Should prednisolone be the first line for glucocorticoid replacement in adrenal insufficiency?

At 18.30 on Monday 7 November Professor Jeremy Tomlinson is chairing a debate on the treatment of adrenal insufficiency at SfE BES 2016. Ahead of the debate, we asked Professors Stafford Lightman and Karim Meeran to give you a little taste of their stance on this hot topic in endocrinology.

 

Professor Jeremy Tomlinson, University of Oxford – Chair

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The optimal strategy for glucocorticoid replacement in patients with adrenal insufficiency remains a contentious issue. In the majority of cases, hydrocortisone is used, but there are issues relating to the need for three times a day administration alongside the high costs of treatment. Are there alternatives?

Prednisolone is significantly cheaper, has a longer duration of action and therefore can be administered twice daily. However, it is a synthetic glucocorticoid that does not act in an identical way to hydrocortisone.

Head-to-head comparisons with meaningful clinical end points are lacking, and in the modern NHS, treatment costs play an increasingly important role.

Let the debate begin!

 

Professor Stafford Lightman, University of Bristol – AGAINST

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The evolution of Homo sapiens from early mammals has taken about 200,000,000 years. During this time we have developed many highly specialised physiological systems –including the key homeostatic system we call the Hypothalamo-Pituitary-Adrenal axis. This system maintains key cognitive, metabolic and immunological systems in optimal state and is also a rapid response system to protect us against stress. The hormone that has evolved to do this is cortisol.

In the absence of endogenous cortisol no-one would disagree that the gold standard therapeutic hormone replacement should be the closest we can get to normal physiology, so if we have to go second-best and provide a different steroid or pattern of plasma steroids it is incumbent on us to prove that this alternative treatment is as good as the best possible therapy available with the native compound.

Prednisolone differs from cortisol in many ways. Not only does it have different characteristics of glucocorticoid mediated gene transcription with no simple dose response comparison to cortisol, but its plasma half-life and metabolism are also unphysiological.

During the debate, I shall demonstrate why these aspects of prednisolone replacement are potentially disadvantageous at cognitive, metabolic and immunological levels. I will explain why I feel it would be dangerous to submit patients to such long duration therapy unless appropriate long term studies are able to show non-inferiority of this regime.

 

Professor Karim Meeran, Imperial College London – For

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Patients with endocrine deficiency need replacement therapy.

We are getting better at making new analogues of replacement hormones that are more patient friendly and improve compliance by lasting longer. Thus for insulin, we have moved away from normal human insulin to analogues of insulin that have variable half-lives, but are a totally different molecule. There is no evidence that the new analogues are any better than native insulin, but production of some preparations of native human insulins have ceased and many of us use these new insulin analogues. Vasopressin is replaced with a modified molecule, 1-desamino-8-D-arginine vasopressin; the D-enantiomer is used (which never occurs in nature) because it lasts longer. The argument in some quarters that “natural” cortisol would be better thus has no basis.

Similarly, rather than give hydrocortisone several times a day, we need to modify the molecule slightly by inserting a double bond, which increases its half-life and potency, and enables once daily administration. A slow release preparation has been developed and costs £400 per month, but it is far better to use a drug that has an appropriate half-life.

We don’t need to develop one because, remarkably, prednisolone has a half-life that is perfect for a once-daily administration. It happens to be extremely cheap, but that should not deter us from using it!

We now have an assay available for prednisolone, and present data at a number of posters at the BES in November confirming that a once-daily dose of prednisolone 3mg is equivalent to hydrocortisone 10mg plus 5mg plus 5mg. I have converted several patients, who regularly report how well they feel on prednisolone 3mg, and how much easier it is to take.

The main reason that patients should take once-daily prednisolone is its convenience. Added benefits for those in the UK are the low price of prednisolone compared to hydrocortisone, which is substantially more expensive in the UK than in other countries because of a peculiar licensing issue, and the fact that the NHS is not allowed to import it.

We have a serious problem in the UK with the cost of hydrocortisone, and every patient who is switched to prednisolone will save over £100 per month.

 

How to get into peer review and why

Peer Review Week 2016 is taking place from September 19-26. The global event celebrates the essential role that peer review plays in maintaining scientific quality. The central message is that good peer review is critical to scholarly communications.

This year, the theme is ‘Recognition for Review’, so we have asked some of our members to tell us about how they first got involved in peer review, why it’s important to them, and why is it essential for the continuation of high-quality science and clinical research.

 

Li Chan is a clinical scientist in paediatric endocrinology at Queen Mary’s University London. She discusses why peer review is important to her – and you.

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Remember that peer review isn’t just about the journals and funding bodies; it’s also important to the author and the reviewer. The author receives constructive feedback to ensure that their work is presented in the best way and backed up by necessary experimental data. Reading other reviewers’ comments and alternative views on a given set of data may allow you to consider your work from another point of view – and that could make the difference between published and unpublished.

On the other hand, the reviewer gains career development and insight. The reviews you write for others will only aid your own future submissions. Over the years I have learnt an immense amount from both writing reviews and receiving them – and I believe this understanding of both sides of the process is necessary for it to work really effectively.

But how did I get into peer review? During my PhD years, my supervisor would ask me if I wanted to review a submission. I always said yes – working with my supervisor at the start was a useful way of learning the process as I could discuss my final report with someone more experienced. Gradually, I developed my own style and expertise.

If you are a young researcher wanting to get into peer review, I would recommend you speak to senior members of staff. They will only view your enthusiasm with positivity. And don’t think for a moment you’re underqualified; science is such a broad subject – we need reviewers with expertise in all areas, and that includes yours!

 

Karen Chapman is the Society General Secretary, as well as a member of the Editorial Board for the Journal of Endocrinology and Journal of Molecular Endocrinology. She discusses the importance of peer review in career development.

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Publications are the main criterion we are judged on – and I believe the quality of our outputs is dependent upon a thorough review process. With this in mind, I believe we all must do our part to get involved in peer review. We depend on others to review our own papers, and so we all need to reciprocate.

After over 30 years as a research scientist (and not far off 30 years as an Editorial Board member of one sort or another), I have plenty of experience of peer review – from both sides. Yes, it is tough to read the rejection letters and to have your research critically appraised by someone whose identity you can only guess at, but most of the time the reviewers have a fair point, and often their comments substantially improve a manuscript.

Many of us (me included) get into peer review by appraising a manuscript passed to us by a co-worker or lab head. My first one took me forever. I think I read all the references! However, I soon learned to speed up, and concentrate on the data and how they are interpreted. This process also taught me what to look for in my own research and how to evaluate my data through a reviewer’s eyes. I believe reviews work best when a writer suggests a mechanistic experiment that can really nail the conclusions presented. It does happen; and this could be the sign of a great reviewer!

You stand to gain an awful lot from getting involved with peer review, but if you still aren’t convinced, remember that reviewing is also beneficial for keeping up with what is new. It’s a great way to stay ahead of the game!

 

We’ll be on Twitter all week showing our support for the campaign using the official hashtag #RecognizeReview  – and we’d love to hear your experiences of peer review! Also, check out some of our online talks for even more advice on getting into the peer review game:

Wayne Tilley – The Peer Review Process
Dr Josef Koehrle – Responding to reviewers comments

You can also sign up for free webinars and talks through the Peer Review Week 2016 official website.

 

Endocrine Connections celebrates a birthday – and brings you plushies

This month, the Society for Endocrinology’s open-access journal, Endocrine Connections, is marking four years since the publication of its first issue.

To celebrate Endocrine Connections’s achievements, as well as the fourth anniversary of the first issue, you are invited to vote for your favourite article from the shortlist below. This list has been produced based on  scientific quality, originality and level of interest among the wider scientific audience – as well as download numbers to date.

But what’s in it for you? As well as supporting your colleagues’ research, by voting for your favourite, you will be entered into a draw to win an endocrinology-themed plushie; a new mascot, perhaps, for you laboratory or office!

  1. Research paper: Efficacy of increased resistant starch consumption in human type 2 diabetes C L Bodinham et al.
  2. Research paper: Effect of lifestyle intervention on the reproductive endocrine profile in women with polycystic ovarian syndrome: a systematic review and meta-analysis Liza Haqq et al.
  3. Review: The heart as an endocrine organ Tsuneo Ogawa and Adolfo J de Bold.
  4. Review: The appraisal of chronic stress and the development of the metabolic syndrome: a systematic review of prospective cohort studies N Bergmann et al.
  5. Review: Heroes in endocrinology: Nobel Prizes Wouter W de Herder.
  6. Research paper: Variation in the biochemical response to L-thyroxine therapy and relationship with peripheral thyroid hormone conversion John E M Midgley et al.
  7. Review: Mitochondrial dysfunction and insulin resistance: an updateby Magdalene K Montgomery and Nigel Turner.
  8. Review: Update on strategies limiting iatrogenic hypoglycemia Aldo Bonaventura et al.
  9. Research paper: Bone metastases and skeletal-related events from neuroendocrine tumours Katherine Van Loon et al.
  10. Review: Cardiac natriuretic peptides and obesity: perspectives from an endocrinologist and a cardiologist Hugo R Ramos et al.

Vote now and look out for plushies!

Early-career grants: funding to get the all-important first proof of concept

The Society for Endocrinology provides early-career grants to support its members in a number of ways. In this article, Kerry McLaughlin explains how the grant helped her search for an elusive autoantigen, which made a splash on the BBC news page earlier this year.

Dr Kerry McLaughlin PhD JDRF Research Fellow
Dr Kerry McLaughlin, JDRF Research Fellow

 People who have type-1 diabetes lose the ability to control blood sugar levels because of the destruction of insulin-producing cells in their Islets of Langerhans. We know this is because the immune response targets four specific proteins (known as autoantigens), and while the fifth major autoantigen has been known to exist for over 20 years its identity was unknown.

Technical limitations at the time made it impossible to identify the fifth autoantigen, but we used a combination of biochemical techniques alongside high-tech mass spectrometry to discover that this fifth major autoantigen was tetraspanin-7, at last providing a complete picture of the immune targets in type-1 diabetes.

This discovery can now be used to help identify those at risk of future disease development through the detection of antibodies to tetraspanin-7, and to further research into strategies aimed at blocking the immune response to the major autoantigens in order to prevent the disease altogether.

This research came about as a result of work we were doing with a separate autoantigen (IA-2). My postdoctoral supervisor, Dr Michael Christie, was involved in earlier efforts to identify the fifth major autoantigen, and we realised that we could apply the technology developed for IA-2 for this purpose.

This was where the Early Career Grant from the Society for Endocrinology came in and provided some much needed resource to kick-start the project. While it took a little bit more time and effort to finally identify tetraspanin-7 as our elusive fifth autoantigen, this early funding was instrumental to the project’s successful completion.

I have since been awarded a 3-year fellowship by JDRF to continue my research into tetraspanin-7 in the laboratory of Professor Patrik Rorsman FRS, FMedSci at the University of Oxford. We published our study in Diabetes, and it was covered in the mainstream media by the BBC, at one point trending in the top 10 news articles, as well as by the Huffington Post. It was great to have the opportunity to share our research with the wider public, and I was very motivated to see how interested people were in hearing about scientific advances.

For young researchers, getting enough preliminary data to put together a competitive grant application for a major funding body can be tricky. The Early Career Grant from the Society for Endocrinology provides postdocs with the opportunity to explore a new avenue of research and can be used to provide that all-important first proof-of-concept.

The second advantage to this scheme is that it gives early-stage researchers a chance to go through the process of preparing an application for funding as well as managing an award,  but on a much smaller scale and without the heavy administrative burden of larger grants. I would certainly recommend the scheme to those keen to take the first step towards an independent career in research.

Kerry McLaughlin, originally from Cape Town, South Africa, was awarded her PhD in Immunology from King’s College London in collaboration with The Pirbright Institute. She then spent six years as a postdoc in the laboratory of Dr Michael Christie at King’s College London before taking up a JDRF fellowship at the University of Oxford in 2016.

For details on how to apply for our Early Career Grant, visit our website. The next deadline for applications is 27 November 2016.

SfE BES – Call for abstracts!

The annual Society conference, SfE BES, takes place this year in Brighton on 7-9 November 2016. It’s a great chance to network with colleagues, showcase your work and explore new research in your area of endocrinology. Our programme of events is varied yet specific – bringing together the best of basic science, clinical investigation and clinical practice, you have the chance to expand your horizons into other parts of the field whilst also attending those lectures which are really specific to you.

The submission system for abstracts is open until midnight on Wednesday 22nd June – so you have more than enough time to polish your final abstract and send it along. It’s not just a chance to show your colleagues across the whole field of endocrinology what you’ve been working on – it’s a chance to tell them why what you’ve been working on is important.

Last year at SfE BES, a great programme highlight was a session entitled ‘Evolving model systems for complex tissues’, which was chaired by Kevin Doherty and Shareen Forbes. In the ’90s, manipulation of human embryonic stem cells (hESCs) was something of a new thing. It was anticipated that the ability to grow human tissues in culture using hESCs would provide incredible model systems for drug development, toxicity testing and cell therapy.

However, it wasn’t until 2005 that reliable markers had been developed and a significant number of important signalling pathways had been elucidated in the path to differentiation. By this point, some ten years later, finally a tool box existed for nearly every tissue type. This lead to some of the first clinical trials, using pluripotent cells to treat age-related macular degeneration. However, liver disease, diabetes and neurodegeneration were still elusive and challenging goals.

By 2014, fully functional human beta cells has been generated, and they took only 45 days and 7 stages in culture. This was a hugely exciting moment for diabetologists and researchers across the world. But then, of course, the question sprang up: could they be used as a source of islet cells for replantation? Or would they merely serve as an invaluable model?

At Kevin and Shareen’s BES session, they gave a detailed overview of both the background to the field of complex tissue model systems, and the current state of basic science and clinical research, highlighting very recent advances, and discussing the potential future.

The stem cell field continues to expand rapidly. 2016 has already been the year that Chinese scientists grew functioning mouse spermatozoa from skin cells – these went on to fertilise egg which developed into embryos and grew to successful progeny. What will the second half of 2016 bring?

With over 1000 delegates, 100 abstract lectures, 10 plenary lectures, and an evening of awards and prizes, SfE BES is the best place for you to spread the word on your research, and meet the colleagues that you want to work with in future. Your lecture might be the one were talking about all the way into June 2017.

So submit your abstract now through our submission system. Submissions close on Wednesday 22nd June at midnight.brighton 2

See you in November!