Issue 51 Spring 2021
Issue 51 Spring 2021
Bringing The Latest In Paediatric Endocrinology To You
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Editorial
Welcome
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
Sarah.Ehtisham@mediclinic.a
News
Intro
Follow ESPE
online…
Keep an eye on
the latest ESPE news
and activities at
www.eurospe.org
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News
Research Fellowship
One Research Fellowship of €125 000 is available to support up
to 2 years of research training in a centre of excellence, for those
intending to pursue a career in paediatric endocrinology. The grant
will also cover the fellow’s living expenses. An additional €15 000 is
available for the 2-year period, to cover the costs of consumables
(travel and laboratory expenses).
Apply by 20 April 2021
Find out more at www.eurospe.org/grants-awards/
grants/research-fellowshi
News
Undergraduate Achievement Award
The ESPE Undergraduate Achievement Award is open to all
undergraduates, including those studying medicine or other
subjects. It is awarded for scientific achievement in paediatric
endocrinology. Recipients will receive free registration for
ESPE 2021 Online in September 2021 and a grant of €750 to
support their travel and accommodation at the next physical ESPE
Meeting in Rome, Italy, in 2022. The student must submit an
abstract as first author to the Annual ESPE Meeting.
News
Early Career Scientific
Development Grant
Three grants of €2500 are available each year. This grant supports
personal development by means of a short visit to an external
laboratory/hospital/institute. During the COVID-19 pandemic, and
while international travel restrictions are in place, it can be used for
a research period of up to 3 months at your home institution. It may
be used to finance the visit of an outside expert to your institution,
to provide essential guidance, consultation or advice.
The grant is intended to help you:
• learn a new technique
• troubleshoot existing methods
• discuss new methods/techniques in a research seminar
• compile statistics on joint research projects
• test samples in the framework of a joint research project
Apply by 31 May 2021
Find out more at www.eurospe.org/grants-awards/
grants/early-career-scientific-development-grant
News
Clinical Fellowship
Due to COVID-19, selection of the next intake for this fellowship
has been postponed until later in 2021. At this point, those who
have already applied for the 2020−2021 intake will be considered.
Therefore, there will be no further call for applications this year.
Find out more at www.eurospe.org/grants-awards/
grants/clinical-fellowship
News
ESPE e-Learning
The ESPE e-Learning portal provides learning modules on
almost all aspects of paediatric endocrinology and diabetes
mellitus.
The General Content section features 78 chapters and
over 120 real life problem-solving cases, concisely describing
physiology, pathophysiology and practical approaches to
management and treatment in English.
The Resource Limited Countries (RLC) section is targeted
towards frontline healthcare providers in these areas, and
provides 24 chapters and 24 real life problem-solving cases in
five languages (English, French, Spanish, Chinese and Swahili). A
recent article highlights the development of our RLC resource:
see JMIR Formative Research 2020 4 e18555.
New additions
Problem-solving cases have been added to the Courses
section, under ESPE Maghreb School: ‘An infant with
dehydration’ and ‘Persistent convulsions in a 12-month-old girl’.
The content is in English and French.
See www.espe-elearning.org
Registration is free of charge
Hot topics
Bringing you recent highlights from the world of research
Hot topics
Islet autoantibody dynamics in genetically predisposed children
The appearance of autoantibodies against islet proteins is usefulin determining subjects at risk of type 1 diabetes (T1D).
Pöllänen and colleagues sought to understand changesin islet autoantibodies in human leukocyte antigen (HLA)-
predisposed children up to the age of 15. They observed 1006children from birth for a median of 14.9 years. The dynamics ofzinc transporter 8 autoantibodies (ZnT8A), islet cell antibodies(ICA), insulin antibodies (IAA), glutamate decarboxylase antibodies
(GADA) and islet antigen-2 antibodies (IA-2A) were noted, as wasthe presence of T1D.Development of islet autoimmunity was seen in 275 (27.3%)at a mean age of 7.4 years, with 35 (3.5%) children diagnosed withT1D by the age of 15.5 years. ZnT8A and IAA appeared as the firstautoantibodies at less than 2 years of age, whereas IA-2A andGADA increased in the preschool years, with numbers positive forGADA increasing until 10−15 years of age.With these findings, disease subpopulations can be identifiedto predict and prevent T1D.
Read the full article at Pöllänen et al. 2020 Journal of
Clinical Endocrinology & Metabolism 105 e4638−e4651
Hot topics
Gut microbiome determines
offspring’s skeletal phenotype
The gut microbiome is a potential regulator of skeletal maturation both in animals and humans. Recent studies showed that, in most cases, the maternal dominant intestinal bacterial strains were transmitted to the offspring. In contrast, few studies have shown that phenotypes elicited by dominant strains are also transferred between generations. Segmented filamentous bacteria (SFB) are intestinal bacteria that have been shown to lower bone density in healthy mice. SFB induce the expansion of intestinal osteoclastogenic Th17 cells, their migration to the bone marrow, increased secretion of interleukin-17 and the stimulation of bone resorption. Using different germ-free and conventional mouse models, Tyagi et al. showed that skeletal phenotypes can be transferred by transferring the faecal microbiome, specifically SFB, through maternal contacts or cohabitation, and are independent of the mouse genetic background. Bone volume, structure and turnover of the offspring are permanently influenced. With these results, the authors see a therapeutic option for microbiome transfer to overcome suboptimal skeletal maturation. Read the full article at Tyagi et al. 2021 eLife 10 e64237
Hot topics
6-monthly s.c. leuprolideacetate for central precociouspuberty
Klein et al. report the results of a phase 3 trial of a 6-monthly, 45mg s.c. injection of leuprolide acetate in central precocious puberty (CPP). This was approved for use by the US Food and Drug Administration in May 2020. This open label, single arm study was performed on 64 gonadotrophin-releasing hormone agonist (GnRHa)-naive children with CPP (aged 7.5±0.1 years), who were enrolled from 25 centres across six countries. Participants received two doses (0.375ml s.c.) at 0 and 24 weeks and were followed for 48 weeks. At week 48, 49 of the 56 girls (88%) and 1 of the 2 boys achieved remission (maintained peak luteinising hormone <4IU/l at 30 minutes following GnRHa stimulation). Clinical remission could be achieved in more than 97% of participants. There were no significant adverse events to cause any discontinuation of treatment. The authors concluded that the new preparation with a polymeric gel delivery system, administering a small volume 6-monthly, effectively suppressed pubertal hormones and stopped or caused regression of pubertal progression among children with CPP. Long term efficacy and improved quality of life and compliance with reduced frequency and reduced volume of s.c. injection need to be evaluated. Read the full article at Klein et al. 2020 Journal of Clinical Endocrinology & Metabolism 105 e3660−e3671
Hot topics
Sleep disturbances in children with suprasellar tumours
Sleep problems or daytime sleepiness are common in children with suprasellar tumours and are associated with reduced quality of life and increased risk of obesity. The aetiology is multifactorial, including disturbed circadian rhythm, physical damage caused by the tumour or its treatment in important hypothalamic structures that regulate sleep, and also psychological, behavioural and social environmental factors. van Schaik and colleagues illustrate different aetiologies of disturbed sleep among four patients who benefited from specific and individualised treatment. Among these, one received nocturnal ventilation for difficulty in sleep initiation and maintenance and daytime sleepiness associated with severe obstructive sleep apnoea. Educational support was provided for another who had sleep hygiene problems causing difficulty initiating sleep, and daytime sleepiness. A patient with secondary organic hypersomnia received behavioural therapy and modafinil. This article highlights the importance of specialised sleep investigations and provides a flowchart to aid clinicians in the diagnostics of sleep problems in children with suprasellar tumours. Read the full article at van Schaik et al. 2020 Pituitary 23 613−62
Feature
Feature
Starting With A Kiss
Understanding the enigma of kisspeptin In 2003, two seminal reports demonstrated that inactivating variants in the kisspeptin receptor gene resulted in hypogonadotrophic hypogonadism and a failure of gonadotrophin-releasing hormone (GnRH) secretion.1,2 An inactivating variant in the KISS1 gene was similarly reported to result in normosmic hypogonadotrophic hypogonadism.3 Conversely, an activating variant in the kisspeptin receptor gene led to central precocious puberty.4 This all pointed to kisspeptin’s central role in control of GnRH secretion and gonadarche. It has since been established that hypothalamic kisspeptin neurones stimulate GnRH neurones and, in turn, the remainder of the reproductive axis. In animal models, kisspeptin was shown to colocalise with neurokinin B and dynorphin in ‘KNDy’ neurones.5 These neuropeptides act in an autocrine manner to generate pulsatile secretion of GnRH. Both central and peripheral administration of exogenous kisspeptin in animal models potently induces gonadotrophin secretion.6,7 These data place kisspeptin above GnRH at the top of the reproductive endocrine axis. Physiologically, kisspeptin neurones integrate a number of signals, such as those reflecting metabolic status, to affect hypothalamic GnRH secretion and play a key role in mediating their effects on reproductive health. The therapeutic potential of kisspeptin In 2005, our group was the first to administer kisspeptin to humans. We found that it potently induces gonadotrophin secretion in healthy men8 and women.9 From a therapeutic perspective, kisspeptin offers a unique mode of action as a hypothalamic GnRH secretagogue. With kisspeptin, stimulation of the reproductive axis remains subject to the usual feedback checks and balances, in contrast to stimulation using gonadotrophins or treatment with sex steroids. Consequently, we looked to give kisspeptin to restore reproductive health in people with functional reproductive disorders associated with reduced hypothalamic function. For instance, functional hypothalamic amenorrhoea (FHA) is characterised by reduced pulsatile secretion of GnRH. Data from rodent models suggest that FHA is associated with reduced hypothalamic KISS1 expression and a compensatory increase in kisspeptin receptor expression. We demonstrated that exogenous kisspeptin infusions can restore GnRH pulsatility in women with FHA.10 Novel, stable, long-acting kisspeptin analogues offer a further avenue for realising kisspeptin’s therapeutic potential to restore physiology in patients with functional hypogonadism. Recently, we reported that the kisspeptin analogue MVT-602 induces a greater gonadotrophin rise in women with FHA than in healthy women, highlighting its potential as an ovulation induction agent.11 Hypothalamic kisspeptin signalling is essential for the mid-cycle luteinising hormone (LH) surge and subsequent physiological ovulation.12 Accordingly, we showed that kisspeptin-based treatments have promise in in vitro fertilisation treatment. A single bolus of kisspeptin induces an LH surge sufficient to efficaciously mature oocytes, but with markedly reduced rates of ovarian hyperstimulation syndrome (the major complication of using human chorionic gonadotrophin). Kisspeptin as a diagnostic test Kisspeptin’s ability to directly stimulate the hypothalamus means it can also be used as a diagnostic test of hypothalamic function. Patients with congenital hypogonadotrophic hypogonadism (CHH) have a failure of GnRH neuronal migration or secretion. Responses to exogenous kisspeptin in CHH are markedly attenuated.13 Furthermore, patients with anosmia (a feature more consistent with failed GnRH neuronal migration than decreased GnRH secretion) have even more diminished responses to kisspeptin than other CHH patients.14 Likewise, patients with identified pathological variants in CHH genes have even lower LH rises in response to kisspeptin than other CHH patients.14 Conspicuously, up to 20% of patients with CHH can have spontaneous reversal and regain of hypothalamic GnRH function.15 Notably, these patients regain responsiveness to kisspeptin following reversal of CHH.15 Thus, kisspeptin could be used to test a patient’s current hypothalamic function and to rapidly identify reversal of CHH. These data suggest that kisspeptin could be useful in investigation of children with delayed puberty. Most have constitutional delay of growth and puberty (CDGP) and will spontaneously initiate puberty in time. However, some will have CHH and require treatment. Kisspeptin was evaluated as a diagnostic test in 16 children with delayed puberty, and response to kisspeptin was associated with CDGP rather than CHH.16 Work in a larger group of patients with delayed puberty is needed to confirm kisspeptin’s potential as a clinical diagnostic test. In summary Kisspeptin’s discovery has been a major advance in understanding the hypothalamic initiation of puberty. Although variants causing abnormal kisspeptin signalling are exceedingly rare, their study has shed light on a fundamental constituent of the physiological control of hypothalamic GnRH secretion in humans. Future work will pursue research to realise kisspeptin’s therapeutic and diagnostic potential in improving patient health. Ali Abbara and Waljit S Dhillo Section of Investigative Medicine, Imperial College London, U
Feature
Pharmacological treatment
for rare obesity syndromes
The melanocortin 4 receptor (MC4R) agonist setmelanotide offers insights into future treatment options for rare monogenic obesity, as Peter Kühnen explains. The leptin-melanocortin signalling pathway plays a pivotal role in body weight regulation (see Figure). Gene mutations in this highly conserved pathway lead to severe hyperphagia and early onset obesity. Setmelanotide Until recently, a pharmacological treatment option with metreleptin has been available only for leptin-deficient patients.1 However, in the last few years, based on the results of an investigator-initiated phase 2 study2,3 and multicentre phase 3 studies,4 the melanocortin 4 receptor (MC4R) agonist setmelanotide has been evaluated as a treatment option for obese patients with a mutation in one of the genes POMC (pro-opiomelanocortin), PCSK1 (proprotein convertase subtilisin and kexin type 1) or LEPR (leptin receptor). Within the phase 3 trial, treatment led to a reduction of 25.6% in baseline body weight in POMC-deficient patients and of 12.5% in baseline body weight in LEPR-deficient patients after approximately 1 year. This weight reduction was based on a significant reduction in hunger scores. Skin hyperpigmentation was a treatment-related adverse event. This presumably occurred due to cross activation of the melanocortin 1 receptor (MC1R) expressed in the skin. No treatment-related serious adverse events have been observed so far.4 Interestingly, in contrast to first generation MC4R agonists investigated in the past, no increase in blood pressure or heart rate has yet been observed in patients treated with setmelanotide.4 Setmelanotide has recently been approved by the US Food and Drug Administration for patients with obesity due to POMC, PCSK1 or LEPR deficiency. Mechanism of action Until recently, it has been postulated that Gs signalling, and thereby activation of intracellular cyclic AMP levels, would be the major signalling cascade for MC4R-dependent regulation of satiety. To evaluate whether recruitment of further G proteins and signalling proteins might be relevant for ligand-induced MC4R signalling, and might explain different safety profiles, in vitro studies were initiated. These in vitro assays were performed after stimulation with different ligands (e.g. setmelanotide and further melanocyte-stimulating hormone (MSH) derivatives), to gain further knowledge of the ligand-activated MC4R signalling spectrum. It was observed that setmelanotide was approximately 100-fold more potent in activating MC4R related Gq signalling than a first generation MC4R agonist.3 This capacity to activate different downstream signalling cascades compared with other ligands is termed biased signalling and might be an important aspect in explaining the different safety profiles of different MC4R agonists tested in clinical studies (e.g. increased blood pressure). It should be pointed out that a genetic variant in the MC4R gene is identified in approximately 5% of severely obese individuals. However, this genetic variant leads to impaired MC4R function in in vitro experiments analysing Gs signalling in only 1.7% of severely obese individuals5 (though the identified MC4R genetic variants were only tested for Gs signalling). Given the newly identified role of MC4R-related biased signalling, the significance of impaired cascades such as Gq signalling due to an MC4R genetic variant might be more relevant to the MSH-activated satiety signal within the hypothalamus than previously expected. Therefore, in initial studies, different MC4R mutations were re-evaluated regarding the recruitment of the four major G protein families, ERK activation, arrestin recruitment and ligand-dependent internalisation.6 It became obvious that some MC4R mutations did not lead to any altered Gs signalling, but led to impaired Gq signalling and might therefore be relevant in explaining the obese phenotype of the MC4R variant carrier (see Figure). Based on these findings, a new MC4R mutation classification system has been proposed.6,7 Finally, it became evident that each ligand (NDP-α MSH, α-MSH and β-MSH) tested in combination with MC4R genetic variants in vitro has its own signalling profile.6,7 In conclusion Setmelanotide might be a new pharmacological treatment option for patients with monogenic obesity due to mutations in the genes POMC or LEPR. Furthermore, it has become evident that MC4R signaling is much more complex than previously expected. This must be taken into account when the identified MC4R genetic variants of obese patients are interpreted. It is important to understand this central regulation of body weight, and to evaluate whether more common variants in one of the pathway-related genes (which might lead only to mildly impaired gene function) contribute to individual risk of developing obesity later in life. This might allow the establishment of new treatment strategies for a subgroup of patients with more common types of obesity. Peter Kühnen Institute for Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin, Germany
Feature
Caring for transgender/gender
diverse youth
Stephen Rosenthal considers the factors that should be taken into account when supporting transgender/gender diverse youth. In many parts of the world, increasing numbers of transgender/gender diverse (TGD) youth are seeking medical care to bring their physical sex characteristics into alignment with their gender identity: their inner sense of self as male, female, or somewhere on the gender spectrum. Compelling studies in the last decade have produced evidence supporting the concept that gender identity is not simply a psychosocial construct, but probably reflects a complex interplay of biological, environmental and cultural factors. In addition, while there are uncertainties in the care of TGD youth, and a need for long term safety and efficacy research, several studies have demonstrated the clear mental health benefits of gender-affirming medical care (including pubertal blockers and gender-affirming sex hormones), first pioneered bythe Dutch. These have informed the Endocrine Society’s currentClinical Practice Guideline forgender-dysphoric/gender incongruent persons,1 whichwas co-sponsored by ESPE andnumerous other professionalassociations Despite the above-noted advances in the care of TGD youth, significant barriers have recently emerged that would greatly restrict access to gender-affirming medical care. In the UK, the High Court has issued a ruling that would prevent youths under the age of 16 from receiving pubertal blockers without a court order. In the USA, legislation pending in several states would prohibit gender-affirming medical care to those under 18 years of age and would criminalise providers who follow the existing Endocrine Society Clinical Practice Guidelines. My upcoming presentation at the ESPE 2021 Online Meeting will review advances in our understanding of the prevalence of TGD youth, the mental health impact of gender-affirming medical care, potential adverse effects of such care, gaps in knowledge, priorities for research, and an overview of ethical dilemmas and barriers to care. Stephen M Rosenthal Professor of Pediatrics, University of California-San Francisco, CA, USA
Events
Ali Abbara and Waljit Dhillo reflect on kisspeptin’s potential
therapeutic and diagnostic roles in hypothalamic disorders
Events
ESPE 2021 Online
22−26 September 2021 ‘Lifelong endocrine care through collaboration, discovery and innovation’ Due to the ongoing pandemic, the 59th Annual ESPE Meeting will take place virtually on 22–26 September. • 5 days of rich basic and clinical science • Participate with colleagues from around the world • Enjoy all the usual top quality sessions A rich and diverse programme • Plenary lectures • Symposia • Meet the Expert sessions • How Do I…? • Debates on controversies Submit your abstracts now The programme will feature oral communications and e-posters from scientists and clinicians around the world. Submitting an abstract to ESPE 2021 Online is an unrivalled opportunity to share your research and connect with potential collaborators. Abstract submission deadline 10 May 2021 See www.eurospe.org/espe2021online/abstracts Make sure you’re kept informed! Register your interest at www.eurospe.org/espe2021online
Events
ESPE Science Symposium:
Congenital Adrenal Hyperplasia
29−30 October 2021, Nijmegen, The Netherlands This symposium, postponed from 2020, will now take place at Radboud University Medical Centre, Nijmegen, The Netherlands, in October 2021 (unless circumstances change). It will focus on ‘Congenital adrenal hyperplasia: from molecular medical research to clinical application’. • Attendance is limited to 100, including faculty • Delegates may come from any professional clinical and scientific discipline related directly or indirectly to the topic • The fee is €80 per attendee, including dinner on the first night • Accommodation is not included in this fee ESPE offers 25 free registration spaces for young clinicians and scientists-in-training (individuals less than 8 years (full-time equivalent) since completion of doctorate training). Apply for a free place by emailing your application form (available at the web address below) to Hedi.Claahsen@radboudumc.nl. Find out more and register at www.espe-science-symposium-2021.com
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