We appreciate the letter from of Dr Soh et al. regarding our review on the use of etomidate in the treatment of Cushing's syndrome. We note that in their experience, our recommended dose regimen of 2.5 mg/h or thereabouts appears to be a safe and effective starting dose in most patients, and we note the utility and ease of use of the lipid formulation and its relative freedom from side effects compared with the more commonly used propylene glycol formulation; these are very helpful comments. Their experience in treating a further four patients is indeed further evidence of the usefulness of this agent.
Veronica A Preda and Ashley B Grossman
Veronica A Preda, Jonathan Sen, Niki Karavitaki and Ashley B Grossman
The authors apologise for the publication of an error in Table 2 of this article published in the European Journal of Endocrinology 167 137–143. They wish to make clear in Table 2 that they are stipulating the dose of etomidate and that the corresponding dose of hydrocortisone for complete blockade should be 0.5–1.0 mg/h. The correct table is published in full below.
Treatment of hypercorticolism with etomidate: Recommendations.
|Infusion rate options||Blockade||Cortisol level||Biochemical monitoring||Other|
|Etomidate (IV) 0.04–0.05 m/kg per h=2.5–3.0 mg/h||Partial to complete depending on clinical circumstance of the patient||Titrate to serum cortisol 500–800 nmol/l in physiologically stressed patient, 150–300 nmol/l in non-physiologically stressed patient||Potassium level Cortisol level||Sedation scoring initially every two hours then every 12 hours after first 24 hours|
|Hydrocortisone IV 0.5–1.0 mg/h||Complete (will need steroid replacement)||<150 nmol/l||Potassium level Cortisol level|
This table could now be used as a practical guide for clinicians commencing infusions on the ward of etomidate and required hydrocortisone replacement.
Veronica A Preda, Jonathan Sen, Niki Karavitaki and Ashley B Grossman
This review addresses the practical usage of intravenous etomidate as a medical therapy in Cushing's syndrome. We reviewed the relevant literature, using search terms ‘etomidate’, ‘Cushing's syndrome’, ‘adrenocortical hyperfunction’, ‘drug therapy’ and ‘hypercortisolaemia’ in a series of public databases. There is a paucity of large randomised controlled trials, and data on its use rely only on small series, case study reports and international consensus guideline recommendations. Based on these, etomidate is an effective parenteral medication for the management of endogenous hypercortisolaemia, particularly in cases with significant biochemical disturbance, sepsis and other serious complications such as severe psychosis, as well as in preoperative instability. We suggest treatment protocols for the safe and effective use of etomidate in Cushing's syndrome.
Andrea M Isidori, Marianna Minnetti, Emilia Sbardella, Chiara Graziadio and Ashley B Grossman
Glucocorticoids (GCs) target several components of the integrated system that preserves vascular integrity and free blood flow. Cohort studies on Cushing's syndrome (CS) have revealed increased thromboembolism, but the pathogenesis remains unclear. Lessons from epidemiological data and post-treatment normalisation time suggest a bimodal action with a rapid and reversible effect on coagulation factors and an indirect sustained effect on the vessel wall. The redundancy of the steps that are potentially involved requires a systematic comparison of data from patients with endogenous or exogenous hypercortisolism in the context of either inflammatory or non-inflammatory disorders. A predominant alteration in the intrinsic pathway that includes a remarkable rise in factor VIII and von Willebrand factor (vWF) levels and a reduction in activated partial thromboplastin time appears in the majority of studies on endogenous CS. There may also be a rise in platelets, thromboxane B2, thrombin–antithrombin complexes and fibrinogen (FBG) levels and, above all, impaired fibrinolytic capacity. The increased activation of coagulation inhibitors seems to be compensatory in order to counteract disseminated coagulation, but there remains a net change towards an increased risk of venous thromboembolism (VTE). Conversely, GC administered in the presence of inflammation lowers vWF and FBG, but fibrinolytic activity is also reduced. As a result, the overall risk of VTE is increased in long-term users. Finally, no studies have assessed haemostatic abnormalities in patients with Addison's disease, although these may present as a consequence of bilateral adrenal haemorrhage, especially in the presence of antiphospholipid antibodies or anticoagulant treatments. The present review aimed to provide a comprehensive overview of the complex alterations produced by GCs in order to develop better screening and prevention strategies against bleeding and thrombosis.
Emilia Sbardella, Carlotta Pozza, Andrea M Isidori and Ashley B Grossman
The transition age is the period between childhood to adulthood; it refers to a broad set of physical, cognitive and sociocultural modifications, arbitrarily defined as starting in late puberty and ending with full adult maturation. Pituitary disorders in adolescence represent a challenge that requires careful management during the transition to adult care.
Given the complexity of care of pituitary disorders in the transition age, we have reviewed the relevant medical literature focusing on aetiology, clinical manifestations, treatment strategies of GH deficiency (GHD), hypogonadotrophic hypogonadism (HH) in male and female adolescents, central hypothyroidism (CH), central adrenal insufficiency (CAI) and cranial diabetes insipidus (CDI) at this time. The objective of the present review is to provide an up-to-date evaluation of the transition period to evaluate the specific needs of adolescents with chronic pituitary disease in order to optimise their management.
We provide an overview of current clinical management of GHD, HH, CH, CAI and CDI in the transition age.
Specific changes occur in pituitary function during the transition period. A holistic approach including discussion of patients’ concerns and emotional support should constitute a key component of managing pituitary disorders in adolescence. Special transition clinics where paediatric and adult endocrinologists work together, should be increasingly created and strengthened to bridge care, to promote continuity and adherence to treatment and to limit potential negative development, metabolic, skeletal and cardiovascular sequelae of discontinuity of care among adolescents with pituitary disorders.
Veronica Preda, Márta Korbonits, Simon Cudlip, Niki Karavitaki and Ashley B Grossman
To study the prevalence of germline mutations of the aryl-hydrocarbon receptor interacting protein (AIP) gene in a large cohort of patients seen in the Oxford Centre for Diabetes Endocrinology and Metabolism (OCDEM), UK, with apparently sporadic pituitary adenomas, who were either diagnosed or had relevant clinical manifestations by the age of 40 years.
We prospectively investigated all patients who were seen at Oxford University Hospital, OCDEM, and a tertiary referral centre, between 2012 and 2013, and presented with pituitary tumours under the age of 40 years and with no family history: a total of 127 patients were enrolled in the study.
Leukocyte-origin genomic DNA underwent sequence analysis of exons 1–6 and the flanking intronic regions of the AIP gene (NM_003977.2), with dosage analysis by multiplex ligation-dependent probe amplification.
AIP variants were detected in 3% of the 127 patients, comprising four of 48 patients with acromegaly (8%), 0 of 43 with prolactinomas, 0 of the 20 patients with non-functioning adenomas, 0 of 15 with corticotroph adenomas and 0 of one with a thyrotroph adenomas. Definite pathogenetic mutations were seen in 2/4 variants, comprising 4.2% of patients with acromegaly.
This prospective cohort study suggests a relatively low prevalence of AIP gene mutations in young patients with apparently sporadic pituitary adenomas presenting to a tertiary pituitary UK centre. Those with somatotroph macroadenomas have a higher rate of AIP mutation. These findings should inform discussion of genetic testing guidelines.
Emilia Sbardella, Robin N Joseph, Bahram Jafar-Mohammadi, Andrea M Isidori, Simon Cudlip and Ashley B Grossman
Disease processes that affect the pituitary stalk are broad; the diagnosis and management of these lesions remains unclear.
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.
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%).
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.
Agata Juszczak, Avinash Gupta, Niki Karavitaki, Mark R Middleton and Ashley B Grossman
Ipilimumab (Yervoy; Medarex and Bristol-Myers Squibb) is a human MAB against cytotoxic T-lymphocyte antigen 4, which enhances co-stimulation of cytotoxic T-lymphocytes, resulting in their proliferation and an anti-tumour response. It is licensed for the treatment of unresectable or metastatic malignant melanoma, while multiple clinical trials using this medication in the treatment of other malignancies are ongoing. As a clinical response to ipilimumab results from immunostimulation, predictably it generates autoimmunity as well, causing immune-related adverse events in the majority of patients. Of those, endocrinopathies are frequently seen, and in particular, autoimmune lymphocytic hypophysitis with anterior panhypopituitarism has been reported a number of times in North America. We present a case of a male referred to our department with manifestations of anterior panhypopituitarism after his third dose of ipilimumab for metastatic malignant melanoma, and we discuss the management of his case in the light of previous reports. We also review the published literature on the presenting symptoms, time to presentation, investigations, imaging, treatment and follow-up of ipilimumab-induced autoimmune lymphocytic hypophysitis.
Damian G Morris, Mädälina Muşat, Sándor Czirják, Zoltán Hanzély, Debra M Lillington, Márta Korbonits and Ashley B Grossman
Objectives: Microarray technology allows for the expression profile of many thousands of genes to be quantified at the same time, and has resulted in novel discoveries about the tumour biology of a number of cancers. We sought to do this in pituitary adenomas, the most common intracranial neoplasm.
Methods: Affymetrix GeneChip HG-U133A oligonucleotide arrays covering 14 500 well-characterised genes from the human genome were used to study pooled RNA for each of the four major pituitary adenoma subtypes. Individual gene-expression levels in the tumours were compared relative to the expression profile in normal pooled pituitary RNA. Three differentially expressed genes with potential importance in tumourigenesis were chosen for validation by real-time quantitative PCR on the original tumours and on an additional 26 adenomas.
Results: Bioinformatic analysis showed that 3906 genes and 351 expressed sequence tags were differentially expressed among all pituitary tumour subtypes. Lysosomal-associated protein transmembrane- 4-β (LAPTM4B), a novel gene upregulated in hepatocellular carcinoma, was significantly over-expressed in adrenocorticotrophin (ACTH)-secreting adenomas and non-functioning pituitary adenomas (NFPAs). Bcl-2-associated athanogene (BAG1), an anti-apoptotic protein found at high levels in a number of human cancers, was significantly over-expressed in growth hormone-secreting and prolactin-secreting adenomas and NFPAs. The cyclin-dependent kinase inhibitor p18, in which murine gene deletion has been shown to produce pituitary ACTH cell hyperplasia and adenomas, was significantly under-expressed in ACTH-secreting adenomas.
Conclusions: Expression array analysis of pituitary adenomas using the Affymetrix GeneChip HG-U133A arrays appears to be a valid method of identifying genes that may be important in tumour pathogenesis.
Márta Korbonits, Peter J Trainer, Giuseppe Fanciulli, Osvaldo Oliva, Alessandra Pala, Alessandra Dettori, Michael Besser, Giuseppe Delitala and Ashley B Grossman
Korbonits M, Trainer PJ, Fanciulli G, Oliva O, Pala A, Dettori A, Besser GM, Delitala G, Grossman AB. l-Arginine is unlikely to exert neuroendocrine effects in humans via the generation of nitric oxide. Eur J Endocrinol 1996;135:543–7. ISSN 0804–4643
There is now considerable evidence that nitric oxide is an important neuroregulatory agent, but there has been very little investigation of its possible role in neuroendocrine mechanisms in humans. We have investigated the effects of two nitric oxide precursors, l-arginine and molsidomine, under basal conditions on the pituitary hormones growth hormone (GH), prolactin, luteinizing hormone, folliclestimulating hormone, thyrotrophin, adrenocorticotrophin (ACTH) and vasopressin, and also on serum cortisol; we have also studied the effect of l-arginine on circulating prolactin, ACTH and cortisol in normal human subjects under hypoglycaemic stress. l-Arginine stimulated both GH and prolactin release under basal conditions but had no effect on the other hormones studied, while the nitric oxide donor molsidomine showed no effect on any hormone studied. l-Arginine potentiated the hypoglycaemia-stimulated release of ACTH but did not influence the rise in GH. The current studies suggest that the effects of l-arginine on the stimulation of GH and prolactin release are unlikely to be mediated via the generation of nitric oxide.
A Grossman, Department of Endocrinology, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK