Passing on the exercise baton: What can endocrine patients learn from elite athletes?

Abstract As elite athletes demonstrate through the Olympic motto ‘Citius, Altius, Fortius‐ Communiter’, new performance records are driven forward by favourable skeletal muscle bioenergetics, cardiorespiratory, and endocrine system adaptations. At a recreational level, regular physical activity is an effective nonpharmacological therapy in the treatment of many endocrine conditions. However, the impact of physical exercise on endocrine function and how best to incorporate exercise therapy into clinical care are not well understood. Beyond the pursuit of an Olympic medal, elite athletes may therefore serve as role models for showcasing how exercise can help in the management of endocrine disorders and improve metabolic dysfunction. This review summarizes research evidence for clinicians who wish to understand endocrine changes in athletes who already perform high levels of activity as well as to encourage patients to exercise more safely. Herein, we detail the upper limits of athleticism to showcase the adaptability of human endocrine‐metabolic‐physiological systems. Then, we describe the growing research base that advocates the importance of understanding maladaptation to physical training and nutrition in males and females; especially the young. Finally, we explore the impact of physical activity in improving some endocrine disorders with guidance on how lessons can be taken from athletes training and incorporated into strategies to move more people more often.

What can the elite athlete teach the general population about the value of physical exercise? In line with governmental guidelines, with an array of different sports and exercise patterns that can be performed alone or in social groups, the recreational exerciser can benefit from a healthier lifestyle with increased longevity and reduced incidence of many noncommunicable diseases (NCDs). Indeed, many can benefit from structuring their training in alignment with the very same principles that athletes use to safely allow their bodies to adapt to many hundreds of hours of training a year. Importantly, many of the endocrine, metabolic, and cardiovascular benefits of regular exercise are beneficial for cohorts with endocrine disorders and may attenuate the risk of various long-term cardiometabolic complications.
Thus, it seems timely to detail in this review the role of exercise that is of clinical relevance for the management of some endocrine disorders. Athletes can be great role models and their achievements inspire the wider population to 'move more, and more often'. The purpose of this review is to help provide greater confidence to clinicians that physical exercise can be promoted more.

| ENERGY METABOLISM IN ATHLETES AND THE ENDOCRINE RESPONSE TO ACUTE EXERCISE
An athletes' ability to push the boundaries of modern sporting performance limits is dependent on their ability to optimize physiological adaptations from rigorous, chronic progressive training. Increased muscular energy fuel demand at the onset of, and during, exercise elicits important neuroendocrine responses, regardless of training status. The provision of different fuels for exercise (i.e., phosphocreatine, carbohydrate, and lipids) are fine-tuned by the interactions of several endocrine hormones viz, insulin, glucagon, catecholamines, growth hormone (GH), and cortisol. 3 Volitional muscle contraction initiates parasympathetic withdrawal and sympathoadrenal activity which releases adrenaline and noradrenaline from the adrenal medulla, inhibiting pancreatic insulin secretion to below basal levels. 4 Concurrently, catecholamines and glucagon (and later GH and cortisol) increase hepatic glucose output via glycogenolysis and gluconeogenesis, in addition to facilitating lipid mobilization from adipose tissue by adrenaline-mediated increases in hormone-sensitive lipase activity.
Catecholamines stimulate hepatic and skeletal muscle glycogen phosphorylase activity towards glycogenolytic reactions, opposing insulin-driven glycogenesis. As a result of chronic exercise training, endurance athletes possess greater intramuscular glycogen stores (see Hearris et al. 5 ) which are relatively distributed towards intramyofibrillar regions (in type 1 'endurance' muscle fibres) compared with nonathlete individuals. 6,7 Similarly, intramuscular lipids are distributed as smaller droplets and are more concentrated in the intramyofibrillar compartment in endurance athletes compared with subsarcolemmal spaces in untrained individuals which are further from muscle contractile proteins. 8 Furthermore, the droplets are in closer proximity to mitochondria, which themselves have a higher volume density after training. 9 Accordingly a greater capacity for energy production is enabled and a shift in metabolic fuel preference applies a greater reliance on fat, rather than carbohydrate, metabolism. 9 This is favourable in the avoidance of glycogen depletion and subsequent fatigue-induced reduction in force output. 10 Several factors can influence the neuroendocrine system response to an acute bout of exercise including, but not limited to, manipulations to acute programme variables (e.g., exercise intensity, duration, and volume), environmental factors (e.g., temperature and altitude), and individual demographics (e.g., age, gender, and training history). 11 During acute exercise, blood catecholamine concentrations can increase in an intensity-dependent manner to over tenfold basal concentrations (e.g., adrenaline >5 nmol.L −1 and noradrenaline >20 nmol.L −1 after repeated sprints) in well-trained athletes, resulting in augmented hepatic glycogenolysis and raised blood glucose. 12,13 Significant resistance exercise also induces a rise in catecholamines, as well as raised testosterone, GH, and insulin-like growth factor-1 (IGF-1) ('anabolic' hormones) concentrations, creating a milieu for maximizing strength and muscle mass gains. 14 Conversely, exercise programmes that elicit the greatest acute GH response also elicit the greatest cortisol response-the primary protein 'catabolic' hormone. 15,16 This reflects the dual process of tissue remodelling, consisting of an initial phase of breakdown before a period of growth and repair. 17

| ENDOCRINOLOGICAL ADAPTATIONS IN ATHLETES
Structured and planned regular training can be thought of as repeated exposure to acute exercise 'stress'. As part of an adaptive process, long-term adherence to exercise training potentiates alterations in several neuroendocrine responses to subsequent stressors (exercise or otherwise). 11,18 Many endocrine hormones are essential in initiating and regulating the training-induced adaptations that occur in various organs and readers are directed to some excellent early references for detailed appraisals (SeeGalbo and Bunt 19,20 ).
Exercise training typically attenuates the magnitude of the plasma hormonal response to any given submaximal absolute workload; resulting in lower plasma hormone concentrations in trained compared with untrained individuals ( Table 1). The influence of training status on the exercise-stimulated release of gonadotropins, prolactin, and gonadal hormones is ambiguous within literature and discussed in detail elsewhere. 19,21 Trained athletes may present with lower secretion of aldosterone and vasopressin (hormones involved in the maintenance of body fluid and electrolyte balance) during exercise, 22 possibly reflecting the influence of training on plasma volume shifts (i.e., hypervolaemia): an important early adaptation to endurance training. 23 In pancreatic hormones, trained individuals experience a lesser decline in plasma insulin levels during exercise (resulting in higher relative circulating concentrations than in those who are untrained) while the glucagon response is attenuated. 24 This athletic hormonal milieu reflects a greater sensitivity of the target tissue to the hormonal stimulus and the degree of increase in neural, humoral, and hormonal factors that influence the responsiveness of various endocrine glands being lower. 25 This training adaptation has significant metabolic consequences such as lowered adrenaline-mediated hepatic glycogen breakdown. The exception to this general rule is maximal or supramaximal exercise, for which trained athletes may present with augmented sympathoadrenal system responses compared with untrained subjects. This is due to the higher absolute workloads necessary to elicit a maximum response and/or possible training-induced glandular adaptations (i.e., adrenal medulla hypertrophy) that increase its hormonal secretory capacity. 25 Trained sportspeople can present with decreased resting basal glucagon concentrations as well as lower fasted and stimulated insulin concentrations. 26,27 The influence of training status on resting levels of basal levels of hormones related to the hypothalamic-pituitary-gonadal axis in men and women is somewhat equivocal in literature and detailed explorations of the topic have been reviewed elsewhere. 28 Ultimately, endocrine adaptations to exercise training translate as an improved ability to maintain energy homoeostasis in the face of subsequent physiological or metabolic stressors. These hormonal changes are paralleled with metabolic and/or morphological adaptations in several organs with wider health benefits. This underscores the potential value of physical exercise as a therapeutic tool for the management of many NCDs. However, exposure to intense training regimes with inadequate rest and recovery can result in 'Overtraining Syndrome'. 29 In such instances, imbalances within endocrine function become apparent, with possible downregulation of the hypothalamic-pituitary-gonadal axis.

| RELATIVE ENERGY DEFICIENCY SYNDROME
Despite the name, RED-S is not restricted to athletes participating in competitive sport. RED-S can occur in exercisers of all levels, wherever an imbalance in exercise and nutritional behaviours occurs, resulting in low energy availability (LEA). 30 The clinical consequences of LEA were first described in the female athlete triad. 31 The triad covers a clinical spectrum from normal eating patterns, bone health, and menstrual function through to eating disorders, osteoporosis, and amenorrhoea. Furthermore Management of a patient with RED-S will require a multidisciplinary team approach to provide medical, dietetic, and psychological input as clinically indicated. 40 T A B L E 1 The endocrine response to acute and chronic endurance and resistance exercise in healthy individuals Note: Hormonal responses to exercise differ based on specific exercise protocols, individual responses, and other factors (e.g., time of day and feeding status).
In nontraining columns: ↓ denotes lower plasma concentrations with increased exercise characteristic (column title).
↑ denotes higher plasma concentrations with increased exercise characteristic (column title).
↔ denotes no change in plasma concentrations with increased exercise characteristic (column title).
In training column (independent of changes in background concentrations): ↓ denotes lower plasma concentrations relative to concentrations at the same (absolute) workload before training.
↑ denotes higher plasma concentrations relative to concentrations at the same (absolute) workload before training.
↔ denotes no change in plasma concentrations relative to concentrations at the same (absolute) workload before training.
Regular menstrual periods are the barometer of a healthy hormonal milieu for all women of reproductive age. This is normal physiology, regardless of how much physical activity is being taken. Given that a responsive, healthy endocrine network is essential for driving beneficial adaptative changes to exercise, then regular fluctuation in menstrual cycle hormones is essential not only for health but also for exercise performance (Figure 2). Note that the average age of me-

| ENDOCRINOLOGICAL ISSUES IN PAEDIATRIC ATHLETES
In many sports, the pursuit of elite status starts early, such that by the time a child reaches their teens they already have undertaken several years' worth of intense training and competition accompanied by the considerable bodily demands these events entail. Despite the consensus beneficial effects of exercise on a child's health overall, 47,48 there are inherent physical, psychological, dietetic, and physiological concerns associated with intense, long-term training that should be considered when dealing with paediatric athletes.
The 'female athlete triad' is a common disorder among young female athletes 49 who often encounter disruption to normal menstrual function (i.e., delayed menarche, oligomenorrhea, and amenorrhoea). 50 Exercise-related reproductive dysfunction may compromise growth velocity and peak bone mass acquisition with an accelerated risk of developing osteoporosis in later life. 51   The process of the body getting accustomed to a particular exercise or training programme through repeated exposure. All training is aimed at creating long-term physical changes in the body systems. (vi) Maintenance/Reversibility: Physiological and metabolic systems will revert to pretrained state unless training is continued, and performance will decrease. Also known as 'use it or lose it'. Specific Training Outcomes are usually directed to the development of either endurance or strength power and capacity. Optimizing programme design and identifying the specific training outcome can lead to improvement in exercise performance (e.g., power, speed, or time) and functional outcome, for example, ease of completion of daily tasks and improved quality of life emphasize the potential value of exercise, even in minor amounts, in alleviating or averting the progression of numerous NCDs. 66 Beyond the local adaptations that occur within skeletal muscle, exercise induces positive adaptions in several other tissues. Though these adaptive processes undoubtedly serve to benefit the elite athlete from a sports performance perspective, they also lead to various health-related outcomes that reduce the risk of disease onset or progression ( Figure 4). 66 8.  73 and/or those who are overweight or obese. 74 Given that cardiovascular disease (CVD) prevails as the leading cause of mortality in many NCDs, the benefits of exercise in mitigating its risk are noteworthy. 75 Physical inactivity is emerging as an independent risk for NCDs, causing an estimated 9% of premature all-cause mortality, 6% of CVD, and 7% of T2D. 74 The associated economic costs are astronomical, equating to £39 billion/year worldwide (2013) 76 and £1 billion/year to the UK National Health Service (2006-7). 77 It is reasonable to suggest that physical activity promotion should be a public health priority.

| Putting it into practice
Individuals with NCDs that are routinely seen in clinical practice may be among those most unlikely to exercise. Hence, primary health-care providers are well placed to communicate the benefits of regular exercise to those who may stand to benefit most. 78,79 Advocation of regular exercise in clinical practice could be a simple, cost-effective strategy that yields impactful results. 80 The ideal training regimen should include a variety of exercise activities (namely those the patient most enjoys, and is therefore most likely to sustain) that contribute to some form of daily movement in alignment with governmental guidelines (i.e., The UK's Chief Medical Officers Guidelines for Physical Activity 81 ). The 'FITT' (i.e., exercise Frequency, Intensity, Time, and Type) mnemonic is commonly used as a guidance source for exercise prescription guidelines and could be implemented alongside achievable goal setting ( Figure 5).
Clearly not everyone is able to exercise intensely or indeed has the resources available to undertake bespoke exercise regimes with qualified professionals. However, many community-based projects and online guidance material are free. Not to forget, walking is a practical, free, and user-friendly means of contributing to physical Undoubtedly primary health-care providers have a valuable role to play in exercise promotion at the population level. However, many report time constraints, inadequate resources, and a lack of confidence/knowledge as leading barriers to exercise prescription. 79 Unfortunately, not all countries offer referral schemes to a sports and exercise medicine specialist. Ongoing efforts are needed to address these concerns to optimize patient adherence and outcomes.

| Next steps
Recent texts have given appraisals of exercise prescription in primary health care (See Khan and Seth 78,79 ) with resource direction and practical implementation points. Some prudent next steps could be: • Administer a physical activity questionnaire (i.e., the UK general practice physical activity questionnaire 83 ) to establish baseline activity levels.
• Prescribe a periodized exercise plan according to acute programme variables and training principles for the patient (Figure 3).
Align these with governmental guidelines if appropriate.
• Establish a plan that is both feasible and effective for the patient.
Set small, achievable goals to build confidence.
• Provide a recorded exercise prescription plan that states the agreed upon goals. Free resource material can be found in the 'exercise is medicine' initiate co-created by the American College of Sports Medicine and the American Medical Association (www. exerciseismedicine.com).
• Know your local resources for physical activity and communicate these to the patient.
• Follow-up with the patient to assess progress, identify problems, fine tune the 'dose' and reset the goals.
• Remember 'no size fits all' and potential health risk's need consideration. If uncertain about the appropriate advice to give, reach out to exercise professionals for help.

| CONCLUSIONS
Many positive adaptations occur in athletes in a training-dependent manner. Structuring training in a periodized fashion helps avoid maladaptation to physical training, an especially important factor for consideration in paediatric athletes. Great feats of exercise performance begin with small amounts of physical activity that are progressively increased and many of the principles of fitness can be employed to improve several endocrine disorders. Taken collectively, it is clear to see the reason behind the 'exercise is medicine' mantra with recognition of its value as a nonpharmacological therapy option for the treatment of many NCDs. Though not everyone can become an Olympian or professional athlete, adopting a healthy lifestyle can bring great health benefits to many, including people with endocrine disorders.

DATA AVAILABILITY STATEMENT
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
F I G U R E 5 Exercise prescription model in alignment with Chief Medical Officers (CMO) physical activity guidelines using the 'FITT' principals alongside positive behaviour modification