Robert D. Murray

Objective: The acromegaly-associated arthropathy (AcAA) is a determinant of long-term impaired quality of life. There are limited data assessing the impact of arthropathy, determinants of future arthropathy, and current management. Design: Multicentre cross-sectional questionnaire study of arthropathy in 6 UK endocrine centres. Methods: The study incorporated questionnaires relating to distribution of arthralgia, severity of pain, and clinical management of AcAA. Demographics and laboratory data were extracted from medical records. Results: We enrolled 411 patients (210 female, median 60, IQR 50-69 years) and median 13 (IQR 6-22) years since diagnosis. Joint pain was reported by 82.5%, with 43.3% and 13.1% experiencing moderate and severe joint pain respectively. The most frequently affected joints were knees (54.7%), lower back (47.7%), hips (38.9%), and shoulders (38.6%). Two hundred and forty-seven (60.1%) were taking at least one analgesic, 137 (33.3%) at least 2 classes of analgesics. One hundred and nine (26.5%) patients had at least one joint injection (median 2, 1-20). Seventy (17.0%) had at least one joint prosthesis (median 2, 1-6), at median age 59 (32-82) years. A similar percentage (17.0%) had other forms of joint surgery. Patients aged ≤50 years experienced less pain, required fewer joint injections and less joint surgery, but a similar prevalence of analgesic use, with 36.4% and 10.3% reporting moderate or severe pain. Conclusion: This study therefore highlights the burden of arthropathy in patients with acromegaly, estimates the need for therapeutic interventions, and the impact on health services.

Familial isolated pituitary adenoma (FIPA) accounts for approximately 2%–5% of all pituitary adenomas, with inactivating variants of the aryl hydrocarbon receptor‐interacting protein ( AIP ) gene representing the most frequent known genetic cause. Clinically, patients with AIP variants often have young‐onset macroadenomas with growth hormone hypersecretion, although disease severity and penetrance are variable. Most reported AIP variants are point mutations, whereas large deletions are rare and potentially underdiagnosed. Accurate detection of AIP copy‐number variants requires methods such as multiplex ligation‐dependent probe amplification or validated copy‐number analysis of next‐generation sequencing data, as Sanger sequencing alone may fail to identify these alterations. Due to the rarity of the disease, it is unknown whether large deletions in the ubiquitously expressed AIP gene are associated with potentially more severe phenotype. Available data suggest that large deletions may occur in 8%–10% of AIP mutation‐positive pedigrees, highlighting the importance of incorporating copy‐number variant detection into AIP testing workflows. We analysed data from all published patients with large AIP deletions ( n = 25) and report here two novel large AIP deletions (Exons 3–4 and Exons 2–6 deletions) and three additional three families, including an Albanian kindred associated with metastatic Hürthle cell thyroid carcinoma. No major differences compared with other AIP variants were found in age at diagnosis, tumour size, hormonal profile, sex distribution or presence of other tumours. A role for AIP variants in thyroid carcinogenesis is unlikely.

Objective: Surveillance is often adopted for asymptomatic non-functioning pituitary macroadenomas (macroNFPAs). Due to low-quality evidence, uncertainty remains on optimal frequency of imaging/biochemical monitoring and indications for surgery. We assessed the natural history and outcomes of patients with macroNFPA who had monitoring as initial management choice from the UK NFPA Consortium. Design: This was a multicentre, retrospective, cohort study involving 21 UK endocrine departments. Methods: Clinical, imaging, and hormonal data of 949 patients followed up between January, 1, 2005 and March, 1, 2022 were analysed. Results: Incidence rate for tumour enlargement was 9.8 per 100 patient-years (95% CI, 8.8-10.8), with cumulative probabilities 1.6%, 8.1%, 18.4%, 29.2%, and 43.6% at 6-month, 1-year, 2-year, 3-year, and 5-year follow-up, respectively; rates were higher in tumours abutting/displacing optic chiasm than those not in contact with it. Amongst macroNFPAs not in contact with optic chiasm showing enlargement within 6 months, none impacted visual fields. In tumours with enlargement and continued monitoring (median 2.6 years), further growth occurred in 60.5% (33.8% probability at 2 years), stability in 35.5%, and shrinkage in 4.0%. Rates of new pituitary hormone deficits were 4.0%-4.9%, mainly driven by tumour enlargement. After transsphenoidal surgery, rates of hypopituitarism reversal were 12%-17% and those of additional anterior pituitary hormone deficits were 12%-15% (permanent vasopressin deficiency 3.5%). Conclusions: Our data provide evidence for monitoring protocols. MacroNFPAs not in contact with optic chiasm require less frequent imaging, and first follow-up scan can be delayed to 1 year. After first enlargement, variable tumour behaviour can occur. New hypopituitarism in stable tumours is rare, challenging necessity of regular pituitary function assessment.

Objective: Survivors of childhood, adolescent, and young adult (CAYA) cancer have an increased risk of metabolic syndrome (MetS). MetS describes the clustering of cardiovascular risk factors including overweight or obesity, hypertension, (pre)diabetes, and dyslipidaemia. While associated cardiovascular sequelae can be serious, MetS is preventable, manageable, and potentially reversible with the appropriate pharmacological and/or behavioral interventions. To optimize health outcomes in CAYA cancer survivors, international, harmonized surveillance recommendations are essential. Design: Systematic review and guideline development. Methods: A multidisciplinary guideline panel evaluated concordances and discordances across national guidelines for MetS surveillance and performed a systematic literature review. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and formulate recommendations considering the strength of the underlying evidence as well as potential harms and benefits associated with MetS surveillance. In case evidence was lacking, recommendations were based on expert opinion. In addition, recommendations for surveillance modalities were derived from existing guidelines for MetS components where applicable. Results: The systematic literature review included 20 studies and highlighted 2 high-risk groups, namely CAYA cancer survivors treated with total body irradiation and those treated with cranial or craniospinal irradiation (moderate-quality evidence). Recommendations were formulated for MetS surveillance in these risk groups, covering preferred screening modalities, age at screening initiation, and surveillance frequency. Conclusions: In this international surveillance guideline for MetS in CAYA cancer survivors, we provide evidence-based recommendations for clinical practice, with the aim of ensuring optimal MetS surveillance for CAYA cancer survivors.

Background: Despite steroid replacement therapy, patients with adrenal insufficiency (AI) experience excessive infections and related hospital admissions. However, data examining the evolution of admissions, healthcare resources utilisation and cost burden is sparce.Design: Analysis of National Hospital Episode Statistics (HES) data set which contains details of all admissions and outpatient appointments at NHS hospitals in England.Methods and Measurements: Spells spanning financial years 2018/19 to 2022/23, focusing on HES codes E27.1 (Primary Adrenocortical Insufficiency; PAI) [n = 57,125], E27.2 (Addisonian Crisis; AC) [n = 12,640] and E27.4 (Other and Unspecified AI; UAI) [n = 79,965] were analysed for admissions, main diagnosis, bed‐days, costs, follow‐up, and readmissions.Results: Over the study period, admissions for AC remained stable; admissions involving UAI increased, whereas PAI admissions reduced transiently during COVID‐19. Mean length of stay for AC increased from 5.1 to 6.8 days (34%). Patients with primary pneumonia and AI had longer hospital stays than those without AI and were more likely to require critical care. Mean cost per hospital stay increased, rising 25% for AC since 2019/20, reaching £2959 per stay. 10% of patients had >1 non‐elective readmission within 12 months. Endocrinologist follow‐up was lower than expected. Centres treating > 225 spells/year reviewed 20−46% of AI patients within 26 weeks of admission, and only 46% with a main diagnosis of AC in 2022/23.Conclusions: AI admissions have increased since 2018/19. Bed‐days and cost for AC episodes have also risen. Patients with concomitant AI were more likely to have longer stays and be re‐admitted. Endocrinology follow‐up appears surprisingly low despite published guidelines.

With the current therapeutic modalities available to endocrinologists, control of GH and IGF‐I is now possible in almost all patients with acromegaly with multi‐modality therapy. Despite biochemical control of GH and IGF‐I, patients with acromegaly continue to experience impaired quality of life. Although there are likely multiple factors contributing to this dissatisfaction with current medical therapies, in particular the widely utilised injectable long‐acting somatostatin receptor ligands (iSRL), is a contributor. The iSRLs require intramuscular or deep subcutaneous injection with a wide bore needle that can be complicated by injection site pain, erythema, subcutaneous nodule formation, and for most individuals require attendance with a healthcare professional every 28 days to safely administered the medication. Two oral SRL (oSRL) formulations, Oral Octreotide Capsules and Paltusotine have been developed with clinical studies showing them to have promise as a therapeutic alternative to iSRL.

Background A proportion of patients with adrenal insufficiency (AI) require increases in their maintenance glucocorticoids following the Covid-19 vaccine as a result of vaccine-related symptoms or development of incipient or frank adrenal crisis. In a large cohort of AI patients, we aim to characterise symptoms, changes in glucocorticoid dosage, occurrence of adrenal crises and whether there are differences between the mRNA and adenovirus vector vaccines. Patients and methods Patients with AI of any aetiology were invited to complete a short, structured questionnaire of their experience of the Covid-19 vaccination. Results 279 of the 290 patients enrolled to this study fully completed the questionnaires. 176, 100 and 3 received the Astra Zeneca (AZ), Pfizer-BioNTech (PB) and Moderna (MD) as initial vaccine respectively; and for the second vaccine, 170, 99 and 10 received AZ, PB and MD respectively. Moderate to severe symptoms occurred in 44.8 and 39.7% after the first and second vaccines respectively, were of early onset (6.0 h, IQR 2–12 &. 6.0 h, IQR 2–24 h) and short duration (24 h, IQR 12–72 h & 26 h, IQR 12–72 h). 34.4 and 29.7% increased their maintenance glucocorticoid dose. Discussion The Covid-19 vaccines appear well-tolerated in patients with AI, with similar frequency of symptoms to that reported in the background population. The AZ vaccine leads to slightly greater post-vaccination symptom burden and need to increase glucocorticoid dosage, but this does not translate to greater adverse outcomes.

Multimodality cancer therapy has led to remarkable improvements in survival of childhood and young adult cancer, with survival rates exceeding 85%. Such remission rates come with their own adverse sequelea or ‘late-effects’. Although the cause of these late-effects is multi-factorial, radiation-related adverse effects are one of the most prevalent. Hypopituitarism is a recognised complication of irradiation of brain tumours distant to the hypothalamo-pituitary (HP) axis when the axis is included within the exposed field. Much of the data concerning development of hypopituitarism, however, relates to early forms of photon-based radiotherapy. In this narrative review we discuss advances in individual radiotherapy techniques currently used in treating brain tumours and their theoretical benefits based primarily on dosimetric studies. Increasingly precise radiation techniques, including advances in delivery of photons (i.e IMRT) and proton beam therapy are now available options. The premise behind these newer techniques is to reduce the dose and volume of normal tissue irradiated whilst maintaining an effective radiation dose to target tissue. When treating brain tumours distant to the HP-axis the expectation, based upon dosimetric studies, is that newer forms of radiotherapy will less frequently involve the HP-axis in the exposed field, and where incorporated within the field it will be exposed to a lower radiotherapy dosage. Intuitively the dosimetric studies should translate into significant reductions in prevalence of HP-dysfunction. These data are promising, however, to date there are minimal robust clinical data to determine if the theoretical benefits of these newer techniques on HP-dysfunction is to be realised.

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.

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.