Copeptin and the syndrome of inappropriate antidiuresis (SIAD) after pituitary transsphenoidal surgery.

OBJECTIVE: This study evaluates the predictive value of copeptin for syndrome of inappropriate antidiuresis (SIAD) postpituitary transsphenoidal surgery (TSS). DESIGN: Data from 133 consecutive patients undergoing TSS (November 2017-October 2022) at Oxford University Hospitals NHS trust are presented in this retrospective study. METHODS: Logistic regression (LR) and receiver operating characteristic (ROC) curves were performed to evaluate the diagnostic utility of copeptin. The Mann-Whitney U test was used to compare copeptin levels between the SIAD and no SIAD groups. RESULTS: Fourteen patients (10.8%) developed SIAD. Copeptin was available in 121, 53 and 87 patients for Days 1, 241 and 8 post-TSS, respectively. LR for Day 1 copeptin to predict SIAD gave an odds ratio (OR) of 1.0 (95%CI 42 0.84-1.20, p = .99), area under-ROC curve (AUC) was 0.49; Day 2 copeptin OR was 0.65 (95%CI 0.39-1.19, 43 p = .77), AUC was 0.57 LR for Day 1 sodium to predict SIAD gave an odds ratio (OR) of 1.0 (95%CI 0.85-1.21, p = .99), AUC was 0.50. CONCLUSIONS: In conclusion, our data provide no evidence for copeptin as a predictive marker for post-TSS SIAD.

Efficacy of cabergoline in non-irradiated patients with acromegaly: a multi-centre cohort study.

OBJECTIVE: Elucidate the efficacy (as per current biochemical criteria) of cabergoline monotherapy or as addition to long-acting somatostatin receptor ligand (SRL) in patients with acromegaly and no previous pituitary radiotherapy. DESIGN: Multi-centre, retrospective, cohort study (four UK Pituitary centres: Birmingham, Bristol, Leicester, Oxford). METHODS: Clinical, laboratory, imaging data were analysed. RESULTS: Sixty-nine patients on cabergoline monotherapy were included [median IGF-1 xUpper Limit of Normal (ULN) pre-cabergoline 2.13 (1.02-8.54), median treatment duration 23 months, median latest weekly dose 3 mg]. 31.9% achieved normal IGF-1 (25% GH-secreting, 60% GH+prolactin co-secreting tumours); median weekly cabergoline dose was similar between responders and non-responders. IGF-1 normalisation was related with GH+prolactin co-secreting adenoma (B 1.50, p=0.02) and lower pre-cabergoline IGF-1 xULN levels (B -0.70, p=0.02). Both normal IGF-1 and GH<1 mcg/L were detected in 12.9% of cases and tumour shrinkage in 29.4% of GH-secreting adenomas.Twenty-six patients on SRL+cabergoline were included [median IGF-1 xULN pre-cabergoline 1.7 (1.03-2.92), median treatment duration 36 months, median latest weekly dose 2.5 mg]. 23.1% achieved normal IGF-1 (15.8% GH-secreting, 33.3% GH+prolactin co-secreting tumours). Normal IGF-1 and GH<1 mcg/L were detected in 17.4%. CONCLUSIONS: In non-irradiated patients, cabergoline normalises IGF-1 in around one-third and achieves both IGF-1 and GH targets in approximately one out of ten cases. SRL+cabergoline is less efficient than previously reported possibly due to differences in studies methodology and impact of confounding factors.

Predictors of pituitary tumour behaviour: an analysis from long-term follow-up in 2 tertiary centres.

OBJECTIVES: To determine the clinical utility of assessment of tumour invasion, markers of proliferation, and the French clinicopathological classification in pituitary tumour prognostication. METHODS: This is a retrospective evaluation of adult patients undergoing pituitary surgery at Oxford University and St Vincent's Hospitals, between 1989 and 2016, with at least 12 months of clinical data. Invasion was assessed radiologically, proliferative markers (Ki67, mitotic count, p53) by immunohistochemistry. Tumours were graded according to the clinicopathological classification. Intra- and interlaboratory variability of histopathology reporting was evaluated. OUTCOMES: (1) Tumour recurrence (radiological or reintervention ≥12 months postoperatively) and/or (2) "aggressive behaviour" (≥4 interventions and/or invasive tumour with recurrence/reintervention between 12 and 24 months postoperatively). RESULTS: A total of 386 patients were included, age at surgery was 56 (interquartile range [IQR] 41-67) years, 54% were male, and median follow-up was 90 months (range 44-126). Tumours were predominantly clinically nonfunctioning (252, 65%), with overall 53% invasive, and 10% that demonstrated ≥2 proliferative marker positivity. Recurrence was predicted by invasiveness (hazards ratio [HR] 1.6 [1.10-2.37], P .02), elevated mitotic count (HR 2.17 [1.21-3.89], P .01), grade (2b vs 1a HR 2.32 [1.06-5.03], P .03), and absence of gross total resection (HR 3.70 [1.72-8.00], P .01). Clinically defined aggressiveness was associated with elevated Ki67, mitotic count, and invasiveness. Ki67 reporting methodologies showed moderate correlation across laboratories (Phi 0.620), whereas p53 reporting reproducibility was poor (Phi 0.146). CONCLUSIONS: Proliferative markers, including Ki67 and mitotic count, but not p53, are important in predicting the development of aggressive pituitary tumour behaviour.

"A morning cortisol is the most effective clinical predictor of short synacthen test outcome": A tertiary care centre experience.

OBJECTIVE: Increasing referrals to Endocrinology with nonspecific symptoms of suspected adrenal insufficiency (AI) has increased use of the short-synacthen test (SST). Prevailing resource and safety concerns emphasise importance of patient selection criterion to optimise SST use. This study aimed to (1) document the adverse event profile of the SST (2) identify any pretest predictors of SST outcome. DESIGN, PATIENTS AND MEASUREMENTS: Retrospective data analysis of all patients referred for SST in Oxford from 2017 to 2021. Pretest clinical variables (age, sex, BMI, blood pressure and electrolytes), symptoms (fatigue, dizziness, weight loss) and pretest morning cortisol were included in the statistical model with the aim of identifying any variables that could predict SST outcome in Group 1 primary AI, Group 2 central AI and Group 3 glucocorticoid induced AI. Symptoms and signs during and post SST were also noted with the aim of describing adverse effects to synacthen across a large cohort. RESULTS: A total 1480 SSTs (Males:38%, age 52 [39-66] years) were performed: 505 (34.1%) in Group 1, 838 (57%) in Group 2, and 137 (9.3%) in Group 3. Adverse-effects were recorded in 1.8% of tests, including one episode of anaphylaxis. Pretest morning-cortisol was the only predictor for an "SST pass" (whole cohort: B = 0.015, p < 0.001, Group 1: B = 0.018, p < .001; Group 2: B = 0.010, p < 0.012; Group 3: B = 0.018, p = <.001). A threshold of ≥343 nmol/l (receiver-operating characteristic [ROC] area under the curve [AUC] = 0.725, 95% confidence interval [CI] 0.675-0.775, p < 0.001) for the whole cohort, ≥300 nmol/L (ROC AUC = 0.763, 95% CI 0.675 to 0.850, p < 0.001) for Group 1, ≥340 nmol/L (ROC AUC = 0.688, 95% CI 0.615 to 0.761, p < 0.001) for Group2, and ≥376 nmol/L [baseline cortisol] (ROC AUC = 0.783, 95% CI 0.708 to 0.859, p < 0.001) for Group 3, predicted an 'SST pass' with 100% specificity. CONCLUSIONS: Adverse effects to synacthen are rare. Pretest morning cortisol is a reliable predictor for SST outcome and is a helpful tool to rationalise use of the SST. Predictive morning-cortisol thresholds vary according to the aetiology of AI.

Natural history of non-functioning pituitary microadenomas: results from the UK non-functioning pituitary adenoma consortium.

OBJECTIVE: The optimal approach to the surveillance of non-functioning pituitary microadenomas (micro-NFPAs) is not clearly established. Our aim was to generate evidence on the natural history of micro-NFPAs to support patient care. DESIGN: Multi-centre, retrospective, cohort study involving 23 endocrine departments (UK NFPA consortium). METHODS: Clinical, imaging, and hormonal data of micro-NFPA cases between January, 1, 2008 and December, 21, 2021 were analysed. RESULTS: Data for 459 patients were retrieved [median age at detection 44 years (IQR 31-57)-152 males/307 females]. Four hundred and nineteen patients had more than two magnetic resonance imagings (MRIs) [median imaging monitoring 3.5 years (IQR 1.71-6.1)]. One case developed apoplexy. Cumulative probability of micro-NFPA growth was 7.8% (95% CI, 4.9%-8.1%) and 14.5% (95% CI, 10.2%-18.8%) at 3 and 5 years, respectively, and of reduction 14.1% (95% CI, 10.4%-17.8%) and 21.3% (95% CI, 16.4%-26.2%) at 3 and 5 years, respectively. Median tumour enlargement was 2 mm (IQR 1-3) and 49% of micro-NFPAs that grew became macroadenomas (nearly all >5 mm at detection). Eight (1.9%) patients received surgery (only one had visual compromise with surgery required >3 years after micro-NFPA detection). Sex, age, and size at baseline were not predictors of enlargement/reduction. At the time of detection, 7.2%, 1.7%, and 1.5% patients had secondary hypogonadism, hypothyroidism, and hypoadrenalism, respectively. Two (0.6%) developed hypopituitarism during follow-up (after progression to macroadenoma). CONCLUSIONS: Probability of micro-NFPA growth is low, and the development of new hypopituitarism is rare. Delaying the first follow-up MRI to 3 years and avoiding hormonal re-evaluation in the absence of tumour growth or clinical manifestations is a safe approach for micro-NFPA surveillance.

Complete sequencing of a cynomolgus macaque major histocompatibility complex haplotype.

Macaques provide the most widely used nonhuman primate models for studying the immunology and pathogenesis of human diseases. Although the macaque major histocompatibility complex (MHC) region shares most features with the human leukocyte antigen (HLA) region, macaques have an expanded repertoire of MHC class I genes. Although a chimera of two rhesus macaque MHC haplotypes was first published in 2004, the structural diversity of MHC genomic organization in macaques remains poorly understood owing to a lack of adequate genomic reference sequences. We used ultralong Oxford Nanopore and high-accuracy Pacific Biosciences (PacBio) HiFi sequences to fully assemble the ∼5.2-Mb M3 haplotype of an MHC-homozygous, Mauritian-origin cynomolgus macaque (Macaca fascicularis). The MHC homozygosity allowed us to assemble a single MHC haplotype unambiguously and avoid chimeric assemblies that hampered previous efforts to characterize this exceptionally complex genomic region in macaques. The high quality of this new assembly is exemplified by the identification of an extended cluster of six Mafa-AG genes that contains a recent duplication with a highly similar ∼48.5-kb block of sequence. The MHC class II region of this M3 haplotype is similar to the previously sequenced rhesus macaque haplotype and HLA class II haplotypes. The MHC class I region, in contrast, contains 13 MHC-B genes, four MHC-A genes, and three MHC-E genes (vs. 19 MHC-B, two MHC-A, and one MHC-E in the previously sequenced haplotype). These results provide an unambiguously assembled single contiguous cynomolgus macaque MHC haplotype with fully curated gene annotations that will inform infectious disease and transplantation research.

A study of acromegaly-associated headache with somatostatin analgesia.

The aim of this study is to characterise somatostatin analogue-responsive headache in acromegaly, hitherto not systematically documented in a significant cohort. Using the UK pituitary network, we have clinically characterised a cohort of 18 patients suffering from acromegaly-related headache with a clear response to somatostatin analogues. The majority of patients had chronic migraine (78%) as defined by the International Headache Society diagnostic criteria. Headache was present at the time of acromegaly presentation and clearly associated temporally with disease activity in all cases. Short-acting somatostatin analogues uniquely resolved pain within minutes and the mean duration of analgesia was 1-6 h. Patients on long-acting analogues required less short-acting injections (mean: 3.7 vs 10.4 injections per day, P = 0.005). 94% used somatostatin analogues to control ongoing headache pain. All patients presented with macroadenoma, most had incomplete resection (94%) and headache was ipsilateral to remnant tissue (94%). Although biochemical control was achieved in 78% of patients, headache remained in 71% of them. Patients selected for this study had ongoing headache post-treatment (mean duration: 16 years after diagnosis); only four patients reached headache remission 26 years (mean range: 14-33) after the diagnosis. Headache in acromegaly patients can be persistent, severe, unrelieved by surgery, long-lasting and uncoupled from biochemical control. We show here that long-acting analogues allow a decrease in the number of short-acting analogue injections for headache relief. Further studies are needed to understand the mechanisms, markers and tumour tissue characteristics of acromegaly-related headache. Until then, this publication serves to provide the clinical characteristics as a reference point for further study.

Post-pituitary surgery copeptin analysis as a 'rule-out' test for post-operative diabetes insipidus.

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.

Central diabetes insipidus from a patient's perspective: management, psychological co-morbidities, and renaming of the condition: results from an international web-based survey.

BACKGROUND: Central diabetes insipidus is a rare neuroendocrine condition. Data on treatment-associated side-effects, psychological comorbidities, and incorrect management are scarce. The aim of this study was to investigate patients' perspectives on their disease. METHODS: This study used a cross-sectional, web-based, anonymous survey, developed by endocrinologists and patient representatives, to collect the opinions of patients with central diabetes insipidus on management and complications of their disease, psychological comorbidities, degree of knowledge and awareness of the condition among health-care professionals, and renaming the disease to avoid confusion with diabetes mellitus (diabetes). FINDINGS: Between Aug 23, 2021, and Feb 7, 2022, 1034 patients with central diabetes insipidus participated in the survey. 91 (9%) participants were children and adolescents (37 [41%] girls and 54 [59%] boys; median age 10 years [IQR 6-15]) and 943 (91%) were adults (757 [80%] women and 186 [20%] men]; median age 44 years [34-54]). 488 (47%) participants had isolated posterior pituitary dysfunction and 546 (53%) had combined anterior and posterior pituitary dysfunction. Main aetiologies were idiopathic (315 [30%] of 1034 participants) and tumours and cysts (pre-surgical 217 [21%]; post-surgical 254 [25%]). 260 (26%; 95% CI [0·23-0·29]) of 994 patients on desmopressin therapy had hyponatraemia leading to hospitalisation. Patients who routinely omitted or delayed desmopressin to allow intermittent aquaresis had a significantly lower prevalence of hyponatraemia compared with those not aware of this approach (odds ratio 0·55 [95% CI 0·39-0·77]; p=0·0006). Of patients who had to be hospitalised for any medical reason, 71 (13%; 95% CI 0·10-0·16) of 535 patients did not receive desmopressin while in a fasting state (nil by mouth) without intravenous fluid replacement and reported symptoms of dehydration. 660 (64%; 0·61-0·67) participants reported lower quality of life, and 369 (36%; 0·33-0·39) had psychological changes subjectively associated with their central diabetes insipidus. 823 (80%; 0·77-0·82) participants encountered a situation where central diabetes insipidus was confused with diabetes mellitus (diabetes) by health-care professionals. 884 (85%; 0·83-0·88) participants supported renaming the disease; the most favoured alternative names were vasopressin deficiency and arginine vasopressin deficiency. INTERPRETATION: This is the largest survey of patients with central diabetes insipidus, reporting a high prevalence of treatment-associated side-effects, mismanagement during hospitalisation, psychological comorbidities, and a clear support for renaming the disease. Our data are the first to indicate the value of routinely omitting or delaying desmopressin. FUNDING: Swiss National Science Foundation, Swiss Academy of Medical Sciences, and G&J Bangerter-Rhyner-Foundation.

Management of cranial diabetes insipidus: clinical outcomes and patient perception of care.

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.

Risk of second brain tumour after radiotherapy for pituitary adenoma or craniopharyngioma: a retrospective, multicentre, cohort study of 3679 patients with long-term imaging surveillance.

BACKGROUND: Radiotherapy is a valuable treatment in the management algorithm of pituitary adenomas and craniopharyngiomas. However, the risk of second brain tumour following radiotherapy is a major concern. We assessed this risk using non-irradiated patients with the same primary pathology and imaging surveillance as controls. METHODS: In this multicentre, retrospective cohort study, 4292 patients with pituitary adenoma or craniopharyngioma were identified from departmental registries at six adult endocrine centres (Birmingham, Oxford, Leeds, Leicester, and Bristol, UK and Ferrara, Italy). Patients with insufficient clinical data, known genetic predisposition to or history of brain tumour before study entry (n=532), and recipients of proton beam or stereotactic radiotherapy (n=81) were excluded. Data were analysed for 996 patients exposed to 2-dimensional radiotherapy, 3-dimensional conformal radiotherapy, or intensity-modulated radiotherapy, and compared with 2683 controls. FINDINGS: Over 45 246 patient-years, second brain tumours were reported in 61 patients (seven malignant [five radiotherapy, two controls], 54 benign [25 radiotherapy, 29 controls]). Radiotherapy exposure and older age at pituitary tumour detection were associated with increased risk of second brain tumour. Rate ratio for irradiated patients was 2·18 (95% CI 1·31-3·62, p<0·0001). Cumulative probability of second brain tumour was 4% for the irradiated and 2·1% for the controls at 20 years. INTERPRETATION: Irradiated adults with pituitary adenoma or craniopharyngioma are at increased risk of second brain tumours, although this risk is considerably lower than previously reported in studies using general population controls with no imaging surveillance. Our data clarify an important clinical question and guide clinicians when counselling patients with pituitary adenoma or craniopharyngioma on the risks and benefits of radiotherapy. FUNDING: Pfizer.

A case of ChAdOx1 vaccine-induced thrombocytopenia and thrombosis syndrome leading to bilateral adrenal haemorrhage and adrenal insufficiency.

Summary: Vaccine-induced thrombosis and thrombocytopenia (VITT) after vaccination against SARS-CoV-2 with the adenoviral vector-based vaccines ChAdOx1 and Ad26.COV2.S has been associated with adrenal pathology, such as bilateral adrenal vein thrombosis, adrenal cortex haemorrhage and adrenal insufficiency in 6% of patients. We report the case of a 23-year-old woman who presented at 8 days after ChAdOx1 vaccination with a low platelet count of 43 × 109/L, raised d dimers >100 000 ng/mL and multiple lobar and segmental pulmonary emboli. Anti-platelet factor 4 antibodies were detected confirming definite VITT in accordance with the UK diagneostic criteria. At 16 days post-vaccine, further imaging showed bilateral adrenal haemorrhage, non-occlusive splenic vein thrombosis and right ventricular thrombosis. Her cortisol level was <25 nmol/L. She was treated with anticoagulation, plasmapheresis, immunosuppression and steroid replacement. She had high anti-spike titre and positive anti-nucleocapsid titres for SARS-CoV-2. She developed seizures secondary to posterior reversible encephalopathy, requiring intensive care. After 4 weeks in hospital, she was discharged on warfarin, hydrocortisone and fludrocortisone replacement. Short synacthen tests 3 and 9 months later showed no recovery of adrenal function, although magnetic resonance imaging of the adrenal glands showed resolving adrenal haemorrhage. Adrenal insufficiency secondary to bilateral adrenal vein thrombosis and adrenal haemorrhage should be suspected in patients with VITT and treated promptly. Adrenal vein thrombosis can occur either as the initial presentation of VITT or days to weeks after the development of thrombosis in other sites. Further studies are required to provide insight on adrenal function recovery after VITT. Learning points: Adrenal insufficiency secondary to bilateral adrenal vein thrombosis and adrenal cortex haemorrhage should be suspected in patients with vaccine-induced thrombosis and thrombocytopenia (VITT) and treated promptly. Adrenal vein thrombosis can occur as the initial presentation of VITT or even days to weeks later after the development of thrombosis in other more classic sites (e.g. pulmonary or cerebral vasculature). Completion of vaccination schedule against SARS-CoV-2 post-VITT using an mRNA-based vaccine should be recommended to patients post-VITT as mRNA-based vaccines have not been associated with VITT but confer protection against SARS-CoV-2. There is paucity of data regarding the potential for recovery of adrenal function after bilateral adrenal haemorrhage in the context of VITT, and thus, more studies are needed to inform clinical practice. The need for disease registries for rare conditions, such as VITT, is crucial as direct cooperation and sharing of information by clinicians might enable quicker identification of disease patterns than would have been possible via established reporting tools of adverse events.

Delayed diagnosis of T3 supplementation in a bodybuilder presenting with tachycardia and features of sepsis.

A 25-year-old man presented generally unwell to the emergency department. Initial assessment identified systemic inflammatory response syndrome markers with an insect bite as a potential source of infection and he was treated for presumed sepsis. Tachycardia persisted and baseline thyroid function testing showed undetectable free thyroxine and thyroid-stimulating hormone (TSH), prompting further endocrine investigation. Triiodothyronine (T3) was markedly raised with normal TSH receptor antibodies, and the patient later confessed to supplementary testosterone and T3 use as part of bodybuilding activities. Following counselling, thyroid function normalised and the patient returned to his usual health. This case describes the diagnostic work up in a case of persistent tachycardia caused by T3 supplementation, demonstrating the potential for endocrine supplementation by bodybuilders which may be poorly understood and recognised by clinicians. T3 supplementation should be considered and a thorough drug history obtained in bodybuilders presenting with symptoms of thyrotoxicosis and deranged thyroid function tests.

Pituitary gigantism: a rare learning opportunity.

INTRODUCTION: Pituitary gigantism is a rare but significant paediatric condition with complexities surrounding diagnosis and management. Transsphenoidal surgery (TSS) is the treatment of choice; however, medical treatment is often considered as adjuvant therapy. CASE: A 10½ -year-old boy presented with tall stature and a height velocity of 11 cm/year. His height was 178.7 cm (+5.8 SD above mean) and insulin-like growth factor-1 (IGF-1) was elevated. An oral glucose tolerance test demonstrated non-suppression of growth hormone (GH). Initial contrast MRI was inconclusive, but C-11 methionine functional positron emission tomography CT identified a 6 mm pituitary microadenoma. A multidisciplinary team clinic held with the family allowed discussion about medical and surgical treatment options. Due to a number of factors including the patient's young age, prepubertal status, a wish to allow him to settle into his new high school and his desire to reach a final height taller than his father's height, it was decided to try medical therapy first with a somatostatin analogue. Pubertal induction was also commenced and bilateral epiphysiodesis surgery performed. Initial response to octreotide was positive; however, 4 months into therapy his IGF-1 was climbing and a repeat GH profile was not fully suppressed. The patient therefore proceeded to have successful TSS excision of the adenoma. CONCLUSION: Rare cases such as this require sharing of knowledge and expertise, so the best possible care is offered. It is often necessary to work across sites and disciplines. Each case requires an individual approach tailored to the patient and their family.

Outcomes of Patients with Nelson's Syndrome after Primary Treatment: A Multicenter Study from 13 UK Pituitary Centers.

CONTEXT: Long-term outcomes of patients with Nelson's syndrome (NS) have been poorly explored, especially in the modern era. OBJECTIVE: To elucidate tumor control rates, effectiveness of various treatments, and markers of prognostic relevance in patients with NS. PATIENTS, DESIGN, AND SETTING: Retrospective cohort study of 68 patients from 13 UK pituitary centers with median imaging follow-up of 13 years (range 1-45) since NS diagnosis. RESULTS: Management of Cushing's disease (CD) prior to NS diagnosis included surgery+adrenalectomy (n = 30; eight patients had 2 and one had 3 pituitary operations), surgery+radiotherapy+adrenalectomy (n = 17; two received >1 courses of irradiation, two had ≥2 pituitary surgeries), radiotherapy+adrenalectomy (n = 2), and adrenalectomy (n = 19). Primary management of NS mainly included surgery, radiotherapy, surgery+radiotherapy, and observation; 10-year tumor progression-free survival was 62% (surgery 80%, radiotherapy 52%, surgery+radiotherapy 81%, observation 51%). Sex, age at CD or NS diagnosis, size of adenoma (micro-/macroadenoma) at CD diagnosis, presence of pituitary tumor on imaging prior adrenalectomy, and mode of NS primary management were not predictors of tumor progression. Mode of management of CD before NS diagnosis was a significant factor predicting progression, with the group treated by surgery+radiotherapy+adrenalectomy for their CD showing the highest risk (hazard ratio 4.6; 95% confidence interval, 1.6-13.5). During follow-up, 3% of patients had malignant transformation with spinal metastases and 4% died of aggressively enlarging tumor. CONCLUSIONS: At 10 years follow-up, 38% of the patients diagnosed with NS showed progression of their corticotroph tumor. Complexity of treatments for the CD prior to NS diagnosis, possibly reflecting corticotroph adenoma aggressiveness, predicts long-term tumor prognosis.

Recovery of the Hypothalamo-Pituitary-Adrenal Axis After Transsphenoidal Adenomectomy for Non-ACTH-Secreting Macroadenomas.

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.

Plurihormonal Pit-1 lineage adenoma presenting as meningitis with recurrence after somatostatin analogue.

A 21 year-old woman was found to have a pituitary macroadenoma following an episode of haemophilus meningitis. Biochemical TSH and GH excess was noted, although with no clear clinical correlates. She was treated with a somatostatin analogue (SSA), which restored the euthyroid state and controlled GH hypersecretion, but she re-presented with a further episode of cerebrospinal fluid (CSF) leak and recurrent meningitis. Histology following transsphenoidal adenomectomy revealed a Pit-1 lineage plurihormonal adenoma expressing GH, TSH and PRL. Such plurihormonal pituitary tumours are uncommon and even more unusual to present with spontaneous bacterial meningitis. The second episode of CSF leak and meningitis appears to have been due to SSA therapy-induced tumour shrinkage, which is not a well-described phenomenon in the literature for this type of tumour. Learning points: Pit-1 lineage GH/TSH/PRL-expressing plurihormonal pituitary adenomas are uncommon. Moreover, this case is unique as the patient first presented with bacterial meningitis. Inmunohistochemical plurihormonality of pituitary adenomas does not necessarily correlate with biochemical and clinical features of hormonal hypersecretion. Given that plurihormonal Pit-1 lineage adenomas may behave more aggressively than classical pituitary adenomas, accurate pathological characterization of these tumours has an increasing prognostic relevance. Although unusual, a CSF leak and meningitis may be precipitated by SSA therapy of a pituitary macroadenoma via tumour shrinkage.

Clinical, Endocrine and Imaging Characteristics of Patients with Primary Hypophysitis.

Primary hypophysitis (PH) is a rare disease with a poorly-defined natural history. Our aim was to characterise patients with PH at presentation and during prolonged follow-up. Observational retrospective study of 22 patients was conducted from 3 centres. In 14 patients, PH was confirmed histologically and in the remaining 8 clinically, after excluding secondary causes of hypophysitis. All patients had hormonal and imaging investigations before any treatment. Median follow up was 48 months (25-75%: 3-60). There was a female predominance with a female/male ratio: 3.4:1. Eight out of 22 patients had another autoimmune disease. Headaches and gonadal dysfunction were the most common symptoms. Five patients presented with panhypopituitarism; 17 patients had anterior pituitary deficiency, and 7 had diabetes insipidus. At presentation, 9 patients were treated surgically, 5 received replacement hormonal treatment, and 8 high-dose glucocorticoids from whom 5 in association with other immunosuppressive agents. Six patients showed complete recovery of pituitary hormonal deficiencies while 6 showed a partial recovery during a 5-year follow-up period. No difference was found between patients treated with surgery and those treated medically. The overall relapse rate was 18%. PH can be manifested with a broad spectrum of clinical and hormonal disturbances. Long-term follow-up is required to define the natural history of the disease and response to treatment, since pituitary hormonal recovery or relapse may appear many years after initial diagnosis. We suggest that surgery and immunosuppressive therapy be reserved for exceptional cases.