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Objective There is growing recognition of morbidity and mortality that can occur in patients with cranial diabetes insipidus (CDI) during hospitalisation, due to prescribing errors and dysnatraemia, often related to confusion between CDI and diabetes mellitus among non-specialists. We aimed to investigate this. Methods Data for each hospitalisation in patients with CDI attending Oxford University Hospital (OUH) were collected retrospectively. The same cohort were invited to complete a questionnaire by telephone. Results One hundred and nine patients were included, median age was 42 (range: 6–80) years. Route of desmopressin was tablet, melt and nasal spray in 74%, 7% and 17% of patients, respectively, while two patients used a combination of tablet and nasal spray. There were 85 admissions to OUH by 38 patients between 2012 and 2021. Daily measurement of serum sodium was performed in 39% of admissions; hyponatraemia and hypernatraemia occurred in 44 and 15% of admissions, respectively. Endocrine consultation was sought in 63% of admissions post-2018. Forty-five of 78 patients (58%) self-reported ≥1 admission to any hospital since diagnosis. Of these, 53% felt their medical team did not have a good understanding of the management of CDI during hospital admission. Twenty-four per cent reported delay in administration of desmopressin, while 44% reported confusion between CDI and diabetes mellitus, often leading to unnecessary blood glucose monitoring. Conclusion Dysnatraemia is common in hospitalised patients with CDI. More than half of patients perceived their medical team’s understanding of CDI to be poor when admitted with intercurrent illness. A coordinated approach, including early consultation of specialists, frequent serum sodium monitoring, and education of hospital specialists is needed to address this.

The aim of this study is to describe two clinical cases, which we believe highlight the need to consider routine genetic testing of all patients with new diagnosis of a tympanic paraganglioma (PGL).Two patients seen in the ENT clinic at a tertiary center with a diagnosis of isolated tympanic PGL, without family history.Since 2016, all patients with newly diagnosed isolated tympanic PGL (glomus tympanicum) are offered review by the clinical genetic team and genetic testing of a panel of paraganglioma/phaeochromocytoma predisposition genes. Previously only those with multiple PGL or a family history were tested.We describe the results of genetic testing, the clinical course and discuss the ongoing implications for management.Both cases were identified to have a pathogenic variant in the SDHB gene after initial surgery. The clinical course for both cases was complicated by disease recurrence, as well as metastatic and secretory disease in one case. Knowledge of genetic status has influenced ongoing management, with annual MRI surveillance for other SDH-related tumors.These two cases reinforce the importance of offering genetic testing for all cases of isolated tympanic PGL. The discovery of a significant underlying genetic variant may affect management decisions and subsequent follow-up.

Background In patients with phaeochromocytomas or paragangliomas (PPGLs), 24-h urine collections for metanephrines (uMNs) are cumbersome. Objective To evaluate the diagnostic utility of ratios to creatinine of ‘spot’ uMNs. Methods Concentrations of uMNs and plasma metanephrines (pMNs) were measured by HPLC-mass-spectrometry. We retrospectively compared correlations of 24-h-urine output and ratio to creatinine in historical specimens and prospectively assessed 24-h and contemporaneous spot urines and, where possible, pMNs. Using trimmed log-transformed values, we derived reference intervals based on age and sex for spot urines. We used multiples of upper limit of normal (ULNs) to compare areas under curves (AUCs) for receiver-operator characteristic curves of individual, and sum and product of, components. Results In 3143 24-h-urine specimens on 2416 patients, the correlation coefficients between the ratios and outputs of metanephrine, normetanephrine and 3-methoxytyramine in 24-h urines were 0.983, 0.905 and 0.875, respectively. In 96 patients, the correlations between plasma concentrations, urine output and ratios in spot specimens were similar to those for raw output or ratios in 24-h specimens. Of the 160 patients with PPGLs, the CIs for AUCs for individual metabolites overlapped for all four types of measurement, as did those for the sum of the multiple ULNs although these were slightly higher (AUC for spot urine: 0.838 (0.529–1), plasma: 0.929 (0.874–0.984) and output: 0.858 (0.764–0.952)). Conclusions Ratios of fractionated metanephrines to creatinine in spot urine samples appear to have a similar diagnostic power to other measurements. The ease of spot urine collection may facilitate diagnosis and follow-up of PPGLs through improved patient compliance.

Introduction. Adrenocortical carcinomas (ACCs) are infrequently reported to present with severe hypoglycemia syndrome resulting from the secretion of insulin-like growth factor II (IGF-II) by tumor cells. Adrenocorticotropic hormone- (ACTH) independent hypercortisolism is the norm of hormonally active ACCs, but aberrant ACTH production by tumor cells can theoretically cause ACTH-dependent hypercortisolism. The purpose of this report was to present a case of an ACC manifested with the co-occurrence of two extremely rare presentations. Case Description. We present a rare case of a 43-year-old male patient admitted with recurrent episodes of severe non-ketotic and non-insulin-mediated hypoglycemia due to IGF-II mediated disease and ACTH-dependent Cushing’s syndrome. He was diagnosed with a diffusely disseminated adrenocortical carcinoma with immunohistochemistry of tumor cells showing focal ACTH immunostain positivity. Conclusion. Non-islet cell tumor hypoglycemia and ACTH-dependent Cushing’s syndrome are extremely rare presentations of an ACC, and co-occurrence of these entities in a single patient is never reported in the literature.

Background: Diabetes insipidus (DI) is a recognised complication of pituitary surgery, with diagnosis requiring clinical observation aided by plasma and urine electrolytes and osmolalities. Copeptin is a stable surrogate marker of AVP release and has potential to facilitate prompt diagnosis of post-operative DI. This assay has been shown to accurately predict which patients are likely to develop DI following pituitary surgery. Objective: To determine whether copeptin analysis can be used to predict which patients are at risk of developing DI following transsphenoidal adenomectomy (TSA).Methods: 78 patients undergoing TSA had samples taken for copeptin pre-operatively and at day 1 post-TSA. The majority of patients also had samples from day 2, day 8, and week 6 post-TSA. Results from patients who developed post-operative DI (based on clinical assessment, urine and plasma biochemistry and the need for treatment with DDAVP) were compared to those who did not. Patients with any evidence of pre-operative DI were excluded.Results: Of 78 patients assessed, eleven were clinically determined to have developed DI. Differences were observed between patients with DI and those without in post-operative samples. Of note, there was a significant difference in plasma copeptin at day 1 post-operation (p=0.010 on Kruskal-Wallis test), with copeptin levels greater than 3.4 pmol/L helping to rule out DI (91% sensitivity, 55% specificity at this cut off).Conclusion: In the post-TSA setting, copeptin is a useful rule-out test in patients with values above a defined threshold, which may facilitate earlier decision making and shorter hospital stays.

Background Diabetes insipidus (DI) is a recognised complication of pituitary surgery, with diagnosis requiring clinical observation aided by plasma and urine electrolytes and osmolalities. Copeptin is a stable surrogate marker of AVP release and has potential to facilitate prompt diagnosis of post-operative DI. This assay has been shown to accurately predict which patients are likely to develop DI following pituitary surgery. Objective To determine whether copeptin analysis can be used to predict which patients are at risk of developing DI following trans-sphenoidal surgery (TSS). Methods Seventy-eight patients undergoing TSS had samples taken for copeptin pre-operatively and at day 1 post-TSS. The majority of patients also had samples from day 2, day 8, and week 6 post-TSS. Results from patients who developed post-operative DI (based on clinical assessment, urine and plasma biochemistry and the need for treatment with DDAVP) were compared to those who did not. Patients with any evidence of pre-operative DI were excluded. Results Of 78 patients assessed, 11 were clinically determined to have developed DI. Differences were observed between patients with DI and those without in post-operative samples. Of note, there was a significant difference in plasma copeptin at day 1 post-operation (p = 0.010 on Kruskal–Wallis test), with copeptin levels greater than 3.4 pmol/l helping to rule out DI (91% sensitivity, 55% specificity at this cut off). Conclusion In the post-TSS setting, copeptin is a useful rule-out test in patients with values above a defined threshold, which may facilitate earlier decision making and shorter hospital stays.

Background: Clinical manifestations and treatment outcomes in children and adolescents with multiple endocrine neoplasia type 1 are not well characterized. Methods: We conducted a retrospective cohort study of 80 patients with multiple endocrine neoplasia type 1 who commenced tumor surveillance at ≤18 years of age. Results: Fifty-six patients (70%) developed an endocrine tumor by age ≤18 years (median age = 14 years, range = 6–18 years). Primary hyperparathyroidism occurred in >80% of patients, with >70% undergoing parathyroidectomy, in which less-than-subtotal (70% had nonfunctioning tumors, >35% had insulinomas, and 55% undergoing surgery. Pituitary tumors developed in >30% of patients, and ∼35% were macroprolactinomas. Tumor occurrence in male patients and female patients was not significantly different. Genetic analyses revealed 38 germline MEN1 mutations, of which 3 were novel. Conclusions: Seventy percent of children aged ≤18 years with multiple endocrine neoplasia type 1 develop endocrine tumors, which include parathyroid tumors for which less-than-subtotal parathyroidectomy should be avoided; pancreaticoduodenal neuroendocrine tumors that may metastasize; and pituitary macroprolactinomas.

Non-functioning pituitary adenoma (NFPA) is the most prevalent pituitary macroadenoma. No prognostic marker has been found to explain the behavior of these tumors. We aimed to explore cell proliferation, apoptosis, proangiogenic markers, and microvascular density (MVD) in noninvasive and invasive NFPAs. Adenoma invasiveness was defined according to Knosp and Hardy classifications based on preoperative magnetic resonance imaging scans. Cell proliferation was examined using Ki67 and P53. Tissue expression of Bcl-2 was used to assess the antiapoptosis pathway. CD34 and CD105 were measured to evaluate MVD, while VEGF expression was assessed as an indicator of pro-angiogenesis. Moreover, VEGF, bFGF, endocan, and endostatin were measured on preoperative serum samples. Tissue and serum markers were examined in 18 patients with invasive and 21 patients with noninvasive NFPAs. Ki67 less than 3% was reported in 10 invasive and 14 noninvasive NFPAs (P = 0.752). P53 staining was negative in all subjects. In addition, Bcl-2 staining was negative in 15 and 20 subjects, respectively (P = 0.718). VEGF-A expression 2+ or 3+ was reported in 9 invasive and 11 noninvasive macroadenomas (P = 0.83). Moreover, CD34 and CD105 positivity were comparable between the two groups. Furthermore, the comparison of serum markers showed no significant differences. Cell proliferation, apoptosis, and angiogenesis play a limited role in NFPA behavior.

Context The 250-μg short Synacthen (corticotropin) test (SST) is the most commonly used tool to assess hypothalamo-pituitary-adrenal (HPA) axis function. There are many potentially reversible causes of adrenal insufficiency (AI), but no data to guide clinicians as to the frequency of repeat testing or likelihood of HPA axis recovery. Objective To use the SST results to predict adrenal recovery. Design A retrospective analysis of 1912 SSTs data. Patients Seven hundred seventy-six patients with reversible causes of AI were identified who had at least two SSTs performed. A subgroup analysis was performed on individuals previously treated with suppressive doses of glucocorticoids (n = 110). Main Outcome Measures Recovery of HPA axis function. Results SST 30-minute cortisol levels above or below 350 nmol/L (12.7 μg/dL) best predicted HPA axis recovery [area under the curve (AUC) receiver operating curve (ROC) = 0.85; median recovery time: 334 vs 1368 days, P = 8.5 × 10-13]: 99% of patients with a 30-minute cortisol >350 nmol/L recovered adrenal function within 4 years, compared with 49% in those with cortisol levels

Objective A major cause of readmission after transsphenoidal surgery (TSS) is delayed hyponatraemia. The purpose of this study was to identify predictors of hyponatraemia one week post surgery and predictors of 30-day readmissions for hyponatraemia. Design A retrospective cohort study including patients who had TSS performed for pituitary lesions. Method The risk of readmission for hyponatraemia was assessed in consecutive patients between January 2008 and March 2016. The risk of hyponatraemia one week post surgery was assessed in patients admitted for TSS between July 2011 and March 2016. Results Of all included patients, 56/522 (10.7%) were readmitted within 30 days. Hyponatraemia was found in 14/56 (25%) of 30-day readmissions. We did not identify any predictive variable for hyponatraemia on readmission. The number of patients with hyponatraemia on the seventh post-operative day was 26/314 (8.3%). The risk of hyponatraemia one week post surgery was increased by an odds ratio of 2.40 (95% CI: 1.06–5.40) in patients with a tumour abutting the optic chiasm and by an odds ratio of 1.16 (1.04–1.31) per mmol/L decrease in sodium levels on the first post-operative day. Conclusions Hyponatraemia occurred in 25% of readmissions; however, we did not identify any predictive variable for readmission with hyponatraemia. One week post surgery, 8.9% had hyponatraemia. Tumours pressing on the optic chiasm as well as a fall in sodium levels on the first post-operative day were associated with an increased risk of hyponatraemia one week post surgery. We suggest that a day 7 serum sodium

Neuroendocrine tumors (NETs) are being seen increasingly frequently, and recent data show that long-acting somatostatin analogues have become a major initial treatment, regardless of whether the tumors are functioning or not. However, test dosing with subcutaneous (sc) octreotide is usually advised to assess longer-term tolerability, although this advice is mainly based on results with functioning tumors. The aim of the study was to assess the value of an initiating test dose of sc octreotide on the prediction of subsequent adverse events after treatment with the long-acting analogue.In a single, large Centre of Excellence for NETs, a first cohort of patients (n = 24) was admitted overnight after an sc injection of octreotide, and then administered the analogue; a subsequent group (n = 53) had the test dose performed on an outpatient basis. Side effects were recorded after the test dose and subsequent treatment with the long-acting analogue.The test dose injection was of little value in predicting adverse events following the long-acting somatostatin analogue.Unless there are serious symptoms associated with a functioning NET, it is unnecessary to carry out a test dose; a change to this procedure will improve resource allocation and should enhance early initiation onto maintenance therapy.CLARINET = Controlled study of lanreotide antiproliferative response in neuroendocrine tumors LAR = long-acting repeatable NET = neuroendocrine tumor PROMID = Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with meta-static neuroendocrine midgut tumors.

Background Hypopituitarism is a potential sequelea of pituitary macroadenoma or trans-sphenoidal adenomectomy (TSA). Recovery of pituitary function can occur post-TSA, and reassessment is required to avoid needless hormonal replacement. The timing and frequency of re-testing is variable across centres and the aim of this study was to determine rate of, and time to recovery of hypothalamic-pituitary adrenal (HPA), gonadal and thyroid axes postTSA. Methods We performed a single-centre retrospective analysis of TSA patients from February 2015 to September 2018. Patients with apoplexy, corticotroph adenomas, redo-surgery, emergency TSA, craniotomy or pituitary radiotherapy were excluded. Thyroid, gonadal and HPA axis adequacy was respectively assessed with TSH/freeT4, FSH/LH/estradiol or testosterone measurement and short synacthen test (SST), performed pre-TSA and at 6-weeks, 3-, 6-, and 9 to 12-months post-TSA. Results Data on 135 patients (mean age 54±17 years; 80M) were analysed. Macroadenomas occurred in 118 (87.4%), microadenoma in 8 (5.9%). Histology confirmed gonadotroph (53%), somatotroph (10.4%), plurihormonal (13.3%), lactotroph (5.2%), meningioma (1.5%), craniopharyngioma (12.6%), thyrotroph (1.5%) and metastatic malignancy (2.2%). 53.7%, 30.2% and 19.1% of patients had pre-op gonadal, thyroid and HPA function deficit respectively. 59% of patients had at least one deficit at baseline. Age was associated with the number of deficits manifested (F=6.026, p6 weeks post-op.

Context Secondary adrenal insufficiency is a potential complication of transsphenoidal adenomectomy (TSA). Most centers test recovery of the hypothalamo-pituitary-adrenal (HPA) axis after TSA, but, to our knowledge, there are no data predicting likelihood of recovery or the frequency of later recovery of HPA function. Objective To assess timing and predictors of HPA axis recovery after TSA. Design Single-center, retrospective analysis of consecutive pituitary surgeries performed between February 2015 and September 2018. Patients Patients (N = 109) with short Synacthen test (SST) data before and at sequential time points after TSA. Main outcome measures Recovery of HPA axis function at 6 weeks, and 3, 6, and 9 to12 months after TSA. Results Preoperative SST indicated adrenal insufficiency in 21.1% Among these patients, 34.8% recovered by 6 weeks after TSA. Among the 65.2% (n = 15) remaining, 13.3% and 20% recovered at 3 months and 9 to 12 months, respectively. Of the 29% of patients with adrenal insufficiency at the 6-week SST, 16%, 12%, and 6% subsequently recovered at 3, 6, and 9 to 12 months, respectively. Preoperative SST 30-minute cortisol, postoperative day 8 cortisol, and 6-week postoperative SST baseline cortisol levels above or below 430 nmol/L [15.5 μg/dL; AUC ROC, 0.86]; 160 nmol/L (5.8 μg/dL; AUC ROC, 0.75); and 180 nmol/L (6.5 μg/dL; AUC ROC, 0.88), were identified as cutoffs for predicting 6-week HPA recovery. No patients with all three cutoffs below the threshold recovered within 12 months after TSA, whereas 92% with all cutoffs above the threshold recovered HPA function within 6 weeks (OR, 12.200; 95% CI, 5.268 to 28.255). Conclusion HPA axis recovery can occur as late as 9 to 12 months after TSA, demonstrating the need for periodic reassessment of patients who initially have SST-determined adrenal insufficiency after TSA. Pre- and postoperative SST values can guide which patients are likely to recover function and potentially avoid unnecessary lifelong glucocorticoid replacement.

Context Disease processes that affect the pituitary stalk are broad; the diagnosis and management of these lesions remains unclear. Objective The aim was to assess the clinical, biochemical and histopathological characteristics of pituitary stalk lesions and their association with specific MRI features in order to provide diagnostic and prognostic guidance. Design and methods Retrospective observational study of 36 patients (mean age 37years, range: 4–83) with pituitary stalk thickening evaluated at a university hospital in Oxford, UK, 2007–2015. We reviewed morphology, signal intensity, enhancement and texture appearance at MRI (evaluated with the ImageJ programme), along with clinical, biochemical, histopathological and long-term follow-up data. Results Diagnosis was considered certain for 22 patients: 46% neoplastic, 32% inflammatory and 22% congenital lesions. In the remaining 14 patients, a diagnosis of a non-neoplastic disorder was assumed on the basis of long-term follow-up (mean 41.3months, range: 12–84). Diabetes insipidus and headache were common features in 47 and 42% at presentation, with secondary hypogonadism the most frequent anterior pituitary defect. Neoplasia was suggested on size criteria or progression with 30% sensitivity. However, textural analysis of MRI scans revealed a significant correlation between the tumour pathology and pituitary stalk heterogeneity in pre- and post-gadolinium T1-weighted images (sensitivity: 88.9%, specificity: 91.7%). Conclusions New techniques of MRI imaging analysis may identify clinically significant neoplastic lesions, thus directing future therapy. We propose possible textural heterogeneity criteria of the pituitary stalk on pre- and post-gadolinium T1 images with the aim of differentiating between neoplastic and non-neoplastic lesions with a high degree of accuracy.

Several new gene mutations have been reported in recent years to be associated with a risk of familial pheochromocytoma. However, it is unclear as to whether extensive genetic testing is required in all patients. The clinical data of consecutive patients operated for pheochromocytoma over a decade in a tertiary referral center were reviewed. Genetic screening was performed using a 10-gene panel: RET, VHL, SDHB, SDHD, SDHA, SDHC, SDHAF2, MAX, TMEM127 and FH. A total of 166 patients were analyzed: 87 of them had genetic screening performed (39 M: 44.8%, 48 F: 55.2%, age range 6–81 years, mean 45±16.8 years). In total, 22/87 (25.3%) patients had germline mutations, while 65/87 (74.7%) patients presented with apparently sporadic tumors. Germline VHL mutations were identified in 11.7% of patients, RET in 6.8% (five MEN2A/MEN2 and one MEN2B/MEN3), SDHD in 2.3%, MAX in 2.3%, SDHB in 1.1%, and TMEM127 in 1.1% of patients. At diagnosis, 15.1% of patients with unilateral non-syndromic pheochromocytoma showed germline mutations. We identified 19.7% of mutations in patients with unilateral-non-recurrent pheochromocytomas within 5 years vs. 50% in the recurrent-bilateral-metastatic group (p = 0.01). Germline mutations were more frequently seen with bilateral pheochromocytomas (p = 0.001): 80% of patients with bilateral disease had germline mutations (4 VHL, 3 RET, 1 MAX). The advent of rapid genetic screening using a gene-panel makes it feasible to screen large cohorts of patients and provides a valuable tool to contribute to the prediction of bilateral and malignant disease and to screen family members.