Introduction: Youth and adults with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) are at risk for cognitive deficits and brain structural changes. Although factors inherent to CAH have been implicated in cognitive dysfunction, little is known about early developmental skills in these patients. Thus, we aimed to investigate development in younger children with CAH. Methods: Cross-sectional study of 13 infants and toddlers (0.4-3.5 yrs) and 21 children (3.5-11 yrs) with classical CAH due to 21OHD. Infants and toddlers completed cognitive and motor skills screening (Bayley-4). Children also completed age-appropriate assessment of cognition (WISC-V Digit Span and Spatial Span subtests, NIH Toolbox-Version 2, WRAML-2 Design Memory subtest, CVLT-C) and motor skills (NIH Toolbox-Version 2). Their parents completed standardized reports of adaptive behavior and motor skills (Vineland-3). T-tests compared the CAH group (mean percentile, mean ± SD) with normative means. Results: Infants and toddlers with CAH exhibited lower gross motor skills (27th percentile, 8.2±2.4, p=0.03) compared to the normative mean. Children with CAH exhibited decreased auditory working memory skills (WISC-V, 27th percentile, 8.2±1.8, p=0.01), and lower nonverbal learning skills (WRAML-2, 21st percentile, 7.6±3.4, p=0.02). Their parents reported lower adaptive behavior (Vineland-3, 30th percentile, 92.2±9.1, p=0.004) and overall motor skills (26th percentile, 90.3±11.4, p=0.006) than the normative mean. Conclusions: Pediatric patients with CAH due to 21OHD exhibit distinct, age-dependent developmental deficits, with infants and toddlers displaying lower gross motor performance, and children exhibiting decreased auditory working memory and adaptive behavior skills. These findings suggest that early signs of developmental deficits in CAH may emerge at a younger age than previously recognized, emphasizing the role of clinical factors inherent to the disease.

BACKGROUND:Few studies have evaluated the influence of gestational HIV/antiretroviral exposure on pubertal onset in children who are HIV-exposed but uninfected (CHEU). METHODS:CHEU in the Surveillance Monitoring for ART Toxicities study and children HIV-unexposed uninfected (CHUU) in the Bone Mineral Density in Childhood Study with Tanner staging at age 9 years were included. Pubertal onset was defined as Tanner stage ≥2 for each sex-specific puberty indicator. Log-binomial regression models were fit to estimate relative risks (RRs) of pubertal onset in CHEU vs. CHUU, adjusted for exact age and other covariates. Among CHEU, models were fit to assess the association of pubertal onset with maternal protease inhibitor exposure, CD4 count, and earliest HIV viral load (VL) during pregnancy. RESULTS:In total, 227 CHEU (114 female, 113 male) and 344 CHUU (182 female, 162 male) were included. Among male CHEU, the adjusted likelihood of pubertal onset by age 9 years was 2.07 times higher [95% CI: 0.89 to 4.79] for genitalia and 3.55 times higher [95% CI: 0.92 to 13.81] for pubic hair than male CHUU. Pubertal onset was similar in female CHEU and CHUU. Among male CHEU, a maternal VL ≥400 copies/mL was associated with a greater likelihood of pubertal onset (adjusted RR: 12.6 [95% CI: 1.56 to 102] for genitalia and 9.85 [95% CI: 1.17 to 83] for pubic hair). CONCLUSIONS:Gestational HIV exposure and exposure to higher maternal HIV viral load were associated with greater likelihood of pubertal onset by age 9 years in male CHEU. Further confirmatory and mechanistic studies are warranted.

Disclosure: M.E. Geffner: research support from Ascendis, Diurnal, Neurocrine Biosciences, Novo Nordisk, Pfizer, and Spruce Biosciences, serves on advisory boards or as a consultant for Adrenas Therapeutics, Ascendis, Eton Pharmaceuticals, Neurocrine Biosciences, Novo Nordisk, Pfizer, Spruce Biosciences, and Theratechnologies, Inc., serves as an adjudication committee member for ICON Clinical Research, LLC/Aeterna Zentaris, receives royalties from McGraw-Hill and UpToDate. R.S. Newfield: clinical trial investigator for Neurocrine Biosciences and Spruce Biosciences; consultant for Spruce Biosciences on behalf of UCSD but does not receive personal income for this consultancy. Y. Hsu: Consultant for Neurocrine. M.T. Dattani: Lecturing fees: Meck Serono, Pfizer, Novo Nordisk, Sandoz. Advisory Boards: Pfizer, Novo Nordisk. Consultancy: Sandoz, Pfizer, Besins. M. Bettendorf: None. J.L. Chan: Full-time employee of Neurocrine Biosciences, Inc. R.H. Farber: Full-time employee of Neurocrine Biosciences, Inc. G.B. Rosales: Full-time employee of Neurocrine Biosciences, Inc. G.S. Jeha: Full-time employee of Neurocrine Biosciences, Inc.. Background: Crinecerfont, a corticotropin-releasing factor type 1 receptor (CRF1) antagonist, is a first-in-class medication that is FDA-approved for adjunctive treatment to glucocorticoid (GC) replacement to control androgens in patients with classic congenital adrenal hyperplasia (CAH). In two phase 3 trials, crinecerfont significantly reduced excess androgens, enabling subsequent reductions in GC doses in pediatric and adult patients with CAH. Objective: To evaluate changes in adrenocorticotropic hormone (ACTH) and 17-hydroxyprogesterone (17-OHP) levels in pediatric patients with classic CAH who received up to 1 year of crinecerfont. Methods: Participants from the 28-week double-blind placebo-controlled (DBPC) period of CAHtalystTM Pediatric (NCT04806451) continued taking crinecerfont (25, 50, or 100 mg BID based on weight) (CFT/CFT) or switched from placebo (PBO/CFT) in the 24-week open-label (OL) period. In both periods, GC doses were kept stable for the first 4 weeks to measure the impact on androgens and then reduced to a target of 8-10 mg/m2/d in hydrocortisone equivalents while maintaining or improving androstenedione (A4) relative to Day 1 baseline (BL). Changes in plasma ACTH and serum 17-OHP (before morning GC dose) were analyzed after stable GC dosing (Week 4) and after GC reduction (Week 28) in the DBPC period and at the end of OL treatment (Week 52). For predefined endpoints in the DBPC period, results are presented as least-squares (LS) mean changes with LS mean difference (LSMD) and p-value. Results: During the DBPC period, mean decrease from BL in ACTH was greater with crinecerfont than placebo at Week 4 (-218 vs -54 pg/mL) and at Week 28 (-111 vs -1.5 pg/mL; LSMD -110 pg/mL, P=0.0671), despite a significant mean percent reduction in GC dose with crinecerfont at Week 28 (-18% vs +5.6%; LSMD -23.5%, P<0.0001). 17-OHP decreased with crinecerfont and increased with placebo at Week 4 (-5865 vs +556 ng/dL; LSMD -6421 ng/dL, P<0.0001); at Week 28, after GC dose reduction, the mean decrease was greater with crinecerfont than placebo (-2345 vs -430 ng/dL). In the OL period, mean ACTH and 17-OHP remained below Day 1 BL at Week 52 in participants who continued crinecerfont (ACTH: -124 pg/mL; 17-OHP: -1612 ng/dL) and those who switched from placebo (ACTH: -104 pg/mL; 17-OHP: -1891 ng/dL) despite reductions in GC dose (-17.3% [CFT/CFT], -6.1% [PBO/CFT]). Conclusion: In children/adolescents with CAH who received up to 1 year of crinecerfont, ACTH and 17-OHP were reduced to below BL levels, even after reductions in GC dose. These decreases were consistent with the significant A4 reduction reported in the DBPC period. Crinecerfont, a novel oral CRF1 antagonist, is a non-GC approach to manage excess ACTH and adrenal androgens in CAH, enabling GC doses to be lowered and thus achieving the dual goals of reducing androgen excess and the risks associated with long-term supraphysiologic GC exposure. Presentation: Sunday, July 13, 2025

Disclosure: B.P. Hoffman-Kipp: None. H. Wang: None. S. Dettweiler: None. A. Mockler: None. M.E. Geffner: Neurocrine Biosciences, Spruce Biosciences, Eton Pharmaceuticals, UpToDate, Adrenas Therapeutics. M.S. Kim: Neurocrine Biosciences, Spruce Biosciences, Eton Pharmaceuticals, UpToDate, Adrenas Therapeutics. Introduction: Classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most common primary adrenal insufficiency in children, involving androgen excess due to impaired steroidogenesis. Older children, adolescents, and adults with CAH exhibit up to double the prevalence of obesity compared to controls, with an earlier adiposity rebound (1.5-3 years) than normative populations reported in the U.K., Japan, and the U.S. However, more needs to be understood about the early onset of obesity in younger children with classical CAH. We aimed to examine disease-specific growth trajectories from early childhood (0-6 years) in a large cohort of children with classical CAH in the U.S. Methods: Early childhood growth data were studied in 95 children (55.8% female) with classical CAH due to 21-hydroxylase deficiency (86.3% salt-wasting form). Measurements from 1060 patient visits of children between birth to 6 years in the Endocrinology clinic at Children’s Hospital Los Angeles (1998-2024) were analyzed. Cohort-wide growth trajectories were visualized using generalized additive models and compared to reference population growth data (WHO < 2 years, CDC 2-6 years). The LMS modeling approach for non-normally distributed data was applied to estimate percentiles and z-scores for weight, weight-for-length (WFL, < 2 years), and BMI (2-6 years), and to generate total and sex-specific growth curves in early childhood. We categorized patients between 2-6 years of age for weight based on BMI percentile. Results: In infants with CAH, the median WFL began to surpass the 50th percentile for the reference population in the second month of life (6 weeks). The median WFL z-score in infants with CAH increased rapidly until 5 months of age, when it remained more stable until 2 years of age. This upward drift from the reference median became more pronounced with age in children with CAH, who exhibited a median BMI z-score of +1 at 4-5 years, reaching a BMI z-score of +1.4 (overweight) by 6 years. These trajectory patterns appeared to be driven by males with CAH compared to females. In children with CAH between 2-6 years of age, the percentage of children who were overweight ranged from 22-27% depending on the year of life. The percentage living with obesity increased with each year of life: 2-3 years, 14.1%; 3-4 years, 18.5%; 4-5 years, 21.2%; and 5-6 years, 30.0%. By 5 years, these children exhibited 2.3 times the prevalence of obesity seen in typical 2-5 year old children in the U.S. (NHANES). Conclusions: Infants with classical CAH exhibit different patterns of growth from month two of life, compared to reference populations, with a steadily increasing prevalence of obesity through their toddler and preschool years. Presentation: Monday, July 14, 2025

Introduction: Children and adolescents with congenital adrenal hyperplasia (CAH) are at increased risk for obesity and exhibit differences in brain regions associated with food reward and decision-making. We aimed to understand differences in dietary decision-making between youth with CAH compared to controls. Methods: 37 youth with CAH (12.2 ± 3.1y, 59.5% female) and 100 controls (11.7 ± 2.4y, 57% female) rated 30 low- and 30 high-calorie foods for health, taste, and liking. Participants then chose between 100 food pair trials using a mouse-tracking paradigm; 75 were discordant for health and taste ratings. Self-control success was measured as the percentage of trials in which the healthier food was chosen instead of the tastier food. Area under the curve (AUC) and maximum deviation (MD) are used as real-time indices of decision-making. Results: Patients with CAH exhibited higher AUCs (CAH: 9.48 ± 8.08, Control: 6.40 ± 7.33; p < 0.05) and MDs (CAH: 0.20 ± 0.13, Control: 0.15 ± 0.12; p < 0.05) in self-control trials. However, patients with CAH and controls did not differ in their self-control success (CAH: 28.47 ± 24.27%, Control: 35.16 ± 25.01%; p = 0.16). In youth with CAH, testosterone was correlated with AUC (R = 0.46, p < 0.01) and MD (R = 0.38, p = 0.02) during successful self-control trials. Conclusions: Children and adolescents with CAH exhibit more cognitive conflict when choosing between healthy and tasty foods. Two indicators of disease severity were associated with cognitive conflict during food choice in patients with CAH. Our findings suggest impaired dietary decision-making in CAH could contribute to obesity risk.

Introduction: Histrelin acetate implant (HI) is an approved treatment option for children with central precocious puberty. Implant duration has been reported to surpass the recommended replacement interval of 1-2 years. Implant breakage is a known potential adverse effect during the extraction procedure. However, the bioactivity of the retained fragment has not been reported previously. Case Presentation: We present 3 cases of females with central precocious puberty, who received HI for pubertal suppression and experienced implant breakage during extraction. In 2 cases, the retained fragment suppressed pubertal hormone for 5 years. In the third case, the HI was left in place due to loss of follow-up, and the patient was amenorrheic for the next 6 years. In all 3 cases, menstruation occurred after the HI fragments were surgically removed. Conclusion: Our case series demonstrates that retained HI fragment can be bioactive for up to 5 years. If HI breakage occurs during removal, ultrasound localization and surgical extraction of the fragment should be performed.

Disclosure: R.S. Newfield: Clinical trial investigator for Neurocrine Biosciences, Inc. and Spruce Biosciences; consultant for Spruce Biosciences. M.E. Geffner: Research support from Ascendis, Diurnal, Neurocrine Biosciences, Novo Nordisk, Pfizer, and Spruce Biosciences; serves on advisory boards or as a consultant for Adrenas Therapeutics, As. Y. Hsu: Consultant for Neurocrine. M.T. Dattani: Lecturing fees: Meck Serono, Pfizer, Novo Nordisk, Sandoz. Advisory Boards: Pfizer, Novo Nordisk. Consultancy: Sandoz, Pfizer, Besins.. M. Bettendorf: None. R.H. Farber: Full-time employee of Neurocrine Biosciences, Inc. G.B. Rosales: Full-time employee of Neurocrine Biosciences, Inc. G.S. Jeha: Full-time employee of Neurocrine Biosciences, Inc. J.L. Chan: Full-time employee of Neurocrine Biosciences, Inc.. Background: Crinecerfont, a corticotropin-releasing factor type 1 receptor (CRF1) antagonist, is a first-in-class medication that is FDA-approved for adjunctive treatment to glucocorticoid (GC) replacement to control androgens in patients with classic congenital adrenal hyperplasia (CAH). In two phase 3 trials, crinecerfont significantly reduced excess androgens, enabling subsequent reductions in GC doses in pediatric and adult patients with CAH. Objective: To evaluate changes in androstenedione (A4) levels and GC doses in pediatric patients with CAH who received up to 1 year of crinecerfont. Methods: Participants from the 28-week double-blind placebo-controlled (DBPC) period of CAHtalystTM Pediatric (NCT04806451) continued crinecerfont (25, 50, or 100 mg BID based on weight) (CFT/CFT) or were switched from placebo (PBO/CFT) in the 24-week open-label (OL) period. In both periods, GC doses were kept stable for the first 4 weeks and then decreased to a target dose of 8-10 mg/m2/d while maintaining or improving A4 relative to Day 1 baseline (BL). Changes in serum A4 levels (before morning GC dose) were analyzed after stable GC dosing (Weeks 4 and 32) and end of DBPC and OL treatment (Weeks 28 and 52). Changes in GC dose were analyzed at end of DBPC and OL treatment. Decreases in GC dose were set to zero if A4 was not maintained or improved relative to BL. For predefined endpoints in the DBPC period, results are presented as least squares (LS) mean changes with LS mean difference (LSMD) and p-value. Results: At BL, mean A4 was 431 ng/dL; mean GC dose was 16.4 mg/m2/d. In the DBPC period, A4 decreased from BL at Week 4 with crinecerfont and increased with placebo (-197 vs. +71 ng/dL; LSMD: -268 ng/dL, P=0.0002) and Week 28 (-94 vs. +147 ng/dL). A4 reduction with crinecerfont enabled a subsequent percentage decrease in GC dose from BL at Week 28, compared to an increase with placebo (-18% vs. +5.6%; LSMD: -23.5%, P<0.0001). In the OL period, mean A4 decreased to below BL at Week 32 (CFT/CFT, -121 ng/dL; PBO/CFT, -174 ng/dL) and after GC dose reduction at Week 52 (CFT/CFT, -13.8 ng/dL; PBO/CFT, -60.9 ng/dL). Mean changes and mean percentage changes in GC dose at Week 52 were as follows: CFT/CFT (-3.0 mg/m2/d, -17.3%); PBO/CFT (-1.1 mg/m2/d, -6.1%). Moreover, 33.8% and 17.2% of participants achieved a GC dose ≤11 mg/m2/d while maintaining or improving A4 in the CFT/CFT and PBO/CFT groups, respectively. Conclusion: In children and adolescents with CAH, reductions in excess A4 and GC doses observed with crinecerfont during the DBPC period were maintained during the OL period. By the end of OL treatment, mean A4 was maintained below BL levels despite a significant reduction in GC dosing to lower, more physiologic doses. Thus, not only can crinecerfont reduce androgen excess, but by enabling GC doses to be lowered, crinecerfont may also reduce the adverse effects of chronic exposure to supraphysiologic GCs over a lifetime of treatment. Presentation: Saturday, July 12, 2025

Disclosure: N.L. Yamashita: None. B. Jafar: None. S. Dettweiler: None. T.A. Pickering: None. B.P. Hoffman-Kipp: None. A. Mockler: None. E.A. Deras: None. S.H. O'Neil: None. G. Simon: None. M.J. Kilberg: None. M.E. Geffner: Up To Date, Adrenas, Diurnal, Neurocrine Biosciences, Novo Nordisk, Spruce Biosciences, Aeterna Zentaris, Ascendis, Eton Pharmaceuticals, Theratechnologies, Inc., Tolmar, Inc., McGraw-Hill. M.G. Vogiatzi: Neurocrine Biosciences, Spruce Biosciences, Adrenas Therapeutics, Crinetics Pharmaceuticals, Eton Pharmaceuticals. M.S. Kim: Diurnal, Adrenas, Neurocrine Biosciences, Spruce Biosciences, Eton Pharmaceuticals, Up To Date. Background: Classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency results in cortisol deficiency and androgen excess starting in utero. Over a lifetime, individuals with CAH may experience comorbidities, including differences in cognitive function and brain structure, though these are not fully understood. Adults with CAH exhibit deficits in working memory, along with reduced corticolimbic structures and white matter abnormalities, while adolescents show decreased inhibitory control and similar brain changes. Additional research is needed to clarify the links between these cognitive differences, brain development, and clinical factors such as age, treatment, and disease severity. Methods: We conducted a cross-sectional, observational study in patients with classical CAH due to 21-hydroxylase deficiency at two national Comprehensive Care Centers for CAH. All participants completed iPad-based cognitive testing using the NIH Toolbox Cognition Battery, assessing inhibitory control (Flanker), cognitive flexibility (Dimensional Change Card Sort), working memory (List Sort), and processing speed (Pattern Comparison). Patient scores were compared to normative means of 100 using Welch’s t test. Within the CAH cohort, Spearman’s correlation was used to assess relationships between cognition scores and age or glucocorticoid dose (mg/m²/day). Disease severity was categorized by CYP21A2 genotype as Null (0% enzyme activity, including deletions and large gene conversions) or Non-Null (< 1% or 1-2% enzyme activity), with severity groups compared via t test. Data are reported as mean ± SD. Results: In 105 patients with CAH (3-23 years old, 10.8 ± 5.4 years; 54% female), scores for inhibitory control (94.4 ± 17), working memory (94.1 ± 21), and processing speed (94.9 ± 12) were significantly lower than normative means (p’s < 0.05), but remained within the average range. In the CAH cohort, inhibitory control (R = -0.6), cognitive flexibility (R = -0.3), and processing speed (R = -0.3) were inversely correlated with age (p’s < 0.01). Additionally, cognitive flexibility (R = -0.3) and processing speed (R = -0.3) were inversely correlated with glucocorticoid dose (p’s < 0.05). Among 68 patients with genotype data, 41% (28/68) had Null genotypes and showed reduced cognitive flexibility (91.0 ± 8) compared to Non-Null (100.0 ± 10; p < 0.05). Conclusions: In a large cohort of patients with classical CAH, we observed lower cognitive function compared to controls, worsening with age and higher glucocorticoid doses. Additionally, patients with the most severe genotypes exhibited lower cognitive functioning. Future longitudinal studies are essential to explore the implications of these cognitive impairments and their relationship to developmental trajectories in patients with CAH. Presentation: Saturday, July 12, 2025

Disclosure: V.X. Yu: None. M.E. Geffner: Diurnal, Novo Nordisk, Neurocrine Biosciences: Research support, Advisory board/Consultant, Spruce Biosciences: Research support, Advisory board/Consultant, Ascendis: Advisory board/Consultant, Eton Pharmaceuticals: Advisory board/Consultant, Theratechnologies, Inc: Advisory board/Consultant, McGraw-Hill: Royalties, Up To Date. L.M. Randolph: BioMarin Pharmaceuticals- Advisory board/consultant. Z. Laron: None. A. Ryabets-Lienhard: Ultragenyx, Principal investigator receiving grant support for research, Takeda, Principal investigator receiving grant support for research, Alexion Pharmaceuticals, Inc., Advisory board/consultant, BioMarin Pharmaceuticals- Advisory board/consultant. Introduction: Laron syndrome (LS) is a rare autosomal recessive disorder with an estimated 500 global cases, characterized by GH resistance due to pathogenic variants in the GH receptor (GHR) gene, resulting in primary IGF-1 deficiency. Affected patients exhibit severe short stature, distinctive facial features, and extremely low levels of IGF-1 despite normal or elevated GH levels. The broad spectrum of pathogenic GHR variants in LS includes missense, nonsense, splice-site, and deletion variants that often involve the extracellular (EC) GH binding domain of the GHR (exons 1-7) and result in low GH-binding protein (GHBP) levels. We present a unique case of an adolescent male with severe LS associated with a novel missense variant in GHR exon 7, but normal GHBP levels. Case: An almost 16-yr-old male of Mexican ancestry with no known significant family history or consanguinity presented with severe relatively proportional short stature (height -7.06 SD, BMI 0.37 SD). He had an infantile face with round cheeks, depressed nasal bridge, high-pitched voice, slightly blue sclerae, Tanner Stage (TS) 2 puberty with testosterone 77 ng/dL (8-66), and bone age 11.6 yr. He was found to have undetectable IGF-1 (<10 ng/mL, 201-609) and low IGFBP-3 (0.8 mg/L, 3.5-10.0) with normal GH stimulation (peak GH 10.9 ng/mL) and GHBP (1446 pmol/L, 290-3140). TSH was elevated (6.43 mlU/mL, 0.50-5.00) with normal FT4 (1.09 ng/dL, 0.70-1.65). Genetic testing using the Discover Dysplasias gene panel (Invitae) identified a novel homozygous c.650T>G (p.Val217Gly) variant in GHR exon 7, classified as a variant of uncertain significance, in the last codon of the EC binding domain. There was no response in IGF-1 generation testing to GH 33 mg/kg/day x 7 days (IGF-1 averaged 11 ng/dL, 201-609; -5.5 SD), further supporting a diagnosis of LS. After 3 mo, height remained -7.08 SD while puberty progressed to TS3 with increased testosterone (526 ng/dL, 26-800). TSH increased further to 9.74 mlU/mL with normal FT4 1.13 ng/dL. Patient started recombinant human IGF-1 therapy at 0.1 mg/kg once daily x 1 wk, then increased to 0.18 mg/kg once daily x 1 wk and subsequently to 0.12 mg/kg twice daily (with no hypoglycemia or other side effects). Letrozole (2.5 mg daily) was also started to delay epiphyseal fusion. Conclusion: This unique case of severe Laron syndrome involves a novel homozygous missense variant of uncertain significance in the EC GH binding domain of GHR with unexpectedly normal GHBP levels, potentially expanding the scope of known GHR pathogenic variants. Its position in the last codon of the EC domain adjacent to the transmembrane domain may explain normal GHBP levels with disruption of GH action downstream. Functional studies are planned to further analyze this novel variant and confirm its pathogenicity. The co-occurrence of subclinical hypothyroidism also warrants further study regarding its contribution to the LS phenotype. Presentation: Saturday, July 12, 2025

BackgroundAdrenal crisis is the leading cause of death in patients with adrenal insufficiency, and prevention requires immediate parenteral hydrocortisone administration. However, most patients do not receive their home emergency hydrocortisone injection. Our study aimed to investigate barriers and enablers to using emergency hydrocortisone injections in managing adrenal crises.MethodsThis mixed-methods observational study utilized an online survey distributed through two U.S.-based patient advocacy groups. A total of 688 respondents completed the survey, including 485 (70%) parents/caregivers of individuals with adrenal insufficiency and 203 (30%) adults with adrenal insufficiency. Qualitative free-text responses were analyzed using thematic content analysis, with subsequent quantification of identified barriers and enablers to administering parenteral hydrocortisone during adrenal crises.ResultsOver 60% of patients with adrenal insufficiency had required parenteral hydrocortisone for an adrenal crisis, yet fewer than 20% managed to self-inject. Thirteen barriers and nine enablers were identified across three thematic domains: device factors, external factors, and emotional factors. Key barriers included the complexity of the multi-step hydrocortisone injection process (81%), injection-related anxiety and lack of confidence (18%), challenges accessing the correct hydrocortisone formulation or equipment (38%), and inadequate support for managing adrenal crises (29%). Key enablers included the effectiveness of hydrocortisone (14%), the convenience of the combined powder-and-diluent hydrocortisone vial (36%), and patient education (4%). Notably, 97% of participants expressed a preference for a hydrocortisone autoinjector to enhance self-injection capabilities.ConclusionEffective adrenal crisis management requires comprehensive, evidence-based interventions across patient, healthcare, and societal levels. This should include the development of user-friendly hydrocortisone delivery devices, individualized patient education, healthcare system reforms, and public awareness.

Researchers looked at data from the largest and longest-running database of children with growth disorders who were treated with daily injections of a brand of growth hormone called Genotropin. The researchers used these data to better understand the safety and effectiveness of daily growth hormone treatment. Researchers showed that daily growth hormone treatment: ○ Increased the children's heights, measured after 1 year of treatment. This was seen for all of the growth disorders studied. ○ Increased growth in children of different ages, with higher growth seen in children who had begun treatment before they started puberty. ○ Allowed short children to reach an adult height within the normal range. This was true even for children who did not begin treatment until early adolescence. ○ Was safe. Only a very small percentage (3%) of children had any side effects related to growth hormone treatment, the most common of which was headaches. When children reach the end of puberty, their growth plates close and they are unable to grow any taller. Once this happens, growth hormone treatment cannot increase their growth further and treatment should be stopped. The purpose of this plain language summary is to help you to understand the findings from recent research. Somatropin is used to treat the conditions under study that are discussed in this summary. Approval varies by country; please check with your local healthcare provider for more details.The results of this study may differ from those of other studies. Health professionals should make treatment decisions based on all available evidence and not on the results of a single study.

Objective: Adults with classical congenital adrenal hyperplasia (CAH) exhibit a higher lifetime prevalence of depression, but little is known about onset or etiology of mood disorders in this population. We therefore aimed to assess depression in youth with CAH, compared to controls, using the Children’s Depression Inventory (CDI). Methods: Youth with classical CAH due to 21-hydroxylase deficiency and age- and sex-matched controls completed the CDI and had analyte and genetic testing. Results: A total of 31 patients with CAH and 36 controls were included. Youth with CAH exhibited CDI measures that differed significantly by glucocorticoid dose and type. For glucocorticoid dose, significant correlations were found between CDI total T-score (r=0.42, p<0.05), as well as multiple subscores. Dose also predicted total T-score (β=1.75), Emotional-Problems (β=1.41), Negative-Self-Esteem (β=1.91), Functional-Problems (β=1.90), Ineffectiveness (β=1.56), and Interpersonal-Problems (β=2.11) (all p<0.01). For glucocorticoid type [dexamethasone n=7, hydrocortisone (HC) n=24], scores were higher in patients treated with dexamethasone for total T-score [dexamethasone: 59 (53.5-72), HC: 50 (43.75-55.75)], Emotional-Problems [dexamethasone: 63 (51.0-67.0), HC: 45 (42.0-56.5)], and Negative-Self-Esteem [dexamethasone: 53 (50.0-73.5), HC: 44 (44.0-51.0)] (all p<0.05). Conclusion: Higher HC doses and use of dexamethasone were both found to be associated with higher CDI scores in children and adolescents with classical CAH.

BackgroundSeveral maternal hormones regulate fetal growth, but concentrations of these hormones in pregnancy among women living with HIV and associations between hormone levels and infant anthropometrics is limited.MethodsPregnant women with HIV receiving dolutegravir/tenofovir/emtricitabine and HIV-seronegative women and their infants prospectively enrolled in the Botswana-based Tshilo Dikotla study were included in this analysis. Estradiol, sex-hormone binding globulin (SHBG), progesterone, cortisol, pituitary growth hormone-1 (GH1), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-1 (IGFBP-1) concentrations were measured in maternal plasma collected between 24 and 29 weeks’ gestation. Bioavailable estradiol was derived using estradiol and SHBG concentrations. Generalized linear models were fit to evaluate associations between HIV status and each maternal hormone. Similar models were fit to assess effect modification by HIV status on the relationship between each maternal hormone and infant anthropometrics at birth and 1-year of age.ResultsMaternal plasma specimens were available from 114 women (46 with HIV). Women with HIV had lower mean log bioavailable estradiol (β: −0.22, p = 0.031), cortisol (β: −0.22, p = 0.001), and IGF-1 (β: −0.81, p = 0.007), but higher GH1 (β: 0.91, p = 0.007) than women without HIV. Infant HIV-exposure status modified associations of log GH1 (β: −0.21, p = 0.05) and log IGF-1 (β: 0.40, p = 0.004) with infant 1-year weight-for-age z-score (WAZ), adjusting for maternal age, BMI, exclusive breastfeeding duration, and birth WAZ. Among infants who were HIV exposed uninfected, lower GH1 and higher IGF1 levels were associated with higher WAZ at 1 year of age. These associations were not observed in HIV-unexposed infants.ConclusionAssociations between maternal growth-promoting hormones and infant weight at 1 year of life differ significantly by maternal HIV status, reflecting potential perturbations in the maternal-fetal-infant growth axis among pregnant women with HIV. Additional research is needed to identify mechanisms and possible interventions.

INTRODUCTION:Patients with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency require lifelong glucocorticoid treatment, often at supraphysiologic doses, which increases their risk for obesity starting in early childhood and osteoporosis later in life. While obesity and inflammation have been shown to negatively impact bone health in the general population, the relationship between bone mineral density (BMD) and abdominal adiposity in youth with CAH remains unclear. We examine the association between BMD, adiposity, inflammation, and adrenal androgens in youth with CAH. METHODS:Thirty-five youth with CAH (12.33 ± 3.20 years; 12 males) and 38 age- and sex-matched controls (12.70 ± 2.83 years; 14 males) underwent dual-energy X-ray absorptiometry for BMD, MRI for abdominal adiposity (visceral adipose tissue [VAT] and subcutaneous adipose tissue [SAT]), and bone age X-ray. Linear regression models assessed associations between whole body and lumbar spine areal BMD height-adjusted Z-score (LS aBMDHAZ), adiposity, hormones, and inflammatory markers, adjusting for GC dose and BMI-z. RESULTS:Adiposity measures were significantly higher in CAH patients (SAT, VAT, total % body fat, Ps <0.01). LS aBMDHAZ negatively correlated with SAT (β = -1.21; 95% CI: -2.17, -0.24; p = 0.014), VAT (β = -0.38; 95% CI: -0.77, 0.02; p = 0.061), and total % body fat (β = -0.63; 95% CI: -1.23, -0.03; p = 0.039) in youth with CAH, independent of BMI-z and GC dose. In controls, only VAT (β = -0.39; 95% CI: -0.77, -0.01; p = 0.044) was negatively associated with LS aBMDHAZ. Areal BMDHAZ remained within normal limits for both groups, but in CAH patients, LS aBMDHAZ declined with age. No associations were found between BMDHAZ and adrenal hormones or MCP-1. CONCLUSION:Adiposity negatively impacts BMD in CAH youth, independent of BMI and GC dose, potentially increasing the risk of osteoporosis in adulthood. Further research is needed to explore strategies to mitigate these effects.

The relationships between alterations in the intestinal barrier, and bacterial translocation with the development of metabolic complications in youth with perinatally acquired HIV (YPHIV) have not been investigated.The PHACS Adolescent Master Protocol enrolled YPHIV across 15 U.S. sites, including Puerto Rico, from 2007 to 2009. For this analysis, we included YPHIV with HIV viral load 1000 c/ml or less, with at least one measurement of homeostatic assessment of insulin resistance (HOMA-IR) or nonhigh density lipoprotein (non-HDLc) between baseline and year 3 and plasma levels of intestinal fatty-acid binding protein (I-FABP), lipopolysaccharide-binding protein (LBP), and zonulin levels at baseline. We fit linear regression models using generalized estimating equations to assess the association of baseline log10 gut markers with log10 HOMA-IR and non-HDLc at all timepoints.HOMA-IR or non-HDLc was measured in 237, 189, and 170 PHIV at baseline, Yr2, and Yr3, respectively. At baseline, median age (Q1, Q3) was 12 years (10, 14), CD4+ cell count was 762 cells/mu l (574, 984); 90% had HIV RNA less than 400 c/ml. For every 10-fold higher baseline I-FABP, HOMA-IR dropped 0.85-fold at baseline and Yr2. For a 10-fold higher baseline zonulin, there was a 1.35-fold increase in HOMA-IR at baseline, 1.23-fold increase in HOMA-IR at Yr2, and 1.20-fold increase in HOMA-IR at Yr3 in adjusted models. For a 10-fold higher baseline LBP, there was a 1.23-fold increase in HOMA-IR at baseline in the unadjusted model, but this was slightly attenuated in the adjusted model. Zonulin was associated with non-HDLc at baseline, but not for the other time points.Despite viral suppression, intestinal damage may influence downstream insulin sensitivity in YPHIV.The relationships between alterations in the intestinal barrier, and bacterial translocation with the development of metabolic complications in youth with perinatally acquired HIV (YPHIV) have not been investigated.The PHACS Adolescent Master Protocol enrolled YPHIV across 15 U.S. sites, including Puerto Rico, from 2007 to 2009. For this analysis, we included YPHIV with HIV viral load 1000 c/ml or less, with at least one measurement of homeostatic assessment of insulin resistance (HOMA-IR) or nonhigh density lipoprotein (non-HDLc) between baseline and year 3 and plasma levels of intestinal fatty-acid binding protein (I-FABP), lipopolysaccharide-binding protein (LBP), and zonulin levels at baseline. We fit linear regression models using generalized estimating equations to assess the association of baseline log10 gut markers with log10 HOMA-IR and non-HDLc at all timepoints.HOMA-IR or non-HDLc was measured in 237, 189, and 170 PHIV at baseline, Yr2, and Yr3, respectively. At baseline, median age (Q1, Q3) was 12 years (10, 14), CD4+ cell count was 762 cells/mu l (574, 984); 90% had HIV RNA less than 400 c/ml. For every 10-fold higher baseline I-FABP, HOMA-IR dropped 0.85-fold at baseline and Yr2. For a 10-fold higher baseline zonulin, there was a 1.35-fold increase in HOMA-IR at baseline, 1.23-fold increase in HOMA-IR at Yr2, and 1.20-fold increase in HOMA-IR at Yr3 in adjusted models. For a 10-fold higher baseline LBP, there was a 1.23-fold increase in HOMA-IR at baseline in the unadjusted model, but this was slightly attenuated in the adjusted model. Zonulin was associated with non-HDLc at baseline, but not for the other time points.Despite viral suppression, intestinal damage may influence downstream insulin sensitivity in YPHIV. The relationships between alterations in the intestinal barrier, and bacterial translocation with the development of metabolic complications in youth with perinatally acquired HIV (YPHIV) have not been investigated.The PHACS Adolescent Master Protocol enrolled YPHIV across 15 U.S. sites, including Puerto Rico, from 2007 to 2009. For this analysis, we included YPHIV with HIV viral load 1000 c/ml or less, with at least one measurement of homeostatic assessment of insulin resistance (HOMA-IR) or nonhigh density lipoprotein (non-HDLc) between baseline and year 3 and plasma levels of intestinal fatty-acid binding protein (I-FABP), lipopolysaccharide-binding protein (LBP), and zonulin levels at baseline. We fit linear regression models using generalized estimating equations to assess the association of baseline log10 gut markers with log10 HOMA-IR and non-HDLc at all timepoints.HOMA-IR or non-HDLc was measured in 237, 189, and 170 PHIV at baseline, Yr2, and Yr3, respectively. At baseline, median age (Q1, Q3) was 12 years (10, 14), CD4+ cell count was 762 cells/mu l (574, 984); 90% had HIV RNA less than 400 c/ml. For every 10-fold higher baseline I-FABP, HOMA-IR dropped 0.85-fold at baseline and Yr2. For a 10-fold higher baseline zonulin, there was a 1.35-fold increase in HOMA-IR at baseline, 1.23-fold increase in HOMA-IR at Yr2, and 1.20-fold increase in HOMA-IR at Yr3 in adjusted models. For a 10-fold higher baseline LBP, there was a 1.23-fold increase in HOMA-IR at baseline in the unadjusted model, but this was slightly attenuated in the adjusted model. Zonulin was associated with non-HDLc at baseline, but not for the other time points.Despite viral suppression, intestinal damage may influence downstream insulin sensitivity in YPHIV.The relationships between alterations in the intestinal barrier, and bacterial translocation with the development of metabolic complications in youth with perinatally acquired HIV (YPHIV) have not been investigated.The PHACS Adolescent Master Protocol enrolled YPHIV across 15 U.S. sites, including Puerto Rico, from 2007 to 2009. For this analysis, we included YPHIV with HIV viral load 1000 c/ml or less, with at least one measurement of homeostatic assessment of insulin resistance (HOMA-IR) or nonhigh density lipoprotein (non-HDLc) between baseline and year 3 and plasma levels of intestinal fatty-acid binding protein (I-FABP), lipopolysaccharide-binding protein (LBP), and zonulin levels at baseline. We fit linear regression models using generalized estimating equations to assess the association of baseline log10 gut markers with log10 HOMA-IR and non-HDLc at all timepoints.HOMA-IR or non-HDLc was measured in 237, 189, and 170 PHIV at baseline, Yr2, and Yr3, respectively. At baseline, median age (Q1, Q3) was 12 years (10, 14), CD4+ cell count was 762 cells/mu l (574, 984); 90% had HIV RNA less than 400 c/ml. For every 10-fold higher baseline I-FABP, HOMA-IR dropped 0.85-fold at baseline and Yr2. For a 10-fold higher baseline zonulin, there was a 1.35-fold increase in HOMA-IR at baseline, 1.23-fold increase in HOMA-IR at Yr2, and 1.20-fold increase in HOMA-IR at Yr3 in adjusted models. For a 10-fold higher baseline LBP, there was a 1.23-fold increase in HOMA-IR at baseline in the unadjusted model, but this was slightly attenuated in the adjusted model. Zonulin was associated with non-HDLc at baseline, but not for the other time points.Despite viral suppression, intestinal damage may influence downstream insulin sensitivity in YPHIV.

Abstract Disclosure: P.N. Surampudi: Research Investigator; Self; Spruce Biosciences. A.H. Hamrahian: Consulting Fee; Self; Spruce Biosciences. Research Investigator; Self; Spruce Biosciences. R. Charlton: Employee; Self; Spruce Biosciences. P. Ramtin: Employee; Self; Spruce Biosciences. M.E. Geffner: Consulting Fee; Self; Spruce Biosciences, Ferring Pharmaceuticals, Adrenas, Neurocrine Biosciences, Novo Nordisk, Eton, Pfizer, Inc., Nutritional Growth Solutions, Nutritional Growth Solutions. Research Investigator; Self; Novo Nordisk. Background: Relative to the general population, patients with classic congenital adrenal hyperplasia (CAH) have increased risks for morbidity and mortality which require specialized management across life stages[1]. Endocrine care, particularly as part of multi-disciplinary teams, can help mitigate risks of developing adrenal crises as well as the impact of glucocorticoid under- or overexposure, including adrenal insufficiency; cardiometabolic risk associated with insulin resistance and excess weight gain; fertility issues associated with irregular menses and gonadal adrenal rest tumors; diminished quality of life; increased mental health issues, including anxiety, depression, and sleep disturbance; and increased fracture risk associated with decreased bone mineral density. Study Objectives and Design: We hypothesized that the utilization of endocrine and multi-disciplinary care by patients with CAH in the United States (U.S.) could be adversely affected by non-therapeutic factors related to geographic location and access to health care. In this cross-sectional study, we utilized the Definitive Healthcare database (Nov. 2020-Nov. 2022) to gain insight into these factors in adults with CAH. Study Findings: Analysis of healthcare provider utilization revealed that only ∼30% of U.S. adults with CAH received care from endocrinologists. The rest utilized primary-care providers (PCPs: IM, FP, NP, PA, and Ob-Gyn) to obtain care. A review of insurance coverage of U.S. adults with CAH suggests that ∼70% had access to commercial insurance and over 50% resided in states with the largest populations (California, Texas, New York, Florida, Ohio, Michigan, and Illinois), both factors which should ordinarily increase accessibility of subspecialty endocrine and multi-disciplinary care. Conclusions: In our study, only 30% of U.S. CAH adults received care from an endocrinologist. Limited utilization of specialty care does not appear to be due to either diverse geographical distribution or access to healthcare. The gap in expert care may adversely affect the management of CAH and contribute to associated comorbidities. Increased partnership between PCPs and endocrinologists, and increased awareness and education regarding specialty care among patients with CAH are needed to improve health outcomes and thereby reduce the risk of morbidity and mortality in adults with CAH. References [1] Falhammar H, Frisén L, Norrby C, Hirschberg AL, Almqvist C, Nordenskjöld A, Nordenström A. Increased mortality in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 2014;99:E2715-21. Presentation: 6/1/2024

Background There are little data on changes in insulin sensitivity during the first few years of life following in utero human immunodeficiency virus (HIV) and antiretroviral (ARV) exposure.Methods The Tshilo Dikotla study enrolled pregnant persons with HIV (PWH) (receiving tenofovir/emtricitabine or lamivudine plus dolutegravir or efavirenz) and pregnant individuals without HIV, as well as their liveborn children. Newborns were randomized to receive either zidovudine (AZT) or nevirapine (NVP) postnatal prophylaxis. Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) was assessed at birth and 1, 18, 24, and 36 months of life. We fit linear mixed-effects models to evaluate the association between in utero HIV/ARV exposure and average HOMA-IR from birth through 36 months of life, adjusting for confounders.Results A total of 419 children were included (287 with in utero HIV/ARV exposure and uninfected [CHEU] and 132 without in utero HIV/ARV exposure [CHUU]). CHEU were born to older women (29.6 vs 25.3 years of age) with higher gravidity (3 vs 1). HOMA-IR was persistently higher in CHEU versus CHUU in adjusted analyses (mean difference of 0.07 in log10 HOMA-IR, P = .02) from birth through 36 months of life. Among CHEU, no differences in HOMA-IR were observed from birth through 36 months by in utero ARV exposure status or between AZT and NVP infant prophylaxis arms.Conclusions In utero HIV/ARV exposure was associated with lower insulin sensitivity throughout the first 36 months of life, indicating persistent early life metabolic disturbances which may raise concern for poorer metabolic health later in life. In utero human immunodeficiency virus (HIV) and antiretroviral (ARV) exposure is associated with lower insulin sensitivity through the first 36 months of life, indicating metabolic disturbances and potentiallly poorer metabolic health later in life for children with perinatal HIV/ARV exposure. Graphical Abstract This graphical abstract is also available at Tidbit: https://tidbitapp.io/tidbits/lower-insulin-sensitivity-through-36-months-of-life-with-in-utero-hiv-and-antiretroviral-exposure-in-botswana-results-from-the-tshilo-dikotla-study?utm_campaign=tidbitlinkshare%26utm_source=IO

Introduction: Patients with classical congenital adrenal hyperplasia (CAH) exhibit an increased prevalence of obesity from childhood including central adiposity and inflammation. There is also an emerging affected brain phenotype in CAH, with decreased cortico-limbic gray matter volumes and white matter abnormalities. We aimed to study the relationship between brain structure, obesity, and inflammation in children and adolescents with CAH compared to controls. Methods: 27 CAH (12.6 ± 3.4 y, 16 females) and 35 control (13.0 ± 2.8 y, 20 females) participants had MRI of gray matter regions of interest (prefrontal cortex [PFC], amygdala, hippocampus) and white matter microstructure (fornix, stria terminalis [ST]). Anthropometric measures and lab analytes were obtained. Relaimpo analyses (relative importance for linear regression; percent variance) identified which brain structures were most different between groups. Subsequent regressions further quantified the magnitude and direction of these relationships. Correlations analyzed relationships between brain structure, obesity, and inflammation in the context of CAH status. Results: PFC (13.3% variance) and its superior frontal (SF) subregion (14%) were most different between CAH and controls for gray matter; ST (16%) for white matter. Patients with CAH had lower caudal middle frontal (β = −0.56 [−0.96, −0.15]) and superior frontal (β = −0.58 [−0.92, −0.25]) subregion volumes, increased orientation dispersion index in the fornix (β = 0.56 [0.01, 1.10]) and ST (β = 0.85 [0.34, 1.36]), and decreased fractional anisotropy in the fornix (β = −0.91 [−1.42, −0.42]) and ST (β = −0.83 [−1.34, −0.33]) (all p’s < 0.05) indicating axonal disorganization, reduced myelin content, and/or higher microglial density within the affected white matter tracts. For the full cohort, SF was correlated with MCP-1 (r = −0.41), visceral adipose tissue (r = −0.25), and waist-to-height ratio (r = −0.27, all p’s < 0.05); ST was correlated with MCP-1 (r = 0.31) and TNF-α (r = 0.29, all p’s < 0.05); however, after adjusting for CAH status, almost all correlations were attenuated for significance. Conclusions: Relationships among key brain structures, body composition, and inflammatory markers in pediatric patients with CAH could be largely driven by having CAH, with implications for obesity and neuroinflammation in this high-risk population.