Symptoms and steroid dose adjustments following the Covid-19 vaccine in patients with adrenal insufficiency.

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.

The impact of radiotherapy on the hypothalamo-pituitary axis: old vs new radiotherapy techniques.

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 the development of hypopituitarism, however, relate 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 the delivery of photons (i.e. intensity-modulated radiotherapy) 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 the 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.

Dataset for the cumulative unmanned aerial vehicle routing problem.

The Cumulative Unmanned Aerial Vehicle Routing Problem applies to area covering operations using UAVs. It is defined on a graph, the nodes of which, ensure the complete coverage of the underlying area of interest. The data generation process takes into account the characteristics of such operations, in particular, the viewing window of the UAVs' sensor, their maximum range, the size of the UAV fleet and the unknown locations of the targets within the area of interest. Instances are created simulating different scenarios, using different values for those UAV characteristics, as well as the different locations where the search targets might be positioned in the area of interest.

Evaluation of cardiovascular risk factors in long-term survivors of adult- and childhood-onset brain tumours: a pilot study.

Background: Survivors of childhood brain tumours (SCBT) and teenage and young adult cancer survivors have an adverse cardiovascular risk profile, which translates into an increased vascular mortality. Data on cardiovascular risk profiles in SCBT are limited, and furthermore, there are no data in adult-onset (AO) brain tumours. Patients and: methods: Fasting lipids, glucose, insulin, 24-h blood pressure (BP), and body composition were measured in 36 brain tumour survivors (20 AO; 16 childhood-onset (CO)) and 36 age- and gender-matched controls. Results: Compared with controls, patients had elevated total cholesterol (5.3 ± 1.1 vs 4.6 ± 1.0 mmol/L, P = 0.007), LDL-C (3.1 ± 0.8 vs 2.7 ± 0.9 mmol/L, P = 0.011), insulin (13.4 ± 13.1 vs 7.6 ± 3.3 miu/L, P = 0.014), and increased insulin resistance (homeostatic model assessment for insulin resistance (HOMA-IR) 2.90 ± 2.84 vs 1.66 ± 0.73, P = 0.016). Patients showed adverse body composition, with increased total body fat mass (FM) (24.0 ± 12.2 vs 15.7 ± 6.6 kg, P < 0.001) and truncal FM (13.0 ± 6.7 vs 8.2 ± 3.7 kg, P < 0.001). After stratification by timing of onset, CO survivors showed significantly increased LDL-C, insulin, and HOMA-IR compared with controls. Body composition was characterized by the increased total body and truncal FM. Truncal fat mass was increased by 84.1% compared with controls. AO survivors showed similar adverse cardiovascular risk profiles, with increased total cholesterol and HOMA-IR. Truncal FM was increased by 41.0% compared with matched controls (P = 0.029). No difference in mean 24-h BP was noted between patients and controls irrespective of the timing of cancer diagnosis. Conclusion: The phenotype of both CO and AO brain tumour survivors is characterized by an adverse metabolic profile and body composition, putatively placing long-term survivors at increased risk of vascular morbidity and mortality.

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.

The severity of obstructive sleep apnoea does not influence ambient IGF-I levels.

OBJECTIVE: Obstructive sleep apnoea (OSA) is reported to have effects on a number of hormone systems including the hypothalamo-pituitary axis. We aimed to determine the impact of OSA severity on insulin-like growth factor-I (IGF-I) levels. DESIGN AND METHODS: This is a prospective cohort study performed between November 2014 and May 2017. IGF-I was measured on serum samples, and data were collected on demographics, BMI and parameters of OSA. RESULTS: 611 participants were recruited (202 female, 53.5 ± 12.5 years; mean BMI 36.2 ± 8.0 kg/m2 ). 26.2% had mild OSA; 27.3%, moderate OSA; and 44.5%, severe OSA. 15.2% of IGF-I values were below the age-related reference range. Increasing BMI correlated with greater AHI (r = .28, p < .001), ODI (r = .30, p < .001), severity of OSA (r = .17, p < .001), duration with oxygen saturation (SaO2 ) <90% (r = .29, p = .001) and reduced median SaO2 levels (r = .19, p < .001). IGF-I levels correlated negatively with age (r = -.13, p = .001), BMI (r = -.16, p < .001), diabetes (r = -.108, p = .009), AHI (r = -0.10, p = .043) and severity of OSA (r = -.10, p = .013). No association of IGF-I was observed with ODI, median SaO2 levels or duration of SaO2  < 90%. Regression analyses were used to examine determinants of IGF-I, all of which contained the independent variables of age, gender and BMI. All models showed IGF-I to be predicted by age and BMI (p < .05); however, none of the parameters of OSA were significant within these models. CONCLUSION: Insulin-like growth factor-I levels in OSA are dependent on age and BMI; however, no additional effect of any OSA parameter was observed, supporting the hypothesis that OSA effects on IGF-I are indirect through concomitant body composition and metabolic parameters.

Management of persistent acromegaly following primary therapy: The current landscape in the UK.

Acromegaly is the clinical consequence of chronic exposure of the tissues to excess GH and IGF-I. It is almost exclusively the result of a GH-secreting pituitary adenoma. In addition to the somatic features, uncontrolled acromegaly is associated with a number of complications and excess mortality. Management is aimed at control of the tumour; normalization of GH and IGF-I secretion and relief of symptoms. Initial management of GH-secreting pituitary adenoma is widely accepted as endonasal trans-sphenoidal surgery, with second-line therapy where disease is uncontrolled in most cases being somatostatin analogue therapy. With the combination of surgery and somatostatin analogue therapy, control is achieved in around 75% of patients; however, this leaves a significant proportion of patients requiring multimodality therapy to achieve remission. Within the UK, the health system has finite resources, and decisions for management require consideration of efficacy and cost-effectiveness. To add to the complexity, subtle differences exist in availability of high-cost medications used in the treatment of patients with acromegaly across the devolved nations of the UK. In this article, we discuss options for the management of persistent acromegaly following initial surgery and somatostatin analogue therapy, and explore earlier use of dopaminergics and conservative management.

Prothrombotic fibrin network characteristics in patients with acromegaly: a novel mechanism for vascular complications.

OBJECTIVE: There remains increased cardiovascular mortality in patients with acromegaly. This study aims to evaluate whether GH/IGF-1 excess increases vascular disease by adversely affecting fibrin network characteristics. DESIGN: Cross-sectional study in 40 patients with acromegaly (21 males, age 53 ± 13 years) and 40 age/gender-matched controls. METHODS: Clot structure was analysed using a validated turbidimetric assay and fibrin networks were visualised by laser scanning confocal microscopy (LSCM). Metabolic profile parameters, body composition, plasma fibrinogen and PAI-1 were also assessed. RESULTS: Twenty-two patients had active acromegaly and 18 were in remission. There was no difference in qualitative patient characteristics between the two groups. Both groups had less favourable body composition and cardiovascular risk profile compared with controls. Despite no difference in clot formation and lysis parameters between the two patient groups, active disease patients had higher fibrinogen and clot maximum absorbance compared with controls, after adjusting for BMI (3.8 ± 0.2 vs 2.6 ± 0.2 mg/mL, P < 0.001; and 0.39 ± 0.02 vs 0.33 ± 0.01 arbitrary units, P = 0.03, respectively). Patients in remission had higher fibrinogen compared with controls following adjustment for BMI (3.3 ± 0.2 vs 2.6 ± 0.2 mg/mL, P = 0.02) but not clot maximum absorbance (0.35 ± 0.03 vs 0.33 ± 0.02 arbitrary units, P = 0.6). LSCM showed increased fibrin network density only in active disease patients, consistent with turbidimetric analysis. In addition to active disease, BMI, fat mass and skinfold thickness were associated with higher clot density and longer lysis time. CONCLUSIONS: Patients with active acromegaly have more compact clots, thus conferring increased thrombosis risk. Prothrombotic fibrin networks may represent one mechanism for enhanced vascular risk in active acromegaly.

Hypothalamic-pituitary axis irradiation dose thresholds for the development of hypopituitarism in adult-onset gliomas.

BACKGROUND: Childhood brain tumour survivors who receive cranial radiotherapy undergo regular surveillance for the development ofhypothalamic-pituitary (HP) axis dysfunction. Much less attention has been given to radiation-induced hypopituitarism in patients with malignant brain tumours of adult onset. DESIGN: Retrospective cohort study. PATIENTS/MEASUREMENTS: We assessed the effects of cranial radiotherapy (cXRT) on pituitary function in 58 adults (32 male) with gliomas distant to the HP axis. The XRT dose exposure at the HP axis was correlated with individual axis dysfunction to establish dose thresholds. RESULTS: Mean age at cXRT was 41.2 ± 10.9 years and duration of endocrine follow-up 8.2 ± 5.2 years. Mean XRT dose to the HP axis was 35.9 ± 15.5 Gy. Overall prevalence of radiation-induced hypopituitarism was 84.5%. GH, LH/FSH, ACTH and TSH deficiency were present in 82.8%, 20.7%, 19% and 6.9% of patients, respectively. Hyperprolactinaemia was noted in 10.3% (n = 6) and was persistent in one case. GH deficiency and "any degree of hypopituitarism" positively correlated with the radiotherapy dose to the hypothalamic-pituitary axis. HP axis XRT dose thresholds for the development of GHD, LH/FSH, ACTH and TSH deficiency were established at 10, 30, 32 and 40.8 Gy, respectively. A gradual increase in the prevalence of all anterior pituitary hormone deficits was observed throughout the follow-up period. CONCLUSIONS: Hypopituitarism post-cXRT in adults with gliomas is a frequent, progressive and dose-dependent phenomenon. Dose thresholds suggest long-term endocrine surveillance is important where the HP axis XRT dose is higher than 30 Gy. Identification of deficits to allow early and appropriate hormone replacement therapy is important to improve well-being in these individuals with limited prognosis.

Late-onset X-linked adrenal hypoplasia (DAX-1, NR0B1): two new adult-onset cases from a single center.

PURPOSE: DAX-1 (NR0B1) is an orphan nuclear receptor, which plays a critical role in development and regulation of the adrenal gland and hypothalamo-pituitary-gonadal axis. Mutations in NR0B1 lead to adrenal hypoplasia congenita (AHC), hypogonadotropic hypogonadism (HH) and azoospermia in men. Presentation is typically with adrenal insufficiency (AI) during infancy or childhood. To date only eight cases/kindreds are reported to have presented in adulthood. METHODS: We describe two new cases of men with DAX-1 mutations who presented in adulthood and who were diagnosed at a large University Hospital. RESULTS: Case 1 presented with AI at 19 years. At 38 years he was diagnosed with HH. Detailed history revealed a brother diagnosed with AI at a similar age. Sequencing of the DAX-1 (NR0B1) gene revealed a heterozygous c.775T > C substitution in exon 1, which changes codon 259 from serine to proline (p.Ser259Pro). Case 2 was diagnosed with AI at 30 years. Aged 37 years he presented with HH and azoospermia. He was treated with gonadotropin therapy but remained azoospermic. Testicular biopsy showed maturational arrest and hypospermatogenesis. Analysis of the NR0B1 gene showed a heterozygous c.836C > T substitution in exon 1, resulting in a change of codon 279 from proline to leucine (p.Pro279Leu). This change alters the structure of the repression helix domain of DAX-1 and affects protein complex interactions with NR5A family members. CONCLUSIONS: We describe two missense mutations within the putative carboxyl-terminal ligand binding domain of DAX-1, presenting with AHC and HH in adulthood, from a single center. DAX-1 mutations may be more frequent in adults than previously recognized. We recommend testing for DAX-1 mutations in all adults with primary AI and HH or impaired fertility where the etiology is unclear.

Impaired quality of life in patients with treated acromegaly despite long-term biochemically stable disease: Results from a 5-years prospective study.

OBJECTIVE: Patients with acromegaly demonstrate impaired quality of life (QoL), but data on long-term QoL changes in treated acromegaly are limited. This study evaluates and identifies factors that influence QoL in patients with long-term biochemical remission. DESIGN: The study consists of a cross-sectional arm comparing QoL between patients with treated and controlled acromegaly and healthy controls; and a longitudinal arm assessing QoL changes in patients with biochemically stable disease during 5.7±0.6 years of follow-up. PATIENTS: A total of 58 patients and 116 matched controls were recruited for the cross-sectional arm; 28 patients completed the longitudinal arm. MEASUREMENTS: Three generic questionnaires (Psychological General Well-Being Schedule [PGWBS], 36-item Short-Form [SF-36], EuroQoL [EQ-5D]) and the disease-specific acromegaly QoL questionnaire (AcroQoL) were applied. RESULTS: Quality of life assessment was performed 11.6±8.2 years following diagnosis and treatment of acromegaly. Patients with treated acromegaly had lower QoL scores compared with controls in all questionnaires with the exception of the PGWBS "Anxiety" subscale. The AcroQoL "Appearance" subscale and the "Physical Function" subscales of the remaining questionnaires were the most underscored domains. No difference in the total and subscale scores of all questionnaires was observed between baseline and follow-up, with the exception of the SF-36 "Physical Function," where a decline was found (58.5±24.7% vs 43.1±31.1%; P=.002). However, after adjusting for covariates, no significant change in any of the QoL scores was seen. Duration of IGF-1/GH control was positively correlated with QoL scores in most questionnaires at baseline, whereas use of GH lowering therapy at the time of QoL assessment was a negative predictive factor of QoL. CONCLUSION: Patients with biochemically controlled acromegaly demonstrate impaired QoL, which persists despite long-term disease control. This primarily consists of impaired physical function and secondly of impaired psycho-social well-being. Duration of biochemical disease control and current use of GH lowering therapy was the predominant factors determining patients' QoL.

Diagnostic challenges and management of a patient with acromegaly due to ectopic growth hormone-releasing hormone secretion from a bronchial carcinoid tumour.

A male patient presented at the age of 30 with classic clinical features of acromegaly and was found to have elevated growth hormone levels, not suppressing during an oral glucose tolerance test. His acromegaly was originally considered to be of pituitary origin, based on a CT scan, which was interpreted as showing a pituitary macroadenoma. Despite two trans-sphenoidal surgeries, cranial radiotherapy and periods of treatment with bromocriptine and octreotide, his acromegaly remained active clinically and biochemically. A lung mass was discovered incidentally on a chest X-ray performed as part of a routine pre-assessment for spinal surgery 5 years following the initial presentation. This was confirmed to be a bronchial carcinoid tumour, which was strongly positive for growth hormone-releasing hormone (GHRH) and somatostatin receptor type 2 by immunohistochemistry. The re-examination of the pituitary specimens asserted the diagnosis of pituitary GH hyperplasia. Complete resolution of the patient's acromegaly was achieved following right lower and middle lobectomy. Seventeen years following the successful resection of the bronchial carcinoid tumour the patient remains under annual endocrine follow-up for monitoring of the hypopituitarism he developed after the original interventions to his pituitary gland, while there has been no evidence of active acromegaly or recurrence of the carcinoid tumour. Ectopic acromegaly is extremely rare, accounting for <1% of all cases of acromegaly. Our case highlights the diagnostic challenges differentiating between ectopic acromegaly and acromegaly of pituitary origin and emphasises the importance of avoiding unnecessary pituitary surgery and radiotherapy. The role of laboratory investigations, imaging and histology as diagnostic tools is discussed. LEARNING POINTS: Ectopic acromegaly is rare, accounting for less than 1% of all cases of acromegaly.Ectopic acromegaly is almost always due to extra-pituitary GHRH secretion, mainly from neuroendocrine tumours of pancreatic or bronchial origin.Differentiating between acromegaly of pituitary origin and ectopic acromegaly can cause diagnostic challenges due to similarities in clinical presentation and biochemistry.Serum GHRH can be a useful diagnostic tool to diagnose ectopic acromegaly.Pituitary imaging is crucial to differentiate between a pituitary adenoma and pituitary hyperplasia, which is a common finding in ectopic acromegaly.Diagnosing ectopic acromegaly is pivotal to avoid unnecessary interventions to the pituitary and preserve normal pituitary function.

The effects of pituitary and thyroid disorders on haemostasis: potential clinical implications.

Disturbances of coagulation and fibrinolysis are usually multifactorial and growing evidence suggests that endocrinopathies modulate the haemostatic balance. The thrombotic alterations in endocrine disorders range from mild laboratory clotting abnormalities with little clinical significance to serious thrombotic and bleeding disorders directly related to hormonal disturbances. This literature review focuses on presenting the current data on the effects of thyroid and pituitary disorders on various parameters of the haemostatic system. With the exception of overt hypothyroidism which appears to cause a bleeding tendency, the rest of the endocrinopathies discussed in this review (subclinical hypothyroidism, hyperthyroidism, endogenous hypercortisolaemia, growth hormone deficiency, acromegaly, prolactinoma/hyperprolactinaemia and hypogonadotrophic hypogonadism) are associated with a hypercoagulable and hypofibrinolytic state, increasing the overall cardiovascular risk and thromboembolic potential in these patients. In most studies, the haemostatic abnormalities seen in endocrine disorders are usually reversible with successful treatment of the underlying condition and biochemical disease remission. High-quality studies on larger patient cohorts are needed to produce robust evidence on the effects of endocrine disorders and their therapeutic interventions on coagulation and fibrinolysis, as well as on the long-term mortality and morbidity outcomes in association with endocrine-related haemostatic imbalance. Given the rarity of some of the endocrine disorders, multicentre studies are required to achieve this target.

Pituitary dysfunction following cranial radiotherapy for adult-onset nonpituitary brain tumours.

OBJECTIVE: There are limited data concerning the evolution of radiation-induced hypopituitarism in adult-onset brain tumour (AO-BT) survivors, in part the consequence of the limited survival of many of these individuals. We aim to characterize the pituitary-related outcomes following cranial radiotherapy (cXRT) for adult-onset primary nonpituitary brain tumours. DESIGN: We retrospectively analysed longitudinal data of patients with AO-BT who received cXRT within a tertiary cancer referral centre. PATIENTS: A total of 107 adults (age 40·0 ± 13·1 years) followed for a median duration of 8 years following cXRT. MEASUREMENTS: Prevalence of radiotherapy-induced hypopituitarism. RESULTS: 94·4% received fractionated photon radiotherapy (median dose 54 Gy), while the remaining patients received proton beam or stereotactic radiotherapy. 88·8% of patients developed hypopituitarism during follow-up. The frequency of GH, gonadotrophin, ACTH and TSH deficiencies was 86·9% (severe GHD 64·5%, partial GHD 22·4%), 34·6%, 23·4% and 11·2%, respectively. ACTH deficiency was clinically significant, necessitating glucocorticoid replacement, in only 10·3% of cases. Hyperprolactinaemia developed in 15% of patients, which was persistent in only 50% of cases. Multiple pituitary hormone deficiencies were present in 47·7% of patients, encountered more frequently in patients with tumours in proximity to the sella. Longitudinal data analysis revealed accumulation of hormone deficits throughout the follow-up period, with incidence of all pituitary hormone deficiencies almost doubling between years 2 and 7 of follow-up. CONCLUSIONS: Pituitary dysfunction in AO-BT survivors following cXRT is a common, evolving, time-dependent phenomenon. It is important that deficits are identified early and replacement therapies introduced to optimize quality of life in these individuals, where prognosis is often guarded.

Lanreotide autogel in acromegaly - a decade on.

INTRODUCTION: The novel formulation of lanreotide, lanreotide (LAN) autogel (ATG), has been available in Europe since 2001 and USA from 2006 for the treatment of acromegaly. It is one of only two clinically available somatostatin analogs available for use in acromegaly. Data relating to the use of ATG in acromegaly, specifically relating to comparison to octreotide (OCT) LAR and patient acceptability and preference, have been slow to accumulate. AREAS COVERED: We performed a comprehensive review of the original literature relating to development, pharmacokinetics, acceptability and clinical efficacy of ATG. EXPERT OPINION: LAN ATG is a novel formulation of LAN consequent on self-assembly of nanotubules in water. Diffusion between molecules within the nanotubules and surrounding tissue fluid in vivo leads to pseudo first-order pharmacokinetics. Efficacy is equivalent to the alternate long-acting somatostatin analog, OCT LAR, normalizing growth hormone and IGF-I levels in around 60 and 50% respectively. Control of tumor growth is observed in over 95% of patients, with 64% seeing a clinically significant reduction in tumor size. ATG is provided in a prefilled syringe for deep subcutaneous injection, allowing self-injection, and may be administered up to 8 weeks greatly improving convenience for the patient. The data strongly support consideration of ATG as the medical therapy of choice for patients with acromegaly.