The curious case of Caster Semenya: intersexed athletes and competitive advantage

Following the recent media coverage of Caster Semenya competing at the Rio Olympics 2016, we have republished an abridged version of Harriet Nerva’s essay on disorders of sexual development, which won the Society for Endocrinology Undergraduate Essay Prize in 2010. You can read the full version here.

Gender verification and sport are two terms which when put together provide a bang louder than any starting pistol. In August 2009, Caster Semenya an 18 year old South African female athlete won the 800m sprint in the World Championship in Athletics in a world-record time. Her muscular build and fast time fuelled rumours of hermaphroditism and levels of testosterone three times that of ‘normal’. She was ordered to take a gender verification test. The worldwide controversy that followed has forced athletic organisations to create new guidelines for intersexed athletes, also known as those with a disorder of sexual differentiation (DSD). These are still being decided as this essay is written.

So are you female or male? The answer may seem simple enough – except that is for the 1.7% of the population who are born intersexed, and, for any young budding intersexed athlete out there, the consequences may be far reaching.

Introduced in 1936, and used to catch male imposters in female sporting events, compulsory gender testing of female athletes was abolished in 1992, with organisations retaining the right to test anyone thought of as ‘suspicious’. Males and females have traditionally been separated in elite sport because of the competitive advantage that men are argued to possess. The advantage stems from biologically determined sex differences in physical characteristics such as height, body composition, muscle mass, endurance and cardiovascular capacity.

However gender testing was never meant to address the issue of intersexed athletes. There is no evidence that female athletes with DSDs have displayed any sport-relevant physical attributes which have not been seen in biologically normal female athletes. Why is Semenya being tested? The grounds for her testing and the test itself have not been clarified.

DSD or ‘intersex’ refers to the atypical appearance of the external genitalia at birth where they differ from the usual development of either sex and create difficulty in sex assignment. The DSDs can broadly be split into 3 groups. Firstly, disorders of chromosomal sex occur when there is nondisjunction of sex chromosomes during meiosis. Secondly in disorders of gonadal sex, chromosomal sex is normal but the differentiation of the gonads is abnormal.

Thirdly there are the disorders of phenotypic sex. Here the phenotypic sex is ambiguous or is completely in disagreement with chromosomal and gonadal sex. Female pseudohermaphrodites (virilised females) have a 46, XX karyotype and female gonads, but ambiguous or male external genetalia. Male pseuodohermaphrodites (undervirlised males) have a 46 XY karyotype and male gonads, but ambiguous or female external genetalia. A true hermaphrodite has both ovarian and testicular tissue, irrespective of karyotype. Internal genetalia may also be mixed and external genetalia may be male, female or ambiguous.

Methods of defining gender in sport have been notoriously controversial. In essence what gender verification tries to do is find a cut-off point between females and males. This is harder than it sounds – sex is not defined by one parameter, it is a complicated combination of many, but athletics bodies have broadly used chromosomal sex for differentiation. Do DSDs always result in competitive advantage and do they always affect chromosomal sex test results? What about all this testosterone rumoured to be flying around?

Whereas in men a testosterone dose-response relationship has been shown to exist in sport, in women this relationship has only been found in relation to ‘explosive performance’. This measurement of height and power output involves performing the lowering portion of a lift at normal speed while the lifting portion is performed as rapidly and forcefully as possible. The dose-response relationship found was weaker in women than in men. It has been argued that this is because of gender differences in skeletal muscle sensitivity to testosterone, but this has not been substantiated. Whether women show a dose response relationship across all sporting attributes (for example endurance) is unknown, possibly because there is a lack of data on the relationship between resting testosterone levels in elite competitors and neuromuscular performance. In 2006 Cardinal and Stone found that testosterone levels varied significantly in different athletic groups, with sprinters having the highest values for both men and women.

And what of Caster Semenya? If judged ineligible to compete as a woman, she would also be ineligible to compete as a man, and if she refuses to consent to treatment (and is not taking anabolic steroids), must she be allowed to compete as an intersexed athlete based in moral obligation of athletic organisations? Finally as these organisations move to open “centres of excellence” around the world that would be equipped to treat intersexed athletes with anything from hormone therapy to surgery (Handley, 2010), what is the role of endocrinologists? Torn between controlling athletic prowess and the best interest of the client, we have to ask how level the playing field can, and should, ever be.

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!

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