Manfred Wildner ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Hospital Admissions ◽  
Discharge Summary ◽  
Severe Illness ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
Classic Congenital Adrenal Hyperplasia ◽  
Classic Cah ◽  
21 Hydroxylase Deficiency

ObjectiveTo evaluate adrenal crises after the start of treatment up to the age of 6 years in children with classic congenital adrenal hyperplasia (CAH).DesignAnalysis of data extracted from a population-based prospective long-term follow-up study of children detected in neonatal screening.MethodsData of 102 Bavarian children with classic CAH due to 21-hydroxylase deficiency were analyzed, using parental questionnaires and medical reports. Parent-reported hospital admissions of children diagnosed with acute health impairment were included in the analysis if salt loss (hyponatremia) or hypoglycemia was documented in the discharge summary.ResultsA total of 74 children (72.5%) had no report of hospital admissions with salt loss or hypoglycemia during the observational period. However, in 27.5% of the children, 22 salt-wasting crises (seven of these also with low blood glucose) and 16 hypoglycemic episodes without salt loss were reported. Furthermore, the cumulative incidence for seizures was elevated; 13 children experienced seizures during hyponatremia or hypoglycemia. Most adrenal crises were triggered by infections, often with inappropriate emergency management, but in 11 cases hypoglycemia occurred unexpectedly, without evidence of severe illness and without any management errors. Frequency of adrenal crises was 6.5 per 100 patient years (95% CI: 4.6–8.8).ConclusionsCrisis prevention remains a permanent challenge for families and physicians caring for children with classic CAH. Expert care and compliance with emergency recommendations are crucial. Further research on the interactions among glucocorticoid deficiency, adrenomedullary dysfunction, and glucose metabolism is necessary for the prevention of hypoglycemia, especially in young CAH patients.

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 Nonvirilized Genitalia in 3 Female Newborns With the Salt-Wasting Congenital Adrenal Hyperplasia Phenotype

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Lauren Yauch ◽  
Allison Mayhew ◽  
Veronica Gomez-Lobo ◽  
Kim Shimy ◽  
Kyriakie Sarafoglou
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Cortisol Secretion ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Primary Adrenal Insufficiency ◽  
Salt Wasting ◽  
Newborn Screen ◽  
Classic Cah ◽  
Simple Virilizing ◽  
21 Hydroxylase Deficiency

Abstract Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a form of primary adrenal insufficiency characterized by impaired cortisol secretion and elevated androgen production, is the leading cause of atypical genitalia in the female newborn. Females with classic CAH, either salt-wasting or simple-virilizing form, usually present at birth with atypical genitalia ranging from clitoromegaly to male-appearing genitalia, due to in utero to elevated androgens (androstenedione and testosterone). Females with mild nonclassic CAH usually present with typical genitalia. Proving the importance of always keeping an open mind for exceptions to the rule, we report on 3 female newborns who presented with the nonvirilized genitalia, salt-wasting CAH phenotype and genotype most consistent with simple-virilizing CAH. It is only through a positive newborn screen identifying the females with CAH that they were diagnosed before developing adrenal and/or salt-wasting crisis.

PLASMA ALDOSTERONE CONCENTRATIONS RELATED TO 17α-HYDROXYPROGESTERONE IN CONGENITAL ADRENAL HYPERPLASIA

1976 ◽  
Vol 82 (3) ◽  
pp. 572-586 ◽  
Author(s):  
M. T. Pham-Huu-Trung ◽  
M. C. Raux ◽  
M. Gourmelen ◽  
M. C. Baron ◽  
F. Girard ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Plasma Aldosterone ◽  
Adrenal Hyperplasia ◽  
Acth Stimulation ◽  
Hydroxylase Deficiency ◽  
Sodium Diet ◽  
Low Sodium Diet ◽  
Low Sodium ◽  
The Mean ◽  
21 Hydroxylase Deficiency

ABSTRACT Plasma aldosterone and 17α-hydroxyprogesterone (17-OHP) concentrations were measured in 35 patients with congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency. Ten patients had never been treated and among them were 4 salt-losing infants. Both aldosterone and 17-OHP were high in the 6 untreated non salt-losers. The values ranged respectively from 110 to 376 pg/ml and from 150 to 292 ng/ml. Results were variable in the 4 salt-losers. Three out of 5 untreated non salt-losers who were submitted to a low sodium diet, responded by doubling their aldosterone levels. When plasma 17-OHP concentrations were < 30 ng/ml, the mean aldosterone level in the treated non salt-losers (n = 6) was 15.3 pg/ml ± 4.3 (se). This value was not different from the mean level found in the control children (n = 7), 18.8 pg/ml ± 3.2. In the treated salt-losers (n = 9), the measured aldosterone levels were ≦ 10 pg/ml 7 times out of 9. When the treated patients exhibited plasma 17-OHP concentrations > 30 ng/ml, the salt-losers (n = 11) were distinguished from the non salt-losers (n = 8) in that they showed a significantly lower aldosterone mean level, 24.6 pg/ml ± 4.3 against 69 pg/ml ± 13.4 found in the non salt-losers. The salt-losers displayed no aldosterone increases to synthetic ACTH stimulation under treatment or at the withdrawal of treatment, while positive aldosterone responses were often observed in the non salt-losers. In the latter group, studied under different conditions (with and without therapy, on low sodium diet, after ACTH test) a significant correlation was found between aldosterone and 17-OHP levels expressed in log. values, (n = 38, r = 0.80, P < 0.001). The relationship could also be established with the values obtained from all the salt-losers, but it was less significant, (n = 35, r = 0.46, P < 0.02).

scholarly journals Late diagnosis of classic congenital adrenal hyperplasia: long-term consequences during adulthood

2021 ◽  
Vol 2021 ◽  
Author(s):  
Mariana Aveiro-Lavrador ◽  
Adriana De Sousa Lages ◽  
Luísa Barros ◽  
Isabel Paiva
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Autosomal Recessive ◽  
List Type ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Primary Infertility ◽  
Classic Cah ◽  
Long Term Consequences ◽  
21 Hydroxylase Deficiency

Summary Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders related to enzyme deficiencies in the adrenal steroidogenesis pathway leading to impaired corticosteroid biosynthesis. Depending on the extension of enzyme defect, there may be variable severities of CAH – classic and non-classic. We report the case of a 37-year-old male patient with a previously unknown diagnosis of classic CAH referred to Endocrinology evaluation due to class III obesity and insulin resistance. A high diagnostic suspicion was raised at the first Endocrinology consultation after careful past medical history analysis especially related to the presence of bilateral adrenal myelolipomas and primary infertility. A genetic test confirmed the presence of a variant of the CYP21A2 in homozygous with an enzymatic activity of 0–1%, corresponding to a classic and severe CAH form. Our case represents an unusually late definitive diagnose of classic CAH since the definition was established only during adulthood in the fourth decade of life. The missing diagnosis of classic 21 hydroxylase deficiency during infancy led to important morbidity, with a high impact on patients’ quality of life. Learning points Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive enzyme disorders responsible for an impaired cortical adrenal hormonal synthesis. CAH may be divided into two major forms: classic and non-classic CAH. If untreated, CAH may be fatal or may be responsible for important multi-organ long-term consequences that can be undervalued during adulthood. Adrenal myelolipomas are associated with chronic exposure to high ACTH levels and continuous androgen hyperstimulation typically found in undertreated CAH patients. Testicular adrenal rest tumours (TART) and primary infertility can be the first manifestation of the disease during adulthood.

scholarly journals Absence of Testicular Adrenal Rest Tumors in Newborns, Infants, and Toddlers with Classical Congenital Adrenal Hyperplasia

2019 ◽  
Author(s):  
Mimi S. Kim ◽  
Christina M. Koppin ◽  
Pankhuri Mohan ◽  
Fariba Goodarzian ◽  
Heather M. Ross ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Hormonal Control ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Young Males ◽  
Testicular Adrenal Rest Tumors ◽  
17 Hydroxyprogesterone ◽  
Adrenal Rest ◽  
21 Hydroxylase Deficiency ◽  
Testicular Adrenal Rest

AbstractINTRODUCTIONTesticular adrenal rest tumors (TART) are a known consequence for males with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. TART are associated with potential infertility in adults. However, little is known about TART in very young males with CAH.OBJECTIVEWe assessed the prevalence of TART in newborn, infant, and toddler males with classical CAH via scrotal ultrasound.METHODSMales with CAH had scrotal ultrasounds during the first 4 years of life, evaluating testes for morphology, blood flow, and presence of TART. Newborn screen 17-hydroxyprogesterone (17-OHP) and serum 17-OHP at the time of ultrasound were recorded. Bone ages were considered very advanced if ≥ 2SD above chronological age.RESULTSThirty-one ultrasounds in 16 males were performed. An initial ultrasound was obtained in four newborns at diagnosis (6.8 ±2.1 days), six infants (2.2 ±0.9 months), and six toddlers (2.4 ±0.9 years). Eleven males had at least one repeat ultrasound. A large proportion (11/16) were in poor hormonal control with an elevated 17-OHP (325 ±298 nmol/L). One infant was in very poor hormonal control (17-OHP 447 nmol/L) at initial ultrasound, and two toddlers had advanced bone ages (+3.2 and +4.5 SD) representing exposure to postnatal androgens. However, no TART were detected in any subjects.CONCLUSIONSTART were not found in males up to 4 years of age with classical CAH despite settings with expected high ACTH drive. Further research into the occurrence of TART in CAH may elucidate factors which contribute to the detection and individual predisposition to TART.

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