bluuebunny/crossref_metadata_2025 huggingface dataset:
The Biggest Man in the Room
Authors: Tariq Sarah
Published: May 2021

A 42 year old gentleman who had been healthy all his life, began to develop new clinical symptoms including acid reflux. He was tested for H. Pylori by his PCP, and treatment was initiated. During this visit he was also noted to have elevated BP and was ultimately diagnosed with HTN, and started on anti-hypertensives. During these revelations he brought up the fact that he has also developed excessive joint pains over the years, and his shoe size has increased from the age of 30 to now by 3 sizes. When asked, he admitted to noticing an increase in his hands size, and also noted that his rings do not fit anymore. His fiancée works in medicine and requested he be screened for acromegaly, thus PCP checked IGF-1 and GH levels, which were noted to be significantly elevated at 887 and 20.9, respectively, leading to a referral to Endocrinology. Under Endocrinology care he underwent a GH suppression test resulting in a non-suppressed GH at 17.8. This was followed by a Pituitary MRI revealing an 18 x 19 x 18 mm solid/partially cystic hypoenhancing lesion consistent with a pituitary macroadenoma, with leftward deviations of the infundibulum, without involvement of the optic chiasm. He was treated with transsphenoidal resection of the pituitary tumor. On post-op day 4, the IGF level had fallen to 456. His thyroid and gonadal axes were assessed and did not show any evidence of deficiency post-operatively. He was however started on Prednisone post-operatively, and was switched to Hydrocortisone in the outpatient setting with plans to taper and re-assess his HPA axis. Overall he is doing well, and there are plans for repeat labs and imaging about 6 weeks post-operatively. When evaluating patients with a variety of newly developing symptoms, remember to consider a unified diagnosis that could explain the cluster of symptoms that they are experiencing. Although rare, pituitary disorders such as Acromegaly should be explored in patients with clinical features of growth hormone excess, such as macrognathia, enlargement of the hands and feet, and in addition development of other clinical symptoms such OSA, CVD, Type 2 DM, and arthropathies.
TSH, GH, and Prolactin Producing Pituitary Adenoma: An Unusual Case Presentation
Authors: Manrique Helard Andres , Pinto Miguel Eduardo
Published: May 2021

Background: Pituitary adenomas are benign and frequent tumors, some of them with tendency to be recurrent or invasive e. several pituitary tumors are positive for secretion of one or more hormones of the same adenohypophysial cell lineage. However, some cases have a subclinical course and are underestimated because they have plurihormonal secretion of different adenohypophyseal cells lineage. Clinical Case: A 38 years old women with chronic headaches, who is in fertility treatment for 12 month ago presents to the clinic with unremarkable physical examination. Her laboratory studies include: Normal campimetry. T3 (triiodothyronine) 2.15 ng/m L (NR:0.8 - 2.0), TSH (thyroid stimulating hormone) 4.4 uU/mL (NR:0.27 - 4.2), T4 (tetraiodothyronine) 13.54 ug/dl, (NR:5.1 - 14.1), Free T4 2.44 ng/d (NR:0.93 - 1.7), Estradiol 60.2 pg/ml, FSH (Follicle stimulating hormone) 4.3 mUI/ml (NR:1,7-12), Cortisol (?8 am) 9.29 ug/dl (NR:4.2 - 38.4), ACTH (Corticotrophin-releasing hormone) 13.1 pg/ml (NR: 0.0 - 46.0), Somatomedin C (IGF-1) 231 .0 ng/ml (NR for age?: 57.0-241.0). Brain MRI with pituitary protocol showed in T1 an isointense lesion and slightly heterogeneous in T2 in the anterior and left aspect of the turkish saddle, of 1 x 1.1 x 1.1 cm of anteroposterior, transverse and cephalocaudal diameter, suggestive of a macroadenoma. The tumor pathology showed, possitive for a pituitary adenoma. Immunohistochemistry results were negative for: ACTH:, positive for GH, TSH: (+++) and for Prolactin:. Her post-operative findings showed a residual pituitary gland without significant findings. Her post operative pituitary axis include: Sodium 139.2 mmol/l (NR”135.0 - 145.0), Chloride 100.8 mmol/l (NR95.0 - 115.0), Potassium 3.71 mmol/l (NR3.5 - 5.1), ACTH 4.1 pg/ml(NR0.0 - 46.0), Cortisol (am) 11.11 ug/dl (NR4.2 - 38.4), Estradiol 106.5 pg/ml, FSH 5.1 mUI/ml, LH (Luteinizing Hormone) 13.53 mIU/ml, Somatomedin C (IGF-1) 134 .0 ng/m, Free T32.4 pg/ml, TSH 0.9 uU/mL Free T4 0.99 ng/dl, and Prolactin 23.4ng/ml. Patient had a satisfactory clinical course after surgery, she maintained normal pituitary function without requirement of hormonal replacement therapy. Conclusion: We present a a prolactin, TSH and GH secreting pituitary adenoma case, which is very unusual. It i is important to make a proper pituitary evaluation, and offer effective treatment to prevent complications
When Your Pituitary Fails - A Rare Case of Pituitary Dysfunction Due to Nivolumab and Ipilimumab
Authors: Khan Areej , Khan Muhammad Ahmed , Phillips Brian
Published: May 2021

Introduction: Immunomodulators like Nivolumab and Ipilimumab are important regimens in many malignancies. However, their use is linked with the rare side effect of pituitary dysfunction that if screened and treated can prevent misdiagnosis.

Case Description: A 56-year-old male with a history of renal cell carcinoma status post bilateral partial nephrectomy with metastasis to the lung on Nivolumab/Ipilimumab presented with dizziness. He endorsed difficulty with balance, nausea, decreased appetite, feeling dehydrated and recent blood pressure readings in the 90s. Vitals on presentation were stable. An MRI, from 2 weeks ago, showed a slightly enlarged sella but no metastatic disease. The next day, he became hypotensive with minimal response to fluids and was started on Midodrine. However, considering his persistent hypotension, his cortisol level was checked and found to be profoundly low (<1). Literature review of his immunomodulator revealed the possibility of central adrenal insufficiency. In addition, he was noted to have a low TSH (0.02) with normal FT4 (1.08). Subsequently, his ACTH level was also found to be low (<1.5) which further elucidated a central cause for his adrenal insufficiency. Therefore, he was ultimately treated with PO hydrocortisone with plans to taper off in the next few weeks.

Conclusion: This case demonstrates a rare yet significant side effect of Nivolumab/Ipilimumab therapy. Timely diagnosis and therapy can alleviate symptoms due to associated hormonal deficiencies. Moving forward it will be interesting to see if starting prophylactic steroids or routine screening will allow us to diagnose pituitary dysfunction due to Nivolumab/Ipilimumab earlier.
Abnormal Pituitary Imaging and Associated Endocrine Dysfunctions in Erdheim-Chester Disease
Authors: Shekhar Skand , Irizarry-Caro Jorge A , Sinaii Ninet , Gahl William , Estrada-Veras Juvianee I , Dave Rahul , Papadakis Georgios Z , Patronas Nicholas , Stratakis Constantine A , O’Brien Kevin , Hannah-Shmouni Fady
Published: May 2021

Background: Erdheim Chester disease (ECD) is a rare histiocytic neoplasm associated with hypothalamic and pituitary infiltration and dysfunction. We determined the abnormal pituitary imaging (API) phenotypes in subjects with ECD and analyzed their associated endocrine dysfunctions. Methods: This was a cross-sectional examination of a natural history cohort study of 61 subjects with ECD performed at a tertiary care clinical research center. The diagnosis of ECD was based on clinical, molecular, and histopathological features. Enrolled subjects underwent baseline endocrine tests of anterior and posterior pituitary function in addition to pituitary imaging. The following variables were analyzed- age, sex, body mass index (BMI), BRAF V600E, hsCRP, ESR, pituitary hormone deficit number, diabetes insipidus (DI), and panhypopituitarism. Fisher’s exact test or t-test/Wilcoxon tests compared patients with and without API. Results: Sixty-one subjects with ECD (age ±SD: 54.3 ±10.9, 46 (75.4%) males) were studied. The prevalence of API was 32.8% (n=20), who were younger than those with normal imaging (50.3 ±10.5 vs 56.3 ±10.7 yrs, p=0.042). The most common pituitary imaging abnormalities included thickened pituitary stalk (18.03%, n=11/61), followed by pituitary encasement, small pituitary and abnormal morphology (6.55%, n= 4/61 for each). A higher prevalence of DI (45.0% vs 9.8%, p=0.003) and panhypopituitarism (45.0% vs 4.9%, p<0.001), and a higher number of pituitary deficits (median (IQR): 2.0 (0-2.5) vs 0 (0-1.0), p=0.007) were noted in patients with API compared to those with normal imaging. Other biochemical markers were similar between both groups. Conclusion: Abnormal pituitary imaging was commonly seen in ECD and was also associated with a younger age and hormone deficits suggesting associations with pituitary structure-function.
Dextroamphetamine Treatment for Children With Hypothalamic Obesity
Authors: van Schaik Jiska , Welling Mila Sofie , De Groot Corjan , Abawi Ozair , Burghard M , Kleinendorst Lotte , van der Voorn Bibian , van Haelst Mieke M , Ophuis S B J Oude , Kamp Gerdien , Rotteveel Joost , van Schouten-Meeteren A Y N , van den Akker Erica L T , van Santen Hanneke Margo
Published: May 2021

Introduction: Hypothalamic obesity (HO) in children can be either genetic or acquired, as a result of a suprasellar tumor or its treatment. HO, resulting from hyperphagia and/or a decreased resting energy expenditure (REE), may have devastating consequences for the child and its family. Currently, no effective drug treatment is yet available for HO. Amphetamines – commonly used in children with attention-deficit/hyperactivity disorder – are known for their stimulant effect on REE and inhibitory effect on appetite. We here present our experiences of dextroamphetamine treatment in children and adolescents with acquired or genetic HO. Methods: A retrospective cohort evaluation was performed of patients (n = 18) treated with dextroamphetamine at 2 endocrine pediatric clinics. Off-label use of dextroamphetamine was initiated in patients with progressive therapy resistant acquired HO (n = 13) and in patients with genetic obesity (n = 5). Initial treatment dosing was once or twice daily 5mg. This dose was weekly increased with 5 mg/day depending on the patient’ wellbeing and the presence of side effects, to a maximum of 0.5 mg/kg/day. Anthropometrics and REE at start and during follow-up, changes in (hyperphagic) behavior, and side effects were assessed.

Results: At start of treatment, mean age was 12.8 years ± 3.4 [range 7.1–17.9] and mean REE was 69.5%± 18.5 (n = 15). At follow-up, mean treatment duration was 18.3 months ± 14.7. Ten out of eighteen children (55.6%) showed clinically relevant weight loss. In 10/13 patients with acquired HO, weight loss was observed (mean ΔBMI SDS -1.09 ± 1.00), in one patient BMI stabilization (ΔBMI SDS +0.03), and in two patients an increase in BMI SDS was seen (mean ΔBMI SDS +0.32 ± 0.05). Of nine children with acquired HO and measurement of REE before and during treatment, a mean REE increase of +15.3% ± 10.5 was observed. In three out of five patients with genetic obesity, initially weight loss was observed resulting in BMI stabilization at end of follow-up due to weight regain (mean ΔBMI SDS -0.08 ± 0.19). In these patients, no difference in REE before and during treatment was observed. In two patients an increase in BMI SDS was seen (mean ΔBMI SDS +0.29 ± 0.25). However, one patient discontinued treatment after one month, due to hypertension. Thirteen out of 18 children (72.2%) reported improvement of either their hyperphagia, energy level, and/or behavior. No serious side effects were reported.

Conclusion: In children and adolescents with acquired HO, treatment with dextroamphetamine may significantly lower BMI, reduce hyperphagia and improve activity level. In genetic HO, these effects were less pronounced. Future studies in a larger cohort and with randomized controlled designs are needed to support these results.
Dehydroepiandrosterone Sulfate, Cortisol and Adrenocorticotropic Hormone Levels in Drug-Naive, First Episode, Male and Female Patients With Psychosis
Authors: Christou Maria , Karampas Andreas , Georgiou Georgios , Plakoutsis Marios , Brikos Spyridon , Petrikis Petros , Tigas Stelios
Published: May 2021

Introduction: Impaired response to stress and a pathological activation of the hypothalamic-pituitary-adrenal axis have been implicated in the pathophysiology of schizophrenia. We aimed to measure serum dehydroepiandrosterone sulfate (DHEA-S), cortisol and adrenocorticotropic hormone (ACTH) levels in drug-naïve, first episode patients with psychosis followed-up in a Greek tertiary center. Methods: Data were included from drug-naïve, first episode patients with psychosis and controls matched for age and sex. Serum DHEA-S, cortisol and ACTH levels were recorded. Results are reported as mean (standard deviation, range). Paired t-test or Wilcoxon signed rank test were performed for group comparisons. The level of significance was set at p less than 0.05. Statistical analysis was performed with Stata 15.1. Results: Data were included for 110 subjects (70 men, 40 women); 55 patients and 55 controls. Mean age was 31.3 years (8.7, 18.0-48.0) in patients and 31.4 years (8.9, 17.0-49.0) in controls. Serum DHEA-S was higher in patients [306.5 μg/dl (165.4, 70.0-790.0)] compared to controls [240.1 μg/dl (113.5, 46.0-597.0)] (p=0.011). Serum ACTH was similar between patients and controls [28.5 pg/ml (15.7, 6.2-73.9) versus 26.5 pg/ml (15.3, 7.0-70.5), p=0.636]. Serum cortisol levels and cortisol/DHEA-S ratio were statistically lower in patients [12.6 μg/dl (4.5, 3.5-24.5) and 5.3 (3.6, 1.3-19.5), respectively] compared to controls [15.5 μg/dl (4.9, 4.2-30.1) and 8.0 (4.7, 1.1-25.5), respectively] (p=0.007 and 0.001, respectively). Sub-analysis, revealed that in men, serum DHEA-S was similar between patients and controls [303.7 μg/dl (149.0, 85.0-744.0) versus 275.0 μg/dl (117.4, 89.0-597.0), respectively, p=0.271) whereas in women serum DHEA-S was higher in patients compared to controls [311.4 μg/dl (194.8, 70.0-790.0) versus 179.2 μg/dl (75.9, 46.0-314.0), respectively, p=0.005]. Serum cortisol and ACTH levels were not different in the above subgroups except serum cortisol in men which was lower in patients compared to controls [12.8 μg/dl (4.4, 3.5-21.6) and 15.9 μg/dl (5.4, 4.2-30.1), respectively, p=0.027]. Conclusions: Serum DHEA-S levels were higher in drug-naïve, first episode female patients, with psychosis compared to controls. DHEA-S levels in male patients and controls were similar.
Diagnostic Threshold for Postoperative Secondary Adrenal Insufficiency After Transsphenoidal Resection of Pituitary Adenomas
Authors: German Massiell , Sharma Anu
Published: May 2021

Transsphenoidal surgery (TSS) is the first line treatment for pituitary adenomas. A well-known complication of TSS is secondary adrenal insufficiency with a reported risk of 4-9% after TSS. Currently, glucocorticoid replacement is recommended if postoperative AM cortisol is < 3 ug/dL. Postoperative adrenal insufficiency is ruled out if AM cortisol is > 15 ug/dL. However, further evaluation of the adrenal axis with ACTH stimulation test is recommended for intermediate cortisol levels 3-15 ug/dL. Other studies have proposed postoperative cortisol threshold of < 4-14 ug/dL for glucocorticoid replacement. Retrospective analysis of all patients undergoing TSS at a tertiary center from January 2013 through April 2016 was performed. ACTH producing adenomas (Cushing’s disease) were excluded. Of the 97 patients included, 17.5% (n=17) had secondary adrenal insufficiency requiring glucocorticoid replacement at 1 year post operatively. Mean age at presentation was 56 ± 16 years and 52% were female. Mean adenoma size was 25.3 ± 11.3 mm. Factors associated with adrenal insufficiency at 1 year post operatively were preoperative secondary adrenal insufficiency (AM cortisol 4.5 ± 1.9 vs 11.0 ± 1.0 µg/dL; p = 0.03), and preoperative adenoma contact with optic chiasm (15.7% vs 2.1%; p = 0.01). Day 1-7 postoperative cortisol was lower in the group with adrenal insufficiency at 1 year (5.6 µg/dL (IQR 1.9-11.5) vs 19.8 µg/dL (IQR 12.75-43.2); p=0.02). Age, gender, adenoma size, and cavernous sinus involvement were not associated with adrenal insufficiency at 1 year. A day 1-7 postoperative cortisol concentration of ≥8.0 µg/dL had a sensitivity of 75% and specificity of 92% in predicting adrenal insufficiency at 1 year. In patients with secondary adrenal insufficiency at 1 year (n=17), there was a higher frequency of concomitant loss of other pituitary hormone function at 1 year: secondary hypothyroidism 82% (n=14), secondary hypogonadism 70.6% (n=12) and diabetes insipidus 17.7% (n=3). A lower postoperative cortisol threshold of 8 µg/dL can be adopted for glucocorticoid replacement on discharge after TSS.
Long-Term Corticotroph Function Following Cure of Cushing’s Syndrome
Authors: Schernthaner-Reiter Marie Helene , Wolf Peter , Micko Alexander , Bögl Magda , Beiglböck Ms, Hannes , Scheuba Christian , Riss Philipp , Wolfsberger Stefan , Kautzky-Willer Alexandra , Luger Anton , Vila Greisa
Published: May 2021

Introduction: Hyper- and hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis in Cushing’s syndrome (CS) and Addison’s disease (AD) is associated with disturbances of classical feedback mechanisms. Time to recovery of adrenal function after CS remission depends on the etiology of CS and is longest after adrenal CS. To date there are no data on the recovery of corticotroph function following CS remission, and the synacthen test is recommended for testing adrenal function in patients with hypopituitarism. Aim Here we aim to test corticotroph function after long-term cure of Cushing’s syndrome following bilateral adrenalectomy (BADx), compared to patients with primary glucocorticoid deficiency due the presence of 21-hydroxylase antibodies or adrenoleucodystrophy, a pathophysiological model of glucocorticoid and mineralocorticoid deficiency. Methods: We retrospectively evaluated data from patients with CS and AD attending our endocrine department between 2000 and 2020, using the following inclusion criteria: BADx performed for pituitary/ectopic/adrenal or occult CS or primary adrenal insufficiency confirmed either by the presence of 21-hydroxylase antibodies or genetically in adrenoleucodystrophy. Results: Full data were available for 93 patients: 43 patients with BADx due to CS (18 patients with pituitary CS, 14 patients with adrenal CS and 11 patients with ectopic/occult CS, F:M 29:14, mean age at BADx 45.4 years age range 13-74 years) and 50 patients with AD (47 cases with positive 21-hydroxylase antibodies, 3 cases with adrenoleucodystrophy, F:M ratio 27:23, mean age at diagnosis 35 years, age range 6-57 years). The observation period was 537.5 patient-years after BADx (mean 12.5 years, range 1-38 years) and 647 patient-years following AD diagnosis (mean 14.2 years, range 1-46 years). At the last visit, there were no differences between the hormone substitution regimes between the groups. ACTH concentrations during the whole observation period and also at the last visit were lowest in patients with adrenal CS (56.5 pg/ml) when compared to patients with AD (487 pg/ml, p<0.001), or with patients with pituitary CS (377.5 pg/mL, p=0.011). ACTH values in patients with AD in long-term follow-up were significantly higher when compared to all patients with CS (141 pg/mL, p<0.001). Conclusion: These data highlight a long-term defective corticotroph function in patients with CS following BADx. Low ACTH concentrations long term after BADx for adrenal CS corroborate that corticotroph function fails to recover after CS cure. In the light of these findings, the utility of the synacthen test for excluding secondary/tertiary adrenal insufficiency following CS remission is disputable and remains to be evaluated in future studies dedicated to CS cohorts.
The Clinical Significance and Utility of Routine Screening for Macroprolactin in Patients With Hyperprolactinemia
Authors: Zeng Wanling , James King Thomas Frederick , Aw Tar Choon , Shern Lau Michael Chin
Published: May 2021

Background: Macroprolactin is a complex of monomeric prolactin (PRL) molecules with immunoglobulin G (IgG) that can result in the elevation of serum prolactin level. Macroprolactin is biologically less active and failure to screen for macroprolactin may lead to unnecessary investigations and treatments in patients with hyperprolactinaemia. Aim: We sought to evaluate the clinical significance and clinical utility of routine screening of macroprolactin in patients with hyperprolactinemia. Methods: We analysed 141 patients from a retrospective database of patients with elevated serum prolactin in Changi General Hospital from Jan 2017 to Dec 2019 with routine screening of macroprolactin with polyethylene glycol (PEG) precipitation using Abbott Architect Prolactin assay. Clinical, biochemical, radiological data and medication usage were extracted from electronic medical records. Macroprolactinaemia was defined as a PRL recovery of < 60%. Approval was obtained from the local research ethics committee. Results: Thirty-six (26%) patients had macroprolactinaemia with a male predominance (72%). There were no significant differences in the presence of symptoms, the percentages of medication-induced hyperprolactinemia, and magnetic resonance imaging (MRI) pituitary scans done between patients with macroprolactinaemia and those with truly elevated serum prolactin. As such clinical features might not be useful to differentiate patients with macroprolactinaemia. Eight MRI pituitary scans were performed in patients with macroprolactinaemia and pituitary abnormalities were detected in 4 of the patients which are likely non-functioning pituitary lesions. As such, not only were unnecessary scans done but it also led to a cascade of further investigations. Eight patients had simultaneous macroprolactinaemia and elevated bioactive serum prolactin, as such post-PEG prolactin level with corresponding reference ranges rather than the percentage recovery should be use as the threshold for defining macroprolactinaemia to avoid misdiagnosis. Conclusion: Macroprolactinaemia is common and routine screening may avert unnecessary investigations. Post-PEG prolactin level with corresponding reference ranges should be used as diagnostic threshold.
Trauma Symptomatology in Patients Successfully Treated for Pituitary Adenoma
Authors: Kovler Jessica Diller , Prevedello Daniel
Published: May 2021

The emotional symptomatology accompanying pituitary adenomas has long been recognized, though research has been scant, varied, and more focused on studies related to quality of life. The present study sought to better codify the psychological presentation of pituitary adenoma patients through the lens of trauma and PTSD symptomatology. 128 patients who were successfully treated for pituitary adenoma were recruited from the Wexner School of Medicine at Ohio State University. Ranging in age from 23 to 74, the participants’ mental health functioning was assessed by the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), the Brief Symptom Inventory (BSI), and the Dissociative Experiences Scale (DES). The findings of this pilot study showed that the rate of traumatization (PTSD) for pituitary adenoma patients was significantly higher than that of the general population. With regard to comorbid trauma-related mental health impairment, our results demonstrated that when moderated by sex, pituitary adenoma patients had significantly higher psychopathology than the non-clinical population. Replicating the existing research, there was a significant positive correlation between trauma symptoms and trauma-related psychopathology in patients successfully treated for pituitary adenoma. Overall, the results of this study demonstrate the traumatic nature of this disease and the need for applied clinical intervention. Further research is needed to replicate these findings, in light of potential selection bias and sample size.
Validity of Different Copeptin Assays in the Differential Diagnosis of the Polyuria-Polydipsia Syndrome
Authors: Sailer Clara Odilia , Refardt Julie , Blum Claudine Angela , Schnyder Ingeborg , Molina-Tijeras Jose Alberto , Fenske Wiebke Kristin , Christ-Crain Mirjam
Published: May 2021

Background: Copeptin is used in the differential diagnosis of diabetes insipidus. Different copeptin immunoassays exist but inter-assay comparability is unclear. The aim of this study was to correlate three commercially available copeptin assays and their diagnostic accuracy in the differential diagnosis of the polyuria-polydipsia-syndrome.

Methods: Analyzed data include three different studies: repeated copeptin measures of 8 healthy volunteers undergoing osmotic stimulation; copeptin measures of 40 patients hospitalized with pneumonia; osmotically stimulated copeptin measures of 40 patients with polyuria-polydipsia-syndrome. Copeptin was measured using the automated B.R.A.H.M.S. KRYPTOR, the manual B.R.A.H.M.S. LIA and the manual Cloud Clone ELISA assay. Primary outcome was the diagnostic accuracy in the polyuria-polydipsia-syndrome.

Results: In total, 150 copeptin measurements were analyzed. In healthy volunteers, there was a moderate correlation for the KRYPTOR and LIA (interrater correlation coefficient (ICC) 0.74; 95%-CI 0.07-0.91), and a poor correlation for the KRYPTOR and ELISA (ICC 0.07; 95%-CI -0.06-0.29), as for the LIA and ELISA (ICC 0.04; 95%-CI -0.04-0.17). The KRYPTOR had the highest diagnostic accuracy (98% (95%-CI: 83-100)), comparable to the LIA (88% (95%-CI: 74-100)), while the ELISA had a poor diagnostic accuracy (55% (95%-CI: 34-68)) in the differential diagnosis of the polyuria-polydipsia-syndrome.

Conclusion: The KRYPTOR and LIA yield comparable copeptin levels and a high diagnostic accuracy, while the ELISA correlates poorly with the other two assays and shows a poor diagnostic accuracy between polyuria-polydipsia patients. Redefining cut-off levels for copeptin assays other than KRYPTOR and LIA must take place before their use in the differential diagnosis of diabetes insipidus.
Dose Escalating and Bioavailability Phase 1 Studies Assessing Safety and Tolerability and Pharmacokinetics of Tildacerfont, a Small-Molecule CRF1 Receptor Antagonist
Authors: Barnes Chris , Offman Elliot , Darago Nora , Moriarty David
Published: May 2021

Background: Tildacerfont (SPR001; LY2371712), a second generation, potent, selective, nonsteroidal, oral small-molecule antagonist of corticotropin-releasing factor type-1 (CRF1) receptors in the pituitary gland, is in late stage development as a potential treatment for adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). We report the results of 3 randomized Phase 1 studies of safety, tolerability, and pharmacokinetics (PK) of tildacerfont in healthy adults and compare the relative bioavailability of 2 tildacerfont formulations. Methods: Two Phase 1 studies were double-blind, placebo-controlled and evaluated escalating doses (2–800 mg QD) as single doses (SAD; n=18) and 50-200mg as multiple doses (MAD; n=47). The studies also included pilot food effect and drug-drug interaction sub studies, respectively. A randomized, balanced, open-label, crossover study (n=42) examined the relative bioavailability (BA) of single oral doses of 2 tildacerfont formulations, 200 mg powder-in-capsule (PIC) compared to 200 mg low-drug load tablet. Results: In the SAD and MAD studies, the most common, non-procedural adverse events were headache and cough. In the BA study, the most common, non-procedural adverse events were constipation and headache. There were no study drug-related serious adverse events (SAEs) in any study. In the SAD and MAD (PIC formulation), tildacerfont concentrations declined in a multi-exponential manner with Cmax occurring moderately late, ~5 hours post dose, and a high degree of variability was observed in AUC and Cmax (CV range: 54–122%). A food effect was observed in the SAD. Fourteen days of dosing achieved near steady state exposure with an AUC accumulation ratio of 2.51 to 3.65 in the MAD study. Midazolam, a sensitive probe substrate for CYP3A4 exhibited ~2-fold increase in AUC and a 1.8 increase in Cmax when co-administered with tildacerfont suggesting moderate CYP3A4 inhibition. The tablet formulation reduced the variability (AUC and Cmax CV range: 69–72%) compared to the PIC formulation resulting in a more predictable pharmacokinetic profile. The half-life of the tablet was ~60 hrs. Bioequivalence in AUC was established with the tablet and PIC formulations (fed state) with Cmax ~20% higher for tablet than PIC due to a reduction in and more consistent Tmax, median [range], from 6 [4.5, 24] hours to 3 [2, 6] hours.

Conclusions: These results suggest that tildacerfont is safe and generally well-tolerated in healthy adults and suitable for further study in patients with CAH. The tablet formulation provided a more consistent pharmacokinetic profile with reduced variability in all parameters and is being evaluated in late stage studies of tildacerfont in adult CAH.
The Effect of Cardiorespiratory Fitness and Insulin Resistance on Bone Health in Hispanic Children
Authors: Shawar Reem S , Puyau Maurice , Shypailo Roman , Musaad Salma , Bacha Fida F
Published: May 2021

Obesity appears to have a negative impact on pediatric bone health, and insulin resistance may mediate this relationship. It is unclear if cardiorespiratory fitness (CRF) has a protective effect on bone in obese children. We tested the hypothesis that CRF attenuates the negative effect of obesity and insulin resistance on skeletal health in a large cohort of Hispanic youth.

We studied 413 (193 males and 220 females) children and adolescents from the Viva la Familia Study. They were all pubertal; mean age (SD) 13.4 ± 2.3 years; 27% were normal weight (NW), 19% overweight (OW) and 54% obese (OB). They underwent measurement of body composition, total body bone mineral content (BMC) and density (BMD) by DXA scan; VO2peak using the ramp protocol on a treadmill for CRF; fasting glucose and insulin. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. BMC increased from NW to OW to OB (mean 1.35 ± 0.4, 1.41 ± 0.4, and 1.49 ± 0.4 kg, respectively, p=.005). Peak VO2 decreased from NW to OW to OB (41.3 ± 9.7, 35.5 ± 7.7, 28.9. ± 5.5 mL/kg per min, respectively, p <.001). After adjusting for sex, age and lean body mass, BMC was inversely related to fat mass (r = -0.34, p <.001) and HOMA-IR (r = -0.29, p <.001). Similar relationships were found for BMD. In a regression model with BMC as the dependent variable, lean body mass (standardized coefficient (β)=0.95, p <.001) was positively and fat mass (β=-0.18, p <0.001) negatively associated with BMC (model R2=0.88, p<.001). HOMA-IR (β=-0.07, p =0.001) and VO2peak (β=0.09, p =0.003) had significant and opposite associations with BMC (model p<.001) but fat mass was no longer a significant contributor. With BMD as the dependent variable, lean body mass (β=0.82, p <.001), HOMA-IR (β=-0.06, p =0.04) and peak VO2 (β=0.17, p <.001), but not fat mass, contributed to the variance in BMD (R2=0.79, p<.001).

In conclusion, lean body mass is the major determinant of BMC and BMD in Hispanic youth. Adiposity associated insulin resistance has a negative effect on BMC and BMD. CRF contributes positively to the variance in BMC and BMD. This suggests that CRF and higher lean mass attenuate the adverse effects of insulin resistance on bone health in children.
Late Endocrine Effects After HSCT in Children With Nonmalignant Diseases; A Single Center Cohort Analysis
Authors: de Kloet Liselotte C , Bense Joëll E , van der Stoep-Yap Eileen , Louwerens Marloes , von Asmuth Erik G J , Lankester Adriaan C , de Pagter Anne P J , Hannema Sabine E
Published: May 2021

Endocrine complications are amongst the most frequent late effects after pediatric hematopoietic stem cell transplantation (HSCT) for malignant diseases. Little is known about the prevalence and risk factors of endocrine complications in children transplanted for nonmalignant diseases. This retrospective study included 134 males and 63 females transplanted for a non-malignant disease between 1997 and 2018 with at least 2 years of follow up. Endocrine late effects and growth were evaluated. Gonadal dysfunction was defined as transient or permanent elevation of gonadotropins or hypogonadotropic hypogonadism.

Median age at HSCT was 5.7 years (IQR 2.8-11.3) and median follow-up was 6.2 years (IQR 3.0-10.4). Underlying diseases were inborn errors of immunity (n=74), hemoglobinopathies (n=66) and bone marrow failure (n=57). The majority of patients had received busulfan-based conditioning (46%) or treosulfan-based conditioning (34%).

Gonadal dysfunction occurred in 24/44 (post)pubertal female patients (55%) and was permanent in 19/44 (43%). 22/44 received hormonal substitution, which could be discontinued in 7. In females who received busulfan-based conditioning 16/17 (94%) developed gonadal dysfunction compared to 5/15 (33%) patients with treosulfan-based conditioning; the odds ratio for permanent gonadal dysfunction was 18.7 (3.61-135, p=0.001).

Gonadal dysfunction occurred in 28/66 (post)pubertal male patients (42%) and was permanent in 23/66 (35%). 6/66 received hormonal substitution, which could be discontinued in 1. Gonadal dysfunction was more common in males (post)pubertal at HSCT, 14/21 (67%), compared to those prepubertal at HSCT, 14/45 (31%), p=0.014. 3/15 treated with a treosulfan-based regimen (20%) developed gonadal dysfunction, all transient, versus 19/39 with a busulfan-based regimen (49%), with 2 transient.

29/187 patients developed hypothyroidism (16%), 7 patients received thyroxine treatment (4%). All patients with persistent primary hypothyroidism (n=6) had positive TPO-antibodies.

17 patients received growth hormone treatment and were excluded from analysis. In patients without growth hormone treatment near adult height (NAH) was -1.2 SDS (median, IQR -2.0- -0.3) below mean parental height (MPH) in males and -0.4 SDS (median, IQR -1.6-0.3) in females. NAH below -2 SDS was seen in 13/43 males (30%) and 2/36 females (6%). The majority of these patients already had a height below -2 SDS before HSCT (73%).

In conclusion, this study on late endocrine effects after HSCT in children with nonmalignant diseases indicates frequent gonadal dysfunction, present in 55% of females and 42% of males. In this cohort, risk of gonadal dysfunction in females was higher after busulfan-based conditioning than treosulfan-based conditioning. Careful long-term endocrine follow-up is indicated.
Extracellular Vesicles From SDHB Deficient hPheo1 Cells Activate STAT3 in Wild-Type Cells
Authors: Ghayee Hans K , Patel Sujal , Tuna Kubra M , Liu Lauren , Xu Yiling , Alli Abdel A
Published: May 2021

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that originate from the adrenal medulla and extra-adrenal paraganglia, respectively. Inactivating mutations in succinate dehydrogenase (SDHx) genes leads to succinate accumulation, increased HIF1-α levels, and uncontrollable growth of PPGLs. We hypothesized that small extracellular vesicles (EVs) released from progenitor cells derived from pheochromocytoma (hPheo1) with a shRNA mediated knockdown of SDHB are enriched in succinate metabolites that play a key role in the activation of various tyrosine dependent signaling pathways that are involved in turmorigenesis and proliferation. We isolated EVs from the conditioned media of human wild-type hPheo1 cells and hPheo1 cells with shRNA SDHB knockdown. The EVs from three separate preparations of each group were characterized by nanoparticle tracking analysis, transmission electron microscopy, and Western blotting using antibodies against different types of EV and one non-EV marker. Our results show small EVs from the SDHB knockdown hPheo1 cells increased the activation of phosphotyrosine residues in wild-type cells compared to cells treated with control EVs from the same cell type. Additionally, our data show these EVs increase phospho-STAT3 compared to the control EVs (3843.10 +/- 1138.89 vs. 213.65+/- 40.75; p<0.05; n=3) in cultured wild-type hPheo1 cells. Protein tyrosine kinases (PTKs) control various cellular processes including growth, differentiation, and metabolism by activating various signaling pathways including STAT3. The significance of these findings is that in some cancers, elevated succinate from a SDHx mutation has been shown to activate STAT3 which may explain a possible pathway for tumorigenesis. Studies from other investigators have shown that STAT3 expression is elevated in malignant PPGL tissues. Through enriched EV analysis our findings have confirmed the role of STAT3 in SDHB deficient cells. Additional studies are needed to identify other metabolites that are enriched in EVs that regulate phosphorylation of tyrosine residues and STAT3 activation.
Impact of BMI on Growth Hormone Stimulation Tests in Children and Adolescents: A Systematic Review and Meta-Analysis
Authors: Abawi Ozair , Augustijn Dieuwertje , Hoeks Sanne , de Rijke Yolanda B , van den Akker Erica L T
Published: May 2021

Background: Peak stimulated growth hormone (GH) levels are known to decrease with increasing BMI, possibly leading to overdiagnosis of GH deficiency (GHD) in children with overweight and obesity. However, current guidelines do not provide guidance how to interpret peak GH values of these children, nor has this been assessed systematically. The aim of this systematic review and meta-analysis was to study the effect of BMI on stimulated peak GH values in children, and to quantify to which extent peak GH values in children with obesity are decreased. Methods: We searched the Medline, Embase, Cochrane, Web of Science, and Google Scholar databases (13 July 2020) for studies reporting impact of BMI on peak GH in children. Where possible, individual participant data was extracted and/or obtained from the authors. Primary outcome was the association between peak GH values and BMI standard deviation score (SDS). Pooled correlation coefficients were calculated under a random effects model, and exploratory moderator analyses and meta-regression were performed. Study heterogeneity was assessed using the I2 statistic. For studies with available individual participant data, linear mixed-models regression analysis was performed with BMI SDS as predictor and ln(peak GH) as outcome, accounting for used GH stimulation agent (fixed effect) and study (random effect). This systematic review was performed in accordance to the PRISMA guidelines. Results: In total, 56 studies were included, providing data on n=5100 children (1346 with individual participant data). Across all studies, a pooled r of -0.37 (95% CI -0.44 to -0.31, n=2785) was found. Study heterogeneity was large (I2=58%). Pubertal status, sex, presence of syndromic obesity, and mean age and BMI SDS of the population did not significantly moderate the pooled r (all p>0.05). Individual participant data analysis revealed a beta of -0.11 (95% CI -0.08 to -0.15, p<0.001), i.e., per 1 point increase in BMI SDS, peak GH decreases by 11% (95% CI 7 to 14%). In the 8 studies performed in children referred for short stature, obesity was present in 27/893 (3.02%) children without GHD and in 36/615 (5.85%) children with GHD (p=0.0069). This corresponds to a RR of 1.43 (95% CI 1.14 to 1.78, p=0.002) for a diagnosis of GHD in children with short stature with obesity compared to children without obesity. Discussion: To our knowledge, this is the first systematic review and meta-analysis to investigate the impact of BMI on peak GH values in children, showing a significant negative correlation and risk of overdiagnosis of GHD in children with obesity. All in all, with ever-rising prevalence of pediatric obesity, our study highlights the urgent need for BMI (SDS)-specific cut-off values for GH stimulation tests in children.
Impact of IGF-1 Normative Datasets on Indication and Outcome of Growth Hormone Stimulation Testing
Authors: de Bie Prim , Heijboer Annemieke C , Deckers Martine M L
Published: May 2021

In the Netherlands, the diagnosis of growth hormone deficiency in children follows the Dutch national guidelines for Triage and Diagnosis of Growth Disorders in Children. Initial biochemical evaluation includes an IGF-1 measurement as screening parameter for growth hormone deficiency. Based on the clinical probability of growth hormone deficiency and the IGF-1 Z-score, a growth hormone stimulation test is performed if serum IGF-1 Z-score is < 0 SD in case of a high probability and if serum IGF-1 Z-score is < -1 SD in case of low probability. An IGF-1 Z-score > 0 SD virtually excludes a growth hormone deficiency disorder. The interpretation of growth hormone stimulation testing is dependent on both the peak growth hormone concentration, but also on the baseline IGF-1 Z-score, particularly in cases of partial deficiency. Although, nation wide, Dutch laboratories have harmonized their measurement for IGF-1 (as was previously done for growth hormone), a Dutch harmonized normative data set has not been widely adopted. Moreover a clinical evaluation of the implementation of this dataset based on dynamic testing has not been published. To assess the impact of choice of a particular normative dataset on the diagnosis of growth hormone deficiency we recalculated Z-scores of IGF-1 measurements between 2016 and 2019, using our home reference values based on de normative dataset by Elmlinger (E)1, and using the normative datasets defined by Bidlingmaier (B)2 and by the Dutch IGF-1 harmonization program (NL). Based on these three Z-scores, the outcomes of growth hormone stimulation tests performed in this period (n=86) were reassessed according to the interpretation described in the Dutch guideline. Using all three normative datasets the same 4 patients were identified as likely to have a growth hormone deficiency, whereas 10(E), 10(B), or 8(NL) patients were identified as possible partial growth hormone deficiency. In 70(E), 66(B) or 72(NL) patients the growth hormone stimulation test was unaffected. Using normative dataset B, 6 patients displayed a pattern associated with a possible growth hormone resistance, or of bio-inactive growth hormone syndromes, which based on its incidence would be unlikely for a secondary care setting. A striking observation was however, that of all patients with a normal stimulation test 9 (E)/16 (B) or 30 (NL) had a IGF-1 Z-score of > 0 SD. This implies that, for the diagnosis of growth hormone deficiency, it is safe to implement the Dutch harmonized dataset, which in addition could result in a reduction in the number of growth hormone stimulation tests that have to be performed.

References: 1. Elmlinger MW et al. Clin Chem Lab Med. 2004;42(6):654-64.

2. Bidlingmaier M et al. J Clin Endocrinol Metab. 2014 May;99(5):1712-21.
Stratifying the Genetic Aetiology in Children Born Small for Gestational Age With Persistent Short Stature (SGA-SS)
Authors: Toni Ledjona , Plachy Lukas , Dusatkova Petra , Elblova Lenka , Amaratunga Shenali Anne , Kolouskova Stanislava , Obermannova Barbora , Snajderova Marta , Sumnik Zdenek , Pruhova Stepanka , Lebl Jan
Published: May 2021

Background: Ten percent of children born small for gestational age with a birth weight and/or length of below -2 SD for their gestational age fail to catch-up and remain short during childhood (SGA-SS). The etiology of SGA-SS is heterogeneous: some children have specific phenotypic features that allow targeted genetic testing; in others, elucidating genetic or environmental background is more challenging. Aim: To decipher genetic etiologies among a large single-center cohort of SGA-SS children and to stratify them according to molecular mechanisms leading to pre- and postnatal growth failure. Patients/Methods: In our center 447 children (223 females) fulfilled the criteria of SGA-SS. Of these 182 families agreed to take part and offered the child’s and both parents’ DNA for genetic testing by a panel of 399 growth-related genes, or by Whole Exome Sequencing (WES). The results were processed by a bioinformatic pipeline and detected variants were filtered using variant analysis software. Pathogenic or likely pathogenic variants (according to ACMG standards and guidelines) were confirmed by Sanger sequencing. Results: The genetic etiology was elucidated in 73/182 (40%) children so far. We confirmed (likely) pathogenic gene variants affecting pituitary development and/or the GH-IGF-1 axis in 10/73 (14%) patients (PTCH1, HGMA2 [in two], OTX2, LHX4, GHSR, STAT3, IGFALS, IGF1R [in two]), abnormal components of cartilaginous matrix in 17/73 (23%) (ACAN [in two], FLNB [in three], FBLN5, COL11A1[in four], COL1A2, COL2A1[in five], MATN3), impaired paracrine regulation of chondrocytes in 4/73 (6%) (NPR2 [in three], FGFR3), SHOX gene defects in 12/73 (16%), gene variants affecting other components of intracellular regulation and signaling in 9/73 (12%) (CDC42, KMT2A, KMT2D, NSD1, SRCAP, PRG4, PTPN11, SON, LMNA), Silver-Russell syndrome (11p15 [in seven] or UPD7) in 11/73 (15%), and miscellaneous single-gene or chromosomal conditions (TRPS1, TRHR, RAI1, chromosomal microdeletions and/or translocations) in an additional ten (14%) children. Conclusions: In our study we showed that by using current genetic techniques we were able to elucidate the genetic cause in a significant number of patients born SGA-SS. The genetic etiology spectrum of SGA-SS reflects the complex system of growth regulation, with a significant role of growth plate genes that are causative in 33/73 (45%) cases clarified thus far. Acknowledgements: The study was co-funded by grants AZV NV18-07-00283 and GAUK 408120.