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Thanks to our excellent speakers, we are fortunate in this issue of ESPE News to have
insights into several of the talks you will be able to enjoy at ESPE 2021 Online. On page 6, Ali Abbara and Waljit Dhillo review our
understanding of kisspeptin’s role in puberty, with exciting potential developments in its therapeutic and diagnostic use. Meanwhile, on page 7, Peter Kühnen examines the melanocortin
4 receptor (MC4R) agonist setmelanotide as a treatment option in rare obesity syndromes. He explains the capacity of MC4R agonists to activate
different downstream signalling cascades (‘biased signalling’) and therefore elicit a range of effects. Supporting transgender/gender diverse youth
remains a complex and topical area of healthcare. Stephen Rosenthal discusses the associated issues, which he will address in his forthcoming presentation (page 8).
You can find out more about ESPE 2021
Online at www.eurospe.org/espe2021online.
As always, your contributions will form a central part of the meeting, so please make sure to submit your abstracts by 10 May 2021.
On page 4, we are extremely pleased to have contributions from colleagues in India about their lives in the time of COVID. Researchers
Anuradha Khadilkar and Vandana Jain reflect on the pandemic’s impact on their work with patients and other aspects of their research and daily
lives.The rest of the issue is bursting with the opportunities and support available to you from
ESPE. These extend from grants and committee vacancies to the prospect of future events such as ESPE Schools and the postponed ESPE Science
Symposium. Read on to learn more!We thank all this issue’s contributors for writing for us at such a busy and stressful time.
We wish them, you, and all your families and friends, health and peace in the coming months.
Sarah Ehtisham
Editor, ESPE News
[email protected]
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ESPE 2018 takes place in Athens, Greece on 27–29 September. Register by 22 June to benefit from significantly reduced registration fees. You can find out more about the exciting plans for this year’s meeting on page 8, where Mehul Dattani (Programme Organising Committee Chair) outlines the programme’s highlights
We will be holding an e-vote this summer for ESPE members to elect the Society’s next Secretary General. Watch out for further information by email, and please make sure we have your current email address.
This Fellowship enables talented young investigators and paediatric endocrinologists to conduct research at leading institutions worldwide. It has helped launch powerful careers at the leading edge of clinical research in our field. One large grant of €125 000 is available for up to 2 years of research training at a centre of excellence. An additional €15 000 is available for consumables. Applicants should demonstrate the potential to perform high quality research in any field of paediatric endocrinology, other than projects related to diabetes and obesity, which will not be considered in this call. Please refer to www.eurospe.org/grants-awards/ grants/research-fellowship before applying. Deadline: 11 June 2018. The Fellowship is supported by an unrestricted grant from Novo Nordisk Health Care AG, Switzerland
The deadline is fast approaching for applications to attend the 2018 ESPE Diabetes, Obesity & Metabolism School. This year’s event takes place on 30 September–2 October 2018 in Delphi, Greece, immediately after the ESPE 2018 Annual Meeting in Athens. Themes covered include: • treatment of paediatric patients with type 1 diabetes • obesity and metabolic syndrome • epidemiology and intervention in diabetes • monogenetic diabetes and other disorders of glucose control Students will benefit from interactive lectures and small group sessions, enabling networking with peers and senior paediatric endocrinologists. For more information or to apply see www.eurospe.org/education/ diabetes-obesity-and-metabolism-school. Don’t miss the 1 July deadline
A new chapter entitled ‘Hypopituitarism’ can now be found in the ‘General content’ section under ‘Pituitary’. It discusses embryology, aetiology of anterior/posterior pituitary-related hormone deficiencies, diagnostic tests and treatment. A chapter on ‘Polycystic ovary syndrome’ is now available under ‘Puberty’, featuring pathogenesis, risk factors, diagnostic criteria, management and long term consequences.
The Science of Gender 1st ESPE Science Symposium 18–19 October 2018, London UK What influences gender development and gender dysphoria? What effects do nature and nurture have? These are the questions we’ll be discussing at ESPE’s first Science Symposium, as we examine the latest evidence. We will also explore the potential psychological–psychosocial impacts of endocrine treatment for gender dysphoria and the science behind this. If you would like to attend this exciting new event at Tavistock House, London, UK, on 18–19 October 2018, visit www.eurospe.org/education/ espe-science-symposium. Clinicians and scientists who have completed their doctorate training within the last 8 years can apply for one of 25 fully sponsored places (the deadline for these free places is 31 July). After 31 July, places will be available for a registration fee of €80 (which includes accommodation). The ESPE Science Symposium is organised with an educational grant from Pfizer
Adrenals’ in e-Learning This issue of ESPE News has a focus on the adrenal gland. Those of you with an interest in this topic should note that ESPE e-Learning has a chapter on ‘Adrenal disorders’, which you will find in ‘General content’. It discusses the fetal development, steroidogenesis and (patho)physiology, diagnostic approaches and therapeutic interventions concerning adrenal hyper- and hypofunctioning. Four interactive cases are also available. The e-Learning section entitled ‘Resource limited countries’ features two chapters, ‘Adrenal disorders’ and ‘Adrenal insufficiency’, which discuss the subject in the context of primary, secondary and tertiary healthcare levels. Vignettes (short interactive cases) will be added shortly
Bringing you recent highlights from the world of research
Fragile X syndrome (FXS) is the most common genetic form of intellectual disability in males. It is caused by silencing of the FMR1 gene associated with hypermethylation of the CGG expansion mutation in the gene’s regulatory region. In this study, Lui et al. restored FMR1 expression for the first time, adopting recently developed DNA methylation editing tools using a modified CRISPR/Cas9 system. They successfully removed methylation from CGG repeats at the FMR1 locus in multiple FXS patient-derived induced pluripotent stem cells. Furthermore, epigenetic editing rescued the electrophysiological abnormalities of FXS neurones, and the reactivation of FMR1 was found to be maintained in edited neurones in vivo following transplantation into mouse brain. The reversion of gene inactivation by epigenome editing may perhaps be a therapeutic strategy for disorders that involve epigenetic silencing.
In Graves’ disease (GD), the balance between intra- and extracellular oxidants and antioxidants is disturbed. Researchers in Berlin consequently conducted a double-blind, placebo controlled, randomised supplementation trial to assess the safety and efficacy of adjuvant selenium (Se) intake on clinical course and serological parameters in GD. The efficacy of antithyroid drugs (ATD) was compared with their therapeutic effects in combination with supplemental Se. Untreated hyperthyroid patients with GD (n=70) were randomly assigned to receive methimazole (MMI) either with placebo or with Se (as 300μg oral sodium selenite per day) for 24 weeks. The response rate, the number of patients with normal thyroid-related hormones, and the decrease in serum levels of thyroid-related autoantibodies at week 24, as well as the high relapse rate after completion of ATD therapy, were comparable in both trial arms. Se-related side effects were not observed. Addition of a relevant daily dose of Se to MMI was not found to positively impact the clinical course and the serological parameters of Se-sufficient, hyperthyroid patients with GD.
In this review, Knip & Honkanen describe the involvement of the gut microbiota at two steps in the evolution of type 1 diabetes. First, the intestinal tract is colonised by a microbial community unable to adequately educate the immune system. The infant consequently acquires susceptibility to immune-mediated diseases, including type 1 diabetes. Secondly, the young child seroconverts to positivity for diabetes-associated autoantibodies. This is preceded or accompanied by a decrease in the diversity of the intestinal microbiota, and an increased abundance of Bacteroides species. These changes affect the disease process, promoting progression towards overt type 1 diabetes. The authors hypothesise that, by providing specific probiotics, one can affect the colonisation of the newborn intestinal tract or strengthen immune education in early life. For example, human milk oligosaccharides or modified starches from a dietary intervention can function as nutrients for ‘healthy’ bacteria. Modulation of the intestinal microbiome thus holds the promise of effective protection against human type 1 diabetes.
In Silver-Russell syndrome (SRS), children are not only short, but also underweight and malnourished, with patterns of poor eating often from infancy. Management has always included nutritional management before initiation of growth hormone (GH) therapy. Colleagues in Paris investigated whether cyproheptadine, an orexigenic antihistamine, promotes appetite, weight gain and growth in SRS. Of 34 children with SRS who received cyproheptadine, 23 took the drug alone, while the other 11 received it in conjunction with enteral nutrition, GH therapy or as a combination of all three. Cyproheptadine was started at a mean age of 2 years and increased gradually to 0.25mg/kg per day orally over the first 4 weeks. After 1 year of treatment, gains in overall length/height and weight were observed (W: +1.1 SDS; H: +0.5 SDS). Weight improved in 21 patients (91%) by at least +0.5 SDS, and in 12 (52%) by at least +1 SDS. The treatment was well tolerated: only 2 patients stopped due to side effects of irritability. The study demonstrates significant improvements in growth velocity and nutritional status with cyproheptadine prior to initiation of GH therapy
You don’t have to spend long training in endocrinology before you discover how poor we are at replacing corticosteroids in patients with adrenal insufficiency (AI). So, how can we do better?
Glucocorticoid (GC) replacement therapy has poor outcomes in children and adults. The risk of acute adrenal crisis remains unacceptably high, and chronic risks include growth retardation, osteoporosis, obesity, hypertension, cardiovascular disease and poor quality of life. Many of these are shared with patients with spontaneous or iatrogenic Cushing’s syndrome, and can be attributed to chronic overexposure to GCs. Patients with congenital adrenal hyperplasia (CAH) appear especially prone to complications of GC excess. Despite having biochemical markers – adrenal androgen levels – against which to titrate the dose, recent cohort studies in children and adults confirm that only a minority achieve biochemical control, and there is an excess of obesity, hypertension and metabolic dysfunction which is correlated with the dose of GCs. Moreover, in patients receiving synthetic GCs – particularly dexamethasone – the risk of adverse effects appears even higher. Addressing the challenge of GC toxicity Some have advocated frequent careful measurement of cortisol to generate ‘cortisol day curves’, but conventional hydrocortisone (i.e. cortisol) tablets produce a short-lived peak of cortisol in the blood, and lack the pharmacokinetic properties required to mimic the physiological circadian rhythm, unless taken unfeasibly frequently. Modified release preparations, such as Plenadren® (Shire Pharmaceuticals, London, UK) and Chronocort® (Diurnal, Cardiff, UK), can achieve more physiological profiles, but they too have been criticised as they cannot mimic the ultradian pulses of cortisol which occur every couple of hours in health. Trials of cortisol infusion using insulin pumps are intended to overcome this deficiency but have yet to provide compelling evidence. Evidence to date suggests that whatever cortisol exposure is achieved by these approaches, efficacy goes hand-in-hand with toxicity. Can we dissociate efficacy from toxicity? Cortisol activates intracellular corticosteroid receptors which are present in virtually every mammalian cell
and regulate expression of many genes. In the field of anti-inflammatory steroid therapy, much work has gone into searching for ‘selective glucocorticoid receptor modulators’ (SGRMs) which facilitate regulation of genes involved in suppressing inflammation more so than those involved in inducing metabolic toxicity. In principle, an SGRM which suppressed POMC expression, and hence adrenocorticotrophin (ACTH) secretion, with greater potency than it affected any other genes, could be uniquely useful in patients with CAH. It would be much simpler, however, to consider whether some steroids might achieve higher concentrations in some cells than in others. In the early 2000s, the ATP-binding cassette transporter ABCB1 (p-glycoprotein) was found to be expressed on the blood–brain barrier and to export cortisol and dexamethasone from the brain.1 Crucially, however, ABCB1 does not export corticosterone, the principal GC in rats and mice, which is present at about 5–10% of the levels of cortisol in human blood. More recently, we showed that another transmembrane transporter, ABCC1, exports corticosterone but not cortisol from adipose tissue.2 This suggests that, in tissues expressing more ABCB1 than ABCC1 (e.g. brain), there will be greater accumulation of corticosterone than of cortisol, while the opposite will be true in tissues expressing more ABCC1 than ABCB1 (e.g. adipose tissue and bone). Corticosterone as a replacement therapy This indicates that corticosterone could provide an alternative to cortisol (i.e. hydrocortisone) as a replacement therapy. Corticosterone has the potential to act as effectively as cortisol in most tissues, but to be exported from tissues where cortisol induces adverse effects, including adipose tissue and bone. Moreover, corticosterone is predicted to be more effective than cortisol in the brain, including in the hippocampus and hypothalamus, where it can mediate suppression of the hypothalamic-pituitary-adrenal axis. Thus, corticosterone could be especially effective at suppressing undesirably high ACTH levels in CAH, without paying the price of GC toxicity in peripheral tissues. The pharmacokinetics of corticosterone in humans dictate that a modified release preparation would be required. Unfortunately, no suitable product currently exists for clinical trials, but we now aim to pursue this approach. Brian R Walker Pro-Vice-Chancellor and Chair of Medicine, Newcastle University, Newcastle upon Tyne, UK, and Honorary Professor, University of Edinburgh, Edinburgh, UK Brian Walker will be delivering his plenary lecture ‘Dynamic control of tissue glucocorticoids – lessons for optimising replacement therapy’ at ESPE 2018. Book now at www.espe2018.org.
The 2017 European Commission report on paediatric medicines stated, ‘There is a broad consensus that children deserve access to medicines that have been specifically developed and researched for their use.’ Despite this, children with adrenal insufficiency (AI) usually receive crushed tablets of hydrocortisone.
In Europe, hydrocortisone is only licensed in 10 and 20mg tablet doses, and children require doses of 1–2mg. Pharmacists or parents compound hydrocortisone either by tablet crushing or by using hydrocortisone base. A recent study reported that 21.4% of hydrocortisone compounded batches failed to meet European Pharmacopoeial guidelines on net mass or drug content, and that 3.6% contained no hydrocortisone! When parents crush tablets the results are worse. This can lead to severe clinical consequences, with poor disease control due to under-treatment and Cushing’s syndrome due to over-treatment. Sucrose or lactose is often added to compounded tablets to mask hydrocortisone’s bitterness, leading to adverse effects on dental health and in children with lactase deficiency. Thus, there is a need for a licensed paediatric formulation of hydrocortisone. The TAIN project The TAIN (Treatment of AI in Neonates) Consortium addressed development of such a formulation. It was led by the University of Sheffield (UK) with input from Diurnal Ltd (Cardiff, UK), Charité Universitätsmedizin (Berlin, Germany), Glatt GmbH (Binzen, Germany), ADD Technologies (Reinach, Switzerland), Simbec Research Ltd (Merthyr Tydfil, UK), the University of Birmingham (UK) and Genetic Alliance UK (London, UK). It was awarded an EU-FP7 Grant to take a paediatric formulation of hydrocortisone from concept to a paediatric use market authorisation (PUMA).
A formulation was designed for neonates, infants and children using multiparticulate granules. The granules are presented within a transparent capsule that is opened for dosing, allowing for 0.5, 1.0, 2.0 and 5.0mg doses to be accurately administered directly onto the tongue or as sprinkles on soft food. The granules are so small that even the 0.5mg capsule contains ~900. Each granule has an inert cellulose core, a hydrocortisone layer and an external taste-masking layer to disguise the bitterness of hydrocortisone. Clinical studies Development was under a European Medicines Agency Paediatric Investigation Plan to show bioequivalence of granules to a marketed 10mg hydrocortisone (Auden McKenzie, Wakefield, UK) at phase 1, followed by a phase 3 study demonstrating appropriate exposure in paediatric patients. Bioequivalence was demonstrated in a crossover study in 16 dexamethasone-suppressed healthy adult males. The phase 3 study at Charité Universitätsmedizin initially examined 12 patients with AI aged 2–6 years. Following analysis of safety outcomes, a further 6 infants with AI aged 1 month–2 years were included. After analysis of safety in this second cohort, a further 6 neonates with AI aged <28 days were studied. Patients received a morning dose of hydrocortisone granules identical to their normal dose of compounded hydrocortisone (median dose 2mg). In all children, cortisol increased from baseline to a Cmax at 60min. The rapid absorption and clearance of cortisol were similar to findings in previous studies of children dosed with immediate release hydrocortisone and the cortisol Cmax was similar to peak concentrations in children with intact hypophyseal-pituitary-adrenal axes. The granules were well received by parents and children; 95.5% of parents said that they would prefer hydrocortisone granules over their child’s usual formulation. Following the phase 3 study, subjects could choose to continue in a safety extension study. At 1 year, patients on hydrocortisone granules had good disease control, no abnormal progression in pubertal status, and growth as expected. Current status In February 2018, a European PUMA was granted for a hydrocortisone granule preparation as replacement therapy for paediatric AI from birth to <18 years old. This is the first licensed treatment in Europe specifically designed for children with AI, and is only the fourth approved PUMA. This project is an example of great collaboration between centres across the EU taking a drug concept from bench to bedside.
Hundreds of European children at risk of congenital adrenal hyperplasia (CAH) have been treated with prenatal dexamethasone (DEX) to reduce congenital malformations, but the treatment remains controversial.
Prenatal DEX therapy for CAH appears efficient in reducing virilisation in affected girls. For decades it was considered safe, but recent data show that it may involve somatic and cognitive risks. Studies in animal models indicate that prenatal glucocorticoid (GC) treatment leads to metabolic and behavioural disturbances. It is therefore important to investigate its long term consequences. Children with CAH have lifelong GC replacement therapy. Despite attempts to mimic the normal diurnal cortisol rhythm, multiple episodes during their upbringing will result in infra- or supraphysiological GC levels. These may, in time, affect growth, metabolism and cognition. We therefore investigated risks associated with pre and postnatally administered GCs. Our multidimensional approach tested the hypothesis that prenatal DEX treatment and postnatal chronic GC treatment have a negative impact on multiple physiological systems, such as metabolism and brain structure and function. We further hypothesised that DEX induces long-lasting epigenetic changes which underlie the functional effects. Prenatal dexamethasone We investigated cognition and behaviour in children (7–17 years) treated with DEX in the first trimester because of a risk of CAH, but who did not have CAH (34 cases, 66 controls). Treated girls showed cognitive deficits in working memory domains, both verbal and visual–spatial, indicating a sex-dimorphic effect. They also exhibited a poorer verbal intelligence and spatial visualisation compared with population controls.1 The same group of children was assessed using questionnaires to estimate behavioural problems and psychopathology. They were found to be well-adapted without major behavioural problems. However, the first trimester-treated girls scored more highly than controls on almost all measures of anxiety.2 This led us to investigate cognitive profile, psychopathology and autistic traits over time. A subgroup of children who had reached adulthood were retested (23 cases, 58 controls). As adults, first trimester DEX-exposed subjects catch up on measures of working verbal memory and impulse inhibition, and perform at the same level as non-DEX-treated adult controls.3 The underlying compensatory neurostructural or neurofunctional mechanisms are not known, and are being investigated. Preliminary results indicate that first trimester-treated individuals have affected limbic structures. Postnatal glucocorticoids We investigated the impact of postnatal GC treatment on cognition and behaviour. Adult patients with CAH (55 cases, 58 controls) had impaired performance in tests measuring verbal and visual–spatial working memory, and inhibition. In measures of fluid intelligence/ non-verbal logical reasoning, males with CAH performed more poorly than control males. Patients with salt wasting CAH performed equally compared with patients with simple virilising CAH. However, patients with a null genotype performed more poorly than those with a non-null genotype, and significantly worse in fluid intelligence/non-verbal logical reasoning. Women treated with DEX prenatally performed worse on most cognitive measures than did women with CAH who had not been treated prenatally.4 Patients with CAH seem to develop cognitive impairment with time, emphasising the importance of optimising treatment throughout the lifespan. Effects on fetal programming To explore the effects of DEX on fetal programming, we performed quantitative DNA methylation measurements of genomic DNA from T-cells with the Infinium Human Methylation 450K BeadChip Array (Illumina, San Diego, CA, USA). We aimed to identify a set of candidate differential methylated regions to provide insights into DEX-affected regions, laying the ground for mechanistic models of DEX action during embryogenesis. We identified >10 000 differentially methylated probes (DMPs) associated with DEX treatment, and almost as many associated with a DEX x gender interaction. DMPs were enriched in intergenic regions near epigenetic markers for active enhancers. Functional enrichment of DMPs was mostly associated with immune functioning and inflammation, but also with non immune-related functions. DMPs were also identified in genes involved in the regulation and maintenance of methylation.5 In summary, prenatal DEX treatment and postnatal GC treatment affect cognition. DNA methylation is altered after prenatal DEX treatment. This may have implications for the future health of the exposed individual. We conclude that first trimester DEX treatment of fetuses at risk of CAH should not be performed
Megaron Conference Centre, Athens, Greece 27–29 September
ESPE 2018 is set to be a scientifically vibrant and exciting meeting, with something of interest to you all. A rich mix of clinical and basic science, the programme focuses on novel advances in paediatric endocrinology and the wider field of medicine. We have increased the number of plenary lectures to eight (see panel, above right). As you can see, they encompass diverse topics and are presented by internationally renowned speakers. You will also enjoy: • 10 symposia, focusing on novel advances in clinical and basic science • the 1st ESPE ENDO-ERN Symposium, updating you on the exciting new European Reference Network • new ‘How Do I….?’ sessions, where expert clinicians discuss management of common paediatric endocrine conditions (details shown in the righthand column) • our new Young Investigators session, featuring novel research data from several ESPE award winners and grant recipients • special sessions covering Working Groups, Novel Advances, Controversies, Meet the Expert and Yearbook of Pediatric Endocrinology – plus much more besides Find out about these and other sessions at www.espe2018.org. Many networking opportunities will also be available, including the ESPE Connect stand. So visit Athens in September for a great scientific and networking event in a city famed for its beauty, culture and history! Mehul Dattani Chair, Programme Organising Committee
Oncofertility: from bench to bedside to babies Teresa Woodruff (USA) Oxytocin and the healing power of love Sue Carter (USA) Novel aspects in the pathophysiology of obesity Christos Mantzoros (USA) Prediction, identification and treatment of early stage type 1 diabetes Anette-Gabriele Ziegler (Germany) Dynamic control of tissue glucocorticoids – lessons for optimising replacement therapy Brian R Walker (UK) Personalised treatments using gut microbiome and clinical data Eran Segal (Israel) Adrenal gland microenvironment in health and disease Stefan Bornstein (Germany) Turner syndrome: new insights from prenatal genomics and transcriptomics Diana Bianchi (USA)
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