Man, I feel like a woman

The Journal of Molecular Endocrinology is the only Society-owned basic science journal dedicated to looking at hormones at the cellular and molecular level. In a series of blog posts, we look back at some of the most cutting-edge research published by our members in our journals. This first piece was written by Douglas Gibson (@douglasagibson), a postdoctoral research at University of Edinburgh.

Remember that members can now publish in JOE, JME and ERC free of charge!

We often think of hormones as ‘male’ or ‘female’ because of how they shape the features we associate with each sex. So androgens – the ‘male’ hormones – might make you think of ‘manly’ things like body hair, muscles and deep voices, but what if I told you that they play an important role in women becoming pregnant too?

It’s difficult to separate androgens from their macho reputation, particularly when examples of androgen excess in women, such as in athletic doping, also produce masculinizing effects. Despite this, androgens have long been known to be important in controlling many processes in female physiology. Indeed, androgens can be detected at significant concentrations in the blood of women and in some cases may even exceed those of men! However, although androgens are abundant in the blood they are usually only activated in specific tissues when they are needed. In this clever way they don’t have widespread and uncontrolled effects.

One surprising place where androgens were recently found to be activated is inside the womb. Every month, the structure of the womb lining – known as the endometrium – is reorganised to create an environment that can support and sustain pregnancy. However, without the right hormonal signals, the endometrium will not provide the conditions required for a fertilised egg to implant.

Recent studies have found that hormones produced inside the womb play a pivotal role in the early stages of pregnancy. It was previously thought this vital role was carried out solely by hormone signals from the ovary but new research has found that ‘male’ hormones (androgens) help to prepare the womb lining to encourage a successful pregnancy.

In our study, we wanted to understand how the signals inside the womb lining affected the early stages of pregnancy. In fact, we found that androgens can act in two key ways; by acting as a direct signal in the womb but also by being converted into ‘female’ hormones (estrogens) in the early stages of pregnancy. We found that estrogens within the womb signal to cells that control blood vessel development which is essential for promoting exchange of nutrients between mother and baby.

So amazingly, androgens seem to provide a delicate balance to control key changes in the womb in pregnancy. However as fewer of these key hormones are produced as women age, this could partly explain why some older women find it difficult to conceive. Our research is now focussing on how changes in the availability of androgens can affect the way the womb lining prepares for pregnancy. We hope to be able to apply this new understanding to improve fertility treatments which in the future may mean that older women seeking motherhood may have a better chance of successfully conceiving.

Life as a young lab head

Earlier this year, the Endocrine Society and the Endocrine Society of Australia published a paper titled ‘Career advancement: Meeting the challenges confronting the next generation of endocrinologists and endocrine scientists‘. Endocrinologists are facing challenges in reduced funding, competing responsibilities and gender issues. Giving us the personal side of the story, Australian prostate cancer researcher Luke Selth tells us about the ups and downs of life as a young lab head…


“As I sit down to write this, there is a foul odour permeating my cancer research lab. I know what you’re thinking: one of the PhD students has left a Bunsen burner on and I’m on butane high. I wish it was so simple.

No, the stench is a heady mixture of stress and worry. I am expecting the outcomes of two National Health and Medical Research Council (NHMRC) Project Grant applications this week. We also have two research papers currently under review at a prominent journal in the field of cancer biology (seriously, how can it take 62 days to review a paper?).

It feels as though the next week could literally make or break my career. Is this an exaggeration? Well, no, actually. Let me break it down for you…

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The grant applications

My lab’s research is focused on identifying the molecular mechanisms underlying prostate cancer progression, and developing new therapeutic strategies for this important disease. Both of my Project Grant applications are in this field and, realistically, there’s every chance neither will be funded.

I’d like to stress that this isn’t because they are bad applications. ‘You’re biased’, I hear you muttering, and I can’t argue with that – of course everyone thinks their own research is the most novel and exciting. However, I have evidence to back this notion up: both have made it through the dreaded ‘Not for further consideration’ cut, which means they were ranked in the top 50% of applications.

So we are through the first hurdle. However, given that last year’s success rate was 13.7%, this means that both grants still only have around a 1 in 4 chance of being funded. Of course, that’s if the success rate doesn’t decrease even further this year – there’s every indication that it will. When I started writing NHRMC grant applications 5 years ago, 22.9% of applications were being funded. This worrying trend, largely due to the lack of real increase in the overall NHMRC budget, has caused a lot of scientists to change professions or leave the country – a “brain drain” that will be difficult to recover from.

The low success rate means the outcomes often feel like a bit of a lottery. All of the applications still in the hunt are strong; it’s extremely difficult for a review panel to choose the best. In a perfect world (or, more accurately, a perfect Australian economy), most of them would be funded. But this isn’t a perfect world, and so some randomness ensues. This process of assessing applications in this type of funding scheme has been studied: Fang and colleagues provided evidence that the peer review process used by the National Institute of Health (USA) does not necessarily fund the best science – and that using a lottery-style system to awards grants would actually yield equivalent, if not better, research outcomes.

In short, a bit of bad luck could see both of my applications – which collectively took around 2 months of full-time work to prepare – down the drain.

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The papers

The old mantra of “publish or perish” is stronger than ever in Australian science. Consistently publishing in high quality journals is required for grant success, which in turn is required to keep consistently publishing in high quality journals; it’s a feedback loop that sadly consumes much of my attention.

The two papers that are currently under review are both strong bodies of work. But, again, there’s every chance they will be rejected – the current acceptance rate at the journal I have submitted to is around 20-25%.

The possible outcomes

OK, so what happens if my grant applications and research papers are both tossed out like old agar plates? Well, I will have just enough funding to keep my small research group going next year, but virtually nothing for the following year (not even my salary). The stench of worry in my lab will become even more pungent. I’m a passionate guy, and in such a situation I’d like to allow myself the release of smashing a glass beaker or two – but I couldn’t afford the cost of replacements…

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Alternatively, there is the possibility that I win the lottery. Sure, there’s been a lot of work done by my group, but in the end I truly believe there is a significant amount of luck involved. If the papers are accepted and grants are funded, suddenly the lab’s future and finances will look flush again. There will be no need to let anyone go, and I can cancel that online barista course I signed up for!

This roller-coaster we call a science career

Of course I’ve simplified things. There is a whole spectrum of possibilities between total failure and total success. But what I’m hoping to convey is the reality of life for a young lab head trying to make his or her way in the world of biomedical research. This job is a bloody roller-coaster, and it seems perverse that I spend up to half of my time applying for money so that I can simply do my job.

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I’m often asked by my close friends and family why I stick with it. One response is that I’m not sure any café would want a washed-up scientist as their barista! Seriously though, I love my job for many reasons, the most important being that I have a scientific curiosity that can probably only be sated by this type of research and a vision to improve outcomes for cancer patients. Fortunately, the satisfaction of discovery, coupled with a real chance to improve the health of our society, far outweigh my grant- and paper-related pessimism.

So, even if the grants and papers don’t come through this week, I’m going to persist – and I have many inspirational colleagues and mentors who do the same, year in and year out.

References:

  1. Fang FC, Bowen A, & Casadevall A (2016) NIH peer review percentile scores are poorly predictive of grant productivity. Elife 5.

Meet your new Society President

 Meet your new President…

 A new era begins for the Society as Professor Graham Williams takes over as President at SfE BES 2016. Associate Editor of The Endocrinologist, Amir Sam, finds out more about Graham’s background, reflections and aspirations for the Society for Endocrinology. The full interview will be published in the winter issue of The Endocrinologist.

Tell us about your background

I worked as an SHO in Kidderminster and did my general medicine rotation at the Queen Elizabeth and Birmingham General Teaching Hospitals. I then got an MRC Training Fellowship with Michael Sheppard and Jayne Franklyn in Birmingham to work on thyroid hormones.  I did a year of my PhD there and then completed it at Harvard Medical School with Reed Larsen and Greg Brent at the Brigham and Women’s Hospital in Boston, where I also did some of my post-doctoral training.

I came back with an MRC Clinician Scientist Fellowship and started as a Lecturer in Birmingham with a completely empty lab and had to start from nothing!  About six months before I left Boston, I had a meeting with Reed, who was very happy to support me but said that I shouldn’t work on the same subject that he was working on because it was too small a field and it was important I develop my own independence.  He urged me to read the literature and find a new area to pursue.

I had been working on the biochemistry of transcriptional activation by thyroid hormone and retinoid X receptors and wanted to apply the basic science to clinically and physiologically important questions.  I decided to find a relevant thyroid hormone responsive target tissue that wasn’t being studied; most people were working on pituitary, heart and liver and other labs were getting into the brain. I spent a lot of time talking to various people and eventually settled on the skeleton, a clearly important target organ that had not been investigated in the context of thyroid hormones in any detail.  Having not known anything about bone, I had a blank canvas and started from scratch!  In 1995 I was approached by Raj Thakker and James Scott to move to Hammersmith as a senior lecturer.

When did you know you wanted to be an endocrinologist?

When I qualified from medical school I was all set to do surgery, but realised pretty quickly that I did not have the dexterity to be any good.  My first house job was in endocrinology at the Queen Elizabeth Hospital in Birmingham with David London. At the time there were some really fascinating cases, and working with him got me enthused and hooked on endocrinology straight away. He was definitely the biggest influence on my career selection.

By the time you finish your term of office as President, you will have held major roles at the Society for Endocrinology for over a decade.  How has the Society changed over the time?

The financial aspect of the Society has substantially increased over time. When I took over the treasurer’s role the gift aid to the Society from Bioscientifica was around £100,000 per year, and when I ended my term as treasurer it had grown to about £1 million per annum. The Society has grown incredibly in terms of its diversity; it is reaching out further to different countries and continents in a way that was never possible and is now a very professional and superbly run organisation.

How do you see the Society developing over the next few years?

We have a much greater role in education and the development of opportunities for young endocrinologists. I don’t think my plans for the future will be to fix anything in particular because I think the Society is functioning extremely well. We need to develop it further along these roles for the benefit of the next generation. We have to support our younger scientists and clinicians, retain them and hopefully attract more people to the discipline with the ultimate aim of benefiting our patients and endocrine science. We also need to strengthen our international collaborations, both scientifically and clinically.

Post-Radioiodine Graves’ Management: The PRAGMA Study

Petros Perros is a Consultant Endocrinologist at Newcastle Hospitals, and Honorary Senior Lecturer at Newcastle University. He is the Project Lead for the PRAGMA Study, a Society for Endocrinology research project which compares the incidence of dysthyroidism in post-radioiodine patients treated with difference management strategies.

Petros will be presenting the PRAGMA study’s latest findings next week in Brighton, which is hosting this year’s SfE BES conference. Ahead of the event, we asked him to write about the project and why it’s such an important Society project.

For more information, be sure to check out Petros’ talk at 16.45 on Tuesday 8 November in Syndicate One. Our Scientific Programme has more details.

Project Background

Grave’s Disease, an autoimmune condition, is the most common cause of hyperthyroidism. Radioiodine (RI) is an effective, safe and cheap treatment for hyperthyroidism, though it results in most patients with RI-treated Graves’ disease requiring life-long thyroid hormone replacement.

Ideally the transition from hyperthyroidism to a stable thyroid status (through thyroid hormone replacement) should be rapid and smooth. However, in practice fluctuations in thyroid status in the first year after RI are not uncommon.

In an attempt to achieve and maintain euthyroidism (in which the thyroid gland is functioning normally) after RI, endocrinologists employ different strategies. These will eventually include the introduction of levothyroxine, a synthetic thyroid hormone chemically identical to thyroxine. The two most typical treatment strategies are:

  • The use of anti-thyroid drugs for a period of time after RI. These are used either alone or in combination with levothyroxine – with levothyroxine is known as the “block and replace” strategy
  • Watchful monitoring and introduction of levothyroxine when required

This variation in management in response to fluctuations in thyroid status following RI was the inspiration for the PRAGMA Study. We set out to determine the extent of thyroid instability after RI, and to explore whether different strategies of management are associated with different degrees of thyroid instability.

The study was funded by the Clinical Endocrinology Trust and was included in the NIHR portfolio.

What has been achieved so far?

Thirty-four hospitals in the UK have recruited 812 patients over 2 years. One of the most striking findings was that a very large proportion of patients – 67.2% – had at least one episode of hypothyroidism within the first year after RI, and 36% had an episode of hyperthyroidism. Patients treated with the “block and replace” regimen after RI were least likely to experience hypothyroidism and gain weight, though hypothyroidism was still experienced in 26% of cases.

What next?

We continue to collect data in the management of this condition. Additional interventions need to be identified and implemented to improve outcomes for patients with Graves’ disease treated with RI, and this study provides us with great possibility.

The level of engagement of colleagues with the PRAGMA Study proves that large scale studies addressing common, simple, clinically relevant questions can be conducted with ease and minimal cost. It is a great asset to the field of clinical endocrinology research.

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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.