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The Endocrinologist

Issue 135 Spring 2020

Endocrinologist > Spring 2020 > Features

Exploring endocrine physiology during arduous exercise

Robert M Gifford and David R Woods | Features

Exercise is associated with metabolic and cardiovascular benefits for most people, but do positive physiological adaptations occur when exercise is pushed to extreme limits?

‘Arduous exercise’ can imply very strenuous physical activity, or exercise made challenging for other reasons, such as climactic exposure, psychological stress or sleep deprivation. What is arduous is also relative to an individual’s physical condition – the average patient attending a type 2 diabetes clinic and an Olympic rower are likely to perceive this very differently.

Most people planning to undertake extremes of exercise are healthy and physically fit, so studying them allows us to define the limits of what we consider to be healthy physiological adaptation. Studies of extremely arduous exercise are often observational, field-based and opportunistic for ethical reasons. For example, the intrinsic dangers of ascent to high altitude or crossing the Antarctic must be accepted by participants prior to the additional ethical considerations of participating in research.


Hormones are the key mediators of physiological adaptations to exercise, for example by improving metabolic risk from increased insulin sensitivity, increasing muscle mass by upregulating insulin-like growth factor-1, or improving bone mineral density by favouring bone deposition over resorption. However, at sustained extremes of training, some hormonal changes may be considered maladaptive, e.g. catecholamine and/or glucocorticoid excesses thought to mediate overtraining syndrome, impaired spermatogenesis or ovulatory dysfunction during extremely arduous training, or osteopenia and stress fractures seen in ballerinas and distance runners.


Workers in the field have long focused on the balance of caloric energy and its effects on endocrine axes during arduous exercise, specifically the concept of low ‘energy availability’. This is the energy available to cellular processes after exercise energy expenditure is subtracted from energy intake, expressed as kcal/kg lean body mass per day. The concept of low energy availability has gained traction as being central to many putative negative endocrine effects of highly arduous training.1 A value below 30kcal/kg per day is often considered ‘low’, although studies have demonstrated a dose–response relationship between energy availability and some maladaptive effects of exercise.2

The ‘female athlete triad’ comprises reduced bone mineral density and/ or hypothalamic-pituitary-gonadal (HPG) axis function due to low energy availability. Downregulating less important processes like bone turnover and reproduction is thought to be a temporary adaption, limited caloric energy is apportioned to physical activity (e.g. escaping a threat or finding food), as this is of greater importance to immediate survival. Downregulation of certain processes in the context of nutritional deficit should therefore be regarded as an adaptive process and not a pathological one. Sustained low energy availability has been proposed as the cause for a wide array of metabolic and endocrine disturbances during arduous exercise, the ‘relative energy deficiency in sports’ syndrome, and affects both men and women.

These paradigms may present the correction of low energy availability as a panacea for mitigating endocrine maladaptation to arduous exercise. While this carries the advantage of being modifiable, the evidence largely comes from professional or semi-professional athletes, and it may be that a single aetiology cannot explain arduous exercise-associated maladaptation in other populations. Clinicians and researchers should keep an open mind as to other causes of observed hormonal perturbations. For example, HPG or hypothalamic-pituitary-adrenal (HPA) axis dysfunction could be due to psychological stressors during arduous exercise. We studied 52 women undertaking highly physically demanding Army training, in whom energy availability was sufficient, but suppression of ovulation and pituitary gonadotroph function was pronounced, associated with activation of the HPA axis.3 These effects were probably due to a combination of multiple stressors, including sleep deprivation and externalised locus of control.


Studying highly arduous training raises intriguing possibilities of understanding the effects of basic biological covariates like sex on physiological adaptation. It has been reported that the female HPG axis is more sensitive to the effects of low energy availability than the male axis during sustained arduous training.4 Women utilise proportionately more lipid and less carbohydrate than men during prolonged exercise, which may mean they are naturally better-adapted to endurance exercise, and preserve lean mass during ultra-long distance races or expeditions. Elite women athletes have dramatically narrowed the gap in a number of endurance sports.5

Gender differences in psychological resilience could also be important. We found that six women who crossed Antarctica, each hauling 80kg over 1000 miles in austere conditions, had rates of psychological stress that were lower during the expedition than beforehand. They demonstrated preserved dynamic HPG and HPA axis function, despite an overall energy deficit (around 10kg loss in fat mass).6


Research in the field of ‘arduous exercise’, from bench to mountainside, stands to benefit from greater collaboration between physiologists and endocrinologists. Combining the disciplines in a symbiotic approach can refine the questions and finesse the research outputs. Such crosstalk between disciplines and the study of the human physiological and endocrinological responses to extremes of environmental and exercise exposure can serve to optimise the translational benefit.

Exercise at high altitude induces hypoxic and inflammatory responses akin to systemic inflammatory response syndromes seen in intensive care. Brain natriuretic peptide (BNP) and N-terminal pro-BNP, with which many clinicians will be familiar as supporting a diagnosis of heart failure, have been found to be markers of high pulmonary artery systolic pressure at altitude (a key feature of high altitude pulmonary oedema), while copeptin has been found to reflect thermal strain. Prolonged arduous training with sleep deprivation or psychological stress may be relevant to understanding endocrine dysfunction in highly demanding occupations.

Measuring detailed endocrine function during arduous exercise is extremely challenging, and has been limited by difficulty in obtaining samples during or close to extreme exercise. Wearable technologies, which can perform an increasing number of real-time assays and other measurements, have the potential to improve our understanding of endocrine adaptation to arduous exercise. Continuous accelerometers, cardiac monitoring using ECG or plethysmography and interstitial glucose monitoring systems are already in clinical use, and have been used in extreme environments, delivering continuous real-time data to smartphones. Engineers have developed wearable and implantable sensors of steroid hormones and electrolytes which can last weeks or months.

These innovations are not without ethical challenges in the research and clinical setting. How does one respond to real-time data that suggest an individual is recording measurements out of the conventional ‘normal range’, when perhaps, in a remote or dangerous environment, extreme values might just be ‘normal for them’? A peripheral oxygen saturation of 75% is commonplace at high altitude, but would warrant urgent intervention in the ward-based clinical setting. It is likely that our physiological ‘models’ of adaptation to arduous exercise are limited by reference ranges taken in non-exercising individuals.

Engaging endocrinologists, physiologists and engineers to develop new technologies presents the opportunity to explore the limits of adaptation to extremely arduous exercise, while bringing the challenge of understanding the physiological versus the pathological.

Squadron Leader Robert M Gifford and Colonel David R Woods, University Of Edinburgh


  1. Elliott-Sale KJ et al. 2018 International Journal of Sport Nutrition & Exercise Metabolism 28 335–349.
  2. De Souza MJ et al. 2019 Current Opinion in Physiology 10 35–42.
  3. Gifford RM et al. 2019 Endocrine Abstracts 65 OP5.1 doi:10.1530/endoabs.65.OP5.1.
  4. Cano Sokoloff N et al. 2016 Frontiers of Hormone Research 47 27–43.
  5. Lepers R 2019 Frontiers in Physiology 10 973.
  6. Gifford RM et al. 2019 Medicine & Science in Sports & Exercise 51 556–567.

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Spring 2020

Spring 2020