Metabolic and Endocrine System Networks

EndoMetaNetworks

What are the most effective strategies to optimise health and performance? There are ever more emerging possibilities, permutations and combinations to chose from.

The simple answer is that the most effective option will depend on your starting point and what you are trying to achieve. In all cases exercise and activity levels are the fundamental basis for health and performance. Regarding nutritional strategies to support effective exercise adaptations, no single component of your dietary intake can be considered in isolation. After all, the metabolic pathways and Endocrine axes in your body work as an interactive network, with an important temporal dimension.

Emerging evidence implicates resistance to the anabolic pancreatic hormone, insulin, as the underlying pathological process in the development of metabolic syndrome. What type of diet might drive or conversely counter this process involving metabolism and the Endocrine system? The standard approach, of calorie restriction and aggressive pharmacological treatment of raised lipids, does not produce the anticipated reduction in cardiovascular mortality. Rather the synergistic effect of a diet high in both fat and carbohydrate induces hypothalamic inflammation and dysfunction in the control system of energy metabolism. The hypothalamus is the neuroendocrine gatekeeper providing the crucial link between internal and external stimuli and homeostasis of the internal milieu through integrated Endocrine responses. Intriguingly there is as an inflammatory component to the pathogenesis of cardiovascular disease.

The interaction between metabolic, Endocrine and inflammatory networks is seen in polycystic ovary syndrome (PCOS). The clinical diagnosis of PCOS relies on two of three diagnostic criteria (menstrual disturbance, hyperandrogenism, ovarian morphology). However, the underlying metabolic disruption for all phenotypes of the condition, from overweight to slim, is insulin resistance. The link between adverse body composition, metabolic and Endocrine dysfunction has recently been described. Adipokines, a class of cytokine, including adiponectin and resistin are produced by adipose tissue and exert an effect on metabolism, including insulin sensitivity and inflammation. Changes in plasma concentrations and/or expression of adipokines are seen in metabolic dysfunction and potentially have direct and indirect effects on the hypothalmic-pituitary-gonadal axis in PCOS.

Further evidence of the crucial interaction between metabolic and Endocrine systems and health was found in a longitudinal study of children, quantifying heart rate variability and the energy and inflammatory related biomarkers leptin (atherogenic) and adiponectin (anti-atherogenic) as potential predictive markers in cardiovascular screening/prevention.

Exogenous hormones impact not only the endogenous Endocrine system, but have metabolic effects. The intended purpose of the combined oral contraceptive pill (OCP) is to suppress ovulation. Another effect on the Endocrine system is to increase production of sex hormone-binding globulin (SHBG), which binds free testosterone. This has a therapeutic effect in the treatment of PCOS to lower elevated testosterone, however this may not be such a desirable effect in female athletes, where higher range testosterone levels as associated with performance advantages in certain power events. In the case of female athletes with relative energy deficiency in sports (RED-S), use of the OCP masks underlying hypothalamic amenorrhoea and is not effective in bone health protection. Further areas where Endocrine manipulation impacts metabolism are an increase in oxidative stress with OCP use and alterations in nutritional requirements due to alteration of absorption of vitamins and minerals such as vitamin B complex and magnesium, which are vital for enzymic processes involved in energy production. Yet an elevation of ferritin as an acute phase reactant is seen. These interactions of Endocrine and metabolic networks are particularly important considerations for the female athlete.

There is no single elixir for health and performance.  We are individuals with subtle differences in our genetic and epigenetic make up, including the diversity of our microbiome. Furthermore, the Endocrine and metabolic milieu changes during our lifespan. Personalised health and performance strategies must take account of the complex, intricate interactions between the Endocrine and metabolic networks.

For further discussion on Health, Hormones and Human Performance, come to the BASEM annual conference

References

One road to Rome: Metabolic Syndrome, Athletes, Exercise Dr N.Keay

Endocrine system: balance and interplay in response to exercise training Dr N. Keay

Dietary sugars, not lipids, drive hypothalamic inflammation Molecular Metabolism June 2017

Adiponectin and resistin: potential metabolic signals affecting hypothalamo-pituitary gonadal axis in females and males of different species Reproduction: Journal for the Society of Reproduction and Fertility 2017

Longitudinal Associations of Leptin and Adiponectin with Heart Rate Variability in Children Front. Physiol 2017

AKR1C3-mediated adipose androgen generation drives lipotoxicity in women with polycystic ovary syndrome J Clin Endocrinol Metab 2017

Hormones and Sports Performance Dr N. Keay

Mechanisms for optimal health…for all athletes! Dr N. Keay, British Journal of Sport and Exercise Medicine

Oxidative Stress in Female Athletes Using Combined Oral Contraceptives Sports Medicine – Open

Oral contraceptives and changes in nutritional requirements European Review for Medical and Pharmacological Sciences

Inflammation: Why and How Much? Dr N. Keay, British Association of Sport and Exercise Medicine 2017

 

 

Hormones and Sports Performance

WADA

The interactive network effects of the Endocrine system are key in producing effective adaptations to exercise. This in turn results in improved sport performance. Athletes are aware of the crucial role of the Endocrine system in sports performance. Therefore it is not surprising that, on the World Anti-Doping agency (WADA) banned list, the majority of prohibited substances both in and out of competition are hormones, mimetics and hormone and metabolic modulators. In 2013 hormones accounted for 75% of all adverse analytical findings. Use of such substances to enhance performance is not only illegal and against the spirit of sport, but also potentially harmful to the health of the athlete.

Considering some of these prohibited hormones, the usual suspects start with anabolic agents: anabolic androgenic steroids whether these be synthetic derivatives taken exogenously or molecular identical endogenous steroids, including metabolites and isomers, administered exogenously.  In a study recently published in the BJSM, female athletes with free testosterone levels in the highest tertile displayed better performance than those in lowest tertile of up to 4.5% in certain power/anaerobic events such as 400m, 800m, hammer and pole jump. This may be due to associated body composition with increased lean mass and “risk taking” behaviour. In 2015, the Court of Arbitration for Sport ruled that the IAAF should suspend the existing upper limit on female athlete testosterone, of 10nmol/l, because at the time there was insufficient evidence that such levels would improve performance in female athletes. In view of the results of this study, the situation may have to be reviewed. This is clearly an ethical dilemma regarding intersex athletes, whose hyerandrogenism is due to endogenous biological factors.

Next up there are peptide hormones/growth factors/mimetics. As previously discussed, growth hormone (GH) proved a challenging peptide hormone for which to develop a dope test. Firstly what are the “normal” ranges for elites athletes, seeing as exercise and sleep are the two major stimuli for GH release? Furthermore, elite athletes represent a subset of the population, for whom the normal range may differ. Secondly exogenous genetically engineered GH is to all intents and purposes identical to endogenous secreted GH, with a relatively short half life. Hence early on in development of a dope test we realised that downstream markers, particularly of bone turnover would have to be used. This brings the discussion to erythropoietin (EPO). In a similar way to GH and allied releasing factors, increases in key surrogate variables producing performance enhancement are measured. In the case of exogenous EPO these are changes in haemoglobin and haematocrit as recorded in an athletes’ biological passport. A recent study on amateur cyclists given EPO in a double blind randomised placebo controlled trial, reported no improvement in a submaximal field test. Although the effects in elite cyclists would arguably be more relevant, this is not possible for obvious ethical reasons. Nevertheless the effects on elite cyclists during maximal efforts, for example in an attack on a mountainous stage in the Tour de France, would not necessarily correlate to amateurs in submaximal conditions, where there may be other limiting factors to performance. In addition athletes may use supraphysiological dosing regimens (“stacking” or “pyramiding”), not necessarily comparable to those used in clinical studies. In my opinion, apart from potential ergogenic benefits, whatever the degree, the intention to “take a short cut” to improve performance is the issue, not to mention the adverse health sequelae, for example, the study noted a thrombotic tendency with EPO, even in modest doses.

Hormone and metabolic modulators have received attention following the fall from grace of Maria Sharapova. Meldonium which is licensed for use in Baltic countries has beneficial anti-ischaemic effects in cardiovascular, neurological and metabolic disease states. Apparently this drug was use amongst Soviet troops during the war in mountainous Afghanistan. Amongst athletes the intended purpose is to improve endurance exercise performance and recovery post exercise. This is an example where an unfortunate spin off from developing drugs to treat disease states, is that such drugs are also see by some athletes as a short cut to enhance sport performance.

Although thyroxine is not on the banned list, there are certainly arguments that exogenous thyroxine should not be given to athletes, unless there is definitive biochemical evidence that the athlete suffers with hypothyroidism: as defined by criteria for diagnosing this condition with consistently elevated thyroid stimulating hormone (TSH) above the normal range, with paired low T4. Thyroid autoantibodies may also provide extra clinical information. The effect of intense training on the hypothalamic-pituitary-thyroid axis is to slightly suppress both TSH and T4, whilst these remain in the normal range. In this instance medicating with exogenous thyroxine would be to support recovery from training, rather than to legitimately treat a proven medical condition. In a similar way a TUE is only justified for testosterone in pathological disorders of the hypothalamo-pituitary-testicular axis and not for suppressed testosterone as a result of training stress.

Unfortunately supplements are a source of preventable anti-doping rule violations (ADRV) representing up to half of the total ADRVs. Either such supplements have not listed all the contents, or contamination has occurred during manufacture. If an athlete wishes to take supplements, certainly it is advisable only to take reliably tested products. Nevertheless even if an athlete unintentionally ingests prohibited substances, then ultimately they are still liable. If claims of the benefits of such supplements sound too good to be true, they probably are. Ultimately supplements will not win races and there is no substitute for periodised training, nutrition and recovery.

Effectively there is an arms race between would-be doper and medical expertise in Sports Endocrinology. However, freezing samples for potential re-analysis with emerging understanding and technology in the future is an added deterrent for athletes whose intention is to take a short cut to improving sport 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

References

Endocrine system: balance and interplay in response to exercise training

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

Enhancing Sport Performance: Part 1 Dr N. Keay, British Association of Sport and Exercise Medicine 2017

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 Clinical Endocrinology and Metabolism. 85 (4) 1505-1512. 2000.

From population based norms to personalised medicine: Health, Fitness, Sports Performance  Dr N. Keay, British Journal of Sports Medicine 2017

Enabling Sport Performance: part 2

Enhancing Sports Performance: part 3

World Anti-Doping Agency

Serum androgen levels and their relation to performance in track and field: mass spectrometry results from 2127 observations in male and female elite athletes British Journal of Sports Medicine

Doping Status of DHEA Treatment for Female Athletes with Adrenal Insufficiency Clinical Journal of Sports Medicine 2017

Testosterone treatment and risk of venous thromboembolism: population based case-control study British Medical Journal 2016

Effects of erythropoietin on cycling performance of well trained cyclists: a double-blind, randomised, placebo-controlled trial The Lancet, Haematology 2017

Meldonium use by athletes at the Baku 2015 European Games. Adding data to Ms Maria Sharapova’s failed drug test case British Journal of Sports Medicine 2016

Fatigue, sport performance and hormones..more on the endocrine system  Dr N. Keay, British Journal of Sports Medicine 2017

Australian Sport Anti-Doping Authority

 

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.

Slide1

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.

Conclusion

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

References

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

PPARδ Promotes Running Endurance by Preserving Glucose Cell Metabolism

 

Addiction to Exercise

ExerciseAddiction

Health is not just the absence of illness, but rather the optimisation of all components of health: physical, mental and social. Exercise has numerous benefits on all these aspects. However, a recent article in the British Medical Journal described how exercise addiction can have detrimental physical, mental and social effects.

Dedication and determination are valuable qualities required to be successful in life, including achieving sporting prowess. Yet, there is a fine line between dedication and addiction.

To improve sports performance, cumulative training load has to be increased in a quantified fashion, to produce an overload and hence the desired physiological and Endocrine adaptive responses. Integrated periodisation of training, recovery and nutrition is required to ensure effective adaptation. Sufficient energy availability and quality of nutrition are essential to support health and desired adaptations. On the graph above the solid blue line represents a situation of energy balance, where the demands of increased training load are matched by a corresponding rise in energy availability. This can be challenging in sports where low body weight confers a performance or aesthetic advantage, where the risk of developing relative energy deficiency in sport (RED-S) has implications for Endocrine dysfunction, impacting all aspects of health and sports performance.

Among those participating in high volumes of exercise, what distinguishes a healthy level of commitment from exercise addiction? Physical factors alone are insufficient: all those engaging in high levels of training can experience overuse injuries and disruption in Endocrine, metabolic and immune systems. Equally, in all these exercising individuals, overtraining can result in underperformance.

Psychological factors are the key distinguishing features between the motivated athlete and the exercise addict. In exercise addiction unhealthy motivators and emotional connection to exercise can be identified as risk factors. In exercise addiction the motivation to exercise is driven by the obsession to comply with an exercise schedule, above all else. This can result in negative effects and conflict in social interactions, as well as negative emotional manifestations, such as anxiety and irritability if unable to exercise, including the perceived necessity to exercise even if fatigued or injured.

Two categories of exercise addiction have been described. Primary exercise addiction is the compulsion to follow an excessive training schedule. Without balancing energy intake, the physical consequence may be a relative energy deficiency, as indicated on the graph by the dashed blue line. In secondary exercise addiction, the situation is compounded by a desire specifically to control body weight. These individuals consciously limit energy intake, almost inevitably developing the full clinical syndrome described in RED-S, dragging them down to the position indicated by the dotted blue line on the chart. These situations of exercise addiction can lead to varying risk categories of RED-S.

As described at the start of this blog, there is a blurred boundary between the dedicated athlete and the exercise addict. In practice there is most likely a cross over. For example, an athlete may start with healthy motivators and positive emotional connection to exercise, which can become a primary addiction to adhere rigidly to a training schedule, rather than putting the emphasis on the outcome of such training. In the case of an athlete where low body weight is an advantage, it is easy to appreciate how this could become a secondary exercise addiction, where the motivation for exercising becomes more driven by the desire to control weight, rather than performance.

In order to support those with exercise addiction, discussion needs to focus on adopting a more flexible approach to exercise, by recognising that exercise addiction has detrimental effects on all aspects of current and long term health. Furthermore, in the case of athletes, a multi-disciplinary approach is desirable to help the individual refocus on the primary objective of training: to improve performance. In all situations, discussion should explore modifications to exercise and nutrition, in order to prevent the negative effects of RED-S on health and performance.

Exercise has numerous health benefits and is usually viewed as positive behaviour. However, the outcome of exercise is related to the amount of training, appropriate nutrition and motivation for exercising.

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

References

Addiction to Exercise British Medical Journal 2017

Clusters of Athletes British Association of Sport and Exercise Medicine 2017

Sport performance and relative energy deficiency in sport British Journal of Sport Medicine 2017

Balance of recovery and adaptation for sports performance British Association of Sport and Exercise Medicine 2017

Optimal Health for all athletes Part 4 Mechanisms of RED-S British Journal of Sport Medicine 2017

Sports Endocrinology – what does it have to do with performance? British Journal of Sport Medicine 2017

Inflammation: Why and How Much? British Association of Sport and Exercise Medicine 2017

Fatigue, Sport Performance and Hormones…

How do you feel on Monday morning, when the alarm wakes you at 7am with a day of work ahead after the weekend? A bit tired, slightly lethargic, sluggish, maybe a little bit down, perhaps a few regrets about somewhat too much alcohol/food over weekend, frustrated that the exercise training schedule didn’t go according to plan?sleep

There are many causes of fatigue and sport underperformance: Endocrine, immunological, infective, metabolic, haematological, nutritional, digestive, neoplastic….. The adrenal gland in the Endocrine system in particular has come in for some bad press recently.

Adrenal woes

Undoubtedly the adrenal glands have a case to answer. Situated above the kidneys these Endocrine glands produce glucocorticoids, mineralocorticoids, androgens from the adrenal cortex and from the adrenal medulla adrenaline. Glucocorticoids (e.g. cortisol) have a metabolic function to maintain energy homeostasis and an immune function to suppress inflammation. Mineralocorticoids (e.g. aldosterone) maintain electrolyte and water balance. As mineralocorticoids and glucocorticoids are similar biological steroid molecules, there is some degree of overlap in their actions.

Addison’s disease and Cushing’s disease are serious medical conditions, corresponding respectively to under or over production by the adrenal glands of steroid hormones. Someone presenting in Addisonian crisis is a medical emergency requiring resuscitation with intravenous hydrocortisone and fluids. Conversely those with Cushing’s can present with hypertension and elevated blood glucose. Yet, apart from in the extremes of these disease states, cortisol metrics do not correlate with clinical symptoms. This is one reason why it is unwise and potentially dangerous to stimulate cortisol production based on clinical symptoms. Inappropriate exogenous steroid intake can suppress normal endogenous production and reduce the ability to respond normally to “stress” situations, such as infection. This is why the prescription of steroids, for example to reduce inflammation in autoimmune disease, is always given in a course of reducing dose and a steroid alert card has to be carried. Athletes should also be aware that exogenous steroid intake is a doping offence.

However, what is the “normal” concentration for cortisol? Well, for a start, it depends what time of day a sample is taken, as cortisol is produced in a circadian rhythm, with highest values in the morning on waking and lowest levels about 2/3am. Nor is this temporal periodicity of production the only variable, there are considerations such as tissue responsiveness and metabolism (break down) of the hormone. On top of these variables there are other inputs to the feedback control mechanism, which can in turn influence these variables. In other words, focusing on the steroid hormone production of the adrenal gland in isolation, could overlook underlying hypothamalmic-pituitary-adrenal (H-P-A) axis dysfunction and indeed wider issues.

Much maligned thyroid

That is not end of the possible causes of fatigue and sport underperformance: the H-P-A axis is just one of many interrelated, interacting Endocrine systems. There are many neuroendocrine inputs to the hypothalamus, the gate keeper of the control of the Endocrine system. Furthermore there are network interaction effects between the various Endocrine control feedback loops. For example cortisol towards the top end of “normal” range can impede the conversion at the tissue level of thyroxine (T4) to the more active triiodothyronine (T3) by enzymes which require selenium to function. Rather T4 can be converted to reverse T3 which is biologically inactive, but blocks the receptors for T3 and thus impair its action. This in turn can interfere with the feedback loop controlling thyroid function (hypothalamic-pituitary-thyroid axis). The physiological ratio of T4 to T3 is 14:1, which is why supplementation with desiccated thyroid is not advisable with ratio of 4:1. There are other processes which can crucially interfere with this peripheral conversion of T4 to T3, such as inflammation and gut dysbiosis, which can occur as result of strenuous exercise training. So what might appear to be a primary thyroid dysfunction can have an apparently unrelated underlying cause. Indeed amongst highly trained athletes thyroid function can show an unusual pattern, with both thyroid stimulating hormone (TSH) and T4 at low end of the “normal “range, thought to be due to resetting of the hypothalamic-pituitary control signalling system. This highlights that the “normal” range for many hormones comprises subsets of the population and in the case of TSH, the “normal” range is not age adjusted, despite TSH increasing with age. As described by Dr Boelaert at recent conferences, there is certainly no medical justification for reports of some athletes in the USA being given thyroxine with TSH>2 (when the normal range is 0.5-5mU/l). Although thyroxine is not on the banned list for athletes, it could have potentially serious implications for health due to its impact on the Endocrine system as a whole.

Endocrine system interactions

SportsEndocrinologyWordCloud

Symptoms of fatigue are common to many clinical conditions, not just dysfunction in an Endocrine control axis in isolation, nor even the network interactive effects of the Endocrine system in isolation. For example, the impact of nutrition relative to training load produces a spectrum of clinical pictures and Endocrine disturbances seen in Relative Energy Deficiency in Sport (RED-S) in terms of health and sport performance.

Underlying mechanisms of Endocrine dysfunction

There may be predisposing factors in developing any clinical syndrome, the usual suspects being inflammation: whether infective, dysbioses, autoimmune; nutritional status linked with endocrine status;  training load with inadequate periodised recovery to name a few….

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

References

From population based norms to personalised medicine: Health, Fitness, Sports Performance British Journal of Sport Medicine 2017

Sports Endocrinology – what does it have to do with performance? British Journal of Sport Medicine 2017

Advanced Medicine Conference, Royal College of Physicians, London 13-16 February 2017, Endocrine session: Dr Kristien Boelaert, Dr Helen Simpson, Professor Rebecca Reynolds

Subclinical hypothydroidism in athletes. Lecture by Dr Kristeien Boelaert, British Association of Sport and Exercise Medicine Spring Conference 2014. The Fatigued Athlete

Sport Performance and RED-S, insights from recent Annual Sport and Exercise Medicine and Innovations in Sport and Exercise Nutrition Conferences British Journal of Sport Medicine 2017

Relative Energy Deficiency in Sport CPD module British Association of Sport and Exercise Medicine 2017

Sleep for health and sports performance British Journal of Sport Medicine 2017

Inflammation: why and how much? British Association of Sport and Exercise Medicine 2017

Clusters of athletes British Association of Sport and Exercise Medicine 2017

Enhancing Sport Performance: Part 1 British Association of Sport and Exercise Medicine 2017

Balance of recovery and adaptation for sports performance British Association of Sport and Exercise Medicine 2017

Annual Sport and Exercise Medicine Conference, London 8/3/17 Gut Dysbiosis, Dr Ese Stacey

Adrenal fatigue does not exist: a systematic review BMC Endocrine Disorders. 2016; 16(1): 48.

A Controversy Continues: Combination Treatment for Hypothyroidism Endocrine News, Endocrine Society April 2017

Clusters of Athletes

 At some time, most athletes experience periods of underperformance. What are the potential causes and contributing factors?

classification

Effective training improves sports performance through a process of adaptation that occurs, at both the cellular and system levels, during the recovery phase. Training overload must be balanced with sufficient subsequent recovery. A long-term improvement in form is expected, following a temporary dip in performance, due to short-term fatigue.

However, when an athlete experiences a stagnation of performance, what are the potential underlying causes? How should these be addressed to prevent an acute situation developing into a more chronic spiral of decreasing performance?

Depending on clinical presentation, the first step is to exclude medical conditions. Potential infective causes include Epstein Barr virus (particularly in young athletes), Lyme disease and Weil’s disease. Systemic inflammatory conditions should be considered. Endocrine and metabolic causes include pituitary, gonadal, adrenal, thyroid  dysfunction, blood sugar control,  and malabsorption.

If medical conditions are excluded, attention should turn to the athlete’s energy balance in the context of adherence to the current training plan. Potential causes of underperformance, the inability to improve in training and competition, are illustrated in the diagram above.

Athletes in the upper right quadrant fail to live up to performance expectations, in spite of maintaining a good energy balance while adhering to the prescribed training plan. However, they may represent non-functional overreaching, where overload is not balanced with sufficient recovery. In other words, the periodisation of training and recovery is not optimised. The balance between chronic training load (fitness) and acute training load (fatigue) provides a useful metric for assessing form. Heart rate variability (HRV) can be another potentially useful measure in detecting aerobic, endurance fatigue. If the training plan is not producing the expected improvements, then this plan needs revising. Don’t forget that sleep is essential to facilitate endocrine driven adaptations to exercise training.

Athletes in the lower right quadrant are of more concern. Inadequate energy balance, especially during periods of increased training load or intentional weight loss, can be a cause of underperformance, despite the athlete being able to adhere to the training plan. This would correspond to being at risk of developing relative energy deficiency in sport (RED-S) on the amber warning in the risk stratification laid out by the International Olympic Committee.

Both of these groups are able to adhere to a training plan, but suboptimal training and recovery periodisation and/or insufficient energy intake can produce a situation of underperformance. Intervention is required to prevent them moving into the clusters on the left, representing a more chronic underperformance scenarios that are therefore more difficult to rectify.

Athletes in the upper left quadrant exhibit overtraining syndrome: a prolonged maladaptation process accompanied by a decrease in performance (not merely stagnation) and inability to adhere to training plan. The metric of decreased HRV and inability of heart rate to accelerate in response to exercise have been suggested as markers of overtraining.

Those athletes in the lower left quadrant fall into the RED-S category, where multiple interacting Endocrine networks are impacted by an energy deficient state. RED-S not only impairs sports performance, but impacts both current and future health. For example low endogenous levels of sex steroids and insulin-like growth factor 1 (IGF1) disrupt formation of bone microarchitecture and bone mineralisation, resulting in increased risk of recurrent stress fracture in addition to potentially irreversible bone loss in the longer term. In cases of recurrent injury and underperformance amongst athletes it is imperative to exclude Endocrine dysfunction and then consider whether RED-S is the fundamental cause.

There are many potential causes of underperformance in athletes. Once medical conditions have been excluded, the main aim should be to prevent acute situations becoming chronic and therefore more difficult to resolve.

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

References

Sport Endocrinology Dr N. Keay, British Journal of Sport Medicine 2017

Sport Performance and RED-S, insights from recent Annual Sport and Exercise Medicine and Innovations in Sport and Exercise Nutrition Conferences Dr N.Keay, British Journal of Sport Medicine 2017

Relative Energy Deficiency in Sport CPD module for 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

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

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

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

Inflammation: why and how much? Dr N. Keay, British Association of Sport and Exercise Medicine

Fatigue, Sport Performance and Hormones… Dr N.Keay, British Journal of Sport Medicine

Part 3: Training Stress Balance—So What? Joe Friel

Heart Rate Variability (HRV) Science for Sport

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.

Prevention, Diagnosis, and Treatment of the Overtraining Syndrome: Joint Consensus Statement of the European College of Sport Science and the American College of
Sports Medicine. Joint Consensus Statement. Medicine & Science in Sports & Exercise 2012

Sports Endocrinology

SportsEndocrinologyWordCloud

The Endocrine system comprises various glands distributed throughout the body that secrete hormones to circulate in the blood stream. These chemical messengers, have effects on a vast range of tissue types, organs and therefore regulate metabolic and physiological processes occurring in systems throughout the body.

The various hormones produced by the Endocrine system do not work in isolation; they have interactive network effects. The magnitude of influence of a hormone is largely determined by its circulating concentration. This in turn is regulated by feedback loops. For example, too much circulating hormone will have negative feedback effect causing the control-releasing system to down regulate, which will in turn bring the level of the circulating hormone back into range. Ovulation in the menstrual cycle is a rare example of a process induced by positive hormonal feedback.

In the control system of hormone release, there are interactions with other inputs in addition to the circulating concentration of the hormone. The hypothalamus (gland in the brain) is a key gateway in the neuro-endocrine system, coordinating inputs from many sources to regulate output of the pituitary gland, which produces the major stimulating hormones to act on the Endocrine glands throughout the body.

growthhormone

The Endocrine system displays complex dynamics. There are temporal variations in secretion of hormones both in the long term during an individual’s lifetime and on shorter timescales, as seen in the diurnal variation of some hormones such as cortisol, displaying a circadian rhythm of secretion. The most fascinating and complex control system is found in the hypothalamic-pituitary-ovarian axis. Variation in both frequency and amplitude of gonadotrophin releasing factor (GnRH) secretion from the hypothalamus dictates initiation of menarche and the subsequent distinct pattern of cyclical patterns of the sex steroids, oestrogen and progesterone.

So what have the Endocrine system and hormone production got to do with athletes and sport performance?

  1. Exercise training stimulates release of certain hormones that support favourable adaptive changes. For example, exercise is a major stimulus of growth hormone, whose action positively affects body composition in terms of lean mass, bone density and reduction of visceral fat.
  2. Disruption of hormones secreted from the Endocrine system can impair sport performance and have potential long term adverse health risks for athletes. This picture is seen in the female athlete triad (disordered eating, amenorrhoea and low density) and relative energy deficiency in sport (RED-S) with multi-system effects. In this situation there is a mismatch between dietary energy intake (including diet quality) and energy expenditure through training. The net result is a shift to an energy saving mode in the Endocrine system, which impedes both improvement in sport performance and health. RED-S should certainly be considered among the potential causes of sport underperformance, suboptimal health and recurrent injury,  with appropriate medical support being provided.
  3. Caution! Athletic hypothalamic amenorrhoea, as seen in female athletes (in female athlete triad and RED-S) is a diagnosis of exclusion. Other causes of secondary amenorrhoea (cessation of periods >6 months) should be excluded such as pregnancy, polycystic ovary syndrome (PCOS), prolactinoma, ovarian failure and primary thyroid dysfunction.
  4. Unfortunately the beneficial effects of some hormones on sport performance are misused in the case of doping with growth hormone, erythropoeitin (EPO) and anabolic steroids. Excess administered exogenous hormones not only disrupt the normal control feedback loops, but have very serious health risks, which are seen in disease states of excess endogenous hormone secretion.

So the Endocrine system and the circulating hormones are key players not only in supporting health, but in determining sport performance in athletes.

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

References

Sport Performance and RED-S, insights from recent Annual Sport and Exercise Medicine and Innovations in Sport and Exercise Nutrition Conferences Dr N. Keay, British Journal of Sports Medicine 17/3/17

Teaching module on RED-S for British Association of Sport and Exercise Medicine as CPD for Sports Physicians

Optimal Health: Including Female Athletes! Part 1 – Bones Dr N. Keay, British Journal of Sport Medicine 26/3/17

Optimal Health: Including Male Athletes! Part 2 – REDs 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 13/4/17

Optimal health: for all athletes! Part 4 Mechanisms Dr N. Keay, British Association of Sport and Exercise Medicine 13/4/17

Enhancing sport performance: part 1 Dr N. Keay, British Association of Sport and Exercise Medicine

Enhancing sports performance: part 3

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

Sleep for health and sports 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

Clusters of athletes 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

Fatigue, Sport Performance and Hormones…Dr N. Keay, British Journal of Sport Medicine

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

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

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

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

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

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.

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.

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.

Keay N. Bone mineral density in professional female dancers. IOC World Congress on Sports Sciences. October 1997.

Keay N, Bone Mineral Density in Professional Female Dancers, Journal of Endocrinology, November 1996, volume 151, supplement p5.

Sport Performance and Relative Energy Deficiency in Sport

performance-potentialThe Holy Grail of any training program is to improve performance and achieve goals.

Periodisation of training is essential in order to maximise beneficial adaptations for improved performance. Physiological adaptations occur after exercise during the rest period, with repeated exercise/rest cycles leading to “super adaptation”. Adaptations occur at the system level, for example cardiovascular system, and at the cellular level in mitochondria. An increase in mitochondria biogenesis in skeletal muscle occurs in response to exercise training, as described by Dr Andrew Philip at a recent conference at the Royal Society of Medicine (RSM). This cellular level adaptation translates to improved performance with a right shift of the lactate tolerance curve.

The degree of this response is probably genetically determined, though further research would be required to establish causal links, bearing in mind the ethical considerations laid out in the recent position statement from the Australian Institute of Sport (AIS) on genetic testing in sport. Dr David Hughes, Chief Medical Officer of the AIS, explored this ethical stance at a fascinating seminar in London. Genetic testing in sport may be a potentially useful tool for supporting athletes, for example to predict risk of tendon injury or response to exercise and therefore guide training. However, genetic testing should not be used to exclude or include athletes in talent programmes. Although there are polymorphisms associated with currently successful endurance and power athletes, these do not have predictive power. There are many other aspects associated with becoming a successful athlete such as psychology. There is no place for gene doping to improve performance as this is both unethical and unsafe.

To facilitate adaptation, exercise should be combined with periodised rest and nutrition appropriate for the type of sport, as described by Dr Kevin Currell at the conference on “Innovations in sport and exercise nutrition”. Marginal gains have a cumulative effect. However, as discussed by Professor Asker Jeukendrup, performance is more than physiology. Any recommendations to improve performance should be given in context of the situation and the individual. In my opinion women are often underrepresented in studies on athletes and therefore further research is needed in order to be in a position to recommend personalised plans that take into account both gender and individual variability. As suggested by Dr Courtney Kipps at the Sport and Exercise Conference (SEM) in London, generic recommendations to amateur athletes, whether male or female, taking part in marathons could contribute to women being at risk of developing exercise associated hyponatraemia.

For innovation in sport to occur, complex problems approached with an open mind are more likely to facilitate improvement as described by Dr Scott Drawer at the RSM. Nevertheless, there tends to be a diffusion from the innovators and early adapters through to the laggards.

Along the path to attaining the Holy Grail of improved performance there are potential stumbling blocks. For example, overreaching in the short term and overtraining in the longer term can result in underperformance. The underlying issue is a mismatch between periodisation of training and recovery resulting in maladapataion. This situation is magnified in the case of athletes with relative energy deficiency in sport (RED-S). Due to a mismatch of energy intake and expenditure, any attempt at increase in training load will not produce the expected adaptations and improvement in performance. Nutritional supplements will not fix the underlying problem. Nor will treatments for recurrent injuries. As described by Dr Roger Wolman at the London SEM conference, short term bisphosphonante treatment can improve healing in selected athletes with stress fractures or bone marrow lesions.  However if the underlying cause of drop in performance or recurrent injury is RED-S, then tackling the fundamental cause is the only long term solution for both health and sport performance.

Network effects of interactions lead to sport underperformance. Amongst underperforming athletes there will be clusters of athletes displaying certain behaviours and symptoms, which will be discussed in more detail in my next blog. In the case of RED-S as the underlying cause for underperformance, the most effective way to address this multi-system issue is to raise awareness to the potential risk factors in order to support athletes in attaining their full potential.

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

References

Teaching module RED-S British Association Sport and Exercise Medicine

From population based norms to personalised medicine: Health, Fitness, Sports Performance Dr N. Keay, British Journal of Sport Medicine 22/2/17

Balance of recovery and adaptation for sports performance Dr N. Keay, British Association Sport and Exercise Medicine 21/1/17

Sleep for health and sports performance Dr N. Keay, British Journal of Sport Medicine 7/7/17

Fatigue, Sport Performance and Hormones… Dr N. Keay, British Journal of Sport Medicine

Annual Sport and Exercise Medicine Conference, London 8/3/17

Bisphosphonates in the athlete. Dr Roger Wolman, Consultant in Rheumatology and Sport and Exercise Medicine, Royal National Orthopaedic Hospital

Collapse during endurance training. Dr Courtney Kipps, Consultant in Sport and Exercise Medicine. Consultant to Institute of Sport, medical director of London and Blenheim Triathlons

Innovations in Sport and Exercise Nutrition. Royal Society of Medicine 7/3/17

Identifying the challenges: managing research and innovations programme. Dr Scott Drawer, Head of Performance, Sky Hub

Exercise and nutritional approaches to maximise mitochondrial adaptation to endurance exercise. Dr Andrew Philip, Senior Lecturer, University of Birmingham

Making technical nutrition data consumer friendly. Professor Asker Jeukendrup, Professor of Exercise Metabolism, Loughborough University

Innovation and elite athletes: what’s important to the applied sport nutritionists? Dr Kevin Currell, Director of Science and Technical Development, The English Institute of Sport

Genetic Testing and Research in Sport. Dr David Hughes, Chief Medical Officer Australian Institute of Sport. Seminar 10/3/17

Effects of adaptive responses to heat exposure on exercise performance

Over Training Syndrome, Ian Craig, Webinar Human Kinetics 8/3/17

The Fatigued Athlete BASEM Spring Conference 2014

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.

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

References

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

Successful Ageing

As I am discovering, ageing is an inevitable process. However what can you do to keep as healthy as possible in order to get the most out of life?

crop Budapest0571

If you are a Masters athlete, you will know that moving into these age groups means it is advisable to change training emphasis in order to prevent injury and compete successfully. As discussed at the recent conference Royal Society of Medicine on Sports Injuries and Sports Orthopaedics, during the session on “The Ageing Athlete”, older athletes need a longer dynamic warm up with controlled mobilisation and muscle activation, together with strength and conditioning sessions to prevent injury. Moving into next age group every five years gives the opportunity to assess and modify training accordingly.

Childhood development has an impact on long term adult health. Essentially the most rapid changes and potential peaks attained during childhood and adolescence reflect optimal physical and cognitive functioning in later life. The evidence from population cohort studies was presented by Professor Diana Kuh, director of MRC Unit for Lifelong Health and Ageing, at the recent conference at the Royal Society of Medicine. Up to 66% of the decline in functional ability in ageing adults is related to childhood development. In the case of pubertal timing, Professor Kuh described that delay causes 20% reduction of volumetric trabecular bone accrual. In my 3 year longitudinal study of 87 pre and post pubertal girls, high levels of training delayed menarche and blunted attainment of peak bone mass (PBM). Conversely an optimal level of training did not delay menarche and improved bone mineral density compared to age marched sedentary controls. A similar long term effect is seen in older female athletes who have experienced amenorrhoea of more than 6 months duration. Even after retirement and resumption of menses pre-menopause, irreversible loss of bone mineral density (BMD) is seen. Professor Kuh argued for specific and personalised recommendations to individuals to support successful ageing.

From a personalised medical perspective, what about hormonal changes associated with ageing? Although in men testosterone levels decline with age, nevertheless the change is more dramatic in women at menopause where the ovaries stop producing oestrogen and progesterone. This results in increased risk after the menopause of osteoporosis, cardiovascular disease and stroke, together with other vasomotor symptoms and mood changes. With increased life expectancy comes an increasing number of women with menopausal symptoms and health issues which can negatively impact on quality of life. What about hormone replacement therapy (HRT)? HRT improves menopausal symptoms and reduces the risk of post menopausal long term health problems, provided HRT is started within ten years after the menopause. After this window of opportunity replacement oestrogen can actually accelerate cell damage. As with any medical treatment there will be those for whom HRT is contra-indicated. Otherwise the risk:benefit ratio for each individual has to be weighed up so that women can arrive at an informed decision. Regarding the risk of breast cancer, this is increased by 4 cases per 1,000 women aged 50-59 years on combined HRT. This compares to an additional 24 cases in women who have body mass index (BMI)>30 and are not on HRT. This underlines the important of lifestyle which is crucial in all areas of preventative medicine.

What type of HRT has the most favourable risk:benefit ratio? Oral preparations undergo first pass metabolism in the liver, so other routes of delivery such as transdermal may be preferred. There is also an argument that hormones with identical molecular structure are preferable to bio-similar hormones. What functional effect could a slight difference in sex steroid structure have? For example no methyl group and a side chain with hydroxyl group (C-OH) rather than a carbonyl group (C=O)? That is the difference between oestradiol and  testosterone.

img_0373
Testosterone
img_0375
Oestradiol

In the case of hormones with identical molecular structure to those produced endogenously, there are no potential unwanted side effects or immunogenic issues as the molecule is identical to that produced by the body. Although the oestradiol component in most HRT preparations in the UK has an identical molecular structure to endogenous oestradiol, there is only one licensed micronised progesterone preparation that is has an identical molecular structure. Synthetic, bio-similar progestins have additional glucocorticoid and androgenic effects compared to molecular identical progesterone which exerts a mild anti-mineralocorticoid (diuretic) effect.

img_0376
Progesterone
img_0378
Norethisterone (synthetic progestin)

With an increasing ageing population and increase in life expectancy, it is important to support successful ageing and quality of life with a personalised and specific approach.

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

References

Conference Royal Society of Medicine 17/1/17 “Sports Injuries and Sports Orthopaedics” Session on “The Ageing Athlete”

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

From population based norms to personalised medicine: Health, Fitness, Sports Performance Dr N. Keay, British Journal of Sport Medicine 22/2/17

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

Bio-identical hormone replacement therapy course. Marion Gluck Training Academy 27/1/17

The British Menopause Society

Royal College of Obstetricians and Gynaecologists