One road to Rome: Metabolic Syndrome, Athletes, Exercise

One road to Rome

Metabolic syndrome comprises a cluster of symptoms including: hypertension, dyslipidaemia, fatty liver disease and type 2 diabetes mellitus (T2DM).

The underlying pathological process is insulin resistance which distorts metabolism. Temporal and mechanistic connections have been described between hyperinsulinaemia, obesity and insulin resistance. Insulin levels rise, potentially stimulated by excess intake of refined carbohydrates and in addition the metabolic actions of insulin are attenuated on target tissues such as the liver, skeletal muscle and adipose tissue. At a cellular level, inflammatory changes play a part in this metabolic dis-regulation. Mitochondrial action in skeletal muscle is impaired, compromising the ability to oxidise fat as a substrate, thus resulting in muscle glycolysis and a consequent rise in blood lactate.

Although much attention has been focused on restricting calories and treating elevated lipids with medication (statins), evidence is now emerging that this does not have the anticipated effect of reducing mortality from cardiovascular disease. In addition, it has been proposed that the gut microbiota plays a pivotal role in metabolism, inflammation and immunity.

Metabolic syndrome usually conjures an image of an overweight person with or on the verge of developing T2DM. However there is an interesting group of slim people who are also are at risk of developing metabolic syndrome due to insulin resistance. The majority of women with polycystic ovary syndrome (PCOS) present with menstrual disturbance of some description. However not all display the textbook characteristics of Stein-Leventhal syndrome (overweight, hirsute and with skin problems). There is in fact of spectrum of clinical phenotypes ranging from the overweight to the slim. In all phenotypes of PCOS, the crucial uniting underlying metabolic disturbance is insulin resistance. The degree of insulin resistance has been shown to be related to adverse body composition with increased ratio of whole body fat to lean mass.

Although this confuses the picture somewhat, it also simplifies the approach. In all cases the single most important lifestyle modification is exercise.

Exercise improves metabolic flexibility: the ability to adapt substrate oxidation to substrate availability. Endurance exercise training amongst athletes results in improved fat oxidation and right shift of the lactate tolerance curve. Conversely metabolic inflexibility associated with inactivity is implicated in the development of insulin resistance and metabolic syndrome.

What about nutritional strategies that might improve metabolic flexibility? Ketogenic diets can either be endogenous (carbohydrate restricted intake) or exogenous (ingestion of ketone esters and carbohydrate). Low carbohydrate/high fat diets (terms often used interchangeably with all types of ketogenic diets) have been shown to improve fat oxidation and potentially mitigate cognitive decline in older people.

However, in the case of athletes, the benefits do not necessarily translate to better performance. Despite reports of such diets enhancing fat oxidation and favourable changes in body composition, a recent study demonstrates that this, in isolation, does not translate into improved sport performance. A possible explanation is the oxygen demand of increased oxidation of fat needs to be supported by a higher oxygen supply. The intermediate group of endurance athletes in this study, on the periodised carbohydrate intake, fared better in performance terms. Another recent study confirmed that a ketogenic diet failed to improve the performance of endurance athletes, in spite of improving fat metabolism and body composition. Despite small numbers, this warrants particular mention as the majority of participants were women, who are in general very underrepresented in scientific studies.

In all likelihood, the reason that these type of diets (ketogenic, high fat/low carb: not always well defined!) did not improve sport performance is that only one aspect of metabolism was impacted and quantified. Although fat oxidation, modified via dietary interventions, is certainly an important component of metabolism, the impact on the interactive network effects of the Endocrine system should be evaluated in the broader context of circadian rhythm. For athletes this goes further, to include integrated periodisation of nutrition, training and recovery to optimise performance, throughout the year.

In addition to dietary interventions, medical researchers continue to explore the use of exercise mimetics and metabolic modulators, to address metabolic syndrome. Unfortunately, some have sought their use as a short cut to improved sport performance. Many of these substances appear on the WADA banned list for athletes. However the bottom line is that it is impossible to mimic, either through a dietary or pharmacological intervention, the multi-system, integrated interplay between exercise, metabolism and the Endocrine system.

Only one road to Rome!

Whatever your current level of activity, whether reluctant exerciser or athlete, the path is the same to improve health and performance. This route is exercise, supported with periodised nutrition and recovery. Exercise will automatically set in motion the interactive responses and adaptations of your metabolic and Endocrine systems.

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


Insulin action and resistance in obesity and type 2 diabetes Nature Medicine 2017

Inflammation: Why and How Much? Dr N. Keay, British Association of Sport and Exercise Medicine

The cholesterol and calorie hypotheses are both dead — it is time to focus on the real culprit: insulin resistance Clinical Pharmacist 2017

Skeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus Nature Reviews Endocrinology 2016

The essential role of exercise in the management of type 2 diabetes Cleveland Clinic Journal of Medicine 2017

β cell function and insulin resistance in lean cases with polycystic ovary syndrome Gynecol Endocrinol. 2017

The many faces of polycystic ovary syndrome in Endocrinology. Conference Royal Society of Medicine 2017

Association of fat to lean mass ratio with metabolic dysfunction in women with polycystic ovary syndrome Hum Reprod 2014

Sedentary behaviour is a key determinant of metabolic inflexibility Journal of physiology 2017

International society of sports nutrition position stand: diets and body composition J Int Soc Sports Nutr. 2017

A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer’s disease Exp Gerontol. 2017

Low carbohydrate, high fat diet impairs exercise economy and negates the performance benefit from intensified training in elite race walkers J Physiol. 2017

Ketogenic diet benefits body composition and well-being but not performance in a pilot case study of New Zealand endurance athletes J Int Soc Sports Nutr. 2017

Sports Endocrinology – what does it have to do with performance? Dr N. Keay, British Journal of Sports Medicine 2017

Hormones and Sports Performance

Endocrine system: balance and interplay in response to exercise training


Endocrine system: balance and interplay in response to exercise training

The process of homeostasis maintains a steady internal milieu. So how is it possible for adaptations to occur? What are the internal mechanisms that determine a good outcome versus a negative one?

Changes in the external environment, such as exercise training, challenge homeostasis, producing spatial and temporal responses in the internal environment. These cause interactions between muscle, bone and gut, modulated by the Endocrine system. The degree and nature of these responses dictate whether a positive adaptation occurs. An excessive response, or a response not in tune with the networks of the Endocrine system, can hinder adaptation or produce a maladaptive response. The balance and interplay of internal responses are crucial in determining the outcome to exercise training in the individual.


Local responses in exercising tissues

Exercising tissues release exerkines (metabolites, nucleic acids, peptides) which are packaged in exosomes and microvesicles. The content of these vesicle packages increases with intensity of endurance exercise in a dose-dependent manner. These exerkines have autocrine and paracrine effects, which modulate systemic adaptations to endurance exercise in the tissues themselves and those in the vicinity.

The range of these molecular responses from exercising tissues has been identified applying multi-omics (epigenomic, transcriptomic and proteomic analyses). Furthermore variance in trainability has been shown to be correlated with the integrated responses of tissue molecular signalling pathways to endurance exercise.

In a similar manner, the degree of inflammatory response and production of reactive oxygen and nitrogen species (RONS) to exercise mediate favourable adaptations. Inter-individual variations in redox status has been shown to determine the ability to adapt to exercise training. However, unlimited increase in response does not necessarily produce a better outcome. An over response to exercise in these signalling pathways, hinders adaptation.

Exercise promotes bone adaptation in terms of bone material, structure and muscle action. Paracrine crosstalk occurs between muscle and bone. Muscle myokines and insulin like growth factor 1 (IGF1) favour bone formation, whilst inflammatory molecules, such as interleukin 6 (Il-6) released during muscle contractions, favour bone reabsorption. The balance between these opposing processes determines whether bone remodelling is effective, or whether bone stress reactions occur over a pathological continuum. These responses and adaptations occur on the background of lifespan Endocrine environment, which impacts the outcome.

Gut microbiota

The gut microbiota support the regulation of inflammation at the local and systemic level. Furthermore the communication between the gut microbiota and mitochondria has been described as an important interaction in facilitating adaptive responses to exercise. Mitochondria are organelles crucial for production of ATP, as well as RONS. The gut microbiota are involved in mitochondrial biogenesis by regulating key mitochondrial transcriptional factors and enzymes . Furthermore, the metabolites of the gut microbiota such as short chain fatty acids, modulate the inflammatory effects of mitochondrial oxidative stress. Conversely genetic variants in the mitochondrial genome could impact mitochondrial function and thus the gut microbiota in terms of composition and activity.

The gut microbiota have a role in regulating intestinal permeability. Leaky gut is where epithelial integrity is lost at the tight junctions between cells in the gut lining. Leaky gut can occur in gut dysbiosis and also following endurance exercise where re-perfusion injury produces acute hyper-permeability. In these instances, increased gut permeability augments the antigen load and causes increased systemic inflammation and potentially can trigger autoimmune disease. This demonstrates that an excessive inflammatory response to exercise can hinder positive adaptation

Metabolic adaptations

Metabolic flexibility, the ability to respond and adapt to changes in metabolic demand, is enhanced with exercise training through these autocrine, paracrine and Endocrine mechanisms. Metabolic flexibility supports energy availability and fuel selection during exercise. Exercise mimetics, such as artificial metabolic modulators, have been reported to up-regulate gene expression to shift metabolism to fat oxidation in exercising muscle. This would potentially extend the limit of endurance exercise. However this “short cut” to adaptation favouring improved sport performance is illegal, with such molecular ligands on the World Anti-Doping Agency (WADA) banned list.

Hierarchy of control

There is a hierarchy of control in modulating multi-system adaptations to exercise. The Endocrine system is key. Exercise per se produces an Endocrine response, for example exercise is a key stimulus for growth hormone release via the hypothalamus, the neuroendocrine gatekeeper. Growth hormone supports the anabolic response to exercise. In addition, the Endocrine milieu during the lifespan has an impact on response and adaptations to exercise. Any disruption in the Endocrine system hinders adaptive changes. Endocrine dysfunction may occur as a result of non-integrated periodisation of exercise/nutrition and recovery as seen in relative energy deficiency in sports (RED-S). Dysfunction can also occur due to an Endocrine pathology.


Changes in external stimuli, such as exercise and nutrition, produce internal responses on autocrine, paracrine and Endocrine levels. These molecular signalling pathways drive adaptive changes through integrated, network effects. However any imbalances in these interactive responses can hinder desired adaptive changes and even result in negative maladaptive outcomes to exercise training.

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


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.

Sport Endocrinology presentation London 7/7/2017

Sports Endocrinology – what does it have to do with performance? Dr N.Keay, British Journal of Sport Medicine

Balance of recovery and adaptation for sports performance Dr N.Keay, British Association of Sport and Exercise Medicine

Inflammation: Why and How Much? Dr N.Keay, British Association of Sport and Exercise Medicine

Clusters of Athletes – A follow on from RED-S blog series to put forward impact of RED-S on athlete underperformance  Dr N.Keay, British Association of Sport and Exercise Medicine

Optimal Health: For All Athletes! Part 4 – Mechanisms Dr N.Keay, British Association of Sport and Exercise Medicine

The potential of endurance exercise-derived exosomes to treat metabolic diseases Nature Reviews Endocrinology

Exosomes as Mediators of the Systemic Adaptations to Endurance Exercise Cold Spring Harbor Perspectives in Medicine

Genomic and transcriptomic predictors of response levels to endurance exercise training
Journal of Physiology

Adaptations to endurance training depend on exercise-induced oxidative stress: exploiting redox inter-individual variability Acta Physiologica

Mechanical basis of bone strength: influence of bone material, bone structure and muscle action Journal of Musculoskeletal and Neuronal Interactions

The Crosstalk between the Gut Microbiota and Mitochondria during Exercise Frontiers in Physiology

Leaky Gut As a Danger Signal for Autoimmune Diseases Frontiers in Immunology

Metabolic Flexibility in Health and Disease Cell Metabolism

Hormones and Sports Performance

PPARδ Promotes Running Endurance by Preserving Glucose Cell Metabolism


Inflammation: why and how much?

Inflammation: optimal or overreaction

Systemic autoimmune disease is a chronic overreaction of the inflammatory system. Exercise training is structured to provoke the optimal level of inflammation for adaptation to facilitate sport performance. This blog describes some of the recent significant advances in the understanding of the underlying mechanisms of inflammation and its interactions with the endocrine system, immunity and the microbiome, in relation to autoimmune disease. Applying this knowledge to the adaptive inflammatory effects of training in sport represents a potentially hugely beneficial area of future research.

The ubiquitous microbiomea-muciniphila-233x300

There has been much discussion on the key role of the microbiome, eloquently described by Professor Tim Spector, Professor of Genetic Epidemiology, King’s College, London at recent conferences at the Royal Society of Medicine and The Royal College of Physicians. The microbiome is the DNA of all the microbes in our body. The diversity of the microbiota community in the gut wall of the colon appears to have the most profound effects in terms of disease prediction and indeed a better indicator of developing autoimmune conditions (such as inflammatory bowel disease and rheumatoid arthritis) and metabolic conditions (such as obesity and diabetes mellitus) than our own DNA. So how does the diversity of the gut microbiome have such a profound impact?

It appears that in order to promote diversity of the gut micobiota, prebiotics such as inulin found in fibrous foods should be ingested and then “fertilised” with probiotics found in fermented foods. Enhancing the diversity of the gut microbiome supports the production of short-chain fatty acids which have far reaching influences on epigenetic and immune regulation, the brain, gut hormones and the liver. Furthermore, the diurnal rhythmic movement of the gut microbiota have been shown to regulate host circadian epigenetic, transcriptional and metabolite oscillations which impacts host physiology and disease susceptibility.

In inflammatory conditions such as autoimmune disease, a decrease in the diversity of “good” microbiota has been described. Furthermore, if a decrease in beneficial microbiota is the primary event, then this can lead to an increase in the likelihood of developing autoimmune disease. What is the mechanism of this dynamic interaction between the microbiome and immunity?

Immunity and inflammation

In recent research, the protein receptor marker of microbiota in the gut has been shown to modulate intestinal serotonin transporter activity. Serotonin (5-hydroxytryptamine 5-HT) has shown to be an essential intestinal physiological neuromodulator that is also involved in inflammatory bowel disease. In addition, an increase in inflammatory cytokines such as interleukin 6 and tumour necrosis factor alpha, is know to be associated with low levels of cerebral serotonin and dopamine. The causal link between disrupted immune function and increased inflammation, as in autoimmune disease, is an unfavourable microbiome. Development of autoimmune disease is often multifactorial, for example,  a change in the microbiome might trigger gene expression with adverse effects. Indeed gene expression (independent of sex steroids) has been shown to account for increased prevalence of autoimmune disease in women.

Depression of serotonin levels

Low levels of the neurotransmitter serotonin are know to be linked to depression. Hence prescription of selective serotonin uptake inhibitors to those suffering with depression. However recent research has now revealed a dynamic interaction between peripheral and cerebral effects of the microbiome on immunity and mood, mediated via the circadian release of key hormones such as serotonin. Serotonin is synthesised from precursor tryptophan in the gastrointestinal tract and central nervous system. Low mood in autoimmune disease could be due to psychological factors: knowing that this is a chronic condition with reduced life expectancy. Reduced serotonin, may be a further biochemical reason. Potentially lack of sleep due to pain in autoimmune disease would also suppress serotonin levels.

Applications for microbiome/immunity/inflammation interactions

How will these findings from recent research help in optimising inflammatory mediated adaptations to exercise training and support the understanding and treatment of autoimmune disease? It has been suggested that serotonin could be a treatment for rheumatoid arthritis, as 5HT appears to have a peripheral immuno-regulatoty role in the pathophysiology of this autoimmune disease. Optimising the microbiome, with prebiotics and probiotics, may improve disease activity and improve response to treatment with biologics.

Is the nature of an autoimmune disease such as rheumatoid arthritis (RA) changing? Deformed hands with swollen joints were a perennial favourite for medical examinations. However as described recently at a conference at Royal College of Physicians, although joint destruction is still a feature of RA, this seems to be accompanied by less joint swelling and involvement of greater range of joints. Are the triggers changing rather than a change in the nature of disease? How do nutrition and medication impact the microbiome?

For athletes, apart from periodising energy requirements and micronutrients to support training, encouraging a diverse microbiome will potentially support adaptive changes to training.

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


Balance of recovery and adaptation for sports performance. Dr N. Keay, British Association of Sports and Exercise Medicine

Sleep for health and sports performance. Dr N. Keay, British Journal of Sport and Exercise Medicine

Conference Royal Society of Medicine. “Food: the good, the bad and the ugly” 1/2/17

“Food, microbes and health” Professor Tim Spector, Professor of Genetic Epidemiology, King’s College, London

“Nutrition and the gut: food as trigger for disease; food as medicine” Dr Charlie Lees, Chair Scottish Society of Gastroenterology IBD Interest Group. European Crohn’s and Colitis Organisation Committe

“Nutrition and its effect on the immune system” Dr Liam O’Mahony, Head of Molecular Immunology, swiss Institute of Allergy and Asthma Research

Advanced Medicine Conference. Royal College of Physicians 13-16 February 2017

” The gut microbiome clinical and physiological tolerance” Professor Tim Spector, Professor of Genetic Epidemiology, King’s College, London

“Rheumatoid arthritis-ensuring everyone gets the best treatment” Dr Neil Snowden

Microbiota Diurnal Rhythmicity Programs Host Transcriptome Oscillations Cell Volume 167, Issue 6, p1495–1510.e12, 1 December 2016

Intestinal Serotonin Transporter Inhibition by Toll-Like Receptor 2 Activation. A Feedback Modulation. Eva Latorre , Elena Layunta, Laura Grasa, Marta Castro, Julián Pardo, Fernando Gomollón, Ana I. Alcalde †, José E. Mesonero. Published: December 29, 2016

A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases. Yun Liang, Lam C Tsoi, Xianying Xing, Maria A Beamer, William R Swindell, Mrinal K Sarkar, Celine C Berthier, Philip E Stuart, Paul W Harms, Rajan P Nair, James T Elder, John J Voorhees, J Michelle Kahlenberg & Johann E Gudjonsson
Nature Immunology 18, 152–160 (2017)

Serotonin Is Involved in Autoimmune Arthritis through Th17 Immunity and Bone Resorption. Yasmine Chabbi-Achengli, Tereza Coman, Corinne Collet, Jacques Callebert, Michelangelo Corcelli, Hilène Lin, Rachel Rignault, Michel Dy, Marie-Christine de Vernejoul, Francine Côté. The American Journal of Pathology. April 2016 Volume 186, Issue 4, Pages 927–937

Optimal health: for all athletes! Part 4 Mechanisms

As described in previous blogs, the female athlete triad (disordered eating, amenorrhoea, low bone mineral density) is part of Relative Energy Deficiency in sports (RED-S). RED-S has multi-system effects and can affect both female and male athletes together with young athletes. The fundamental issue is a mismatch of energy availability and energy expenditure through exercise training. As described in previous blogs this situation leads to a range of adverse effects on both health and sports performance. I have tried to unravel the mechanisms involved. Please note the diagram below is simplified view: I have only included selected major neuroendocrine control systems.


Low energy availability is an example of a metabolic stressor. Other sources of stress in an athlete will be training load and possibly inadequate sleep. These physiological and psychological stressors input into the neuroendocrine system via the hypothalamus. Low plasma glucose concentrations stimulates release of glucagon and suppression of the antagonist hormone insulin from the pancreas. This causes mobilisation of glycogen stores and fat deposits. Feedback of this metabolic situation to the hypothalamus, in the short term is via low blood glucose and insulin levels and in longer term via low levels of leptin from reduced fat reserves.

A critical body weight and threshold body fat percentage was proposed as a requirement for menarche and subsequent regular menstruation by Rose Frisch in 1984. To explain the mechanism behind this observation, a peptide hormone leptin is secreted by adipose tissue which acts on the hypothalamus. Leptin is one of the hormones responsible for enabling the episodic, pulsatile release of gonadotrophin releasing hormone (GnRH) which is key in the onset of puberty, menarche in girls and subsequent menstrual cycles. In my 3 year longitudinal study of 87 pre and post-pubertal girls, those in the Ballet stream had lowest body fat and leptin levels associated with delayed menarche and low bone mineral density (BMD) compared to musical theatre and control girls. Other elements of body composition also play a part as athletes tend to have higher lean mass to fat mass ratio than non-active population and energy intake of 45 KCal/Kg lean mass is thought to be required for regular menstruation.

Suppression of GnRH pulsatility, results in low secretion rates of pituitary trophic factors LH and FSH which are responsible for regulation of sex steroid production by the gonads. In the case of females this manifests as menstrual disruption with associated anovulation resulting in low levels of oestradiol. In males this suppression of the hypothamlamic-pituitary-gonadal axis results in low testosterone production. In males testosterone is aromatised to oestradiol which acts on bone to stimulate bone mineralisation. Low energy availability is an independent factor of impaired bone health due to decreased insulin like growth factor 1 (IGF-1) concentrations. Low body weight was found to be an independent predictor of BMD in my study of 57 retired pre-menopausal professional dancers. Hence low BMD is seen in both male and female athletes with RED-S. Low age matched BMD in athletes is of concern as this increases risk of stress fracture.  In long term suboptimal BMD is irrecoverable even if normal function of hypothamlamic-pituitary-gonadal function is restored, as demonstrated in my study of retired professional dancers. In young athletes RED-S could result in suboptimal peak bone mass (PBM) and associated impaired bone microstructure. Not an ideal situation if RED-S continues into adulthood.

Another consequence of metabolic, physiological and psychological stressor input to the hypothalamus is suppression of the secretion of thyroid hormones, including the tissue conversion of T4 to the more active T3. Athletes may display a variation of “non-thyroidal illness/sick euthyroid” where both TSH and T4 and T3 are in low normal range. Thyroid hormone receptors are expressed in virtually all tissues which explains the extensive effects of suboptimal levels of T4 and T3 in RED-S including on physiology and metabolism.

In contrast, a neuroendocrine control axis that is activated in RED-S is the hypothalamic-pituitary-adrenal axis. In this axis, stressors increase the amplitude of the pulsatile secretion of CRH, which in turn increases the release of ACTH and consequently cortisol secretion from the adrenal cortex. Elevated cortisol suppresses immunity and increases risk of infection. Long term cortisol elevation also impairs the other hormone axes: growth hormone, thyroid and reproductive. In other words the stress response in RED-S amplifies the suppression of key hormones both directly and indirectly via endocrine network interactions.

The original female athlete triad is part of RED-S which can involve male and female athletes of all ages. There are a range of interacting endocrine systems responsible for the multi-system effects seen in RED-S. These effects can impact on current and future health and sports performance.

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


Teaching module on RED-S for BASEM as CPD for Sports Physicians

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

Optimal health: including male athletes! Part 2 Relative Energy Deficiency in sports Dr N.Keay, British Journal of Sport Medicine 4/4/17

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

Keay N, Fogelman I, Blake G. Effects of dance training on development,endocrine status and bone mineral density in young girls. Current Research in Osteoporosis and bone mineral measurement 103, June 1998.

Jenkins P, Taylor L, Keay N. Decreased serum leptin levels in females dancers are affected by menstrual status. Annual Meeting of the Endocrine Society. June 1998.

Keay N, Dancing through adolescence. Editorial, British Journal of Sports Medicine, vol 32 no 3 196-7, September 1998.

Keay N, Effects of dance training on development, endocrine status and bone mineral density in young girls, Journal of Endocrinology, November 1997, vol 155, OC15.

Relative Energy Deficiency in sport (REDs) Lecture by Professor Jorum Sundgot-Borgen, IOC working group on female athlete triad and IOC working group on body composition, health and performance. BAEM Spring Conference 2015.

Mountjoy M, Sundgot-Borgen J, Burke L, Carter S, Constantini N, Lebrun C, Meyer N, Sherman R, Steffen K, Budgett R, Ljungqvist A. The IOC consensus statement: beyond the Female Athlete Triad-Relative Energy Deficiency in Sport (RED-S).Br J Sports Med. 2014 Apr;48(7):491-7.

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

From population based norms to personalised medicine: Health, Fitness, Sports Performance Dr N. Keay, British Journal of Sport Medicine

Optimal health: including male athletes! Part 2 Relative Energy Deficiency in sports


As discussed in my previous blog Optimal health: including female athletes! Part 1 Bones, the female athlete triad is well described since 1984. The triad comprises disordered eating, amenorrhoea and reduced bone mineral density (BMD). What was uncertain was whether this was a reversible training effect. My study of professional retired pre-menopausal female dancers demonstrated that such bone loss is irreversible, despite resumption of menses. Furthermore, low body weight, independent of amenorrhoea, causes BMD loss. A few female athletes in my subsequent longitudinal study of professional dancers in the English National Ballet company were “robust” and continued to menstruate, in spite of low body weight. However this could have involved anovulatory cycles and therefore low oestrogen. One parameter cannot be considered in isolation.

Furthermore, it has become apparent that the female athlete triad is just part of a much larger picture, known as Relative Energy Deficiency in sport (RED-S). The fundamental issue is that of energy deficiency caused by a mismatch of energy intake and energy expenditure from exercise training. Quality of diet, including micronutrients is also important.

If you are a male athlete, you may be thinking that this is all just a problem for female counterparts? No. Male athletes can also develop RED-S, especially in sports where low body weight confers a sport performance advantage, for example long-distance runners and road cyclists (especially climbers). In a fascinating lecture, Professor Jorum Sundgot-Borgen from the Department of Sport Medicine, at the Norwegian School of Sport and Exercise Science, described the occurrence in male ski jumpers.

This energy deficient state in RED-S in both female and male athletes produces a cascade, network effect on multiple systems: immune, cardiovascular, endocrine, metabolic and haematological effects. Clearly suboptimal functioning in these key areas has implications for current physical and psychological health of athletes and therefore their sport performance. The psychological element is of note as this may be both cause and effect of RED-S. After all in order to be a successful, especially in sport, a high level of motivation, bordering on obsession, is required. Although athletes with RED-S may not fall into a defined clinical disease state, they demonstrate a subclinical condition that impacts health. Performance implications include decreased training response with reduced endurance, muscle strength and glycogen storage, alongside an increased risk of injury, probably due to impaired adaptive response to training and a decrease in co-ordination and concentration. Psychological sequelae include depression and irritability.

Some features of RED-S may be lead to irreversible health issues in the future, as seen in the case of athletic hypothalamic amenorrhoea in female athletes with permanent loss of BMD. In both male and female athletes low energy density diet relative to energy expenditure with training results in low levels of insulin like growth factor 1 (IGF-1) and sex steroid hormones which impair not only sport performance but bone microarchitecture and mineralisation. Although hypothalamic suppression in females is manifest by lack of menstruation, there is no such obvious clinical sign in males, who may nevertheless also be experiencing suppression of the hypothalamic-pituitary-gonadal axis. It has been shown that oestradiol is the key sex steroid hormone in promoting bone mineralisation: for both male and female. In males testosterone is aromatised to oestradiol which in turn acts on bone. As the same mechanisms are involved in the aetiology and effects of RED-S, then the long term consequences will most likely be the same for both female and male athletes.

In my next blog I will explore the consequences of RED-S in young athletes and delve into the Endocrine mechanisms involved in the aetiology and multi-system outcomes for male and female athletes of all ages.

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


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

Keay N, Fogelman I, Blake G. Bone mineral density in professional female dancers. British Journal of Sports Medicine, vol 31 no2, 143-7, June 1997.

From population based norms to personalised medicine: Health, Fitness, Sports Performance Dr N. Keay, British Journal of Sport Medicine

Relative Energy Deficiency in sport (REDs) Lecture by Professor Jorum Sundgot-Borgen, IOC working group on female athlete triad and IOC working group on body composition, health and performance. BAEM Spring Conference 2015.

Mountjoy M, Sundgot-Borgen J, Burke L, Carter S, Constantini N, Lebrun C, Meyer N, Sherman R, Steffen K, Budgett R, Ljungqvist A. The IOC consensus statement: beyond the Female Athlete Triad-Relative Energy Deficiency in Sport (RED-S).Br J Sports Med. 2014 Apr;48(7):491-7.

Margo Mountjoy, IOC Medical Commission Games Group. Relative Energy Deficiency in Sport. Aspetar Sports Medicine Journal.

Sleep for Health and Sports Performance

“Sleep.. chief nourisher in life’s feast,” Macbeth.

In my blog for British Association of Sport and Exercise Medicine, I described improving sport performance by balancing the adaptive changes induced by training together with the recovery strategies to facilitate this, both in the short and long term.  alec0120-12x17

A recovery strategy which is vital in supporting both health and sport performance, during all stages of the training cycle is sleep.

Sufficient sleep is especially important in young athletes for growth and development and in order to support adaptive changes stimulated by training and to prevent injury. Amongst teenage athletes, studies have shown that a lack of sleep is associated with higher incidence of injury. This may be partly due to impaired proprioception associated with reduced sleep. Sleep is vital for consolidating neurological function and protein synthesis, for example in skeletal muscle. Sleep and exercise are both stimuli for growth hormone release from the anterior pituitary, which mediates some of these adaptive effects.

Lack of sleep can also interfere with functioning of the immune system due to disruption of the circadian rhythm of secretion in key areas of the Endocrine system. Athletes in heavy training, with high “stress” loads and associated elevated cortisol can also experience functional immunosuppression. So a combination of high training load and insufficient sleep can compound to disrupt efficient functioning of the immune system and render athletes more susceptible to illness and so inability to train, adapt and recover effectively.  Lack of sleep disrupts carbohydrate metabolism and recently found to suppress expression of genes regulating cholesterol transport. In overreaching training, lack of sleep could be either a cause or a symptom of insufficient recovery. Certainly sleep deprivation impairs exercise performance capacity (especially aerobic exercise) although whether this is due to a psychological, physical or combination effect is not certain.

Sufficient sleep quality and quantity is required for cognitive function, motor learning, and memory consolidation. All skills that are important for sports performance, especially in young people where there is greater degree of neuroplasticity with potential to develop neuromuscular skills. In a fascinating recorded lecture delivered by Professor Jim Horne at the Royal Society of Medicine, the effects of prolonged wakefulness were described. Apart from slowing reaction time, the executive function of the prefrontal cortex involved in critical decision making is impaired. Important consequences not only for athletes, but for doctors, especially for those of us familiar with the on call system in hospitals back in the bad old days. Sleep pattern pre and post concussive events in teenage athletes is found to be related to degree and duration of concussive symptoms post injury. The explanation of how sleep deprivation can cause these functional effects on the brain has been suggested in a study where subtle changes in cerebral neuronal structural properties were recorded. It is not known whether these changes have long term effects.

So given that sleep is essential not only for health and fitness, but to support sports performance, what strategies to maximise this vital recovery process? Use of electronic devices shortly before bedtime suppresses secretion of melatonin (neurotransmitter and hormone), which is a situation not conducive for sleep. Tryptophan is an amino acid precursor in the synthesis of melatonin and serotonin (neurotransmitter) both of which promote sleep. Recent research demonstrates that protein intake before bed can support skeletal and muscle adaptation from exercise and also recovery from tendon injury. Conversely there is recent report that low levels of serotonin synthesis may contribute to the pathogenesis of autoimmune inflammatory disease such as rheumatoid arthritis. This highlights the subtle balance between degree of change required for positive adaptation and a negative over-response, as in inflammatory conditions. This balance is different for each individual, depending on the clinical setting. So maybe time to revisit the warm milky drink before bed? Like any recovery strategy, sleep can also be periodised to support exercise training, with well structured napping during the day as described by Dr Hannah Macleod, member of gold winning Olympic Hockey team.

In conclusion, when you are planning your training cycle, don’t forget that periodised recovery to compliment your schedule should be factored in, with sleep a priority recovery and adaptation strategy.

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


Balance of recovery and adaptation for sports performance Dr N. Keay, British Association of Sport and Exercise Medicine

Sleep, Injury and Performance

Keay N. The effects of growth hormone misuse/abuse. Use and abuse of hormonal agents: Sport 1999. Vol 7, no 3, 11-12.

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.

Sleep and sporting performance

Young people: neuromuscular skills for sports performance

Prolonged sleep restriction induces changes in pathways involved in cholesterol metabolism and inflammatory responses

“Sleepiness and critical decision making”. Recorded lecture Professor Jim Horne, Royal Society of Medicine 16/11/16

What Does Sleep Deprivation Actually Do To The Brain?

Pre-Sleep Protein Ingestion to Improve the Skeletal Muscle Adaptive Response to Exercise Training

Exercise and fitness in young people – what factors contribute to long term health? Dr N. Keay, British Journal of Sports Medicine

Serotonin Synthesis Enzyme Lack Linked With Rheumatoid Arthritis

“Science in Elite Sport” Dr Hannah Macleod, University of Roehampton, 6/12/16