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Context: Meta-analyses report that the low dose short Synacthen test (LDSST) is more sensitive but less specific than the standard dose test for the diagnosis of adrenal insufficiency, and there are concerns regarding the accuracy of dosing in the LDSST. Objective: Perform a retrospective, observational study to review the outcomes of LDSSTs performed in a tertiary endocrine service from 2008 to 2014 (N = 335) and 2016 to 2020 (N = 160), and examine for relationships between cortisol measurements and indication for testing, age and sex. Methods: LDSST were performed by endocrine nurses. Synacthen 500 ng/1.73m2 administered as IV bolus, sampling at 0, 15, 25, and 35 minutes. Results: Mean (± 1SD) baseline cortisol was 221 ± 120 nmol/L, peak 510 ± 166 nmol/L and increment 210 ± 116 nmol/L. 336 (70%) patients had a normal response (baseline cortisol >100 nmol/L, peak >450 nmol/L), 78 (16%) a suboptimal response (peak cortisol 350-450 nmol/L) and were prescribed hydrocortisone to during periods of stress only, 67 (14%) an abnormal response (baseline <100nmol/L or peak <350nmol/L) and were prescribed daily hydrocortisone. Basal, peak, and incremental increases in cortisol were higher in females (P =. 03, P <. 001, P =. 03, respectively). Abnormal results occurred most frequently in patients treated previously with pharmacological doses of glucocorticoids or structural brain abnormalities (P <. 001). Conclusion: The low prevalence and strong association of abnormal results with indication for testing, suggests that over diagnosis occurred infrequently in this clinical setting.

Objective To review the outcomes of a simplified low dose Synacthen test (LDSST) performed in a tertiary endocrine service over seven years, and to examine for relationships between cortisol measurements and indication for testing, age and sex. Design Retrospective, observational study of LDSST performed in 2008 – 2014 (N=335) and 2016-2020 (N=160). Methods LDSST were performed by endocrine nurses. Synacthen 500ng/1.73m 2 administered as IV bolus, sampling at 0, 15, 25 and 35 minutes. Results Mean (± 1SD) baseline cortisol was 221 ± 120 nmol/L, peak 510 ± 166nmol/L and increment 210 ± 116 nmol/L. 336 (70%) of patients had a normal response (baseline cortisol >100nmol/L, peak >450nmol/L), 78 (16%) a suboptimal response (peak cortisol 350-450nmol/L) and were prescribed hydrocortisone to during periods of stress only, 67 (14%) an abnormal response (baseline <100nmol/L or peak <350nmol/L) and were prescribed daily hydrocortisone. Basal, peak and incremental increases in cortisol were higher in females (p=0.03, p<0.001, p=0.03 respectively). Abnormal results occurred most frequently in patients treated previously with pharmacological doses of glucocorticoids or structural brain abnormalities (p<0.0001). Discussion There are concerns that the specificity of the LDSST is poor. The low prevalence and strong association of abnormal results with indication for testing, suggests that over diagnosis occurred infrequently in this clinical setting.

An Endo-European Reference Network guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult and 2 patient representatives. The guideline was endorsed by the European Society for Pediatric Endocrinology, the European Society for Endocrinology and the European Academy of Andrology. The aim was to create practice guidelines for clinical assessment and puberty induction in individuals with congenital pituitary or gonadal hormone deficiency. A systematic literature search was conducted, and the evidence was graded according to the Grading of Recommendations, Assessment, Development and Evaluation system. If the evidence was insufficient or lacking, then the conclusions were based on expert opinion. The guideline includes recommendations for puberty induction with oestrogen or testosterone. Publications on the induction of puberty with follicle-stimulation hormone and human chorionic gonadotrophin in hypogonadotropic hypogonadism are reviewed. Specific issues in individuals with Klinefelter syndrome or androgen insensitivity syndrome are considered. The expert panel recommends that pubertal induction or sex hormone replacement to sustain puberty should be cared for by a multidisciplinary team. Children with a known condition should be followed from the age of 8 years for girls and 9 years for boys. Puberty induction should be individualised but considered at 11 years in girls and 12 years in boys. Psychological aspects of puberty and fertility issues are especially important to address in individuals with sex development disorders or congenital pituitary deficiencies. The transition of these young adults highlights the importance of a multidisciplinary approach, to discuss both medical issues and social and psychological issues that arise in the context of these chronic conditions., SCOPUS: ar.j, info:eu-repo/semantics/published

CONTEXT: Growth hormone (GH) treatment has a generally good safety profile; however, concerns about increased mortality risk in adulthood have been raised. OBJECTIVE: This work aims to assess the long-term safety of GH treatment in clinical practice. METHODS: Data were collected from 676 clinics participating in 2 multicenter longitudinal observational studies: the NordiNet International Outcome Study (2006-2016, Europe) and ANSWER Program (2002-2016, USA). Pediatric patients treated with GH were classified into 3 risk groups based on diagnosis. Intervention consisted of daily GH treatment, and main outcome measures included incidence rates (events/1000 patient-years) of adverse drug reactions (ADRs), serious adverse events (SAEs), and serious ADRs, and their relationship to GH dose. RESULTS: The combined studies comprised 37 702 patients (68.4% in low-risk, 27.5% in intermediate-risk, and 4.1% in high-risk groups) and 130 476 patient-years of exposure. The low-risk group included children born small for gestational age (SGA; 20.7%) and non-SGA children (eg, with GH deficiency; 79.3%). Average GH dose up to the first adverse event (AE) decreased with increasing risk category. Patients without AEs received higher average GH doses than patients with more than one AE across all groups. A significant inverse relationship with GH dose was shown for ADR and SAE incidence rates in the low-risk group (P = .003 and P = .001, respectively) and the non-SGA subgroup (both P = .002), and for SAEs in the intermediate- and high-risk groups (P = .002 and P = .05, respectively). CONCLUSIONS: We observed no indication of increased mortality risk nor AE incidence related to GH dose in any risk group. A short visual summary of our work is available (1).

Joanne Blair, 1 Kelly Warth, 2 Yashasvi Suvarna, 3 Marco Cappa 4 1Department of Endocrinology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK; 2Instar, London, UK; 3Global Medical Affairs, Novo Nordisk Global Business Services (GBS), Bangalore, India; 4Endocrinology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, ItalyCorrespondence: Joanne BlairDepartment of Endocrinology, Alder Hey Children’s NHS Foundation Trust, Liverpool, L12 2AP, UKTel +44 151 252 5335 Fax +44 151 282 4606Email Jo.Blair@alderhey.nhs.ukPurpose: This study investigated why some clinicians switched growth hormone (GH) brands in pediatric patients with GH-related disorders to Norditropin® since the start of the COVID-19 pandemic, the clinicians’ perceptions of the results, and whether observations from this period of disruption could inform clinical practice in the future.Patients and Methods: Clinicians (N=106) from the UK, France, Italy, and Japan who had switched at least one patient to Norditropin® from a GH therapy manufactured by a different pharmaceutical company between February and November 2020 participated. They completed an online survey and submitted patient report forms for up to three switched patients.Results: Since the start of COVID-19, 39– 54% of the reported consultations were virtual (ie, via telephone or online means) in the UK, France, and Italy. Overall, 17% of patients seen by respondents in the survey were switched to a different GH brand; approximately two-thirds of switches were to Norditropin®. Clinicians’ top considerations in choosing a GH brand were patient/carer feedback, patient support programs, and the need for easy-to-use therapies in the context of virtual consultations. The top reasons for switching patients to Norditropin® included ease of use, device features and benefits, better patient/carer feedback, and ease of training in device use via

CONTEXT: Growth hormone (GH) treatment has a generally good safety profile; however, concerns about increased mortality risk in adulthood have been raised. OBJECTIVE: This work aims to assess the long-term safety of GH treatment in clinical practice. METHODS: Data were collected from 676 clinics participating in 2 multicenter longitudinal observational studies: the NordiNet International Outcome Study (2006-2016, Europe) and ANSWER Program (2002-2016, USA). Pediatric patients treated with GH were classified into 3 risk groups based on diagnosis. Intervention consisted of daily GH treatment, and main outcome measures included incidence rates (events/1000 patient-years) of adverse drug reactions (ADRs), serious adverse events (SAEs), and serious ADRs, and their relationship to GH dose. RESULTS: The combined studies comprised 37 702 patients (68.4% in low-risk, 27.5% in intermediate-risk, and 4.1% in high-risk groups) and 130 476 patient-years of exposure. The low-risk group included children born small for gestational age (SGA; 20.7%) and non-SGA children (eg, with GH deficiency; 79.3%). Average GH dose up to the first adverse event (AE) decreased with increasing risk category. Patients without AEs received higher average GH doses than patients with more than one AE across all groups. A significant inverse relationship with GH dose was shown for ADR and SAE incidence rates in the low-risk group (P = .003 and P = .001, respectively) and the non-SGA subgroup (both P = .002), and for SAEs in the intermediate- and high-risk groups (P = .002 and P = .05, respectively). CONCLUSIONS: We observed no indication of increased mortality risk nor AE incidence related to GH dose in any risk group. A short visual summary of our work is available (1).

Context: Growth hormone (GH) treatment has a generally good safety profile; however, concerns about increased mortality risk in adulthood have been raised. Objective: This work aims to assess the long-term safety of GH treatment in clinical practice. Methods: Data were collected from 676 clinics participating in 2 multicenter longitudinal observational studies: the NordiNet International Outcome Study (2006-2016, Europe) and ANSWER Program (2002-2016, USA). Pediatric patients treated with GH were classified into 3 risk groups based on diagnosis. Intervention consisted of daily GH treatment, and main outcome measures included incidence rates (events/1000 patient-years) of adverse drug reactions (ADRs), serious adverse events (SAEs), and serious ADRs, and their relationship to GH dose. Results: The combined studies comprised 37702 patients (68.4% in low-risk, 27.5% in intermediate-risk, and 4.1% in high-risk groups) and 130476 patient-years of exposure. The low-risk group included children born small for gestational age (SGA; 20.7%) and non-SGA children (eg, with GH deficiency; 79.3%). Average GH dose up to the first adverse event (AE) decreased with increasing risk category. Patients without AEs received higher average GH doses than patients with more than one AE across all groups. A significant inverse relationship with GH dose was shown for ADR and SAE incidence rates in the low-risk group (P=.003 and P=.001, respectively) and the non-SGA subgroup (both P=.002), and for SAEs in the intermediate-and high-risk groups (P=.002 and P=.05, respectively). Conclusions: We observed no indication of increased mortality risk nor AE incidence related to GH dose in any risk group. A short visual summary of our work is available (1).

Background Saliva is an ideal medium in which to measure cortisol in children. However, there are very few data reporting salivary cortisol or cortisone concentrations in healthy children since the introduction of liquid chromatography mass spectrometry (LC MS/MS) to routine laboratory practice. Design Early morning serum cortisol, salivary cortisol and cortisone were measured on fasting samples, and salivary hormones were measured in samples collected every 2 hours during waking hours, and 30 minutes after waking the following morning. Participants 43 healthy paediatric volunteers (19 female), median age 11.5 years, range 6.2 – 18.7, participated. Results Early morning serum cortisol (265nmol/L, 156 – 516) correlated strongly with salivary cortisol (4.7nmol/L, 1.1‐14.6) and cortisone (28.8nmol/L, 11.7‐56.6), p<0.0001 for both. Serum cortisol, salivary cortisol and salivary cortisone correlated directly with age (p<0.0001, p=0.002 and p=0.015 respectively), and salivary cortisone / cortisol ratio correlated indirectly with age (p=0.007). Between 08.00 and 21.00, area under the curve for salivary cortisol (mean ± 1 SD) was 41.8 ± 19.1 and for cortisone, 213.0 ± 61.2. Salivary cortisol was undetectable in 25/130 (19%) of samples collected after 13.00 while cortisone was always detectable. Discussion Salivary cortisol and cortisone concentrations are strongly related to serum cortisol concentrations, however cortisone may be a preferable measure as cortisol is often undetectable. Age may be an important factor in the interpretation of early morning cortisol measurements made in serum and saliva.

Background: Saliva is an ideal medium in which to measure cortisol in children. However, there are very few data reporting salivary cortisol or cortisone concentrations in healthy children since the introduction of liquid chromatography-mass spectrometry (LC-MS/MS) to routine laboratory practice. Design: Early morning serum cortisol, salivary cortisol and cortisone were measured on fasting samples, and salivary hormones were measured in samples collected every 2 hours during waking hours, and 30 minutes after waking the following morning. Participants: 43 healthy paediatric volunteers (19 female), median age 11.5 years, range 6.2-18.7, participated. Results: Early morning serum cortisol (265 nmol/L, 156-516) correlated strongly with salivary cortisol (4.7 nmol/L, 1.1-14.6) and cortisone (28.8 nmol/L, 11.7-56.6), P <.0001 for both. Serum cortisol, salivary cortisol and salivary cortisone correlated directly with age (P <.0001, P =.002 and P =.015, respectively), and salivary cortisone/cortisol ratio correlated indirectly with age (P =.007). Between 08.00 and 21.00, area under the curve for salivary cortisol (mean ± 1 SD) was 41.8 ± 19.1 and for cortisone 213.0 ± 61.2. Salivary cortisol was undetectable in 25/130 (19%) of samples collected after 13.00, while cortisone was always detectable. Discussion: Salivary cortisol and cortisone concentrations are strongly related to serum cortisol concentrations; however, cortisone may be a preferable measure as cortisol is often undetectable. Age may be an important factor in the interpretation of early morning cortisol measurements made in serum and saliva.

Arundoss Gangadharan,1 Paul McCoy,2 Aye Phyo,1 Michael P McGuigan,3 Poonam Dharmaraj,1 Renuka Ramakrishnan,1 Paul S McNamara,2,4 Joanne Blair1 1Department of Endocrinology, 2Department of Respiratory Medicine, Alder Hey Children’s Hospital, Liverpool, 3Department of Paediatrics, Countess of Chester Hospital NHS Foundation Trust, 4Institute in the Park, University of Liverpool, Alder Hey Children’s Hospital, Liverpool, UK Objective: To describe recovery of adrenal insufficiency in asthmatic children treated with inhaled corticosteroids (ICS) and cortisol replacement therapy.Design: Retrospective, observational study.Patients: A total of 113 patients, 74 male; age 10.4 (3.3–16.5) years; beclomethasone-­equivalent ICS dose, 800 µg, (100–1,000), tested by low dose short Synacthen (tetracosactide) test (LDSST), were studied. Test results were classified by basal and peak cortisol concentration: “normal” (basal >100 nmol/L, peak >500 nmol/L), “suboptimal” (basal >100 nmol/L, peak 350–499 nmol/L), “abnormal” (basal <100 nmol/L and/or peak <350 nmol/L). Patients with suboptimal results received hydrocortisone during periods of stress only, and those with abnormal responses received daily hydrocortisone, increased during periods of stress. A total of 73 patients (68%) had ≥2 LDSSTs over 2.2 years (0.2–7.7).Measurements: Change in cortisol response to repeat LDSST (movement between diagnostic groups, difference in basal and peak cortisol >15% [2× the inter-assay coefficient of variation]), change in BMI and height standard deviation score (SDS).Results: Baseline test results were abnormal in 17 patients (15%) and all of them had repeat tests. In 13 patients (76%), test results improved (normal in six, suboptimal in seven) and four (24%) remained abnormal. Baseline

Arundoss Gangadharan,1 Paul McCoy,2 Aye Phyo,1 Michael P McGuigan,3 Poonam Dharmaraj,1 Renuka Ramakrishnan,1 Paul S McNamara,2,4 Joanne Blair1 1Department of Endocrinology, 2Department of Respiratory Medicine, Alder Hey Children’s Hospital, Liverpool, 3Department of Paediatrics, Countess of Chester Hospital NHS Foundation Trust, 4Institute in the Park, University of Liverpool, Alder Hey Children’s Hospital, Liverpool, UK Objective: To describe recovery of adrenal insufficiency in asthmatic children treated with inhaled corticosteroids (ICS) and cortisol replacement therapy.Design: Retrospective, observational study.Patients: A total of 113 patients, 74 male; age 10.4 (3.3–16.5) years; beclomethasone-­equivalent ICS dose, 800 µg, (100–1,000), tested by low dose short Synacthen (tetracosactide) test (LDSST), were studied. Test results were classified by basal and peak cortisol concentration: “normal” (basal >100 nmol/L, peak >500 nmol/L), “suboptimal” (basal >100 nmol/L, peak 350–499 nmol/L), “abnormal” (basal <100 nmol/L and/or peak <350 nmol/L). Patients with suboptimal results received hydrocortisone during periods of stress only, and those with abnormal responses received daily hydrocortisone, increased during periods of stress. A total of 73 patients (68%) had ≥2 LDSSTs over 2.2 years (0.2–7.7).Measurements: Change in cortisol response to repeat LDSST (movement between diagnostic groups, difference in basal and peak cortisol >15% [2× the inter-assay coefficient of variation]), change in BMI and height standard deviation score (SDS).Results: Baseline test results were abnormal in 17 patients (15%) and all of them had repeat tests. In 13 patients (76%), test results improved (normal in six, suboptimal in seven) and four (24%) remained abnormal. Baseline