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.

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!

Awareness of BRCA2 gene mutations in men becoming women

A recent case study in Endocrine-Related Cancer describes the case of a transgender woman developing breast cancer linked to a mutation in the BRCA2 gene. In this post Dr Adrian Daly talks about the potential implications of their findings – and what it could mean for screening techniques.

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Few medical issues have seen greater changes in public awareness recently than those related to transgender individuals.  Discussions around transgender identity were previously marginalized.

In contrast, today it is front and center in debates related to equality in many countries.  Along with the work of activists, the arts and media have played a central role in this radical change in openness regarding transgendered people and their experiences.  Leading characters in mainstream television drama are played by transgender actors such as Laverne Cox in Orange is the New Black, while popular series like Transparent have the transgender experience as the main theme of the show.

The real life experiences of gender transformation of the former Olympian and reality TV star Caitlyn (formerly Bruce) Jenner have been chronicled intimately. The upshot of this has been to dispel many taboos about discussing transgender related issues in the mainstream media.  This, in turn, improves awareness around these issues and how transgender is managed.

Endocrinologists play a key role in this specialized area of medical care.  Cross hormonal therapy is a cornerstone of gender transformation and is responsible for many desired changes sought by patients.  For male to female transformation, this involves taking doses of female hormones like estrogens and blocking male hormones with anti-androgen therapy.  This process leads to important physical changes like breast growth.

Hormonal therapy not only brings welcomed transformations but also changes in screening activities.  Male to female transgender individuals should learn and adopt breast examination and routine mammography similar to genetic females.  While male to female patients treated with hormones don’t appear to have an increased risk of breast cancer, there is a risk factor in this condition that might need better awareness in patients and doctors alike.

As published on 21 March 2016 in Endocrine-Related Cancer, a study involving the group of Prof. Albert Beckers at the University of Liège, Belgium described the case of a male to female transgender patient that developed breast cancer after 7 years of oestrogen and anti-androgen therapy.  The patient had to stop their hormone therapy and undergo surgery, but despite this, the cancer recurred and required chemotherapy.  Unbeknownst to the patient, multiple cousins had developed breast cancer and were found to have a mutation in the BRCA2 gene.

While the risks of cancer related to BRCA2 gene mutations have focused mainly on women, male mutation carriers are at greatly increased risk of male breast cancer and BRCA2 appears to act as a risk factor for prostate cancer, another hormone related tumor.  Indeed multiple members of the family also had developed prostate cancer.

“This very difficult case highlights two important points.”, said Dr. Vinciane Corman a lead author of the study. “Firstly, the awareness of family cancer risk due to BRCA2 gene mutations needs to involve both males and females, and families need to be thoroughly informed.  Information about a major risk factor like a BRCA2 mutation can lead to better decision making by potential carriers”.

She continued, “Secondly, the current cancer screening guidelines for BRCA2 mutation carriers have been written with the typical (or cisgendered) population in mind.  Due to greater openness about discussing transgendered individuals, future iterations of these guidelines might need to consider how best to manage these rare but difficult cases of BRCA2 mutation carriers that are considering being treated with cross sex hormones.”

World Health Day: Beat Diabetes

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There are currently 422 million people in the world who have diabetes – about 0.6% of the world’s population.

This figure is expected to double in the next 20 years.

In light of this alarming trend, the World Health Organization is dedicating 2016 World Health Day: Beat Diabetes to raising awareness of this life-threatening condition. Here are the basic stats:

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Diabetes is an endocrine disease. So, to mark World Health Day, we have created a collection of recent, high-impact diabetes articles and made them all free to read – for the next two weeks. So have a browse below and find out how science is bringing the fight to diabetes!

Journal of Endocrinology:

Current understanding of metformin effect on the control of hyperglycemia in diabetes Hongying An & Ling He.

Lack of glucagon receptor signaling and its implications beyond glucose homeostasis Maureen J Charron and Patricia M Vuguin.

Defective insulin secretion by chronic glucagon receptor activation in glucose intolerant mice Linda Ahlkvist et al.

Identification of ABCC8 as a contributory gene to impaired early-phase insulin secretion in NZO mice Sofianos Andrikopoulos et al.

Increased Slc12a1 expression in β-cells and improved glucose disposal in Slc12a2 heterozygous mice Saeed Alshahrani et al.

 

Journal of Molecular Endocrinology:

Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes Sumaira Z Hasnain, Johannes B Prins and Michael A McGuckin.

Non-coding genome functions in diabetes Inês Cebola and Lorenzo Pasquali.

miR-410 enhanced hESC-derived pancreatic endoderm transplant to alleviate gestational diabetes mellitus Yang Mi et al.

Inhibition of 11β-HSD1 by LG13 improves glucose metabolism in type 2 diabetic mice Leping Zhao et al.

Demethylation of the MafB promoter in a compromised β-cell model Wataru Nishimura et al.

 

Endocrine Connections:

Update on strategies limiting iatrogenic hypoglycemia Aldo Bonaventura, Fabrizio Montecucco and Franco Dallegri.

Central and peripheral pathogenetic forms of type 2 diabetes: a proof-of-concept study Dmitry M Davydov and Malik K Nurbekov.

Lower fasting blood glucose in neurofibromatosis type 1 Aline Stangherlin Martins et al.

Gut microbiota and diet in patients with different glucose tolerance Lilit Egshatyan et al.

Mendelian randomization studies of biomarkers and type 2 diabetes Ali Abbasi.

 

 Endocrinology, Diabetes & Metabolism Case Reports:

A silent myocardial infarction in the diabetes outpatient clinic: case report and review of the literature M S Draman et al.

Severe hypercalcemia and hypernatremia in a patient treated with canagliflozin Arshpreet Kaur and Stephen J Winters

Spontaneous diabetic myonecrosis: report of four cases from a tertiary care institute Soham Mukherjee et al.

One year remission of type 1 diabetes mellitus in a patient treated with sitagliptin Marcos M Lima-Martínez et al.

Suspension of basal insulin to avoid hypoglycemia in type 1 diabetes treated with insulin pump Mauro Boronat

Oncogenes and predicting clinical outcomes in thyroid cancer

Coinciding with World Cancer Day, this month’s issue of our journal Endocrine-Related Cancer includes an exciting new review of cutting edge research on a putative new oncogene TERT, and its role in affecting clinical outcomes in thyroid cancer. Journal editor Charis Eng is here to tell us why this is such a significant piece of work.

 
Over the last 10 years, thyroid cancer has been the fastest rising incident cancer in women and second fastest in men, without clear aetiology.  In the January 2016 issue of Endocrine-Related Cancer, Liu and Xing from Johns Hopkins University School of Medicine provided an authoritative review article on “TERT promoter mutations and their role in predicting clinical outcome in thyroid cancer”.

Up until recently, BRAF and RAS somatic mutations were utilized to predict outcome in thyroid cancer.  Two years ago, Prof Xing was the first to show that TERT promoter mutations were associated with the most aggressive thyroid cancers.  Now, the authors bring us an erudite and comprehensive review on this new and cutting edge field.

The oncogenic role of TERT promoter mutations involve creation of consensus binding sites for ETS transcriptional factors.   The mutations occur with an increasing prevalence from low- to high-grade thyroid tumours, namely, on average, 0%, 11.3%, 17.1%, 43.2%, and 40.1% in benign thyroid tumours, papillary thyroid cancer (PTC), follicular thyroid cancer, poorly differentiated thyroid cancer, and anaplastic thyroid cancer, respectively (Figure 1). They are strongly associated with aggressive clinicopathological outcomes, including aggressive pathological features, tumour recurrence, and patient mortality.  Importantly, TERT promoter mutations are also associated with BRAF and RAS mutations, and their coexistence has a robust synergistic effect on the poor clinicopathological outcomes of thyroid cancer.

This review by Liu and Xing conclude that the mutated TERT gene is a prominent new oncogene that plays an important role in thyroid tumorigenesis and represents a novel diagnostic and prognostic molecular marker and therapeutic target in this cancer.

 

 

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Figure 1. Prevalence of TERT promoter mutations increases with the grade of the thyroid tumour and is associated with more aggressive clinicopathological outcomes.

 

To find out more on the latest endocrine cancer research across all our journals, visit our new website Hormone-Related Cancer.

Debunking the Open Access Myths, Open Access Week 19-25th October 2015

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Nature’s 2015 Authors’ Insights Survey suggests that open-access (OA) perceptions are changing.  However, our journal’s team find that concerns are still rife. As part of International Open Access Week, SfE’s OA journals, Endocrine Connections and Endocrinology, Diabetes & Metabolism Case Reports (both published by Bioscientifica), are addressing the most commonly expressed OA ‘myths’ and reviewing the evidence to refute them.  Continue reading “Debunking the Open Access Myths, Open Access Week 19-25th October 2015”