Context Children born to mothers with gestational hypothyroidism or hyperthyroidism may have increased risk of adverse neurodevelopmental outcomes. However, the effects of maternal thyroid status on offspring brain development are unclear.Objective This work aimed to establish whether adolescent brain morphology is affected by suboptimal gestational thyroid function (SGTF).Methods The Controlled Antenatal Thyroid Screening (CATS) study randomly assigned mothers with SGTF to levothyroxine or no supplementation from approximately 12 weeks' gestation. At age 9, children born to mothers who were overtreated with levothyroxine had a higher risk of conduct and hyperactivity traits. For the current CATS III study, children underwent neuroimaging studies, including T1-weighted structural magnetic resonance imaging (MRI). A total of 85 children aged 11 to 16 years had usable T1-weighted MRI data (exposed to untreated SGTF [n = 21], normal GTF [n = 24], or treated SGTF [optimally treated (n = 21), overtreated (n = 20)]). The primary outcome was to examine the association of SGTF and its treatment with global brain volumes. Secondary and exploratory outcomes were to investigate the association of maternal thyrotropin (TSH) and free thyroxine (FT4) levels with global and subregional brain volumes. Results were adjusted for age, sex, and pubertal scores.Results There were no significant differences in global brain volumetric measures between groups, including total gray matter volume (P = .373). Weak positive correlations were found between maternal TSH, but not FT4, levels and several brain volumes, but these did not survive testing for multiple comparisons.Conclusion We found no evidence that SGTF was associated with differences in adolescent brain morphology, and no effect of levothyroxine supplementation.

Disclosure: I.A. Bacila: None. R. Welch: None. S. Adam: None. S.F. Ahmed: None. M. Alimussina: None. E. Chinnasamy: None. E.C. Crowne: None. J.H. Davies: None. A. Davis: None. J. Davis: None. M. Debono: None. S. Elford: None. Y. Elhassan: None. G. Gazdagh: None. H. Gleeson: None. L. James: None. M. Korbonits: None. S. Llanaha: None. J.M. Lynch: None. S. McGeoch: None. A. Mitchell: None. R.D. Murray: None. S. Nedelcu: None. G. Okoro: None. M.W. O'Reilly: None. A. Rees: None. R. Scott: None. R.H. Stimson: None. A. Thankamony: None. J.W. Tomlinson: None. B. Vaidya: None. N.P. Krone: None. Background: Congenital adrenal hyperplasia (CAH) is one of the commonest forms of primary adrenal insufficiency with an incidence of about 1 in 15,000. Previous studies have highlighted the suboptimal health status and care provision in adults with CAH and these were associated with significant co-morbidities. In 2023, we implemented CaHASE2 (https://www.endocrinology.org/clinical-practice/research-projects/cahase-2/) to develop a strategy for prospective collection of longitudinal data. Our recent CAH service evaluation suggested significant differences in the approach to CAH patients. Aim: To identify specific unmet needs in the care of people living with CAH, through standardised phenotyping across all participating centres. Methods: In September 2023, PIs agreed a minimal dataset for the collection of real-world data for participating centres. The data is collected using the international CAH registry (I-CAH; https://sdmregistries.org/). CaHASE2 was launched in November 2023. Results: To date, 351 adults (213 females, 138 males) with CAH have been recruited and 1213 clinic visits were available for analysis. There is a preponderance of younger to middle-aged adults in the currently available datasets (median age 42 years, range 23-88). Preliminary analysis suggests a temporal change in glucocorticoid choice over time with an increased use of hydrocortisone and a decreased use of prednisolone. Analysis of 17OHP concentrations shows that a significant proportion of patients are overtreated. A significant proportion of patients are overweight or obese. Currently 18 centres are actively recruiting and 5 are awaiting local approval to use the I-CAH registry. The data will be analysed in 12-month cycles, to assess the current level of care provision and inform the development of CAH standards. In addition, we will establish a report that will provide centres with information about their local care provision in relation to other centres. Conclusions: The CaHASE2 project will provide important information about the health status of adults with CAH and how this might be related to differences in health care provision. Ultimately, such data should lead to a higher degree of equality of service provision in all parts of the UK and Ireland. Presentation: Saturday, July 12, 2025

Disclosure: A. Prete: None. V. Theiler-Schwetz: None. W. Arlt: None. I.O. Chifu: None. B. Harbeck: None. C. Napier: None. J.D. Newell-Price: None. A. Rees: None. N. Reisch: None. G.K. Stalla: None. H. Coope: Neurocrine Biosciences. K. Maltby: Neurocrine Biosciences. J. Porter: Neurocrine Biosciences. J. Quirke: Neurocrine Biosciences. R.J. Ross: Neurocrine Biosciences. Background: Patients with adrenal insufficiency (AI) have impaired quality of life (QoL), low energy and increased mortality. Immediate-release hydrocortisone is first-line replacement therapy, however, fails to restore the physiologic diurnal cortisol rhythm. There are two modified-release hydrocortisone formulations: 1) Plenadren®, taken in a single morning dose, and 2) Chronocort® delayed release, taken twice daily in a toothbrush regimen (last thing at night, first thing in the morning). Chronocort but not Plenadren mimics the physiologic rise in early morning cortisol. We compared Plenadren to Chronocort to test the hypothesis that waking with physiological cortisol levels will reduce fatigue and improve QoL. Methods: double-blind, double-dummy, two-way cross-over, randomised, study comparing Chronocort vs Plenadren, one month on each treatment at 25mg/24 hours. Inclusion criteria were primary AI with morning pre-dose cortisol <50 nmol/L (1.8 µg/dl). The primary endpoint was the difference in 07:00h cortisol after 4 weeks of treatment. The key secondary outcome was the Multidimensional Assessment of Fatigue (MAF) score after 4 weeks. Other secondary outcomes included the disease specific questionnaire AddiQol, the fatigue questionnaire PROMIS 7b, and QoL as measured by SF36 and EQ-5D-5L. Results: Of 49 evaluable participants, 45 achieved a physiological morning cortisol (>140 nmol/l, 5ug/dl) with Chronocort compared with 2 on Plenadren (median serum cortisol 417.0 (15) vs 6.04 (0.2) nmol/L (µg/dl), P<0.0001). The MAF score was not significantly different between the two treatments; however, a sensitivity analysis showed that in the first treatment period Chronocort reduced MAF Score (P=0.008) suggesting a carry-over effect from period 1 to 2. The majority of the other QoL measures in the secondary efficacy analysis showed significant benefit for Chronocort including: The disease specific questionnaire AddiQol (P=0.03), the fatigue questionnaire PROMIS 7b (P=0.02), SF36 physical functioning (P=0.03) and EQ-5D-5L (P=0.02). The sensitivity analysis for all these measures showed greater benefit for Chronocort and patients showed a preference for the Chronocort treatment period. The safety profiles were similar, as expected for patients with AI, with no new safety signals identified. Conclusion: In adrenal insufficiency Chronocort provides physiological waking cortisol levels and is associated with reduced fatigue and improved QoL as compared to Plenadren. Presentation: Saturday, July 12, 2025

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

Background:Prednisolone and prednisone are recommended treatment options for adults with congenital adrenal hyperplasia (CAH); however, there is no randomised comparison of prednis(ol)one with hydrocortisone. Design:Six-month open-label randomised phase 3 study and interim analysis of a single-arm extension study was the design of the study. Methods:The method of the study was hydrocortisone dose equivalent and 09:00-h 17-hydroxyprogesterone (17OHP) from 48 patients taking prednis(ol)one at baseline. Results:At baseline, the median hydrocortisone dose equivalent was 30 mg/day and 17OHP was < 36 nmol/L (3× upper limit of normal) in 56% of patients. Patients were randomised to continue prednis(ol)one or switch to modified-release hydrocortisone capsule (MRHC) at the same hydrocortisone-equivalent dose. At 4 weeks, 94% on MRHC and 71% on prednis(ol)one had 17OHP < 36 nmol/L. At 18 months in the extension study of MRHC, the median MRHC dose was 20 mg/day and 82% had 17OHP < 36 nmol/L. The per cent of patients with 17OHP < 36 nmol/L on a hydrocortisone dose equivalent ≤ 25 mg/day was greater at 18 months in the extension study on MRHC than while on prednis(ol)one at baseline: 57% vs 27%, P = 0.04. In the randomised study, no patients had an adrenal crisis on MRHC and one on prednisolone. In the extension study (221 patient years), there were 12 adrenal crises in 5 patients (5.4/100 patient years). Conclusion:MRHC reduces 17OHP at 09:00 h compared to prednis(ol)one and the dose of MRHC can be down-titrated over time in the majority of patients.

Abstract Disclosure: N.R. Lawrence: None. N.P. Krone: None. J.F. Dawson: None. Z. Lang: None. W. Arlt: Advisory Board Member; Self; Diurnal. A. Brac de la Perriere: Research Investigator; Self; Diurnal. A.L. Hirschberg: Research Investigator; Self; Diurnal. A. Juul: Research Investigator; Self; Diurnal. D.P. Merke: Research Investigator; Self; Diurnal. J.D. Newell-Price: Research Investigator; Self; Diurnal. A. Prete: Research Investigator; Self; Diurnal. A.E. Taylor: None. A. Rees: Research Investigator; Self; Diurnal. N. Reisch: Research Investigator; Self; Diurnal. M. Stikkelbroeck: Research Investigator; Self; Diurnal. P.A. Touraine: Research Investigator; Self; Diurnal. G. Collins: None. R.J. Ross: Consulting Fee; Self; Diurnal. Background: There is no consensus on how to monitor biochemical control of CAH as excess ACTH overnight is common on standard therapy. Modified-release hydrocortisone (MRHC) gives potential for improved disease control and the need to understand this impact on disease monitoring.Aim: To define the relationship between 17OHP and A4, in healthy controls and CAH patients. Methods: Analysis of 24-hour 2-hourly 17OHP and A4 endocrine profiles in patients randomised to either standard treatment or MRHC (n=122, mean age 36.3 (SD 11.6) years, 78 female, 44 male) and a population of healthy controls (n=20, age 30.0 (12.3), 13 male, 7 female). Markers were regressed, cross correlated and assessed by Bayesian Change Point analysis using R. Results: Regressing the natural logarithms of 17OHP on A4, Bayesian multiple change point analysis converged on a stable changepoint equivalent to 17OHP of 4.5 nmol/L 149 ng/dl (95%, CI:4.2 to 4.7 nmol/L, Rhat < 1.008). Below the 17OHP change point A4 is proportionally lower than above, with no evidence of difference between sexes or steroid preparation. The relationship between 17OHP and A4 was different for healthy subjects, who for similar levels of A4 have lower levels of 17OHP than CAH patients in nmol/L (ng/dl): A4 of 1 (29) and 10 (286) associated with 17OHP 1.5 (50) and 8.8 (291) in healthy subjects’ vs 3.3 (109) and 71.2 (2353) in CAH patients, respectively. There was no consistent rhythm in either marker in healthy patients, shown by an autocorrelation function (ACF) that falls quickly to zero. ACF approaches zero more quickly in CAH patients on MRHC than those on standard therapy who more commonly exhibit a diurnal rhythm with an 0700hrs peak. There was no lag between markers, with cross-correlation function plots symmetrical. Conclusions: The relationship between 17OHP and A4 is different in CAH than healthy controls. In CAH, high A4 suggests poor control but a low A4 may still be associated with a raised 17OHP. In CAH patients, 17OHP concentrations within the healthy subject range are associated with A4 below levels seen in healthy subjects. When elevated in CAH patients, A4 and 17OHP rise and fall together with no lag; thus, A4 does not give more information on control over time. On MRHC the biomarkers show a reduced diurnal rhythm; therefore, individual measurements taken in clinic are more likely to reflect the daily average than measurements taken when on standard therapy. Presentation: 6/1/2024

Abstract Disclosure: A. Prete: Research Investigator; Self; Diurnal. V. Theiler-Schwetz: Research Investigator; Self; Diurnal. W. Arlt: Research Investigator; Self; Diurnal. I.O. Chifu: Research Investigator; Self; Diurnal. B. Harbeck: Research Investigator; Self; Diurnal. C. Napier: Research Investigator; Self; Diurnal. J.D. Newell-Price: Research Investigator; Self; Diurnal. A. Rees: Research Investigator; Self; Diurnal. N. Reisch: Research Investigator; Self; Diurnal. G.K. Stalla: Research Investigator; Self; Diurnal. N. Aslam: Employee; Self; Diurnal. H. Coope: Employee; Self; Diurnal. K. Maltby: Employee; Self; Diurnal. J. Porter: Employee; Self; Diurnal. J. Quirke: Employee; Self; Diurnal. R.J. Ross: Consulting Fee; Self; Diurnal. Background: Primary adrenal insufficiency (PAI) is rare: prevalence ∼100-140/million and incidence 4:1 000 000/year in Western societies [1]. The diagnosis of PAI is suggested by an early-morning cortisol <140 nmol/L (5 µg/dL) [1]. The commonest cause in adults is autoimmunity (∼90% in Western countries) and it is generally considered progressive once the diagnosis is made, although it has been reported that residual cortisol secretion is present in ∼30% of patients 2. We have developed a modified-release formulation of hydrocortisone to replace the physiological cortisol circadian rhythm and are undertaking a Double-Blind, Double-Dummy, Two-Way Cross-Over, Randomised, Phase II Study of Modified-Release Hydrocortisones: Chronocort® Versus Plenadren® in PAI. During recruitment, we were surprised by the number of patients who were ineligible as they had detectable morning cortisol levels. Methods: Main inclusion criteria: Participants with known PAI on stable glucocorticoid replacement therapy and an early morning pre-dose cortisol <50 nmol/L (1.8 µg/dl). Baseline serum cortisol was taken at ∼0700h and measured in a central laboratory by ADVIA Centaur® immunoassay with the lower limit of detection <14nmol/l (<0.5 µg/dL). Results: 86 patients with PAI (autoimmune aetiology in 71), median age 52 years (range 20-73), 60 female, were screened in 8 centres in UK and Germany. 18 (21%) patients were excluded from the study based on morning cortisol >50 nmol/L (1.8 µg/dL), and of those 68 patients who qualified on the main inclusion criteria 51 (59% of screened) had a cortisol <14 nmol/L (<0.5 µg/dL). Of the 18 patients (autoimmune aetiology in 10) excluded based on their morning cortisol level, 9 (50%) were female and 11 (13% of screened), had morning cortisol ≥140 nmol/L (5.0 µ/dL). 12 patients with morning cortisol of >50nmol/L (1.8 µ/dL) were retested and only 2 then qualified; their initial morning cortisol levels were 70 and 51 nmol/L. In patients retested the median difference between retest and the initial sample was 13 nmol/L (range 1-421 nmol/L). Conclusions: In patients with an established diagnosis of PAI, the majority had undetectable morning cortisol, but cortisol was detectable in 41% of patients and above 140 nmol/L in 13% confirming previous publications 2. Retesting patients with a cortisol >50nmol/L showed very similar results suggesting that the detectable cortisol was not an artefact and likely due to background cortisol secretion. 1. Bornstein SR, et al. J Clin Endocrinol Metab 2016;101:364-89.2.Pearce SHS, et al. European Journal of Endocrinology (2021) 184, R61–R67 Presentation: 6/1/2024

BACKGROUND:Thyroid testing strategies vary across laboratories. First-line combined thyroid stimulating hormone (TSH) and freeT4 (FT4) have historically been preferred by many laboratories as this detects individuals with undiagnosed central hypothyroidism who can be missed with a first-line TSH-only strategy. However, an up-to-date evaluation of the utility of this approach is lacking.OBJECTIVES:We investigated the clinical utility of first-line TSH and FT4 in the detection of central hypothyroidism in current day practice.DESIGN, PATIENTS, AND MEASUREMENTS:The All-Wales laboratory information system was queried to identify thyroid function tests in patients aged ≥16 years with decreased FT4 and inappropriate TSH (low-FT4). The 1-year incidence of low-FT4 was determined using mid-year population data. Clinical information of patients with low-FT4 was reviewed to determine causes of low-FT4 and the incidence of central hypothyroidism.RESULTS:The incidence of low-FT4 varied according to FT4 assay method (range: 98-301 cases/100,000 population/year). Fifteen new cases of central hypothyroidism were detected in two health boards, equivalent to 2 cases/100,000 population/year. Positive predictive value of low-FT4 for central hypothyroidism was 2%-4%. In a cross-section of primary care patients, low-FT4 was detected in 0.5% of all thyroid tests with assay-related differences in detection rates.CONCLUSIONS:Although low-FT4 is a common laboratory finding, the incidence of central hypothyroidism remains rare. With the currently increased rates of thyroid testing and increased use of medications that decrease FT4, low-FT4 has a much lower predictive value for central hypothyroidism than previously reported. Thyroid screening strategies will need to balance the yield from first line TSH and FT4 testing with the cost of investigating individuals with non-pathological laboratory abnormalities.

Context Trends in incidence of polycystic ovary syndrome (PCOS) and effects on health resource utilization are unclear. Objective To describe trends in prevalence and incidence of PCOS in the United Kingdom. To establish healthcare resource use and associated costs. Methods Data were extracted from the Clinical Practice Research Datalink Aurum and Hospital Episode Statistics databases. Point prevalence and incidence were calculated (2004-2020). Patients with PCOS were matched to controls (1:1) by age, body mass index, and primary care practice. Primary care contacts were assigned an average cost and prescription items assigned a net ingredient cost. Inpatient admissions and outpatient consultations were processed into healthcare resource groups and costed to the national tariff. Results PCOS incidence increased from 1.22 per 1000 person years in 2004 to 1.77 (2012) and 2.20 (2019). Point prevalence increased from 1.02% (2004) to 2.2% (2012) and 3.5% (2020), and was highest in Asians. Mean contacts per person year (ppy) for patients with PCOS vs controls were 0.48 vs 0.29 for inpatients (P < .001), 3.81 vs 2.15 for outpatients (P < .001), and 6.43 vs 4.68 (P < .001) for primary care. Mean healthcare costs (ppy) were 837 pound vs 493 pound (P < .001) for inpatients, 444 pound vs 253 pound (P < .001) for outpatients, 157 pound vs 112 pound for primary care, and 109 pound vs 83 pound (P < .001) for primary care prescriptions. Total healthcare contacts ppy were 10.72 vs 7.11 (P < .001) and total associated costs 1546 pound vs 940 pound (P < .001). Conclusion The incidence of PCOS has risen significantly. Health resource utilization and costs of PCOS are significantly greater than controls.

Abstract Disclosure: A. Prete: Research Investigator; Self; Diurnal. V. Theiler-Schwetz: Research Investigator; Self; Diurnal. W. Arlt: Research Investigator; Self; Diurnal. I.O. Chifu: Research Investigator; Self; Diurnal. B. Harbeck: Research Investigator; Self; Diurnal. C. Napier: Research Investigator; Self; Diurnal. J.D. Newell-Price: Research Investigator; Self; Diurnal. A. Rees: Research Investigator; Self; Diurnal. N. Reisch: Research Investigator; Self; Diurnal. G.K. Stalla: Research Investigator; Self; Diurnal. N. Aslam: Employee; Self; Diurnal. H. Coope: Employee; Self; Diurnal. K. Maltby: Employee; Self; Diurnal. J. Porter: Employee; Self; Diurnal. J. Quirke: Employee; Self; Diurnal. R.J. Ross: Consulting Fee; Self; Diurnal. Background: Current glucocorticoid replacement regimens for patients with primary adrenal insufficiency (PAI) mean patients wake with either low or undetectable cortisol levels[1], associated with fatigue and a reduced quality of life (QoL)2. Plenadren® (Takeda, UK) is a once-daily modified-release formulation of hydrocortisone that replaces daytime cortisol levels whereas Chronocort® (modified-release hydrocortisone hard capsules, Diurnal, UK) when taken twice-daily, has been shown to replicate the normal overnight rise in serum cortisol concentration and provide physiological levels throughout the day. We have undertaken a double-blind, double-dummy, two-way cross-over, randomised, phase II study of efficacy, safety and tolerability of modified-release hydrocortisones: Chronocort® Versus Plenadren®. Aim: To test the hypothesis that Chronocort® provides more physiological waking cortisol levels than Plenadren®. Methodology: The study was conducted across 8 sites in the UK and Germany. Male and female patients, aged ≥18 with confirmed PAI (defined as morning pre-dose cortisol <50 nMol/l) on stable therapy over the preceding three months and not currently treated with Chronocort®/Plenadren®. Participants with congenital adrenal hyperplasia (CAH), secondary or tertiary AI were excluded. Each participant was randomised on a 1:1 basis to either; treatment sequence I (Chronocort® first) or treatment sequence II (Plenadren® first) taking a 25mg total daily dose for 4 weeks; either Plenadren® 25mg in the morning or Chronocort® 10mg in the morning and 15mg at night with the associated dummy preparation followed immediately by the other treatment. The pre-dose morning serum cortisol level was assayed at baseline and after each treatment period. A physiological morning cortisol level was defined as a pre-dose level of >140nMol/L. Secondary measures included: morning fatigue measured using the Multidimensional Assessment of Fatigue (MAF) questionnaire and the PROMIS® 7b questionnaire; QoL was assessed using the EuroQol 5-level Standardised Health Questionnaire (EQ-5D-5L™); Health-related Quality of Life in Addison’s disease (AddiQoL) questionnaire and the 36-Item Short Form Health Survey (SF-36®) questionnaire. Results: Of 49 evaluable participants with PAI, 45 achieved a physiological morning cortisol after four weeks of Chronocort® compared with 2 after four weeks of Plenadren® (P<0.0001). The mean (standard deviation) waking cortisol was 422.85 (203.50) vs 36.98 (113.87), respectively. Conclusion: Chronocort® provides more physiological waking cortisol levels than Plenadren®. Further analysis will test the hypothesis that waking with physiological cortisol levels improves fatigue and QoL in patients with PAI. 1.Mah PM, et al. Clin Endocrinol (Oxf). 2004;61(3):367-75.2.Wichers M, et al. Clin Endocrinol (Oxf). 1999;50(6):759-65. Presentation: 6/3/2024