Control Of Congenital Adrenal Hyperplasia Research Articles

Developing oral chronotherapy for cortisol replacement in congenital adrenal hyperplasia.

The sun imposes a 24-h periodicity to life and circadian rhythms have evolved to maintain homoeostasis through the day/night cycle. In humans, there is a central clock that controls the sleep/wake cycle which is paralleled metabolically by a fast/feed cycle. The clock maintains homoeostasis by synchronising metabolism to the time of feeding. Loss of synchrony between the clock and hormonal rhythms results in loss of homoeostasis as evidenced by obesity, depression, and diabetes in people undertaking shift work. Cortisol has a distinct circadian rhythm; peaking on waking and low at sleep onset. Loss of this rhythm in adrenal insufficiency is associated with a poor quality of life and increased mortality. To replace the cortisol rhythm requires chronotherapy and for this you need to define the key parameters of the target rhythm, create a formulation to replicate that rhythm, and then prove clinical benefit. The physiology of hormones is more complex than that of nonnative drugs. Hormones are secreted with varied rhythms, bound to multiple cognate binding proteins, and actively transported and cleared through enzymatic pathways in multiple organs. We have examined the diurnal rhythm of cortisol in healthy volunteers, created physiologically-based pharmacokinetic models, and tested various oral delayed and sustained formulations of hydrocortisone (development name, Chronocort) in clinical trials. The outcome from this work was the manufacture of modified-release hydrocortisone hard capsules (tradename Efmody, Diurnal Ltd), that replicate the cortisol diurnal rhythm and improve the disease control of congenital adrenal hyperplasia the commonest hereditary form of adrenal insufficiency.

Chronotherapy based on modified-release hydrocortisone to restore the physiological cortisol diurnal rhythm

In this inspirational note, we describe the development of an endocrine chronotherapy to restore the physiological rhythm of the essential adrenal stress hormone, cortisol. The challenges included demonstrating the circadian rhythm of the drug target, creating a drug formulation that replicated that rhythm and then proving benefit in clinical trials. The physiological cortisol circadian rhythm is well defined with cortisol levels high on waking and low on going to sleep. We experimented with different formulation technologies including modified-release tablets and multi-particulates to replicate the cortisol rhythm where absent through disease. We describe the development of Efmody®, a modified-release formulation of hydrocortisone, which replicates the cortisol diurnal rhythm and improves the disease control of congenital adrenal hyperplasia, the commonest hereditary form of adrenal insufficiency. This program shows it is possible, through modified-release technology, to treat chronic endocrine diseases with physiological replacement to preserve health for life.

Modified release hydrocortisone capsules (MRHC, Efmody) improve control of congenital adrenal hyperplasia (CAH) on a lower glucocorticoid dose than standard treatment

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Quality of Life in Children and Young People With Congenital Adrenal Hyperplasia in the United Kingdom - Nationwide Multicentre Assessment

Introduction: Impaired Quality of Life (QoL) in Congenital Adrenal Hyperplasia (CAH) has been demonstrated in adults, but research in children has yielded variable results. We investigated the impact of CAH on QoL of children and adolescents alongside clinical health outcomes (biometric and biochemical profiles). Method: We collected data from 14 tertiary UK centres to explore current health status of 8-18 year olds with CAH. QoL was assessed by using three different questionnaires; strengths and difficulties questionnaire (SDQ), Paediatric Quality of life (PedsQL) and Self-image profile (SIP), the former two completed by both patients and their parents. Height, weight and blood pressure were converted to age and sex adjusted z-scores. Serum markers included 17OH-progesterone (17OHP), androstenedione (D4), testosterone (T) and 11-ketotestosterone (11KT). Statistical Analysis: Statistical analysis comprised of principal component analysis (PCA) followed by multivariate analysis of variance (MANOVA), and post hoc regression. Results: Of the 107 CAH patients included in the study, median age 12.4 years (IQR 10.0-15.1), 55% were female and 104 completed at least 1 questionnaire. Adequate data for PCA was available from 73/107. Three Principal Components (PCs) with observed eigenvalues > 1 explained 71% of the total variance in the observed variables. PC1 reflected ‘disease control’ comprising 17OHP, D4, T and 11KT. PC2 reflected ‘biometrics’ comprising age, and height and weight z-score. PC3 reflected ‘blood pressure’, comprising systolic and diastolic z-score. PC1 correlated with outcomes in the parent and patient SDQ as well as parent PedsQL. PC2 and PC3 did not correlate with QoL. Regression analysis revealed higher scores (indicating lower QoL) in the SDQ domain of emotional problems and PedsQL domain of emotional health in patients where biomarkers suggested good control or overtreatment. Post hoc regression analysis revealed a rise in Androstenedione of 10nmol/L equated to an improved SDQ emotional problems score of 0.5 points and an improved PedsQL emotional health score of 3 points. Conclusion: The study found an interrelation between QoL and biomarkers of disease control in CAH. There were more emotional problems with higher levels of androgen suppression. Biochemical control within normal ranges did not predict emotional problems. However, unexpectedly, patients with very high levels of androgens were highlighted as reporting fewer problems with their emotional QoL. Further research into QoL in CAH and optimal levels of biochemical control will further understanding.

Semen quality and testicular adrenal rest tumour development in 46,XY congenital adrenal hyperplasia: the importance of optimal hormonal replacement

To study the impact of the quality of therapeutic control on fertility and on the prevalence of testicular adrenal rest tumours (TART) in young males with congenital adrenal hyperplasia (CAH). Combined cross-sectional and retrospective clinical study. Twenty-nine patients and age-matched controls underwent clinical investigation, including semen analysis, testicular and adrenal ultrasound imaging, and serum and hair steroid analysis. The quality of therapeutic control was categorized as 'poor', 'moderate' or 'medium'. Evaluation of current control was based on concentrations of 17-hydroxy-progesterone and androstenedione in serum and 3 cm hair; previous control was categorized based on serum 17-hydroxy-progesterone concentrations during childhood and puberty, anthropometric and puberty data, bone age data and adrenal sizes. Semen quality was similar in males with CAH and controls (P = 0.066), however patients with 'poor' past control and large TART, or with 'poor' current CAH control had low sperm counts. Follicle-stimulating hormone was decreased, if current CAH control was 'poor' (1.8 ± 0.9 U/L; 'good': 3.9 ± 2.2 U/L); P = 0.015); luteinizing hormone was decreased if it was 'poor' (1.8 ± 0.9 U/L; P = 0.041) or 'moderate' (1.9 ± 0.6 U/L; 'good': 3.0 ± 1.3 U/L; P = 0.025). None of the males with 'good' past CAH control, 50% of those with 'moderate' past control and 80% with 'poor past control had bilateral TART. The prevalence of TART in males with severe (class null or A) CYP21A2 mutations was 53% and 25% and 0% in those with milder class B and C mutations, respectively. TART development is favoured by inadequate long-term hormonal control in CAH. Reduced semen quality may be associated with large TART. Gonadotropin suppression by adrenal androgen excess during the latest spermatogenic cycle may contribute to impairment of spermatogenesis.

Steroid 17-Hydroxyprogesterone in Hair Is a Potential Long-Term Biomarker of Androgen Control in Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

Introduction: To evaluate scalp hair steroid concentrations as a monitoring tool for androgen control and metabolic outcomes in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Methods: 17-hydroxyprogesterone (17-OHP), androstenedione, testosterone, cortisol, cortisone, progesterone, prednisolone, and prednisone concentrations were measured in scalp hair by means of LC-MS/MS in 27 women and 15 men with CAH and controls (37 women, 42 men). Results: In CAH men and women, 17-OHP levels in hair showed a significant positive correlation with corresponding levels in serum (ρ = 0.654; p = 0.01; ρ = 0.553, p = 0.003 respectively), while total testosterone levels were only significantly correlated in CAH men (ρ = 0.543; p = 0.036). Androstenedione levels did not show a significant correlation. Receiver-operating characteristic (ROC) curve analysis indicated that a cutoff value of 21.7 pg/mg for 17-OHP in hair provided a sensitivity of 100% and a specificity of 88.9% for identifying men with elevated serum androstenedione. Hair 17-OHP in women showed a poorer performance in terms of identifying those with elevated androstenedione serum levels. However, when applying a cutoff value of 5.5 for the free androgen index as a marker of significant hyperandrogenism in CAH women, 17-OHP >27.6 pg/mg in hair provided a sensitivity of 100% and a specificity of 95.8% (AUC 0.986, 95% CI 0.945–1.000; p < 0.001). Neither hair cortisol nor markers of adrenal androgen control in hair showed significant associations with cardiometabolic outcome or bone health. Conclusion: This study shows that scalp hair 17-OHP concentrations may be a promising noninvasive long-term parameter for treatment monitoring in adult patients with CAH.

Plasma renin activity profile of patients with congenital adrenal hyperplasia in Semarang, Indonesia: a preliminary study

Congenital Adrenal Hyperplasia (CAH) is an adrenal disorders due to impaired activity of one of the enzymes required for cortisol and aldosterone biosynthesis. One of the subtypes of CAH is the salt-wasting (SW) form which there is a renal salt loss due to aldosterone deficiency. Plasma Renin Activity (PRA) is the main index used to evaluate the mineralocorticoid control in CAH. PRA testing is almost very rare done for the CAH patients due to high cost, sophisticated laboratory is not available in all region and no compulsary health insurance in Indonesia. The objective of this research was to describe PRA level in patient with Congenital Adrenal Hyperplasia. This study is a part of CAH cohort study in Center for Biomedical Research (CEBIOR), Semarang, Indonesia. Eighteen patients diagnosed as CAH were drawned blood samples for hormonal test, including 17 OHP, Plasma Renin Activity, Cortisol, and Electrolytes. Clinical history and physical examination was performed to each patients. All 18 patients (17 female and 1 male) have high 17-OHP level and normal electrolites levels, but only 14 patients have PRA data. Four patients did not show their PRA level due to fail in too much blood collection. Out of 14 patient, four patients which had history of SW have very high PRA level, while six patients have PRA level more than normal without history of salt wasting. The mean of PRA level in patients with history of SW (47.72 (SD 18.63)) are higher than the patient without history of SW (13.97 (SD 13.3)). This study suggest that PRA level might be useful for evaluating mineralocorticoid level in CAH. It is proposed to the government to subsidize and provide PRA and other hormonal testing for CAH in many regions with affordable cost.

Loss of Therapeutic Control in Congenital Adrenal Hyperplasia due to Interaction between Dexamethasone and Primidone

A 14-year-old girl with congenital adrenal hyperplasia showed rapid conversion from undertreatment to overtreatment when primidone, used to treat coexistent epilepsy, was withdrawn while on a constant steroid dose. In addition to signs of hypercortisolism and a decrease in random measurements of plasma testosterone and 170H-progesterone concentrations, the deterioration in control was also illustrated by changes in the pattern of blood spot steroid profiles. Adequate control was achieved only after a 3-fold reduction in steroid dose. The decrease in dose requirement was probably the result of a reversal of liver enzyme induction consequent upon the withdrawal of primidone.

Plasma Insulin-Like Growth Factor I Levels during Treatment of Congenital Adrenal Hyperplasia

We tested the hypotheses that the levels of insulin-like growth factor I (IGF-I) reflect the degree of control during the treatment of patients with congenital adrenal hyperplasia (CAH), and that suppressed IGF-I levels during puberty contribute to decreased adult height. We measured serial IGF-I levels in 26 CAH patients followed over 6 months to 5 years. The control of CAH was variable, with several cases of overtreatment in infancy, and frequent undertreatment in childhood and adolescence. IGF-I levels were quite variable and inconsistent with the control of CAH. Our results suggest that IGF-I levels are not helpful in monitoring CAH patients; IGF-I does not seem to play a role in the growth failure during CAH therapy.

17-α-OH progesterone determinations in unextracted saliva for treatment control in congenital adrenal hyperplasia

17-α-OH progesterone determinations in unextracted saliva for treatment control in congenital adrenal hyperplasia

Control in congenital adrenal hyperplasia monitored by frequent saliva 17OH-progesterone measurements.

Treatment in a group of 19 patients with congenital adrenal hyperplasia (CAH) has been monitored by frequent, serial measurements of saliva 17OH-progesterone (17OHP) concentrations. Detailed 17OHP profiles were obtained during consecutive weekend days and every 1-2 h over a separate 24-hour period. Patients showed a marked diurnal rhythm in 17OHP levels, particularly when treated with hydrocortisone. In some patients, 10 mg/m2/day of hydrocortisone was sufficient glucocorticoid replacement to produce adequate control, although there was considerable individual variation. Saliva 17OHP profiles provided valuable information on the efficacy of hydrocortisone, cortisone acetate, prednisolone and dexamethasone as glucocorticoid suppressive regimes in the treatment of CAH. Preliminary results suggest that hydrocortisone given in two divided doses during the day, supplemented by a small dose of prednisolone at bedtime, is suitable treatment for CAH patients who are still growing. In the patient who has completed statural growth, single daily dose dexamethasone therapy ensures adequate adrenal suppression and is convenient in the longterm.

Diagnosis and monitoring of therapy of the various enzymatic defects causing congenital adrenal hyperplasia by semiautomatic capillary gas-liquid chromatography.

A semiautomatic capillary gas-liquid chromatographic method for the determination of urinary steroids has been developed. Trimethylsilylenol ethers were used as steroid derivatives instead of the more common methoxime trimethylsilyl ethers. The diagnosis of the various enzymatic defects causing congenital adrenal hyperplasia can be made using the characteristic pattern of urinary steroid chromatograms. Furthermore, the method presented can be used routinely to monitor therapeutic control in congenital adrenal hyperplasia. Reference data for patients of different age groups under good therapeutic control are presented.

Simultaneous plasma and saliva steroid measurements as an index of control in congenital adrenal hyperplasia (CAH): A longitudinal study

Plasma concentrations of 170H-progesterone (17P), testosterone (T) and saliva concentrations of 17P have been determined serially for 3 yr in 16 treated CAH patients with 21-hydroxylase deficiency (present age 4.0-16.5 yr) . Analysis of 71 paired samples showed significant correlations between plasma 17P and T (r=0.70,p 0.1) , presumably because of the marked individual variation in the adrenal suppressive effect of glucocorticoid. The ease of saliva collection permitted 24-hour home 17P profiles in treated patients. All demonstrated a marked diurnal rhythm, but well-controlled patients showed normal 17P levels during the afternoon. Frequent serial measurements of 17P through saliva collection at home is an additional simple and useful parameter for fine-tuning control in CAH patients.

Plasma Adrenocorticotrophic Hormone in Congenital Adrenal Hyperplasia

In a prospective study, assays of plasma adrenocorticotrophic hormone (ACTH) were compared with established criteria to evaluate the determination's usefulness in monitoring the control of congenital adrenal hyperplasia (CAH). In 22 infants and children with 21-hydroxylase deficiency, the plasma ACTH value correctly identified the status of control in 51 of 73 (70%) patient visits. Plasma ACTH concentrations were significantly higher in patients whose conditions were out of control when compared with patients whose conditions were under control, although there was an overlap between the two groups. Plasma ACTH concentrations were significantly higher in patients with sodium-losing CAH than in patients with non-sodium-losing CAH. These findings support the concepts that patients with the sodium-losing condition have a more severe enzyme deficiency and that ACTH stimulation may be affected by sodium balance. Although plasma ACTH determinations are a useful adjunct in the long-term management of CAH, they cannot be relied on as the sole criterion of control.

Assessment of ACTH-Adrenal Activity and Diagnostic Value of Plasma ACTH

In primary adrenal insufficiency plasma ACTH values are 5-10 times above the upper normal limit (80-100 pg/ml) and allow a confirmation of the diagnosis even during substitution therapy. Clearly elevated ACTH levels (mean 720 pg/ml) are found in 50% of treated CAH patients. In cushing's disease ACTH concentrations at or above 500 pg/ml of plasma are found. The ACTH-response to a 3 hour metyrapone test was compared between 18 steroid treated patients (29 tests) and 21 tests performed for growth retardation. The tests were analysed based on the following criteria: basal ACTH, < 50-100 pg/ml, increase ≥ 50 pg/ml, maximum ≥ 100 pg/ml. Cortisol basal value 6-13 μg%, compound-S increase ≥ 4 μg%. In steroid treated patients a normal function was found in 4 tests and signs of incomplete recovery in 10 tests. In 6 tests a partial insufficiency was diagnosed. A complete suppression was found in 4 tests. ACTH adrenal function during and after steroid treatment appears to be largely unpredictable. The metyrapone test is valuable in assessing ACTH adrenal function in suspected secondary insufficiences. Plasma ACTH concentrations without stimulation are helpful for the diagnosis of primary adrenal insufficiency of cushing's disease and for the biochemical control of congenital adrenal hyperplasia.

Chromatography of the 17-ketogenic steroids in the diagnosis and control of congenital adrenal hyperplasia.

ABSTRACT A method for the fractionation of the urinary 17-ketogenic steroids with no oxygen grouping at C11 and those oxygenated at C11, is applied to the clinical problems of congenital adrenal hyperplasia. In normal children the mean ratio of the non-oxygenated to oxygenated steroids is 0.24. In childrern with congenital adrenal hyperplasia the ratio is 2.3. The reason for this difference in ratio is discussed. The changes in ratio found under stimulation of the adrenal gland with exogenous or endogenous corticotrophin and the suppression with cortisone therapy are studied. This test can be applied to isolated samples of urine, a major advantage in paediatric practice, and can be carried out in routine laboratories. It is found to be reliable in the diagnosis and sensitive in the control of congenital adrenal hyperplasia.