“Of Mice and Men….”

“We need to treat individual women, not statistics” was the concluding sentence of an insightful BMJ Editorial 2019 [1]

However, as Caroline Criado Perez points out in her recent, science prizing-winning book, Invisible Women, in many instances there are no scientific or medical statistics on women[2].

Mouse
“Where are the females?”

The efficacy of drugs is predominately initially tested in vivo on male cells. So at inception, potentially many medications, which might have been effective in females are discarded at the earliest stage of research, because no effects are observed in male cells. The trend of the default male organism in research follows through into animal experimentation on male mice. Although animal models may not be entirely predictive of effects in humans, certainly the effects in female humans will be even less certain. Does it matter that research is conducted predominately on male tissue, male organisms and men? Thalidomide, specifically one of the optimal isomers, is a drug that had devastating teratogenic effects when taken by women. Indeed, a wide range of potential sex differences in the effects and metabolism of drugs has been reported. Furthermore the action of drugs, including adverse effects, can vary according the phases of the menstrual cycle, due to variations in circulating sex steroids. For example, certain drugs are likely cause arrhythmia in the follicular phase of the menstrual cycle[3]. Yet the effect of many drugs in females is not well understood, as research had not included females, let alone women in different phases of the menstrual cycle.

Why is research focused on males? There is an argument that the menstrual cycle in females is “too complicated” or including women in a study at difference phases of the menstrual cycle “will interfere with results”. Menstrual cycles have been around since women evolved, so this is not a phenomenon that is going to go away anytime soon. Therefore, welcoming the complexity of the intricate choreography of hormones during the menstrual cycle and during the lifetime of a women, is a more constructive approach. Certainly a more acceptable scientific approach is where the objective is to elucidate similarities and differences between men, rather than excluding the female half of the population and assuming no differences in physiology and metabolism exist. Furthermore there are differences between individual women. Individual women will be impacted by fluctuations of hormones during the menstrual cycle in different ways, depending on varying tissue sensitivities to steroids between individuals.

This concept is especially important in sports science where the vast majority of studies are conducted in males. As I outlined in my presentation recently at Barça Innovation Hub, before discussing external factors (training load, nutrition, recovery), researched in males, for female athletes is is vital to take into account internal bio-chronometers[4]. Circadian misalignment leads to suboptimal health and performance[5]. For female athletes, the most important cyclical variation of hormones during the menstrual cycle. Furthermore, these periodic changes in hormones have individual effects. Only when these are recognised can external factors be integrated with internal periodicity. In other words by taking account of individual internal variations, this makes it possible to provide personalised advice. Tracking menstrual cycles provides an important training metric as menstrual cycles are a barometer of healthy hormones[6]. As it becomes easier to track personal health and performance data on a daily basis, both researchers and individual women can gain a better understanding of how female physiology varies over the menstrual cycle. Optimising health and performance for the individual female athlete, makes for a stronger team.

What about in the clinical medical setting? I recently attended an excellent update on acute medicine for medical doctors. An eminent cardiologist presented a series of case studies, including a woman who started experiencing symptoms in the morning, which both she and doctors thought were due to indigestion. Eventually when this “indigestion” had not settled by later afternoon, she attended A&E. She had suffered an extensive myocardial infarction (heart attack). The cardiologist explained that even though she went to a hospital with an on-site primary percutaneous coronary intervention facility, unfortunately due to the long delay in presenting to hospital, the heart muscle had died. The opportunity had been missed to take her into the catheterisation laboratory to restore blood flow and function to the cardiac muscle. He outlined how this delay in diagnosis would have a big impact on her future quality of life and life span. Unfortunately this is not an isolated case. Women are far more likely to be misdiagnosed as not having acute coronary syndrome, when in fact they are indeed suffering a “heart attack”. Why is this? The “typical” presentation of myocardial infarction of central crushing chest pain with radiation to left neck and arm, disseminated to the public and medical students, is in fact only typical for men. Women present with “atypical” symptoms, in other words atypical for men[7]

Even where female specific statistics do exist, the emphasis should be on considering the individual woman in clinical context. The recent BMJ editorial on HRT emphasised providing women with high quality, unbiased information on which women can weigh up their personal risk/benefit outcomes from HRT. As, each woman can experience changes in hormones differently, including those occurring at the menopause; so the emphasis should be on an individual woman’s quality of life rather than epidemiological statistics[1].

There are important differences between mice, men and women.

References

[1] Rymer J, Brian, K, Regan L. HRT and breast cancer risk. BMJ Editorial 2019. dx.doi. org/10.1136/bmj.l5928

[2] Caroline Criado Perez. Royal Society Book Prize. Invisible Women. Publisher Chatto & Windus 2019

[3] Soldin O, Chung S, Mattison D. Sex Differences in Drug Disposition. Journal of Biomedicine and Biotechnology 2011, Article ID 187103 doi:10.1155/2011/187103

[4] N. Keay “Dietary periodisation for female football players” Barca Innovation Hub conference, Camp Nou, Barcelona, 9 October 2019

[5] N.Keay, Internal Biological Clocks and Sport Performance BJSM 2017

[6] N.Keay, What’s so good about Menstrual Cycles? BJSM 2019

[7] Khamis R, Ammari T, Mikhail G. Gender differences in coronary heart disease. Education in Heart. Acute coronary syndromes. BMJ Heart http://dx.doi.org/10.1136/heartjnl-2014-306463

 

 

 

Raising Awareness of RED-S in Male and Female Athletes and Dancers

Health4Performance is a recently developed BASEM open access educational resource

This is a world premier: a resource developed for and by athletes/dancers, coaches/teachers, parents/friends and healthcare professionals to raise awareness of Relative Energy Deficiency in Sport (RED-S)

What?

Optimal health is required to attain full athletic potential. Low energy availability (LEA) can compromise health and therefore impair athletic performance as described in the RED-S clinical model.

Dietary energy intake needs to be sufficient to cover the energy demands of both exercise training and fundamental physiological function required to maintain health. Once the energy demands for training have been covered, the energy left for baseline “housekeeping” physiological function is referred to as energy availability (EA). EA is expressed relative to fat free mass (FFM) in KCal/Kg FFM.  The exact value of EA to maintain health will vary between genders and individuals, roughly equivalent to resting metabolic rate of the individual athlete/dancer. LEA for an athlete or dancer will result in the body going into “energy saving mode” which has knock on effects for many interrelated body systems, including readjustment to lower the resting metabolic rate in the longer term. So although loss in body weight may be an initial sign, body weight can be steady in chronic LEA due to physiological energy conservation adaptations. Homeostasis through internal biological feedback loops in action.

The most obvious clinical sign of this state of LEA in women is cessation of menstruation (amenorrhea). LEA as a cause of amenorrhoea is an example of functional hypothalamic amenorrhoea (FHA). In other words, amenorrhoea arising as a result of an imbalance in training load and nutrition, rather than an underlying medical condition per se, which should be excluded before arriving at a diagnosis of FHA. All women of reproductive age, however much exercise is being undertaken, should have regular menstrual cycles, which is indicative of healthy hormones. This explains why LEA was first described as the underlying aetiology of the female athlete triad, as women in LEA display an obvious clinical sign of menstrual disruption. The female athlete triad is a clinical spectrum describing varying degrees of menstrual dysfunction, disordered nutrition and bone mineral density. However it became apparent that the clinical outcomes of LEA are not limited to females, nor female reproductive function and bone health in female exercisers. Hence the evolution of the clinical model of RED-S to describe the consequences of LEA on a broader range of body systems and including male athletes.

A situation of LEA in athletes and dancers can arise unintentionally or intentionally. In the diagram below the central column shows that an athlete where energy intake is sufficient to cover the demands from training and to cover basic physiological function. However in the column on the left, although training load has remained constant, nutritional intake has been reduced. This reduction of energy intake could be an intentional strategy to reduce body weight or change body composition in weight sensitive sports and dance.  On the other hand in the column on the right, training load and hence energy demand to cover this has increased, but has not been matched by an increase in dietary intake. In both these situations, whether unintentional or intentional, the net results is LEA, insufficient to maintain health. This situation of LEA will also ultimately impact on athletic performance as optimal health is necessary to realise full athletic potential.

EnergyBalance

Although LEA is the underlying aetiology of RED-S, there are many methodological and financial issues measuring LEA accurately in “free living athletes“. In any case, the physiological response varies between individuals and depends on the magnitude, duration and timing of LEA. Therefore it is more informative to measure the functional responses of an individual to LEA, rather than the value calculated for EA. As such, Endocrine markers provide objective and quantifiable measures of physiological responses to EA. These markers also reflect the temporal dimension of LEA; whether acute or chronic. In short, as hormones exert network effects, Endocrine markers reflect the response of multiple systems in an individual to LEA. So by measuring these key markers, alongside taking a sport specific medical history, provides the information to build a detailed picture of EA for the individual, with dimensions of time and magnitude of LEA. This information empowers the athlete/dancer to modify the 3 key factors under their control of training load, nutrition and recovery to optimise their health and athletic performance.

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Why?

Who is at risk of developing RED-S? Any athlete involved in sports or dance where being light weight confers a performance or aesthetic advantage. This is not restricted to elite athletes and dancers. Indeed the aspiring amateur or exerciser could be more at risk, without the benefit of a support team present at professional level. Young athletes are at particular risk during an already high energy demand state of growth and development. Therefore early identification of athletes and dancers at risk of LEA is key to prevention of development of the health and performance consequences outlined in the RED-S clinical model. Although there is a questionnaire available for screening for female athletes at risk of LEA, more research is emerging for effective and practical methods which are sport specific and include male athletes.

How?

Early medical input is important as RED-S is diagnosis of exclusion. In other words medical conditions per se need to be ruled out before arriving at a diagnosis of RED-S.  Prompt medical review is often dependent on other healthcare professionals, fellow athletes/dancers, coaches/teachers and parents/friends all being aware and therefore alert to RED-S. With this in mind, the Health4Performance website has areas for all of those potentially involved,  with tailored comments on What to look out for? What to do? Ultimately a team approach and collaboration between all these groups is important. Not only in identification of those at risk of LEA, but in an integrated support network for the athlete/dancer to return to optimal health and performance.

References

Heath4Performance BASEM Educational Resource

Video introduction to Health4Performance website

2018 UPDATE: Relative Energy Deficiency in Sport (RED-S) BJSM 2018

What is Dance Medicine? BJSM 2018

Identification and management of RED-S Podcast 2018

Low energy availability assessed by a sport-specific questionnaire and clinical interview indicative of bone health, endocrine profile and cycling performance in competitive male cyclists Keay, Francis, Hind. BJM Open Sport and Exercise Medicine 2018

How to Identify Male Cyclists at Risk of RED-S? 2018

Pitfalls of Conducting and Interpreting Estimates of Energy Availability in Free-Living Athletes IJSNM 2018

Low Energy Availability Is Difficult to Assess but Outcomes Have Large Impact on Bone Injury Rates in Elite Distance Athletes IJSNM 2017

The LEAF questionnaire: a screening tool for the identification of female athletes at risk for the female athlete triad BJSM 2013

IOC consensus statement on relative energy deficiency in sport (RED-S): 2018 update BJSM 2018

 

From population based norms to personalised medicine: Health, Fitness, Sports Performance

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“Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity”. World Health Organisation 1948

There has been criticism of this definition, arguing that the word “complete” has opened the door to today’s more medicalised society. However, this trend coincides with increased volume of “patients” seeking optimal health, together with doctors who have a more extensive repertoire of medical interventions at their disposal. In a time-pressed society there is less opportunity for either patient or doctor to explore longer term adaptive measures and prevention strategies, which facilitate taking responsibility for your health. Fortunately Sport and Exercise Medicine became a recognised medical specialty in the UK in 2006. This encompasses population-based strategies for disease prevention outlined in the global initiative founded in 2007 “Exercise is Medicine“.

What has this got to do with sports performance? There are subgroups within the population, such as athletes already taking plenty of exercise. Elite athletes differ from the general population, due to superior adaptation processes to exercise, probably with a genetic component. So are the same “normal” population-based ranges of quantified medical parameters applicable?

This is precisely the issue that arose when I was on the international medical research team investigating the development of a dope test for growth hormone (GH). Crucially, exercise is one of the major stimuli for growth hormone release from the anterior pituitary. So before we could even start investigating potential downstream markers of exogenous GH abuse, the “normal” range for elite athletes had to be established.

In a similar way, are the “normal” ranges for other hormones applicable to athletes? In a fascinating lecture delivered by Dr Kristien Boelaert, Consultant Endocrinologist, it was explained that the distribution for thyroid stimulating hormone (TSH) is affected by multiple factors, including illness, age and exercise status. So “normal” for the general population is not necessarily normal for specific subgroups.

The other issue, especially with the Endocrine system is that hormones act on a variety of tissues and so produce a variety of multi-system network effects with interactions and control feedback loops. Therefore symptoms of malfunction/maladaptation and subclinical conditions can be non specific. From a doctor’s perspective this makes Endocrinology fascinating detective work, but challenging when dealing with subgroups in the population who require a more intensive work-up and individualised approach.

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The vast majority of research studies involve exclusively male athletes, leaving female athletes under-represented (a recent study on heat adaptation in female athletes being a notable exception). Some areas of research, including my own, have been directed more towards female athletes in the case of female athlete triad, or Relative Energy Deficiency in sports (REDs). REDs is a more appropriate term as it really sums up the important points: male and female can both be affected and therefore should both be studied. There are subgroups within the general population who may not fit the “normal” range: REDs is not necessarily a clinically defined eating disorder from lecture by Professor J. Sundgot-Borgen (IOC working group on female athlete triad and IOC working group on body composition, health and performance).

No medical/physiological/metabolic parameter can be considered in isolation: in the case of REDs, it is not menstrual disturbance and bone health that are affected in isolation. For example, there is currently great debate about whether a low carbohydrate/high fat diet (ketogenic diet) can mobilise fat oxidation and potentially be a training strategy to enhance performance. Needless to say that a recent study contained no female athletes. Given that many female endurance athletes are already lean, potentially driving fat metabolism through diet manipulation may have an impact on Endocrine function, optimal health and hence sport performance. I understand that a forthcoming study will include female athletes.

So a continuum or distinct subgroups in the population? Clearly general medical principles apply to all, with a spectrum from optimal functioning, subclinical conditions through to recognised disease state. We now have evidence of distinct differences between subgroups in the population and even within these subgroups such as male and female athletes. We are moving into a world of personalised medicine, where recommendations for optimal health are tailored for individuals within specific subgroups.

For further discussion on Endocrine and Metabolic aspects of SEM come to the BASEM annual conference 22/3/18: Health, Hormones and Human Performance

References

How should we define health?

Nobody is average but what to do about it? The challenge of individualized disease prevention based on genomics

Exercise is Medicine

Enhancing Sport Performance: part 1

Keay N, Logobardi S, Ehrnborg C, Cittadini A, Rosen T, Healy ML, Dall R, Bassett E, Pentecost C, Powrie J, Boroujerdi M, Jorgensen JOL, Sacca L. Growth hormone (GH) effects on bone and collagen turnover in healthy adults and its potential as a marker of GH abuse in sport: a double blind, placebo controlled study. Journal of Endocrinology and Metabolism. 85 (4) 1505-1512. 2000.

Wallace J, Cuneo R, Keay N, Sonksen P. Responses of markers of bone and collagen turover to exercise, growth hormone (GH) administration and GH withdrawal in trained adult males. Journal of Endocrinology and Metabolism 2000. 85 (1): 124-33.

Wallace J, Cuneo R, Baxter R, Orskov H, Keay N, Sonksen P. Responses of the growth hormone (GH) and insulin-like factor axis to exercise,GH administration and GH withdrawal in trained adult males: a potential test for GH abuse in sport. Journal of Endocrinology and Metabolism 1999. 84 (10): 3591-601.

Keay N, Logobardi S, Ehrnborg C, Cittadini A, Rosen T, Healy ML, Dall R, Bassett E, Pentecost C, Powrie J, Boroujerdi M, Jorgensen JOL, Sacca L. Growth hormone (GH) effects on bone and collagen turnover in healthy adults and its potential usefulness as in the detection of GH abuse in sport: a double blind, placebo controlled study. Endocrine Society Conference 1999.

Wallace J, Cuneo R, Keay N. Bone markers and growth hormone abuse in athletes. Growth hormone and IGF Research, vol 8: 4: 348.

Cuneo R, Wallace J, Keay N. Use of bone markers to detect growth hormone abuse in sport. Proceedings of Annual Scientific Meeting, Endocrine Society of Australia. August 1998, vol 41, p55.

Subclinical hypothydroidism in athletes. Lecture by Dr Kristeien Boelaert at BASEM Spring Conference 2014 on the Fatigued Athlete

Optimal health: especially young athletes! Part 3 Consequences of Relative Energy Deficiency in sports Dr N.Keay, British Association Sport and exercise Medicine

Optimal health: including female athletes! Part 1 Bones Dr N. Keay, British Journal of Sport Medicine

Relative Energy Deficiency in sport (REDs) Lecture by Professor Jorum Sundgot-Borgen, BAEM Spring Conference 2015 on the Female Athlete

Effect of adaptive responses to heat exposure on exercise performance

Low Carbohydrate, High Fat diet impairs exercise economy and negates the performance benefit from intensified training in elite race walkers