Hormone Intelligence

Applying machine learning techniques to modelling female hormones enables women to access hormone intelligence at her fingertips

Female hormone networks form the most complex aspect of the endocrine system. The menstrual cycle depends upon a delicate web of feedback mechanisms that trigger significant changes in hormone levels. This intricate physiological process generally operates reliably, but its timing and the hormone levels are affected by internal and external factors going on in a woman’s life. This is why women differ in their experiences of menstrual cycles and why an individual woman may notice differences between cycles.

Apart from being fascinating from a physiological point of view, why is this so important from a practical point of view for women? The reason is that female hormones are not just about fertility. The ovarian hormones oestradiol (most active form of oestrogen) and progesterone have significant effects through the body. Every biological system is dependent on these hormones: bones, muscle, nervous system, including brain function, skin, the cardiovascular and digestive systems [1]. This is why female hormones impact all aspects of health: physical, mental and social [2].

The cyclical fluctuations in female hormones occurring every menstrual cycle will also change over a woman’s lifespan. Completion of puberty is marked by the start of menstrual cycles: menarche. During her adult life a woman can expect regular menstrual cycles. However, subtle hormone disruption can be missed. Although blood testing is the most accurate way of measuring all four of the key female hormones, the standard protocol of taking a blood test at one time point in the cycle, when hormones are at their most quiescent, can miss subclinical menstrual cycle hormone dysfunction.

For example, in subclinical anovulatory cycles, although a woman may experience regular menstrual periods, subtle mistiming of female hormones will not be detected with a routine single blood test. Yet this type of hormone disruption can have potential adverse consequences on health. This is particularly relevant for exercisers, athletes and dancers who are either on the brink of or recovering from low energy availability. Early identification and prevention of relative energy availability in sport (RED-S) is important for both health and exercise performance [3].

A similar situation arises for women in the perimenopause when the responsiveness of her ovaries starts to decline. This is further complicated by the fact that the decrease in ovarian hormone production is not a smooth linear process. A blood test at a single time point may not identify these changes in key female hormone networks. Although perimenopause is a natural physiological process, it can be a challenging time for women, magnified by uncertainty. All change for female hormones

Women need a new, more supportive approach, to take away uncertainty and to empower them with insights into their hormone networks.

How can a woman understand the details of her female hormone network? In theory she could take daily blood tests for the four key hormones: pituitary control hormones follicle stimulating hormone (FSH), luteinising hormone (LH) and ovarian response hormones oestradiol and progesterone. Clearly this is not practical, but it may be possible to use fewer blood tests over a cycle. Machine learning, specifically Bayesian inference, can help by optimally combining test results with background information. This background knowledge includes medical understanding of hormone networks and the characteristics of the individual woman. Machine learning can revolutionise healthcare, as outlined in the report from the Chief Medical Officer of England [4]. It is an approach widely used in modelling biological systems [5]. Artificial intelligence is an important clinical tool to support the optimisation of personalised health.

It has recently become possible to create a personalised digital fingerprint of a woman’s menstrual cycle hormone network from just two finger prick capillary blood samples taken during a cycle. Machine learning combines deep medical and mathematical understanding of female hormone networks with the individual details of a woman’s menstrual cycle length, age and activity levels. An expert report, providing an explanation of results with actionable, evidence-based advice, can be supplemented with a personal clinical medical discussion. This gives women the long-needed opportunity to connect with their personal female hormone networks. It empowers each woman to adopt a personalised, effective and proactive approach to optimise her hormone health.

To learn more about machine learning applied to female hormone networks, have at look at previous discussions and forthcoming events where I am presenting on this topic and application of this approach for female health.Presentations

To take advantage of this exciting opportunity of fingerprinting hormone networks, you can order Female Hormone Mapping™ which combines medical, mathematical and technology expertise via the Forth website (available on a discounted introductory offer for a limited time). Your personal report is delivered at your fingertips on a mobile app. You can book an appointment for a personal discussion of your report with me Female Hormones

Every woman’s hormone network fluctuations are personal to her. Every woman is an individual.

References

Article St John’s College, Cambridge University

[1] Keay, N. What’s so good about Menstrual Cycles? British Journal of Sport and Exercise Medicine 2019

[2] Keay, N. Of Mice and Men (and Women) British Journal of Sport and Exercise Medicine 2019

[3] Keay, N. Relative energy deficiency in sport (RED-S) British Journal of Sport and Exercise Medicine 2018 and British Association of Sport and Exercise educational website Health4Performance

[4] “Machine learning for individualised medicine” Mihaela van der Schaar, Chapter 10 of the 2018 Annual Report of the Chief Medical Officer. Health 2040 – Better Health Within Reach. Accessed 2021

[5] Van de Schoot, R., Depaoli, S., King, R. et al. Bayesian statistics and modelling. Nat Rev Methods Primers 1, 1 (2021). https://doi.org/10.1038/s43586-020-00001-2

All Change for Female Hormones: Menopause

Issues with body temperature regulation that can disrupt sleep; joint and muscle pain; changeable mood (from low mood, to anxiety and anger); dry, itching skin all over the body (yes, I mean everywhere!); brain fog. These are just some of the symptoms that can disrupt your life and your relationships with family and friends. There is also the accompanying increased risk of cardiovascular disease and osteoporosis.

Understanding the menopause

The underlying cause for all of these problems is not a disease process. The menopause is a normal physiological event that occurs in every woman during her life. On average the age of menopause is 51 years, however, it can occur a couple of years either side of this. In the years leading up to the menopause, the perimenopause, the ovaries start to lose responsiveness, resulting in a decline in the female ovarian hormones (oestradiol and progesterone). These reducing hormone levels can cause women to experience some of the issues above, as well as changes in the menstrual cycle. Cycles can become erratic in timing and nature, reflecting the variable rate of change in female hormone production during this stage in the female hormone journey. This perimenopause phase can vary in length, although ultimately when the ovaries shut up shop, periods cease and the ovarian hormones remain consistently low, signifying that menopause is reached.   

Whilst the menopause is a natural, expected physiological event, that does not mean that this part of a woman’s life is without challenges. Nor does this mean that women should resign themselves, or indeed accept a reduced quality of life. With increasing life expectancy, women may spend at least a third of their lives in the menopausal state. A couple of hundred years ago, even if they survived childbirth, not many women reached the age of menopause. Today, far more women than ever before will experience the consequences of low female hormones that comes with menopause, potentially for 30 years or more of their lives.

Menopause is a significant point a woman’s life from a physical and psychological point of view. Even if she has made an active decision not to have children, menopause closes the chapter on this possibility. It can also be a time of life where things are changing: “children” have grown up and are leaving home, parents are getting older and new work colleagues seem to look very young. It can seem overwhelming, when these events coincide with the seismic changes in female hormones, that are impacting physical and mental wellbeing.

Talking about the menopause

As a woman and a female doctor, having experienced all the calling points of the female hormone journey, I am passionate about explaining the complexities of hormones: how to recognise key changes in hormones and what to do from a practical point of view. Including the menopause as part of the discussion of puberty and menstrual cycles at school (for boys and girls) would mean everyone has at least heard the word “menopause” from a young age. This would help make future conversations less challenging, where “the change” is only whispered amongst our grandmothers. Certainly, when I have been invited to make presentations and speak with teenagers, they have been interested to hear to full story of hormones.

Medical doctors have an important part to play in disseminating accurate information and supporting women through this hormone journey. There are some excellent resources for both non-medically qualified and medical professionals such as the British Menopause Society and Women’s Health Concern[1], Royal College of Obstetrics and Gynaecology[2] and the NICE guidelines[3]. These include advice and current best clinical practice for everyone to peruse. Framing questions empathetically is crucial. Some may be reticent to talk about vaginal dryness. Menopause should not be a source of embarrassment; it is the expected, normal physiology of hormones. Each of us will experience this differently.

As a female doctor, with the time of my menopause approaching, I had done my due diligence on this topic. I had read in detail the excellent resources I mentioned above. Nevertheless, experiencing those symptoms listed at the start of this blog, I appreciated that this would be an even more disconcerting and indeed a very frightening experience, if I did not know that my hormones were changing in a normal and expected way. Fortunately, having done my research based on these open access resources above, I knew that hormone replacement therapy (HRT) would help as HRT improves quality of life and all-cause mortality (death from all causes).

Researching the dose and form of HRT from these resources, it made logical sense that my body would appreciate exactly the same molecular structure of hormones that I had been producing myself to date. Taking oestradiol transdermally, through the skin, avoids any entanglement with the liver. Gel was a more attractive, discrete proposition that a patch. For the progesterone component of HRT (which is a must unless you have had a hysterectomy) micronised progesterone fitted the description of being the same molecular structure as body produced. The extra bonus is that this exact, optimal form of HRT is available on the NHS in a licensed and regulated format. Having no contraindications for HRT, I was left in no doubt that this form of HRT would be what to ask my GP about.

Countering misinformation

In an editorial published in the British Medical Journal, Professor Janice Rymer, Vice President of the Royal College of Obstetrics and Gynaecology, presented unequivocal evidence about the misinformation surrounding HRT, which risks further damaging setbacks for women’s health[4].

It is tragic and bewildering that a replacement therapy that restores hormones to physiological levels and improves quality of life for women has been misrepresented. Sadly, the focus has been almost entirely on potential side effects, to the exclusion of the benefits of improving health and quality of life. After all, there seems to less reluctance giving testosterone replacement to men.

For younger women there are no qualms about giving supraphysiological doses of hormones, in non-molecular identical forms, found in many combined oral contraceptive pills to supress internal hormone production (ironically supressing oestradiol and progesterone to the low levels seen in menopause). The combined oral contraceptive pill continues to be given, in some cases, to those women with functional hypothalamic amenorrhoea (FHA), where this practice is advised against by the Endocrine Society[5].  

In conclusion I think the underlying issue is that, despite inspiring advances across many fields, there continues to be the pervasive perception that female hormones are solely about fertility. Whilst there is no denying that this is the evolutionary purpose of ovulation, female hormones are crucial to all aspects of health. This applies whatever the age of a woman.     

References


[1] British Menopause Society & Women’s Health Concern 2020 recommendations on hormone replacement therapy in menopausal women. https://thebms.org.uk/publications/consensus-statements/bms-whcs-2020-recommendations-on-hormone-replacement-therapy-in-menopausal-women/

[2] Royal College Obstetrics and Gynaecology website “Menopause and women’s health in later life” for patients

[3] National Institute of Clinical Excellence. Menopause: Diagnosis and Management Update 2019.

[4] Janice Rymer, Kate Brian, Lesley Regan. HRT and breast cancer risk. Editorial BMJ 2019;367:l5928 doi: 10.1136/bmj.l5928 (Published 11 October 2019)

[5] Gordon C, Ackerman K, Berga S et al Functional hypothalamic amenorrhea: An endocrine society clinical practice guidelineJournal of Clinical Endocrinology and Metabolism (2017) 102(5) 1413-1439

Energy Availability in Dancers

Here I discuss the findings from our recent study: Indicators and correlates of low energy availability in male and female dancers [1]. Thanks to my co authors and all the dancers who made this important study possible. I personally paid for open access to the entire paper so you and the whole dance community can read the full details.

Dance v Sport

Dance and Sport…plus ça change

There are many similarities between dancers and athletes, in terms of the physical and mental demands of training and performance. In both disciplines, training starts from a young age to hone technical skills. Dance, in particular, shares many of the challenges of aesthetic sports. In some ballets, the visual appearance of the corps de ballet is essential to the story line. In La Bayadere, the warrior sees in a dream multiple images of his true love, the dead temple dancer. In Swan Lake the corps de ballet moves like a flock of birds and in Les Sylphides the corps de ballet portrays ethereal spirits.

Furthermore, in dance and certain sports low body weight is perceived to confer a performance advantage. This is not just for aesthetics, but also to meet the technical dance demands of elevation and pointe work, where the whole of a dancer’s body weight goes through the first metatarsal joint (big toe joint). Indeed, the spotlight was on dancers in some of the early studies on the potential incidence and consequences of low energy availability [2]. However, since initial studies in dancers, the focus has been on athletes involved in sport, culminating in the International Olympic Committee (IOC) consensus statement published in 2014 on relative energy deficiency in sport (RED-S). As the name RED-S indicates, sport is the focus of this clinical syndrome describing the clinical consequences of low energy availability on health and performance [3].

What’s new in dance?

Whilst there are clearly parallels with dance and sport, there are equally some fundamental differences from cultural and organisational perspectives. Furthermore, the demands of dance have changed dramatically over just two generations. The illustration shows my grandmother from 1920s, with loose fitting costume, en pointe on two feet with a “romantic” interpretation, who was invited to join the legendary Dame Ninette De Valois and her company. This contrasts to her granddaughter (me!) at about the same age from 1980s, wearing a tight fitting, shorter length tutu, en pointe on one leg and portraying a different style of ballet.

1920s my grandmother v 1980s granddaughter (me!)

Relative Energy Deficiency in Dance
To explore the current situation of low energy availability in the dance community against the backdrop of these changes in demands, we conducted a study of dancers worldwide to assess indicators and correlates of low energy availability. Building on the sport specific energy availability questionnaire [4], we developed a dance specific version to ensure engagement with dancers [1].

The key findings from this survey of 247 dancers found that 57% of female dancers and 27% of male dancers were at risk of RED-S. Psychological factors are recognised to play a part in both the cause and consequences of RED-S. From our study of dancers a significant cluster of psychological interrelationships was found. Dancers who rated control of eating as important, also did so for control of body weight as well as expressing anxiety about missing training. In order to be a successful dancer, self-discipline and self-motivation are undoubtedly important. However, in contrast to dancers from previous generations the pervasive pressure from social media is ever increasing, alongside perceived dance specific demands of being of a certain weight to gain leading roles.

Strikingly, significant relationships were found between these psychological factors and physical and physiological indicators of low energy availability, including low body weight and menstrual dysfunction.

That is not to say that dancing is an inherently an “unhealthy” pursuit. Far from it: dance has been shown to have beneficial effects on both physical and mental wellbeing, both from a participant and an audience point of view. Dance goes beyond the dimension of physical performance, calling upon musicality, expression and acting. This is why an important message from this study is to raise awareness about misperceptions about body weight, in order to support optimal dance performance. Rather, anxiety about body weight can have negative consequences on physical and mental health, and ultimately impair dance performance. Raising awareness about low energy availability and relative energy deficiency in dance and sport was the rationale for writing the British Association of Sport and Exercise Medicine open access, educational website [5]

The other important message from this study is that early identification of aspiring male and female dancers at risk of developing the clinical consequences of relative energy deficiency in dance could be possible with a dance specific questionnaire used in this study. As with participation in sport, early identification is crucial as a proactive, preventative measure. In other words, keeping in step with the increasing demands of dance in a changing world, rather than relying on reactive measures to deal with the ensuing mental and physical injuries of relative energy deficiency in dance.

The pandemic has impacted everyone. This includes professional dancers and athletes. Whilst the return of professional athletes to some competition has been facilitated, theatres where dancers perform remain shut. These are unprecedented, challenging times for dancers. On the other hand, this does offer the opportunity to plan for ways to ensure future generations of healthy dancers with sustainable careers.

References

1 Keay N, Overseas A, Francis G. Indicators and correlates of low energy availability in male and female dancers BMJ Open Sport & Exercise Medicine 2020;6:e000906. doi: 10.1136/bmjsem-2020-000906

2 Keay N, Fogelman I, Blake G Bone mineral density in professional female dancers. British Journal of Sports Medicine 1997;31:143-147

3 Keay N, Francis G Infographic. Energy availability: concept, control and consequences in relative energy deficiency in sport (RED-S) British Journal of Sports Medicine 2019;53:1310-1311.

4 Keay N, Francis G, Hind K 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 BMJ Open Sport & Exercise Medicine 2018;4

5 www.health4performance.co.uk BASEM educational website

Online Courses for High Performing Female Athletes

Courses for Coaches and Athletes

Coaching High Performing Female Athletes

Training as a High Performing Female Athlete

Increasing numbers of women are participating in exercise and sport. However this has not been matched by female specific research, education and implementation of practical strategies to optimise female health and performance.

Does this matter? Absolutely as there are crucial physiological differences between females and males. To date the majority of clinical medicine, sport science and coaching strategies are based on a blueprint for men.

The result is that female athletes are at risk of not optimising their health and therefore unable to reach their personal full athletic potential.

The most obvious and important difference between men and women on a medical and physiological basis is that women have menstrual cycles, where there are considerable fluctuations of female hormones. So any discussion of exercise training, nutrition and recovery for female athletes has to factor in this fundamental physiological process.

I have developed a suite of courses to support female athletes and their coaches in their quest to optimise health and performance. These courses provide up-to-date, evidence-based information and practical strategies. The objective is to help female athletes become resilient and sustainable athletes in the long term, enabling each individual to to achieve her personal full potential.

There are 2 courses:

Course for coaches working with high performing female athletes from puberty and beyond, across all sports. This course is endorsed by the British Association of Sport and Exercise Medicine. The course includes lectures, interviews with an Olympic coach and a former international female athlete, quizzes and resources. The material covers female physiology; practical strategies of training, nutrition and recovery to optimise health and performance; warning signs to look out for in the case of imbalances, with particular reference to relative energy deficiency in sport (RED-S). Successful completion of he course and reaching pass mark for the quizzes results in a certificate of completion. Link to coach course

Course for high performing female athletes covers female physiology from puberty onwards; training schedule strategies covering training load, nutrition and recovery; risk of relative energy deficiency in sport (RED-S): what to look out for and what to do. There are also interviews with an Olympic coach and a former international female athlete. Link to athlete course

Coach Course Endorsed by BASEM

References

N. Keay “Of Mice and Men” British Journal of Sport Medicine 2019

Thyroid Function in Athletes and Dancers

Now is a good time to revisit a topic discussed in a previous BJSM blog (1), to coincide with guidelines on the management of thyroid disease released by National Institute of Clinical Excellence (NICE) in November 2019 (2) and summarised in the British Medical Journal (BMJ) last month (3).

It has transpired that athletics coach Alberto Salazar facilitated the clinically inappropriate prescription of thyroxine to some of his euthyroid athletes. Thyroxine is not on the World Anti-Doping Agency’s (WADA) banned list, nevertheless as we shall discuss below, administering thyroxine to those with normal thyroid function potentially can have adverse consequences on health and performance. Salazar was banned for four years on the grounds outlined by United States Anti Doping Agency (USADA) (4), falling into three areas: use of a prohibited method (with infusion in excess of the limit), tampering with the doping control process, and trafficking of testosterone.

Recap of thyroid axis

In common with many endocrine axes, the thyroid axis works on a negative feedback loop mechanism to maintain homeostasis of circulating levels of the response hormone thyroxine (T4) in the normal range. TSH (thyroid stimulating hormone) is the control hormone released by the pituitary gland. TSH acts on the thyroid gland to release T4, which in turn is converted peripherally to the more active T3. As with all biological homeostatic mechanisms, there is some physiological variation within the normal range for an individual. Significant changes, beyond that expected from biological and analytical variation can be calculated using the system recently described in BMJ (5).

Screen Shot 2020-03-12 at 17.44.37

Significant patterns in thyroid function

Consecutively raised TSH levels, with paired levels of T4 below the normal range indicate primary hypothyroidism. Conversely, levels of TSH below the normal range with paired levels of T4 above the upper end of the normal range indicate an overactive thyroid. If the situation were that clear-cut, then this would be a very short blog. Needless to say, there are some situations requiring careful scrutiny. Subclinical hypothyroidism is the situation where TSH is raised above the upper end of the normal range, yet T4 remains in range. According to NICE guidelines thyroxine treatment is indicated where TSH >10 mlU/L on 2 occasions, 3 months apart OR in someone under 65 years of age, where TSH is raised above the reference range (but lower than 10 mlU/L) on 2 occasions, 3 months apart AND accompanied by symptoms of hypothyroidism. Furthermore, NICE advises that any treatment with thyroxine should be such that TSH is maintained in the normal range and NOT cause suppression of TSH, nor symptoms of thyrotoxicosis. Based on this clinical criteria, some athletes under Salazar were reportedly treated inappropriately with thyroxine. In other words, even when TSH was in the normal range and the athletes were in euthyroid status, in the absence of an indication of subclinical hypothyroidism, it appears that thyroxine was given in the belief that this might aid with maintaining low body weight, which could be a performance advantage. Nevertheless, WADA does not consider thyroxine to confer a performance advantage, which is why this hormone is not on the banned list.

Screen Shot 2020-03-12 at 17.44.23However, treatment with thyroxine, which is not warranted on clinical grounds, can potentially have adverse effects on health, for example, increased risk of cardiac arrhythmias. Moreover, it is well documented that thyrotoxicosis is a risk factor for bone fracture in the long term. In the short term, stress fractures in athletes are recognised as a consequence of low energy availability (6), which is the underlying aetiology of relative energy deficiency in sport (RED-S) (7). Increased metabolic rate as a consequence of endogenous or exogenous excess thyroxine could theoretically lead to a situation of unintentional low energy availability and the adverse clinical sequalae of RED-S.

“Non thyroidal illness”/ “sick euthyroid”

This is characterised by low-end range TSH and T4. In other words, the negative feedback loop to maintain hormone homeostasis is not functionally normally. This situation is seen in functional hypothalamic-pituitary-endocrine gland suppression: for example, in athletes and dancers with the clinical syndrome of RED-S. In female athletes RED-S often presents as functional hypothalamic amenorrhoea, with low FSH and LH (in the presence of normal prolactin) and low oestrogen. As part of the adaptive response to the situation of low energy availability, metabolic rate is down-regulated to “save energy” (8) characterised by low-end range TSH, T4 and T3 (9). In such a situation, giving exogenous thyroxine will override this physiological response to down regulate metabolic rate and potentially increase energy deficit.

The psychological and physical pressures experienced by athletes and dancers can sometimes have reversible impacts on the hypothalamic-pitutary-thyroid axis, as seen in RED-S. On the other hand, athletes and dancers can also experience medical conditions, which impact this endocrine axis requiring appropriate treatment in line with medical guidelines. The recognition of these different situations provides insights and a deeper understanding of overall endocrine function in this athletic population.

References

1 Keay N. Fatigue, sport performance and hormones….more on the endocrine system. Posted on May 25, 2017 by BJSM

2 Thyroid disease: assessment and management NICE guideline [NG145]Published date: November 2019

3 Thyroid disease assessment and management: summary of NICE guidance BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m41 (Published 29 January 2020) Cite this as: BMJ 2020;368:m41

4 AAA Panel Imposes 4-Year Sanctions on Alberto Salazar and Dr. Jeffrey Brown for Multiple Anti-Doping Rule Violations September 2019 USAD 

5 Your results may vary: the imprecision of medical measurements BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m149 (Published 20 February 2020) Cite this as: BMJ 2020;368:m149

6 Heikura I, Uusitalo A, Stellingwerff T et al Low Energy Availability Is Difficult to Assess but Outcomes Have Large Impact on Bone Injury Rates in Elite Distance Athletes. International Journal of Sport Nutrition and Exercise Metabolism 2018; 28 (4), 403-11

7 Keay N. 2018 UPDATE: Relative Energy Deficiency in Sport (RED-S) Posted on May 30, 2018 by BJSM

8 Staal S, Sjödin A, Fahrenholtz I Low RMR ratio as a Surrogate Marker for Energy Deficiency, the Choice of Predictive Equation Vital for Correctly Identifying Male and Female Ballet Dancers at Risk International Journal of Sport Nutrition and Exercise Metabolism 2018

9 Ihle R, Loucks A Dose-response relationships between energy availability and bone turnover in young exercising women Journal of Bone and Mineral Research (2004) 19(8) 1231-1240

“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

 

 

 

RED-S Research: Bones and Ballet

BJSM Blog 26/8/2019

Dr Nicky Keay

BJSMThere are many areas of RED-S (relative energy deficiency in sport) that are currently being researched. Whilst there is animated discussion about scientific evidence for energy availability thresholds in men and women, in the clinical setting what are the most effective ways to identify and support these athletes and dancers at risk of the health and performance consequences of RED-S?

Bone stress injuries, including stress fractures and other complications of suboptimal bone heath such as compression fractures are some of the most clinically significant sequalae of low energy availability described in the RED-S (relative energy deficiency in sport) clinical model[i]. Suboptimal bone health with associated recurrent stress fractures can be career ending for athletes and dancers.

Therefore early identification of those with suboptimal bone health is crucial. In terms of identifying athletes/dancers at risk of developing bone health consequences due to RED-S, a sport specific questionnaire in male cyclists has been demonstrated to be effective[ii]. The purpose of identifying those at risk of suboptimal bone health is in order to put in place interventions, to prevent progression, and in some cases, improve bone health. Evidence for positive outcomes of these behavioural interventions are reported in male cyclists[iii].

Currently bone mineral density (BMD) is measured using DXA (dual X ray absorptiometry), which although low in dose, nevertheless involves ionising radiation. This limits the frequency of measurement, although bone is metabolically active and often one of first systems to change in response to low energy availability[iv]. The new technology of R.E.M.S. (Radiofrequency Echographic Multi Spectrometry) involves totally safe ultrasound. Furthermore this technology provides information on bone microarchitecture. Currently assessment of bone microarchitecture is only possible with pQCT (peripheral quantitative computerised tomography), which is not only involves a high radiation dose, furthermore is limited to assessment of peripheral skeletal sites. Although BMD is undoubtedly an important factor in determining bone health, nevertheless bone strength and structure also plays an important part.

Therefore the main objective of a forthcoming study[v] is to establish the effectiveness of identifying those at risk of suboptimal bone health with this new specialised ultrasound based technology and correlate with questionnaire and blood markers in both athletic and non athletic populations.

Ballet and other Dance forms

RED-S is more prevalent in sports where being of low body weight confers a performance or aesthetic advantage. Although dance is not a sport, nevertheless this type of activity requires low body weight from both a performance and aesthetic point of view for both male and female dancers. Dance training often starts at a young age[vi] and as with early sport specialisation, there is an increased risk of developing low energy availability during this time of high-energy demand for growth and development[vii]. So much so, that this situation can have a negative impact on accumulation of peak bone mass and adverse potential long-term effects[viii].

Although there is a validated questionnaire LEAF-Q[ix] for assessing low energy availability in female athletes, this excludes half the population and is not sport specific. A questionnaire-based study amongst female athletes was found to be effective at identifying and quantifying the clinical consequences of low energy availability[x]. Our recent study of competitive male road cyclists found that a sport specific energy availability questionnaire combined with interview (SEAQ-I)[xi] was the measured factor most effective in indicating low BMD of the lumbar spine. BMD of the lumbar spine is a quantifiable measure of chronic low energy availability. Other objective measures of low energy availability include indicators of endocrine function. In women menstrual function and in men testosterone, which in turn are clinked to the clinical outcome of impaired bone health and stress fracture in runners[xii]

To date there is a dearth of sport specific questionnaires to assess low energy availability and none that are dance specific. Dance involves both male and female and is certainly a type of activity where individuals are at risk of low energy availability and the clinical consequences of RED-S. Therefore the aim of the current dance study is to use a dance specific energy availability questionnaire (DEAQ)[xiii] to asses awareness, risk factors and consequences of low energy availability and RED-S.

References

[i] Mountjoy M, Sundgot-Borgen J, Burke L et al. IOC consensus statement on relative energy deficiency in sport (RED-S): 2018 update British Journal of Sports Medicine 2018; 52(11): 687-697 DOI: 10.1136/bjsports-2018-099193

[ii] Keay N, Francis G, Hind K. 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 BMJ Open Sport and Exercise Medicine 2018; 4(1) DOI: 10.1136/bmjsem-2018-000424

[iii] Keay N, Francis G, Entwistle I et al. Clinical evaluation of education relating to nutrition and skeletal loading in competitive male road cyclists at risk of relative energy deficiency in sports (RED-S): 6-month randomised controlled trial BMJ Open Sport and Exercise Medicine 2019; 5(1) DOI: 10.1136/bmjsem-2019-000523

[iv] Professor Louise Burke presenting at annual ISENC conference Newcastle 2018

[v] Assessment of Echographic Technology in Measuring Bone Health in the Clinical Setting

[vi] N. Keay. Dancing through adolescence British Journal of Sports Medicine 1998 DOI: 10.1136/bjsm.32.3.196

[vii] N. Keay. The modifiable factors affecting bone mineral accumulation in girls: The paradoxical effect of exercise on bone Nutrition Bulletin 2000 DOI: 10.1046/j.1467-3010.2000.00051.x

[viii] N. Keay, G.Blake, I. Fogleman.  Bone mineral density in professional female dancers British Journal of Sports Medicine 1997; 31(2): 143-147

DOI: 10.1136/bjsm.31.2.143

[ix] Melin A, Tornberg Å, Skouby S et al. The LEAF questionnaire: A screening tool for the identification of female athletes at risk for the female athlete triad British Journal of Sports Medicine 2014: 48 (7)

[x] K. Ackerman, B. Holtzman et al. Low energy availability surrogates correlate with health and performance consequences of Relative Energy Deficiency in Sport British Journal of Sports Medicine 2018; 53(10) 628-633

DOI: 10.1136/bjsports-2017-098958

[xi] N. Keay, G. Francis, K. Hind. 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 BMJ Open Sport and Exercise Medicine 2018 4(1) DOI: 10.1136/bmjsem-2018-000424

x Heikura I, Uusitalo A, Stellingwerff T et al. Low energy availability is difficult to assess but outcomes have large impact on bone injury rates in elite distance athletes, International Journal of Sport Nutrition and Exercise Metabolism 2018; 28(4): 403-411 DOI: 10.1123/ijsnem.2017-0313

[xiii] DEAQ Dance Energy Availability Questionnaire on line with ethical approval from Durham University

Energy Availability: Concept, Control and Consequences in relative energy deficiency in sport (RED-S)

Relative energy deficiency in sport (RED-S) is an issue of increasing concern in sports and exercise medicine. RED-S impact exercisers of all levels and ages, particularly where low body weight confers a performance or aesthetic advantage. Key to mitigating adverse health and performance consequences of RED-S is supporting athletes and dancers to change behaviours. These infographics aim to assist clinicians in communicating the concepts to exercisers and in implementing effective management of athletes in their care[1].

Slide1

Figure 1 illustrates the concept of energy availability (EA) in RED-S. Preferentially energy derived from dietary intake covers the demands of training and the remaining energy, EA, is, quantified in Kcal/Kg of fat free mass[2]. In Figure 1, the central bar illustrates adequate EA in an athlete where energy intake is sufficient to cover the demands of training and fundamental life processes to maintain health. Conversely, low energy availability (LEA) is a situation of insufficient EA to cover basic physiological demands. LEA leads to the adverse consequences of RED-S[3]. LEA can arise unintentionally or intentionally, due to a mismatch between energy intake and energy requirement. In Figure 1 the bar on the left shows LEA resulting from reduced energy intake with maintained training load. On the right, LEA is a consequence of increased training load with maintained energy intake.

Figure 2 illustrates that EA is under the control of an athlete[4]. The three behaviours relating to training, nutrition and recovery determine EA. Integrated periodisation of these behaviours results in optimal health and performance. Conversely, an imbalance in these behaviours results in suboptimal functionally. LEA in the case of high training loads relative to nutritional intake. Thus, this figure reinforces the important point in the IOC statements on RED-S that psychological factors which determine these behaviours are key in both the development, continuation and management of RED-S[2,3].

Slide1

Figure 2 also shows the temporal, synergistic effect of these behaviours to ensure a fully functioning endocrine system. Hormones are key for health and to drive positive adaptations to exercise, to improve athletic performance. Thus hormones can be informative in tracking the response of an individual to these three input variables. Furthermore, endocrine markers relate to the RED-S clinical outcome of stress fracture in athletes, being more reliable as objective, quantifiable indicators of EA than numerical calculation of EA from direct assessment[5].

Authors

Nicola Keay1, Gavin Francis2

1 Department of Sport and Exercise Sciences, Durham University

2 Science4Perforamnce, London

Br J Sports Med 2019;0:1–2. doi:10.1136/bjsports-2019-100611

References

1 http://health4performance.co.uk (accessed 21/01/2019) Health4Performance Educational BASEM website raising awareness of RED-S Working group on RED-S British Association of Sport and Exercise Medicine 2018

2 Mountjoy M, Sundgot-Borgen J, Burke L et al. IOC consensus statement on relative energy deficiency in sport (RED-S): 2018 update Br J Sports Med2018;52(11):687-697

3 Mountjoy M, Sundgot-Borgen J, Burke L et al. The IOC consensus statement: beyond the Female Athlete Triad–Relative Energy Deficiency in Sport (RED-S). Br J Sports Med2014;48(7):491-7

4 Burke L, Lundy B, Fahrenholtz L et al, & Melin. Pitfalls of conducting and interpreting estimates of energy availability in free-living athletes. International Journal of Sport Nutrition and Exercise Metabolism2018; 28(4):350–363. https://doi.org/10.1123/ijsnem.2018-0142

5 2Heikura I, Uusitalo A, Stellingwerff T et al. Low energy availability is difficult to assess but outcomes have large impact on bone injury rates in elite distance athletes. International Journal of Sport Nutrition and Exercise Metabolism2018; 28(4):403–411. https://doi.org/10.1123/ijsnem.2017-0313

Relative Energy Deficiency in Sport (RED-S) and Dance

Relative energy deficiency in sport (RED-S)[1] is a clinical syndrome encompassing adverse health and performance (figure 1) consequences of low energy availability (LEA)[2] in male[3] and female exercisers of all ages and all levels from recreational to elite.

Slide1
Figure1 

LEA is a situation where energy intake is insufficient to cover the combined energy demands of training and baseline physiological processes to maintain health. LEA can arise unintentionally or intentionally (figure 2). Unintentional LEA results from increased training load, which is not matched by an increased energy intake. Intentional LEA is more likely to arise in sports where low body weight confers a performance or aesthetic advantage, for example, gravitational sports including cycling, ski-jumping, climbing; weight-category sports including boxing and judged artistic sports including gymnastics, aquatic disciplines. RED-S is also a risk in dancers of all genres, but in particular ballet[4]. Intentional LEA can be due to spectrum of disordered eating to eating disorders. The body responds to LEA by downregulating fundamental physiological processes. This ‘energy saving mode’ is of particular clinical significance in the endocrine network system (figure 3).

Slide1
Figure 2

For women, LEA can manifest itself as menstrual disruption, in men this corresponds to low testosterone. The net effects of dysfunctional endocrine feedback loops are adverse effects on health and dampened response to training stimuli. For example, endocrine dysfunction manifests as suboptimal bone health with increased risk of bone stress injuries. Increased duration of LEA accrues cumulative effects on endocrine networks and hence health and performance (figure 2). Although the exerciser may initially improve athletic performance with short-term LEA, long-term LEA will lead to deterioration in health and performance.

Slide1
Figure 3

Therefore, early identification of those at risk of LEA is essential in preventing the clinical consequences of RED-S. This is the purpose of the BASEM website Health4Performance[5] to raise awareness of RED-S among athletes/dancers, coaches, parents, friends and healthcare professionals to encourage a multidisciplinary team approach to identifying and supporting those at risk of RED-S.

Authors:

Dr Nicola Keay, Department of Sport and Exercise Sciences, Durham University, UK.

Dr Alan Rankin Department of Sports Medicine, Sport Ireland Institute, Dublin, Ireland

Br J Sports Med 2019;0:1–3. doi:10.1136/bjsports-2018-100354

References
1 Mountjoy M, Sundgot-Borgen J, Burke L, et al. The IOC consensus statement: beyond the Female Athlete Triad–Relative Energy Deficiency in Sport (RED-S). Br J Sports Med 2014;48:491–7.
2 Mountjoy M, Sundgot-Borgen JK, Burke LM, et al. IOC consensus statement on relative energy deficiency in sport (RED-S): 2018 update. Br J Sports Med 2018;52:687–97.
3 Keay N, Francis G, Hind K. 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. BMJ Open Sport Exerc Med 2018;4:e000424.
4 Keay N. Raising Awareness of RED-S in Male and Female Athletes and Dancers. Br J Sport Med blog 2018. https://blogs.bmj.com/bjsm/2018/10/30/raisingawareness-of-red-s-in-male-and-female-athletes-anddancers/ (accessed 19 Jan 2019).

5 Health4Performance. Educational BASEM website raising awareness of RED-S Working group on RED-S. BMJ Open Sport Exerc Med 2018. http:// health4performance.co.uk (accessed 19 Jan 2019).

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. To cite Keay N, Rankin A. Br J Sports Med Epub ahead of print: [please include Day Month Year]. doi:10.1136/ bjsports-2018-100354