training season – Dr Nicky Keay

Internal Biological Clocks and Sport Performance

5 October 2017

A Nobel Prize was awarded this week to researchers who uncovered the molecular mechanisms controlling circadian rhythm: our internal biological clock.

PastedGraphic-2 — Circadian Hormone Release

These mechanisms rely on negative feedback loops found in many biological systems where periodicity of gene expression is key, such as the Endocrine system. Internal biological clocks allow for anticipation of the requirements from body systems at different times of the day and the ability to adapt to changes in external lifestyle factors. What is the clinical significance of biochronometers?

The importance of integration of lifestyle factors, such as timing of eating, activity and sleep with our internal biological clocks is revealed in situations of circadian misalignment that lead to suboptimal health and disease states in the longer term.

Consideration of our biochronometers is especially important for athletes in order to synchronise periodised training, nutrition and recovery and thus optimise health and sports performance.

Athletic Performance Performance in a cycle time trial was found to be better in the evening, rather than the morning, proposed to be due to a more favourable endogenous hormonal and metabolic internal milieu. Certainly there were some disgruntled swimmers at an international event, when the usual pattern of morning heats and evenings finals was switched, to accommodate television viewing spectators.

Female athletes: menstrual cycle/training season Women have an extra layer of endogenous biological periodicity in the form of the menstrual cycle controlled by temporal changes of hormone release in the hypothamalmus-pituitary-ovarian Endocrine axis. Changes in external factors of training load, nutrition and recovery are detected by the neuroendocrine gatekeeper, the hypothalamus, which produces an appropriate change in frequency and amplitude of GnRH (gonadotrophin releasing hormone), which in turn impacts the pulsatility of LH (lutenising hormone) release from the pituitary and hence the phases of the menstrual cycle, in particular ovulation. Even short term reduction of energy availability in eumenorrhoeic female athletes can inhibit LH pulsatility frequency and release of other hormones such as IGF1. Disrupted release of sex steroids and IGF1 has a negative effect on bone turnover: increased resorption and decreased formation. Active females have been found more susceptible to reduction in energy availability impacting bone metabolism than their male counterparts.

Another consequence of the phasic nature of the menstrual cycle relating to external factors such as exercise, is that injury risk could be linked to changes in the expression of receptors for for sex steroids oestrogen and progesterone in skeletal muscle. Certainly during pregnancy and the post partum period, relaxin hormone increases the laxity of soft tissues, such as ligaments, and hence maintenance stretching, rather than seeking to increase flexibility, is recommended to prevent injury, .

In order to produce desired temporal adaptive changes in response to exercise training, signalling pathways mediated by reactive oxidative species and inflammatory markers are stimulated in the short term, with supportive Endocrine interactions in the longer term. However, an over-response can impair adaptive changes and impact other biological systems such as the immune system. This maladaptive response could occur as a result of non-integrated periodisation of training, nutrition and recovery in athletes and, in the case of female athletes, oral contraceptive pill use has been implicated, as this effectively imposes a medical menopause, preventing the phasic release of endogenous hormones.

Considering a longer time scale, such as a training season, female athletes were found to have a more significant fall ferritin during than male athletes. Low normal iron does not necessarily correlate to iron deficiency anaemia, but low levels in athletes can impact bone health. Supplementation with vitamin C to improve absorption may help, although iron overload can have deleterious effects. As training intensity increases as the season progresses, six monthly haematological reviews for female athletes were recommended in this study.

Changes in set point feedback Feedback control of the Endocrine system, for example the hypothalamic-pituitary-thyroid axis is dynamic: both anticipatory and adaptive, depending on internal and external inputs. However, presentation of a prolonged stimulus can result in maladaptation in the longer term. For example, disruption of signalling pathways leading to hyperinsulinaemia results in insulin resistance, which represents the underlying pathophysiological mechanism of obesity and the metabolic syndrome. In other words a situation of tachyphylaxis, where prolonged, repeated stimulus over time results in insensitivity to the original stimulus. This also applies to the nature of exercise training over a training season and diets that exclude a major food type: temporal variety is key.

Lifespan (prematurity, ageing) Changes during the lifespan represent an important biochronometer. Premature and small-for-dates babies are at risk of long term metabolic and Endocrine dysfunction, potentially due to intrauterine reprogramming of the hypothalamic-pituitary axis. At the other end of the biological time scale, with advancing age, DNA methylation and changes in epigenetic expression occur. It has been suggested that this age related methylation drift could be delayed with calorie restriction. Melatonin, a key player in intrinsic biological time keeping has been proposed to attenuate bone resorption by reducing relative oxidative stress. This would potentially explain why shift workers with disrupted sleep patterns are reported to be at risk not only of metabolic dysfunction, but also impaired bone health. Disrupted sleep patterns are a concern for athletes, especially those whose training and competition schedule involve frequent international travel across time zones.

In summary, respecting your internal biological clocks and integrating your lifestyle and your training, nutrition and recovery with these intrinsic pacemakers in mind will optimise health and performance.

For further discussion BASEM annual conference 22/3/18: Health, Hormones and Human Performance

Presentations

References

The Nobel Prize in Physiology or Medicine 2017

Circadian clock control of endocrine factors Nat. Rev. Endocrinol

Temporal considerations in Endocrine/Metabolic interactions Part 1 Dr N. Keay, British Journal of Sports Medicine 2017

Temporal considerations in Endocrine/Metabolic interactions Part 2 Dr N. Keay, British Journal of Sports Medicine 2017

Athletic Fatigue: Part 2 Dr N. Keay 2017

Effect of Time of Day on Performance, Hormonal and Metabolic Response during a 1000-M Cycling Time Trial Plos One 2017

Optimal Health: For All Athletes! Part 4 – Mechanisms Dr N. Keay, British Association of Sport and Exercise Medicine 2017

Effects of reduced energy availability on bone metabolism in women and men Bone 2017

Expression of sex steroid hormone receptors in human skeletal muscle during the menstrual cycle Acta Physiol (Oxf). 2017

Endocrine system: balance and interplay in response to exercise training

Kynurenic acid is reduced in females and oral contraceptive users: Implications for depression Science Direct 2017

Oxidative Stress in Female Athletes Using Combined Oral Contraceptives Sports Medicine

Iron monitoring of male and female rugby sevens players over an international season J Sports Med Phys Fitness. 2017

Thyroid Allostasis–Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming Frontiers in Endocrinology 2017

Stress- and allostasis-induced brain plasticity Annu Rev Med

Optimising Health and Athletic Performance Dr N. Keay 2017

Long-term metabolic risk among children born premature or small for gestational age Nature Reviews Endocrinology 2017

Caloric restriction delays age-related methylation drift Nature Communications 2017

Melatonin at pharmacological concentrations suppresses osteoclastogenesis via the attenuation of intracellular ROS Osteoporosis International 2017

Sleep for health and sports performance Dr N. Keay, British Journal of Sports Medicine 2017

Temporal considerations in Endocrine/Metabolic interactions Part 2

2 August 2017

LifeSeasonDay

As discussed in the first part of this blog series, the Endocrine system displays temporal variation in release of hormones. Amplitude and frequency of hormonal secretion display a variety of time-related patterns. Integrating external lifestyle factors with this internal, intrinsic temporal dimension is crucial for supporting metabolic and Endocrine health and sport performance.

Circadian misalignment and sedentary lifestyle has been implicated in the increased incidence of metabolic syndrome driven by insulin resistance and associated metabolic inflexibility and decrease in fat oxidation. However, a recent study of overweight individuals, found that increases in fat oxidation from lifestyle intervention, corresponded to different clinical outcomes. Both those who maintained weight loss and those who regained weight displayed increased fat oxidation compared to baseline. How could this be? Increased fat oxidation is only part of the equation in overall fat balance. What adaptations in the metabolic and Endocrine networks were occurring during rest periods? In the case of those that maintained weight loss, increased fat oxidation was reflected in biochemical and physiological adaptations to enable this process. Whereas for those that regained weight in the long term, increased fat oxidation was enabled by increased availability of lipids, indicating increased fat synthesis over degradation.

Clearly there is individual variation in long-term Endocrine and metabolic responses to external factors. Focusing on optimising a single aspect of metabolism in the short term, will not necessarily produce the expected, or desired clinical outcome over a sustained period of time. As previously discussed the single most effective lifestyle change that induces synchronised, beneficial sustained Endocrine and metabolic adaptations is exercise.

It will come as no surprise that focusing on maximising use of a single substrate in metabolism, without integration into a seasonal training plan and consideration of impacts on internal control networks, has not produced the desired outcome of improved performance amongst athletes. Theoretically, increasing fat oxidation will benefit endurance athletes by sparing glycogen use for high intensity efforts. Nutritional ketosis can be endogenous (carbohydrate restricted intake) or exogenous (ingestion of ketone esters and carbohydrate). Low carbohydrate/high fat diets have been shown in numerous studies to increase fat oxidation, however, this was at the expense of effective glucose metabolism required during high intensity efforts. Potentially there could be adverse effects of low carbohydrate intake on gut microbiota and immunity.

This effect was observed even in a study on a short timescale using a blinded, placebo-controlled exogenous ketogenic intervention during a bicycle test, where glycogen was available as a substrate. The proposed mechanism is that although ketogenic diets promote fat oxidation, this down-regulates glucose use, as a respiratory substrate. In addition, fat oxidation carries a higher oxygen demand for a lower yield of ATP, compared to glucose as a substrate in oxidative phosphorylation.

Metabolic flexibility the ability to use a range of substrates according to requirement, is key for health and sport performance. For example, during high intensity phases of an endurance race, carbohydrate will need to be taken on board, so rehearsing what types/timing of such nutrition works best for an individual athlete in some training sessions is important. Equally, some low intensity training sessions with low carbohydrate intake could encourage metabolic flexibility. However, in a recent study “training low” or periodised carbohydrate intake failed to confer a performance advantage. I would suggest that the four week study time frame, which was not integrated into the overall training season plan, is not conclusive as to whether favourable long term Endocrine and metabolic adaptations would occur. A review highlighted seasonal variations in male and female athletes in terms of energy requirements for different training loads and body composition required for phases of training blocks and cycles over a full training season.

Essentially an integrated periodisation of training, nutrition and recovery over a full training season will optimise the desired Endocrine and metabolic adaptations for improved sport-specific performance. The emphasis will vary over the lifespan of the individual. The intricately synchronised sequential Endocrine control of the female menstrual cycle is particularly sensitive to external perturbations of nutrition, exercise and recovery. Unfortunately the majority of research studies focus on male subjects.

In all scenarios, the same fundamental temporal mechanisms are in play. The body seeks to maintain homeostasis: status quo of the internal milieu is the rule. Any external lifestyle factors provoke short term internal responses, which are regulated by longer term Endocrine network responses to result in metabolic and physiological adaptations.

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