The Hypothalamic Pituitary Adrenal Axis Biology Essay

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The expectation on athletes to provide repeated optimum performances throughout the forever lengthening competitive season is evermore increasing. The best way for athletes to train to achieve optimum performance over a prolonged period has been the subject of many studies and research and the level of understanding and knowledge has increased significantly. It is well documented that intensifying training load for a few days to weeks, followed by a period of adequate tapering of training load, can bring about improvements in performance. It is noted that the improvements are observed after an initial diminution in performance (over-reaching) and are therefore the result of a super-compensatory effect. However alongside this, studies have also indicated that increased training load can have repercussions in immune system function (REF). Overreaching has been seen to alter the function on hypothalamic-pituitary-adrenal axis and therefore cortisol secretion in the body. This can be linked to immunomodulation, through the anti-inflammatory effect of cortisol. It is through the complicated cytokine network that the functions of both innate and adaptive immunity cells are affected.

Even though the exercise does not leave athletes clinically immunosuppressed, following prolonged intensive exercise a period of declined immune function can be observed. Through this period athletes are at greater risk of infection as viruses can more easily get a foothold in their host.

Supplementation through nutrition has been used as a way to try and counteract athletes' susceptibility to infection through improving athletes' health. Probiotics is a supplement that to date has primarily been focused on a non-athletes environment, being used largely for gastrointestinal disease. Probiotics are able to modulate immune function of innate and adaptive cells through the gut epithelium, which forms part of mucosal immunity. Through the increased interest in other potential uses of probiotics, a few studies to date have looked at probiotics in an athletic setting (Refs). Studies have also looked into the influence of psychological stress on normal gut flora and the associated immune system response; parallels can be drawn between this on the one hand and the stress of exercise on the body and its effect on immune system function.

The knowledge of probiotics influencing the immune system and the interconnection through the central nervous system and other systems of the body suggests that there is significant potential for a link between probiotics and cortisol induced perturbations of the immune system.

1.2 Cortisol

Cortisol is a stress hormone; it is one of the glucocorticoid class of hormones. Cortisol plays an essential function in the control of a large number of metabolic activities in the human body. It affects protein metabolism, gluconeogenesis and parts ofboth the innate and adaptive immune response (Viru & Viru, 2004). The release of cortisol is mediated by the hypothalamus, along the hypothalamic-pituitary-adrenal axis (HPA) (Figure 1). The hypothalamus secretes corticotrophin releasing factor (CRF) which stimulates the release of adrenocorticotrophic hormone (ACTH) from the anterior pituitary gland into the blood stream. The raised concentration of ACTH in the blood stimulates cortisol production from the adrenal glands of the kidneys (Turnball & Rivier, 1999). This process is regulated by negative feedback to the hypothalamus and anterior pituitary gland.

Figure 1.1 The Hypothalamic-Pituitary-Adrenal axis

Cortisol, at rest, is secreted in a pulsatile manner, modulated by the cardiac rhythm (Van Cauter et al. 1996). The interaction between the endocrine system and the central nervous system cause diurnal variations of cortisol concentrations in the body. Concentrations peak early in the early morning hours, just before wakening, after this morning peak, concentrations decrease throughout the day (Turnball & Rivier, 1999). Most of the cortisol in blood plasma is bound to corticosteroid-binding globulin. Various stressors signalling in the body, representing an imbalance of homeostasis, can cause influxes of increased HPA activity and consequently increased serum cortisol. One such stressor is physical activity and exercise.

The HPA axis and exercise

The activation of HPA axis during exercise is due to the metabolic effect cortisol has in the synthesis of energy from non-carbohydrate sources i.e. gluconeogenesis. Therefore when blood glucose levels are decreasing this signals, via the sympathetic nervous system, to the hypothalamus to induce the HPA. The cortisol response to exercise is therefore directly related to exercise intensity, because increased exercise intensity draws on energy from non-carbohydrate sources. It is the time period following the exercise that raised cortisol concentrations are seen. Such as was shown by Urhausen et al. (1991) where chronic elevations of cortisol levels were observed after heavy training loads.

However, more recently studies by Duclos et al. have found training induces an adaptation effect on the HPA axis. They observed a reduced effect of exercise on the HPA axis. Duclos et al. (1997; 1998), noted that this occurs through the mechanism of decreased pituitary sensitivity to cortisol. These findings were followed with a further study, Duclos et al. (2003), which noted that the exercise induced effects of tissue sensitivity to glucocorticoids decreased in endurance trained athletes. This finding is beneficial to athletes because it protects them from prolonged secretion and exposure to cortisol.

It has been shown that cortisol levels can be a "marker" of overtraining or overreaching. This was originally seen in overtrained marathon runners, Barron et al. (1985). This study observed that when hypoglycaemia was induced, the expected increase in cortisol to cause gluconeogenesis did not occur. Since then, development of deciphering categories of athletes' training statuses, and what accounts for each, has been topic of recent overtraining literature. The study by Meeusen et al. (2004) looked at markers of differing training statuses; functionally overreached (FOR) and non-functionally overreached (NFOR). It reported that differing cortisol levels were seen following exercise. Training status definitiions

The development by Meeusen et al. (2004) of using a two bout exercise protocol provides a methodology to study the recovery capacity of an athlete and their response to further exercise; athletes of differing training status would be expected to react differently. This would address the question of whether athletes were well trained or overtrained by considering their hormonal response to a second bout of exercise. The cyclists post training camp had higher absolute resting cortisol values between the two exercise tests than at the same point before the training camp, showing increased levels in the body. Cortisol responses for non-functionally overreached and overreached athletes were the same after the first bout of exercise, however they differed after the second bout; indicating dysfunction in the HPA axis. The Meeusen and colleagues methodology was applied by Nedenhof et al. (2008) to a small study of only three athletes of differing training status. The study showed that the NFOR athlete displayed the largest increases following the second test. Overall these studies show that, when an athlete is overreached an alteration in HPA axis occurs, which, due to cortisol effecting immune function can lead to immunosuppression in athletes. Either those overtrained from competition or those carrying out specific intensified training programmes to improve their performance can be affected in this way.

1.3 The Immune System

The immune system is a complex integration of cells, structures and processes which combats foreign material that enters the body. The immune system can be divided into two parts; innate immunity and adaptive immunity. The innate immunity brings about acute responses to infection or stress and this is followed by signalling that activates adaptive specific immune response.

The innate immune system is the non-specific immune response that forms the first line of defence to incoming foreign matter. The mucosal immune system is central to this first line of defence, comprising of the physical barrier such as the skin or stomach epithelium and the antimicrobial cells of the innate immune system. These cells function non-selectively against the foreign material. The major cells that constitute the innate immune system are phagocytic cells; neutrophils, macrophages and dendritic cells. The former two are effector cells specialised to internalise and destroy microorganisms whereas the latter, internalise and present part of the microorganism (antigens) to adaptive immune system cells. It is worth noting that dendritic cells are essential to the induction of T-cell mediated immunity, which is explored in more detail below. Natural killer cells are also part of innate immunity, they are crucial for viral infection as they have the ability to distinguish and kill virus infected cells.

The adaptive or acquired immune response acts specifically to the invading pathogen. It comes into action when the first line of defence is unable control the infection. This second line of defence has two components to it, cellular and humoral. The cells constitute of T lymphocytes, either T helper (Th) or cytotoxic T (Tc), and B lymphocytes. B lymphocytes form the humoral immunity, producing specific immunoglobulins/antibodies to adhere to and neutralize extracellular pathogens. T-cell mediated immunity is formed of the Tc cells that kill virus or bacteria infected cells, (intracellular pathogens) and Th cells that are helper cells as they produce cytokines to activate the necessary immune cells needed for a successful immune response. Cytokines are the communication tool of the immune system. They are a group of small molecules, interferons (IFN), interleukins (IL) and tumour narcosis factors (TNF),that are pleiotropic in nature. Cytokines are central to the immune response signalling between all cells and factors that make up the immune system and the other systems of the body.

It is through cytokines that different cells of the immune system are recruited and therefore influence the type of immune response. Th cells can be further divided into subsets Th1 and Th2. Each subset causes activation of different cytokine profiles of opposing function. The interaction between the two is mutually inhibitory (Elenkov & Chrousos, 1999). Th1 main cytokines produced interferon-γ (IFN-γ), IL-12, TNF-β; these promote cells of cellular immunity described above. Due to up-regulation of the immune response of these cytokines through increased cellular immunity these cytokines are pro-inflammatory. Th2 cytokines promote humoral immunity, which are primarily IL-4, IL-10 and IL-13 and through their inhibitory effect on the Th1 cytokines, this set of cytokines is said to be anti-inflammatory. The balance of each subset is crucial to maintaining immune homeostasis.

It is the careful integration and co-ordination of all parts of the immune system explained that is required to bring about a successful immune response. The effective functioning of a body's immune response is influenced by both genetic and environmental parameters, including exercise.

Exercise effect on the Immune system

Exercise immunomodulation has been studied over the last century with greatest significance over the past 30 years; due to the increasing knowledge of how exercise can affect the immune system and its implications on athlete's health and performance. Exercise can have both acute and chronic effects on the immune system, in both positive and negative ways, dependant on the type and intensity of the exercise. The J-shaped curve model (Figure...) (Nieman, 1994) summarises the relationship between exercise intensity and the risk of infection. Risk of infection signifies the effect of exercise on immune function. The model shows that moderate levels of exercise enhance immune function, but increasing intensity to extensive amounts of high intensity exercise can lead to detrimental effects on immune function.

Figure1.3 The 'J-shaped' curve model. Based on Nieman, (1994).


The effect from each bout of prolonged intense exercise on immune function causes a proposed 'open-window' of lowered immunity (Niemen, 2000) and hence higher risk of infection. During the 3-72 hours following exercise both acute and chronic effects on cells on the immune function occur. The mechanisms through which this occurs are explained below.

Therefore athletes who use intensified training periods which induce overreaching, will be to a certain degree, susceptible to immunosuppression. This is due to the imbalance of exercise and recovery such as is shown by Lancaster et al., (2004); short periods of intensified training affect the Th1/Th2 balance after only a 6 day intensified training programme.

Mechanisms of exercise induced immunomodulation

It is understood that exercise can cause an altered HPA axis response in overreached athletes and it has been observed that cortisol has immunomodulatory effects. The mechanisms through which cortisol alters immunity are now considered.

One mechanism through which increased cortisol inhibits neutrophils' ability to pass through endothelial membranes and therefore they are unable to infiltrate the site of infection. This is evidenced through increased circulating numbers of neutrophils in blood plasma (Steensberg et al., 2001).

Another mechanism through which cortisol alters immunity is due to its anti-inflammatory effect. Exercise causes a pro-inflammatory effect, increasing pro-inflammatory cytokines circulating such as IL-1 and IL-6 (Ref). In reaction to this, raised levels of cortisol occur inducing the anti-inflammatory cytokines; IL4, IL10 and IL1ra. This causes a skew in the Th1/Th2 balance due to the inhibitory effects of these cytokines. A Th2 immune response shift is seen, through no increase in Th2 cytokines but decreased Th1 cytokines. Studies have shown that the shift is related to strenuous and intensive exercise (Steensberg et al., 2001 and Lancaster et al., 2004). This alteration in cytokine profile implicates macrophage and Tc cell activity decrease. T cells producing IFN-γ have been seen to decrease after intensive exercise (Lancaster et al., 2003), which effects dendritic cell differentiation and maturation (Piemonti et al., 1999). An increase in IL1ra blocks receptors on T-cells for IL-1, therefore the cells cannot be activated for B cell proliferation. Overall the effect induces increased susceptibility to viral (intracellular) pathogens because the immune functions against them are weakened.

PUT IN Th 1/Th2 balance figure. And refer to figure in text.

1.4 Probiotics

Probiotics, defined by the World Health Organisation (WHO), are live microorganisms which when administered in the correct amounts can confer health benefit to the host (FAO/WHO, 2001). The main strains of bacteria used as probiotics are lactic acid bacteria. The most common species belong to the two families, Lactobacilli and Bifidobacteria. The ingestion of probiotics is associated with various numbers of health benefits; from the lesser known relationship of probiotics and anticancer effects (Aso et al., 1992 & 1995), to the well established and many studies showing treatment of gastrointestinal disease. The latter has the strongest evidence of the benefits of probiotics to gut health; this is through the effect of probiotics on the host immune system. Probiotics can modulate and stimulate the host innate and adaptive immune system, to overcome disease and disorders that are detrimental to one's health (Gill & Prasad, 2008).

Lowered immune function is directly related to having an increased risk of infection or disease. It is through the mucosal immune system that forms part of the first line of defence of the innate immune system that probiotics can change immune function. Not only can lactic acid bacteria alter the physical lining itself (West et al., 2009) Probiotic manipulation of the epithelial cells of the stomach induce effects on the antimicrobial factors of the mucosal immune system. Lactobacilli administration has been found to cause an up-regulated innate immune response; enhancement in activity of phagocytic cells, dendritic cells and natural killer cells (de Vrese & Schrezenmeir, 2002; Gill & Parased, 2008; Borchers et al., 2009). Further to this, effects on the adaptive immunity occur to the T and B lymphocytes, this has mainly been seen to occur through the alterations in cytokine production due to the innate cell production creating differing cytokine pathways. Regulation of the Th1/Th2 balance has also been seen through supplementation with probiotics (Gill & Parased, 2008).

Probiotics, Stress and Exercise

Probiotics can be used as a tool to manipulate immune function in the exercise induced altered immunity induced by exercise observed in athletes. There are only a few studies to date that have considered the athletic link and potential benefits of probiotics. Pujol et al. (2000) found that Lactobacillus casei counteracted the normally observed lowered concentration of natural killer cells following exhaustive exercise. Clancy et al. (2006) used Lactobacillus acidophilus and found after taking the supplement for a month fatigued athletes had significant increases in IFN-γ secretion from T-cells compared to the levels of healthy athletes. This shows the reversal capacity of using probiotic supplementation during intense training of athletes where there are immune deficiency risks. The most recently published probiotic and exercise study from Cox et al. (2010) used 20 elite male distance runners, and a double blind, placebo controlled study using Lactobacillus fermentum. It supported Clancey et al (2006) findings that the probiotic athletes showed a greater increase in IFN-γ compared to placebo and correlated to this there was a reduction in reported days of respiratory illness symptoms which were also lower in severity. From both the Clancey and Cox studies, it can be seen that IFN-γ was maintained through exercise, indicating the potential for probiotics to be clinically beneficial in an athletic setting.

The effect of exercise causes stress on the body and leads to raised cortisol levels, which has been seen to have a causational link to impaired immunity. The possible mechanisms through which probiotics can modify the immune system have been considered and therefore the question arises of whether probiotics can be used to mediate cortisol and its immunomodulatory effects.

Studies of non-athletes which considered psychological have reported suggestions of a possible mechanism through which probiotics can alter cortisol production. Marcos et al. (2004) looked at students under examination stress and a parallelel can be draws between this and the physical stress that athletes' bodies endure during intensified training. Cortisol levels increased in both placebo and probiotic groups however the control group increased 2.5 times greater than the placebo group. Along with this there was a significant increase in lymphocyte count compared to the control group which decreased. Findings also support Pujol et al. (2000) seeing natural killer cell numbers increase in probiotic subjects. Marcos et al. (2004) suggest an indirect mechanism between the increased lymphocytes and levels of cortisol, through cytokine control such as IL 1 that can modulate the HPA axis. This may come about through the interlinking of the immune system to the central nervous system (CNS) through receptors on both immune cells and in the CNS (Kusnecov & Rabin 1994). This neurohumoral mechanism between the effects of probiotics on the gut through to the HPA axis has been further developed by Eutamene & Bueno (2007) in a gut-brain neuroimmune reflex pathway, and mechanisms are shown in Figure....This relationship could be applied to the increased HPA axis activity and raised cortisol levels seen in athletes. GO ON TO EXPLAIN SCHEMATIC - EUTAMENE 2007

(response which is inflammatory. may induce further increases in cortisol to cause an anti-inflammatory effect to counteract this.)

1.5 Hypothesis

Immune function can be altered and impaired through athlete's carrying out intensified training (Steensberg 2001, 2003; Lancaster...) to a state of non-functional overreaching. This can be partly attributed to the increased levels of stress hormones produced by the body in response to exercise. Probiotics can be used as a supplement to counteract this due to the known effects probiotics have on the immune system. The diminution in immune function due to cortisol could be altered indirectly through up-regulation of the Th1 profile and cytokine signalling pathways but also directly through a neurohumoral mechanism affecting the HPA axis and therefore cortisol production (REF). However opposed to this it has been noted that the probiotics can cause an up regulation of the immune system (Page...). This is an inflammatory effect which may itself lead to increases in cortisol production, to induce counteracting it through an anti-inflammatory effect.

It is therefore expected that Lactobacillus acidophilus will alter the normal cortisol response seen during a period of intensified training in highly trained athletes. Furthermore the athletes' performance following the training programme is expected to decrease indicating a state of overreaching.