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Adrenocortical carcinomas (ACCs) are invasive tumours arising in the adrenal cortex, and steroidogenic tumours are associated with worse prognostic outcomes. Loss-of-function mutations in sphingosine-1-phosphate lyase (SGPL1) cause primary adrenal insufficiency and as a key degradative enzyme in the sphingolipid pathway, SGPL1 also influences the balance of pro-proliferative and pro-apoptotic sphingolipids. We, therefore, hypothesized increased SGPL1 may be linked to increased disease severity in ACC., This work was supported by Barts Charity grants MGU0361 to L.M. and R.P.; MGU0438 to L.M.; MGU0528 to R.K.; MGU0436 to L.G.; Government of Trinidad and Tobago Research Fellowship to A.M.; Medical Research Council (MRC) UK Clinical Academic Research Partner grant (MR/T02402X/1) to R.P. and MRC clinical research fellowships (MR/S022155/1) to J.P. and (MR/W015935/1) to R.K.

Context In primary aldosteronism, cosecretion of cortisol may alter cortisol-derived adrenal venous sampling indices. Objective To identify whether cortisol cosecretion in primary aldosteronism alters adrenal venous sampling parameters and interpretation. Design Retrospective case–control study Setting A tertiary referral center Patients 144 adult patients with primary aldosteronism who had undergone both adrenocorticotropic hormone-stimulated adrenal venous sampling and dexamethasone suppression testing between 2004 and 2018. Main Outcome Measures Adrenal venous sampling indices including adrenal vein aldosterone/cortisol ratios and the selectivity, lateralization, and contralateral suppression indices. Results 21 (14.6%) patients had evidence of cortisol cosecretion (defined as a failure to suppress cortisol to ≤50 nmol/L post dexamethasone). Patients with evidence of cortisol cosecretion had a higher inferior vena cava cortisol concentration (P = .01) than those without. No difference was observed between the groups in terms of selectivity index, lateralization index, lateralization of aldosterone excess, or adrenal vein cannulation rate. Conclusions Cortisol cosecretion alters some parameters in adrenocorticotrophic hormone-stimulated adrenal venous sampling but does not result in alterations in patient management.

Objective Phaeochromocytomas and paragangliomas (PPGL) are rare, but strongly heritable tumours. Variants in succinate dehydrogenase (SDH) subunits are identified in approximately 25% of cases. However, clinical and genetic information of patients with SDHC variants are underreported. Design This retrospective case series collated data from 18 UK Genetics and Endocrinology departments. Patients Both asymptomatic and disease-affected patients with confirmed SDHC germline variants are included. Measurements Clinical data including tumour type and location, surveillance outcomes and interventions, SDHC genetic variant assessment, interpretation, and tumour risk calculation. Results We report 91 SDHC cases, 46 probands and 45 non-probands. Fifty-one cases were disease-affected. Median age at genetic diagnosis was 43 years (range: 11-79). Twenty-four SDHC germline variants were identified including six novel variants. Head and neck paraganglioma (HNPGL, n = 30, 65.2%), extra-adrenal paraganglioma (EAPGL, n = 13, 28.2%) and phaeochromocytomas (PCC) (n = 3, 6.5%) were present. One case had multiple PPGLs. Malignant disease was reported in 19.6% (9/46). Eight cases had non-PPGL SDHC-associated tumours, six gastrointestinal stromal tumours (GIST) and two renal cell cancers (RCC). Cumulative tumour risk (95% CI) at age 60 years was 0.94 (CI: 0.79-0.99) in probands, and 0.16 (CI: 0-0.31) in non-probands, respectively. Conclusions This study describes the largest cohort of 91 SDHC patients worldwide. We confirm disease-affected SDHC variant cases develop isolated HNPGL disease in nearly 2/3 of patients, EAPGL and PCC in 1/3, with an increased risk of GIST and RCC. One fifth developed malignant disease, requiring comprehensive lifelong tumour screening and surveillance.

Primary Aldosteronism (PA) carries significant cardiometabolic risk, over and above those attributable to hypertension alone. The Endocrine Society guidelines recommend adrenalectomy in those with unilateral disease. However surgery is likely to become unsustainable in public healthcare systems as more patients are diagnosed with PA. Already, surgery may not be feasible in some patients due to co-morbidities, others are reluctant to have the whole adrenal gland removed when excess aldosterone can be localised to small APA(s) in 1 gland. The FABULAS Study explores if EUS-RFA is a safe alternative to left-sided adrenalectomy (ClinicalTrials.gov ID NCT03405025). This multicentre phase-1 study comprises 3 groups of 10 patients with proven PA and left APAs. Successive groups have an increasing benefit:risk ratio for surgery. The first 4 ablation procedures are assessed by an independent safety committee before progression into the next, overlapping group. The primary outcomes are safety and feasibility of EUS-RFA. Safety is assessed throughout the study, including measures of intra-procedure adrenomedullary activation. Efficacy is evaluated by biochemistry, home / clinic BPs, and quantitative 11C-metomidate PET-CT at baseline and 6 months post-ablation. RFA is performed using a Starmed catheter, small enough to pass through a 19-gauge needle, through the stomach. Ablation has been performed in 6 patients (median age 63-years). Mean tumour size was 17mm (range 12-36mm). Plasma metanephrine levels remained stable during RFA. 2 adverse events occurred within the first 48hours post-ablation: AF in a patient with known paroxysmal AF, and an episode of pyrexia and raised CRP attributed to tissue infarction. Both events were deemed ‘not unexpected’ by the safety committee. Most patients have benefited clinically post-ablation. This is illustrated by a 65-year-old man with previously uncontrolled hypertension despite 4 antihypertensive medications, including spironolactone. Baseline aldosterone/renin ratio (ARR) was >200 (PA likely if ARR>60). PET CT revealed a 15mm left adrenal nodule with avid metomidate uptake and an SUVmax ratio of 1.92 (SUVmax ratio >1.25 suggestive of unilateral disease). He underwent uneventful EUS-RFA. 6 months post-ablation his ARR has normalised to 26. On repeat PET CT the metomidate avid adenoma is no longer hot, with a drop in both the SUVmax measured over the APA (31 pre-, and 5 post-ablation) and a reduction in the SUVmax ratio to 1.04. Most importantly, his home BP averages 124/83mmHg and he is thrilled to be off all treatment. Retrospective reports exist of successful percutaneous and retroperitoneal RFA of APAs. FABULAS is the first prospective study, using a minimally invasive, endoscopic route. If proven to be safe and effective EUS-RFA will open the doors for more patients to receive definitive treatment, potentially even those with bilateral disease.

The adrenal cortex governs fundamental metabolic processes though synthesis of glucocorticoid, miner-alocorticoids and androgens. Studies in rodents have demonstrated that the cortex undergoes a self-renewal process and that capsular/subcapsular stem/progenitor cell pools differentiate towards functional steroidogenic cells supporting the dynamic centripetal streaming of adrenocortical cells throughout life. We previously demonstrated that the Notch atypical ligand Delta-like homologue 1 (DLK1)/preadipocyte factor 1 (PREF1) is expressed in subcapsular Sf1 and Shh-positive, CYP11B1-negative and CYP11B2-partially positive cortical progenitor cells in rat adrenals, and that secreted DLK1 can modulate GLI1 expression in H295R cells. Here we show that the human adrenal cortex remodels with age to generate clusters of relatively undifferentiated cells expressing DLK1. These clusters (named DLK1-expressing cell clusters or DCCs) increased with age in size and were found to be different entities to aldosterone-producing cell clusters, another well-characterized and age-dependent cluster structure. DLK1 was markedly overexpressed in adrenocortical carcinomas but not in aldosterone-producing adenomas. Thus, this data identifies a novel cell population in the human adrenal cortex and might suggest a yet-to be identified role of DLK1 in the pathogenesis of adrenocortical carcinoma in humans.

Bioluminescence resonance energy transfer analysis is used to study the interaction between melanocortin 2 receptor (MC2R) accessory protein and the MC2R and provides evidence for protein kinase A-dependent conformational changes in the receptor complex following receptor activation., The melanocortin 2 receptor (MC2R) accessory protein (MRAP) is a small single-transmembrane domain protein that plays a pivotal role in the function of the MC2R. The pituitary hormone, ACTH, acts via this receptor complex to stimulate adrenal steroidogenesis. Using both coimmunoprecipitation and bioluminescence resonance energy transfer (BRET), we show that the MC2R is constitutively homodimerized in cells. Furthermore, consistent with previous data, we also show that MRAP exists as an antiparallel homodimer. ACTH enhanced the BRET signal between MC2R homodimers as well as MC2R-MRAP heterodimers. However, ACTH did not enhance the physical interaction between these dimers as determined by coimmunoprecipitation. Real-time BRET analysis of the MRAP-MC2R interaction revealed two distinct phases of the ACTH-dependent BRET increase, an initial complex series of changes occurring over the first 2 min and a later persistent increase in BRET signal. The slower ACTH-dependent phase was inhibited by the protein kinase A inhibitor KT5720, suggesting that signal transduction was a prerequisite for this later conformational change. The MRAP-MC2R BRET approach provides a unique tool with which to analyze the activation of this receptor.

Summary Aims To evaluate the long-term efficacy and safety of pegvisomant as a treatment for acromegaly. Design Retrospective analysis of clinical and trial data from all patients treated with pegvisomant since 1997 at two centres with common protocols. Results Fifty-seven patients (age range 27–78 years) have been treated with pegvisomant since 1997 for up to 91 months (median 18 months). Before commencing pegvisomant, patients had an IGF-I above the upper limit of normal (ULN) of the age-related reference range (median 1·8 × ULN, range 1·2–4·1). Ninety-five per cent normalized IGF-I using a median dose of 15 mg daily (range 10 mg alternate day to 60 mg daily) with no influence of gender on dose requirement. Five patients had combination therapy with either somatostatin analogues (SSA) or cabergoline. Two patients initially controlled on 10 mg and 20 mg required dose increases (to 20 mg + 40 mg) over 24 months to reduce IGF-I. Twenty-seven patients stopped pegvisomant. Reasons included side-effects [abnormal liver function tests (LFTs)] and patient choice. Two patients developed elevated liver transaminases, which normalized on stopping pegvisomant. Patients had 6–12-monthly pituitary magnetic resonance imaging (MRI) scans. One patient had significant tumour size increase. Conclusion This long-term experience in 57 patients indicates pegvisomant to be effective, safe and well-tolerated. Raised transaminases occurred within the first month of therapy in two patients, and tumour growth was seen in one patient (tumour was growing prior to pegvisomant). In two patients increasing doses of pegvisomant were required to keep IGF-I within the target range.

Familial glucocorticoid deficiency is an autosomal recessive disorder resulting from defects in the action of adrenocorticotropic hormone (ACTH) to stimulate glucocorticoid synthesis in the adrenal. Production of mineralocorticoids by the adrenal is normal. Patients present in early life with low or undetectable cortisol and--because of the failure of the negative feedback loop to the pituitary and hypothalamus--grossly elevated ACTH levels. About half of all cases result from mutations in the ACTH receptor (melanocortin 2 receptor) or from mutations in the melanocortin 2 receptor accessory protein (MRAP), but other genetic causes of this potentially lethal disorder remain to be discovered.

Context: There are at least 24 missense, nonconservative mutations found in the ACTH receptor [melanocortin 2 receptor (MC2R)] that have been associated with the autosomal recessive disease familial glucocorticoid deficiency (FGD) type 1. The characterization of these mutations has been hindered by difficulties in establishing a functional heterologous cell transfection system for MC2R. Recently, the melanocortin 2 receptor accessory protein (MRAP) was identified as essential for the trafficking of MC2R to the cell surface; therefore, a functional characterization of MC2R mutations is now possible.Objective: Our objective was to elucidate the molecular mechanisms responsible for defective MC2R function in FGD.Methods: Stable cell lines expressing human MRAPα were established and transiently transfected with wild-type or mutant MC2R. Functional characterization of mutant MC2R was performed using a cell surface expression assay, a cAMP reporter assay, confocal microscopy, and coimmunoprecipitation of MRAPα.Results: Two thirds of all MC2R mutations had a significant reduction in cell surface trafficking, even though MRAPα interacted with all mutants. Analysis of those mutant receptors that reached the cell surface indicated that four of six failed to signal, after stimulation with ACTH.Conclusion: The majority of MC2R mutations found in FGD fail to function because they fail to traffic to the cell surface.

K Nadarasa, A Theodoraki, T R Kurzawinski, R Carpenter, J Bull, T T Chung and W M Drake Department of Endocrinology, St Bartholomew’s Hospital, London, UK, Department of Diabetes and Endocrinology, UCLH NHS Foundation Trust, London, UK, Department of Endocrine Surgery, UCLH NHS Foundation Trust, London, UK and Department of Neurosurgery, The Royal London Hospital, London, UK (K Nadarasa and A Theodoraki contributed equally to this work)

The melanocortin receptor (MCR) family consists of 5 G protein-coupled receptors (MC1R–MC5R) with diverse physiologic roles. MC2R is a critical component of the hypothalamic–pituitary–adrenal axis, whereas MC3R and MC4R have an essential role in energy homeostasis. Mutations in MC4R are the single most common cause of monogenic obesity. Investigating the way in which these receptors signal and traffic to the cell membrane is vital in understanding disease processes related to MCR dysfunction. MRAP is an MC2R accessory protein, responsible for adrenal MC2R trafficking and function. Here we identify MRAP2 as a unique homologue of MRAP, expressed in brain and the adrenal gland. We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). Collectively, our data identify MRAP and MRAP2 as unique bidirectional regulators of the MCR family.

Trauma, sepsis, and surgery are associated with global hypercatabolism and a negative nitrogen balance. When critical illness is prolonged the relentless loss of lean tissue becomes functionally important. Protein catabolism in the critically ill patient is associated with complex changes in the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Many small clinical studies indicate that treatment with recombinant human (rh) GH would be a safe and effective means of limiting the deleterious effects of the catabolic response. Unexpectedly, however, two large prospective randomized controlled trials (PRCTs) demonstrated that administration of rhGH to long-stay critically ill adults increases morbidity and mortality. Some progress has been made in understanding the mechanisms underlying this observation.

Summary Objective GH replacement is widely used in the management of patients with adult-onset (AO)-GH deficiency (GHD). In most cases, AO-GHD arises as a result of pituitary/peripituitary tumours and/or their treatment, but the effect of GH replacement on recurrence/regrowth of these tumours is unknown. The aim of this study was to examine the effect of GH replacement in a group of patients with primary tumours of the parasellar region, many of which (e.g. craniopharyngioma, glioma or germ cell tumours) might be anticipated to have a higher recurrence rate than secretory and nonsecretory anterior pituitary tumours. Patients and design We report here our experience of prospective imaging in 50 consecutive patients (21 males; mean age 45·9 years) with nonanterior pituitary parasellar tumours treated with GH. All had severe GHD (peak serum GH 9 mU/l or less on dynamic testing) and were treated with an identical dose–titration regimen to maintain serum IGF-I concentrations between the median and upper end of the age-adjusted normal range. The primary diagnoses were: craniopharyngioma (28), germ cell tumour (8), arachnoid cyst (4), meningioma (4), glioma (4) and mensenchymal tumour (2). External pituitary irradiation had been given to 37 (74%) of patients. Measurements Surveillance imaging (magnetic resonance imaging (MRI) 70%, computed tomography (CT) 16%, both 14%) was performed at baseline (prior to GH), at 6–12 months, and then again yearly or as clinically indicated. Median follow-up was 36 months (range 7–129 months). All images were reviewed by the same radiologist. Results Four patients had an apparent increase in tumour volume but in only one patient was it considered necessary to abandon GH replacement. In two of the four cases marginal increases in cystic parasellar tumours were not progressive; and in the fourth case apparent recurrence of a suprasellar germ cell tumour was shown to be acellular fibrous tissue only on biopsy. In all other cases either the appearances were unchanged or the amount of tissue was reduced during long-term follow-up on GH. Conclusions Overall, GH appears safe with respect to tumour recurrence over this time period in this patient group. Comparison with similar prospective series in patients not receiving GH replacement is desirable.

In a person coming from the Indian subcontinent to the UK the combination of fever, night sweats and lymphadenopathy is most likely to be due to tuberculosis; but a less common diagnosis must be borne in mind.

GH replacement (GHR) is well established, and has been widely accepted to be safe in patients with a wide spectrum of pituitary pathologies. However, GHR in patients with treated germ cell tumours (GCTs) remains controversial, and its use has been cautioned (1, 2). Anecdotal experience from our centre and elsewhere (1–3) suggests that vigilant monitoring is mandatory in treated GCTs who are GH replaced. There are no published studies of long-term outcome and recurrence rates after GHR in treated GCTs. We have therefore surveyed our long-term experience with GHR in 18 adult patients with previously treated GCTs and a global experience of 142 patients from the KIMS database (Pfizer International Metabolic Database) in this diagnostic category in order to determine whether GHR plays a role in tumour relapse. This is a longitudinal observational study reporting a single centre experience and global experience using the KIMS database. The study groups comprised 18 consecutive patients with GCT treated at St Bartholomew’s Hospital, London (SBH) (median duration of follow-up from diagnosis of GCT 13 years (range 0.5–44)) and 142 patients with GCT enrolled in the KIMS database (median duration of follow-up 14.8 years (0.7–36.4)). The relapse rates pre-GHR and during GHR and relapse-free survival were evaluated. The characteristic and treatments of SBH and KIMS patients are shown in Table 1. In the SBH cohort, there were three relapses prior to GHR. All three patients had a histological diagnosis of non-germinomatous GCT (NGGCT), and had been treated with chemotherapy and/or surgery as primary treatment; radiotherapy was subsequently used after first relapse of disease; none of the patients received radiotherapy or craniospinal irradiation (CSI) as initial treatment. Four patients, two with germinomatous GCT (GGCT) and two with NGGCT, relapsed after GHR. Of the patients demonstrating a first relapse, only one had been treated previously with CSI. One patient relapsed prior to GHR, and was retreated successfully with external beam radiotherapy to the primary site of disease together with chemotherapy, but subsequently also relapsed after GHR. The estimated relapse rates were 240 and 323 per 10-000 patient-years, pre-GHR and during GHR respectively. The relative risk (RR) of relapsing after GHR was 1.34 (95% confidence interval (95% CI): 0.23–7.83; PZ0.73). Five instances of relapse were reported during KIMS follow-up. Of interest, two of these patients had never been treated with GHR (true nao ¨ve) before KIMS entry. The most relevant comparison of relapse rate during versus prior to GHR is for true nao ¨ve patients. This group had a RR of relapse during KIMS of 3.40 (95% CI: 0.26–101.4; PZ0.36). For the semi- and non-nao ¨ve patients (previously treated with GH within 6 months or !6 months before KIMS entry), the RR of relapse during KIMS was statistically similar to the true nao ¨ve group, or 2.62 (95% CI: 0.45–15.3; PZ0.27). RR for nao ¨ve versus semi- or non-nao ¨ve patients (including pre KIMS experience) was 1.36 (95% CI: 0.28–5.46; PZ0.65), indicating similar reported relapse rates between true nao ¨ve and those not true nao ¨ve. For all KIMS patients, the estimated relapse rates were 26.6 and 77.2 per 10-000 patient-years, pre-KIMS and during KIMS entry respectively. The RR of relapse during KIMS for all patients was 2.90 (95% CI: 0.73–12.13; PZ0.13). Our results do not support the hypothesis that GHR increases the recurrence of GCT. In view of the relative rarity of intracranial GCT, we elected to utilise longitudinal follow-up and calculation of relapse frequency expressed per patient years. Despite the variation in treatment modalities, there appeared to be similar relapse rate before and after exposure to GHR in the SBH cohort. Of particular interest, most relapses were NGGCT, which is well known to have a higher risk of relapse. Furthermore, the risk of relapse is also enhanced with the lack of use of radiotherapy as primary treatment. In general patients with NGGCT and those not treated with CSI appeared to have a worse relapsefree survival but no statistical significance was observed. The data from the KIMS do not provide evidence for an association between GHR and relapse. The KIMS relapse rate appears to be lower pre-KIMS than during KIMS, but the difference was not statistically significant. The disparity in recurrence frequency between the SBH and