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Introduction: Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) is a rare genetic condition characterized by cortisol deficiency and excess adrenal androgens. CAH treatment is a lifelong balancing act between the need to reduce excess androgens, typically with supraphysiologic glucocorticoid (GC) doses, and concerns about potentially serious GC-related adverse events. Tradeoffs between the consequences of excess androgens versus GCs must be constantly reassessed throughout each patient's lifetime, based on current clinical needs and treatment goals. Adding to this burden are limited treatment options and the need for new CAH medications. Areas covered: This narrative review describes the current challenges of CAH treatment, the potential of new non-GC therapies to reduce excess androgens and thereby allow for lower GC doses, and the potential implications of decreasing GC doses to a more physiologic range (i.e. sufficient to replace missing cortisol, but without the need to reduce androgens). Expert opinion: Even with non-GC therapies, patients' needs will continue to shift throughout their lifetimes. Treatment will therefore always require joint decision-making between physicians and patients. However, over the lifetimes of patients with CAH, any reduction in GC daily dose may have a large cumulative impact in decreasing the GC-related burden of this disease. [ABSTRACT FROM AUTHOR]

Context: Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a rare autosomal recessive disorder characterized by cortisol deficiency and androgen excess due to elevated adrenocorticotropin. Objective: To evaluate the safety, tolerability, and efficacy of crinecerfont in adolescents with 21OHD CAH. Methods: This was an open-label, phase 2 study (NCT04045145) at 4 centers in the United States. Participants were males and females, 14 to 17 years of age, with classic 21OHD CAH. Crinecerfont was administered orally (50 mg twice daily) for 14 consecutive days with morning and evening meals. The main outcomes were change from baseline to day 14 in circulating concentrations of ACTH, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone. Results: 8 participants (3 males, 5 females) were enrolled; median age was 15 years and 88% were Caucasian/White. After 14 days of crinecerfont, median percent reductions from baseline to day 14 were as follows: ACTH, -57%; 17OHP, -69%; and androstenedione, -58%. In female participants, 60% (3/5) had =50% reduction from baseline in testosterone. Conclusion: Adolescents with classic 21OHD CAH had substantial reductions in adrenal androgens and androgen precursors after 14 days of oral crinecerfont administration. These results are consistent with a study of crinecerfont in adults with classic 21OHD CAH. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- To determine using the MiniMed continuous glucose monitoring system (CGMS) 1) whether twice-daily insulin injection therapy achieves adequate control in preschool children with type 1 diabetes and 2) whether the CGMS is more informative than self-monitoring of blood glucose (SMBG) regarding glucose control and well tolerated by preschool children and their families. RESEARCH DESIGN AND METHODS -- Ten children <6 years of age with type 1 diabetes were monitored twice using the CGMS. The distribution of glucose values was analyzed, particularly the frequency, duration, and distribution of hypoglycemia. We analyzed the accuracy of the CGMS in detecting hypoglycemia as well as the clinical relevance of the difference between CGMS and SMBG values. RESULTS -- Although hypoglycemia was more frequent during the night (0.8 nighttime episodes ⋅ subject[sup-1] ⋅ 24 h[sup-1] vs. 0.3 daytime episodes, subject[sup-1] ⋅ 24 h[sup-1]), the difference did not reach statistical significance (P = 0.07). However, nighttime episodes lasted longer than daytime episodes (1.2 vs. 0.2 h ⋅ subject[sup-1] ⋅ 24 h[sup-1], P = 0006). Hypoglycemia accounted for 7% and normoglycemia for 24%, while hyperglycemia occurred 64% of the time, with postprandial hyperglycemia being an almost universal feature (94 ± 7% of all postmeal values). The CGMS correlated well with SMBG without significant clinical discrepancy. The CGMS sensitivity to detect hypoglycemia was 70% with a specificity of 99%; however, the CGMS detected twice as many total episodes as SMBG (82 vs. 40). CONCLUSIONS -- Twice-daily insulin injection rarely achieves control in preschool children with type 1 diabetes. The CGMS is well tolerated by patients and has the advantage of revealing daily glucose trends missed by SMBG. [ABSTRACT FROM AUTHOR]

Background: Children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency require treatment with glucocorticoids, usually at supraphysiologic doses, to address cortisol insufficiency and reduce excess adrenal androgens. However, such treatment confers a predisposition to glucocorticoid-related complications. In 2-week phase 2 trials, patients with CAH who received crinecerfont, a new oral corticotropin-releasing factor type 1 receptor antagonist, had decreases in androstenedione levels., Methods: In this phase 3, multinational, randomized trial, we assigned pediatric participants with CAH, in a 2:1 ratio, to receive crinecerfont or placebo for 28 weeks. A stable glucocorticoid dose was maintained for 4 weeks, and the dose was then adjusted to a target of 8.0 to 10.0 mg per square meter of body-surface area per day (hydrocortisone dose equivalents), provided that the androstenedione level was controlled (≤120% of the baseline level or within the reference range). The primary efficacy end point was the change in the androstenedione level from baseline to week 4. A key secondary end point was the percent change in the glucocorticoid dose from baseline to week 28 while androstenedione control was maintained., Results: A total of 103 participants underwent randomization, of whom 69 were assigned to crinecerfont and 34 to placebo; 100 (97%) remained in the trial at 28 weeks. At baseline, the mean glucocorticoid dose was 16.4 mg per square meter per day, and the mean androstenedione level was 431 ng per deciliter (15.0 nmol/liter). At week 4, androstenedione was substantially reduced in the crinecerfont group (-197 ng per deciliter [-6.9 nmol/liter]) but increased in the placebo group (71 ng per deciliter [2.5 nmol/liter]) (least-squares mean difference [LSMD], -268 ng per deciliter [-9.3 nmol/liter]; P<0.001); the observed mean androstenedione value, obtained before the morning glucocorticoid dose, was 208 ng per deciliter (7.3 nmol/liter) in the crinecerfont group, as compared with 545 ng per deciliter (19.0 nmol/liter) in the placebo group. At week 28, the mean glucocorticoid dose had decreased (while androstenedione control was maintained) by 18.0% with crinecerfont but increased by 5.6% with placebo (LSMD, -23.5 percentage points; P<0.001). Headache, pyrexia, and vomiting were the most common adverse events., Conclusions: In this phase 3 trial, crinecerfont was superior to placebo in reducing elevated androstenedione levels in pediatric participants with CAH and was also associated with a decrease in the glucocorticoid dose from supraphysiologic to physiologic levels while androstenedione control was maintained. (Funded by Neurocrine Biosciences; CAHtalyst Pediatric ClinicalTrials.gov number, NCT04806451.)., (Copyright © 2024 Massachusetts Medical Society.)

Context: X-linked adrenal hypoplasia congenita (AHC) is a rare but important cause of primary adrenal insufficiency and can be associated with significant morbidity and mortality. AHC is caused by mutations within the NROB1 gene that codes for the DAX-1 protein, an orphan nuclear receptor essential for the development of the hypothalamic-pituitary-adrenal axis. Affected individuals typically present in early infancy with adrenal insufficiency and growth is usually normal once medical therapy is instituted. Here we report the first case of growth hormone deficiency in an infant with AHC and a novel NROB1 missense mutation., Case: A two-week old infant presented with salt-losing adrenal crises and a normal newborn screen. Tests of adrenal function confirmed adrenal hypoplasia congenita and molecular evaluation revealed a novel missense NROB1 mutation. Replacement steroid therapy was promptly initiated, but he subsequently developed growth failure despite optimal nutritional and medical steroid therapy. Further biochemical analyses confirmed isolated idiopathic growth hormone deficiency., Conclusions: Growth failure in adequately treated infants with adrenal hypoplasia congenita is rare and the role of DAX-1 in the development of pituitary somatotropes is not known. There is variable genotype-phenotype correlation in X-linked adrenal hypoplasia congenita but novel NROB1 missense mutations could offer insight into the function of the various DAX-1 ligand-binding domains.

The clinical chemistry of diabetes care is unique in Endocrinology, because many of the commonly performed tests, such as assays for glucose, ketones and hemoglobin A1c, are done by the patient at home or by the nurse at the bedside or clinic. Hence, some may assume that these tests are accurate and precise. However, measurement of these substances is often problematic. While laboratory-based glucose analyzers are generally accurate, pre-analytic variables may introduce confusion. Hand held glucose meters are in widespread use and a number of variables are assumed regarding their use, such as hematocrit, oxygen tension and pH. Urine ketone assays may be confusing during conditions altering the mitochondrial redox potential and they are prone to interference from medications. Many different assays for HbA1c are in use today and the various assay types may each be prone to interference from abnormal hemoglobins, iron deficiency states and medication use. International efforts are underway to standardize HbA1c measurements. Insulin assays are being more commonly used as the prevalence of type 2 diabetes and the metabolic syndrome increases. Unfortunately, insulin assays are not standardized, making comparisons of results from different laboratories difficult. Finally, the assessment of diabetes-associated autoantibodies is becoming clinically useful as our understanding of the immunologic basis of diabetes develops and as protocols for the prediction (and ultimately prevention) of the disease arise. While a physician's clinical sense should always guide the interpretation of laboratory values, an understanding of the basis of commonly ordered clinical tests is critical in the care of patients with diabetes.