Research Review By Demetry Assimakopoulos©

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Date Posted:

October 2011

Study Title:

Neuroendocrine-Immune Interactions and Responses to Exercise

Authors:

Fragala MS, Kraemer WJ, Denegar CR et al.

Author's Affiliations:

University of Connecticut; University of Central Florida; Pennsylvania State University

Publication Information:

Sports Medicine 2011; 41(8): 621-639.

Background Information:

There is a significant interaction between the neuroendocrine system and the immune system. In fact, any changes in hormonal levels, such as those released by the pituitary or adrenal glands, can cause significant changes in immunity or in the immune response. For example, a deficiency in prolactin, growth hormones or thyroid hormone can cause a decrease in lymphocyte development.

This intricate relationship is mediated by direct communication between the two systems. Communication between them is virtually a two-way street, as lymphokines and cytokines can influence neuroendocrine tissues directly and synthesize peptide hormones, such as adrenocorticotropin (ACTH) and thyrotropin while neuroendocrine polypeptide hormones have the capability of modulating lymphocyte and other immune responses (1).

There are several signaling molecules that mediate these responses. Chiefly among them are the ‘stress’ hormones – namely catecholamines (epinephrine and norepinephrine) and cortisol. It is these stress hormones that appear to be particularly involved in exercise-induced immune responses. These hormones are known to increase in concentration during exercise and return to their normal baseline levels shortly after exercise is terminated. However, they also seem to have a mobilizing effect on immune cells during the period of time the body uses for recovery after exercise.

In fact, there is a hormone-specific distinction in utility, whereby catecholamines appear to be responsible for the immediate and short-term effects of exercise on lymphocytes while cortisol appears to affect the immune system after a lag time of about two hours (2). While ‘stress’ horomones have this effect on the immune system, so do ‘sex’ hormones, such as testosterone and estradiol (3).

It is the goal of this article to outline the effect of cortisol, catecholamines, estrogen and testosterone on the immune system, with particular interest in their neuroendocrine-immune interactions and communication pertaining to exercise.

Pertinent Results:

The response of the body to exercise can be explained in part by the General Adaptation Syndrome, which was first described by Hans Selye. He stated that all of the systems of the human body, including those of the neuroendocrine and immune system, work together to maintain a tightly controlled internal environment and that disruptions of this environment trigger physiological feedback mechanisms to maintain this preferred environment.

Exercise is one medium that can shake the foundation of this homeostatic environment. In fact, the response of the body to exercise is so specific, that responses are unique to the nature, protocol and environmental conditions of the exercise and one’s nutritional status.

The response of the neuroendocrine system to acute exercise is dependent on the intensity and volume of the exercise. The type of exercise that provides that greatest acute hormonal elevation are resistance training protocols that are moderate to high in intensity, high in volume, stress a large proportion of one’s muscle mass and utilize short rest intervals. Another astonishing fact is that only cells which express the specific receptors for these hormones can respond, which creates an ideal physiological control mechanism.

Additionally, only specific types of circulating hormones elevate during an acute exercise bout, including growth hormone and testosterone (in men), cortisol, epinephrine and norepinephrine (4). Their elevation increases the likelihood of their binding to specific receptors on target tissues. Fascinatingly, there is a potential increase in the number of corresponding receptors, which further potentiates their binding.

The aforementioned acute responses are thought, in part, to mediate the resulting increases in strength, power, hypertrophy and muscular endurance that are frequently observed with resistance training (5). Variables such as the intensity of exercise (percentage of 1RM), the amount of muscle mass utilized in the protocol and volume are important in defining the magnitude of hormone responses. In fact, higher volumes of multiple, versus single set programs, produce significantly greater elevations in anabolic hormones following exercise in men.

From here, some short points about the hormones included within the context of the article are necessary:

Catecholamines (epinephrine, norepinephrine, dopamine): The magnitude of their elevation is dependent on the force of muscle contraction, amount of muscle stimulated, volume of resistance exercise and rest intervals. The physiological responses mediated by catecholamines include blood redistribution, energy promotion and facilitation of contractile characteristics of skeletal muscle.

Cortisol: Exercise programs producing the greatest amount of lactate have been proven to create the greatest increase in cortisol circulation (i.e. high volume, high intensity, short rest intervals). This hormone has been implicated in remodeling tissue in response to a bout of exercise, regulating muscle protein content, stimulating protein degradation and inhibiting actin and myosin synthesis in all muscle fibre types.

Estradiol: While little is known about this hormone’s response to acute exercise, acute elevations of this hormone following resistance training have been seen. Specifically, estradiol has been reported to play a protective role in muscle damage by decreasing post-exercise membrane damage and structural damage. It has also been shown to act as an antioxidant and membrane stabilizer in muscle.

Testosterone: This hormone is responsible anabolic muscle adaptations that are normally achieved with resistance training in men. Most evidence shows that it does not respond to acute exercise in women, except after endurance exercise. Much of the anabolic changes that occur in women are due to increases in growth hormone. Testosterone’s response to acute exercise is dependent on the muscle mass involved, the volume and intensity of exercise.

The immune system, much like the endocrine system, is very responsive to acute stressors. The immune system is often thought of as a sensory organ for most pathological states or for external stimuli that cannot be detected by the nervous system. This is so sensitive, that during acute aerobic exercise, lymphocyte and neutrophil counts increase. Specifically, neutrophils increase during exercise and continue to increase for several hours post-exercise.

On the other hand, while lymphocytes increase during the period of exercise, they steadily drop below baseline for 2-6 hours post-exercise. The magnitude of the lymphocyte decrease is mediated by the intensity and duration of the exercise, with the most pronounced changes occurring after bouts of exercise greater than 1.5 hours in duration and intensities between 55-75% of VO2max. The leukocyte counts typically return to baseline within 3-24 hours post-exercise. While this apparent decrease in immune function occurs after acute bouts of exercise, basal immune function seems to be the same in chronically trained athletes when compared to non-athletes (6).

Acute bouts of resistance exercise appear to yield similar effects as aerobic exercise, as leukocyte counts tend to increase. Both heavy resistance training and long-term training appear to increase levels of leukocytes, while reducing basal cytokine levels and reducing low-grade inflammation (7,8).

While there is great paucity in the research, the gender differences as far as positive physiological and immunological changes as a result of acute and chronic exercise appear to be stronger in women compared to men. Not only this, but women also apparently demonstrate an attenuated inflammatory response to exercise that results in considerable muscle damage when compared to men, even when the muscle damage is similar. However, more research needs to be performed to further elucidate this topic when it comes to gender.

While reading this review, the reader may wonder – how does all of this work? Actually, two main neuroendocrine pathways are activated in response to exercise which influence the immune system: the hypothalamic-pituitary-adrenal axis (HPA axis – which results in the release of cortisol and other glucocorticoids, mainly from the adrenal glands) and the sympathetic nervous system (SNS – which results in the release of catecholamines).

Both of these systems, and their respective effects, mediate the number, function, activity and trafficking of immune cells (9). This system is so efficient, that different changes occur with the timed activation of systems and time release of different hormones. For instance, the increase in the circulation of catecholamines during the anticipation of exercise and during the first moments of exercise affects neutrophils and natural killer cells, who act as an early line of defense in muscle tissue, during its inflammatory response to exercise-induced injury.

An important effect of catecholamines on the immune system is to pull leukocytes into circulation, which is more or less stimulated by the binding of epinephrine to ?2-adrenergic receptors. However, the research on the direct interaction of catecholamines with ?2-adrenergic receptors in immune-cell mobilization is scarce and more research needs to be produced before any specific conclusions can be stated.

On the other hand, cortisol, which increases after the onset of exercise, is responsible for the decrease of neutrophils, eosinophils and lymphocytes, as well as a decrease in function in natural killer cells and T-cells; specifically, these changes as a result of cortisol release occur during the recovery phase after high-intensity exercise.

Additionally, secretion of cortisol and other adrenal glucocorticoids plays an important role in the regulation of immunological processes by suppressing and regulating inflammation. They also impact the immune system by affecting the development of immune cells, their trafficking and function (10,11).

Elevated levels of glucocorticoids result in a negative feedback reaction, leading to the decrease in the release of growth hormone from lymphocytes (WRITER'S NOTE: the authors did not discuss when this effect occurs during exercise – although it is presumed that it occurs during the recovery phase. Also, they did not discuss why this occurs and whether it is beneficial or detrimental to the person). However, the authors did state that more research needs to be performed to provide important insights on how these systems interact to accommodate the stress created from exercise.

Much like cortisol and catecholamines, estradiol can exert numerous physiological actions on a number of tissues, in addition to having a role in reproduction. From the perspective of the immune system, estrogen has been shown to stimulate antibody production, while decreasing T-cell mediated delayed-type hypersensitivity, granulocyte-mediated inflammation, and natural killer cell-mediated cytotoxicity.

Additionally, estrogen and other sex steroids are involved in the creation of T and B lymphocytes (lymphopoiesis). However, at other times, especially when estradiol is present in high amounts such as during pregnancy, estradiol can have a negative effect on lymphopoiesis. It has also been shown that B lymphopoiesis is elevated during times of estrogen deficiency in mice that can be corrected when estrogen is replaced. The most interesting phenomenon having to do with estradiol is the fact that hormonal changes during the menstrual cycle have no substantial effect on lymphocyte numbers or their response during acute stress.

This finding may be attributed to the long-term duration of estrogen`s action, which exceeds the time window of the menstrual cycle. Much of these effects are mediated by the fact that estrogen can bind to lymphocytes via 2 receptors: ER-? and ER-?.

Estradiol has also been shown to have an anti-inflammatory effect (12). Systemic administration of this hormone has been shown to attenuate the expression of inflammatory mediators and the infiltration of leukocytes following vascular injury.

Additional research has shown a synergistic role between estrogen and glucocorticoids. For example, higher levels of estradiol enhances glucocorticoid sensitivity. Also, synthetic estrogen administered with oral contraceptive can result in elevated levels of cortisol. Despite all of these concurrent fascinating roles, estradiol`s role in the neuroendocrine-immune interaction in response to exercise requires further research.

Much like estradiol, testosterone appears to impact immune function, as cells like macrophages, lymphocytes and vascular smooth muscles all possess androgen receptors (13). This relationship is exemplified by the fact that the release of testosterone inhibits the secretion of specific cytokines. However, the research on how testosterone interacts with the immune system to modulate exercise-induced responses requires further elucidation.

Clinical Application & Conclusions:

Few studies have been conducted to examine the neuroendocrine-immune communication in response to exercise. Specifically, research is needed to examine and identify the factors that trigger the synthesis of neuroendocrine hormones by immune cells in response to exercise and to understand the factors which control the neuroendocrine hormone receptor expression on immune cells. Examination of the neuroendocrine-immune interactions in response to exercise with consideration of gender interactions also requires further study.

Study Methods:

A number of keyword search strings were searched in the Pubmed database. Appropriate papers were screened and selected and their reference lists were cross-referenced to supplement initial keyword searchers. In addition to these searchers, prominent researchers’ names were searched in the PubMed database to find other appropriate literature.

In order to be included, articles were required to address neuroendocrine-immune interactions/communication, exercise-induced neuroendocrine responses, exercise-induced immune responses or evidence of neuro-endocrine-immune responses mediating adaptations to exercise. Also, articles addressing gender differences in accordance with the subjects headings described above were also included.

Study Strengths / Weaknesses:

Weaknesses:
  • Only the PubMed database was consulted. It is conceivable that there are many other literature databases that could provide some insight into this topic that are not indexed in PubMed.
  • Many of the literary sources are dated, indicating that either more database searching needed to be performed, or the research on the respective subjects need to be updated.
  • No specific statements regarding one’s susceptibility to infection post-exercise, due to the reduction of circulating leukocytes was expressly discussed. They discussed at which intensity and volume of exercise produced the most pronounced immunological responses; however no minimum intensity/volume was discussed in any respect.
Strengths:
  • The subject matter was comprehensive
  • The authors stated exactly where they believed more research needed to be performed – particularly in areas involving gender differences in the immunological responses to stress.

Additional References:

  1. Smith EM & Blalock JE. Human lymphocyte production of corticotropin and endorphin-like substances: association with leukocyte interferon. Proc Natl Acad Sci U S A 1981 Dec; 78 (12): 7530-4
  2. Pedersen BK, Rohde T & Ostrowski K. Recovery of the immune system after exercise. Acta Physiol Scand 1998 Mar; 162 (3): 325-32
  3. Grossman CJ. Regulation of the immune system by sex steroids. Endocr Rev 1984 Summer; 5 (3): 435-55
  4. Kraemer WJ. Endocrine responses to resistance exercise. Med Sci Sports Exerc 1988 Oct; 20 (5 Suppl.): S152-7
  5. Kraemer WJ & Ratamess NA. Hormonal responses and adaptations to resistance exercise and training. Sports Med 2005; 35 (4): 339-61
  6. Gleeson M. Immune function in sport and exercise. J Appl Physiol 2007 Aug; 103 (2): 693-9
  7. Kraemer WJ, Clemson A & Triplett NT, et al. The effects of plasma cortisol elevation on total and differential leukocyte counts in response to heavy-resistance exercise. Eur J Appl Physiol Occup Physiol 1996; 73 (1-2): 93-7
  8. Mathur N & Pedersen BK. Exercise as a mean to control low-grade systemic inflammation. Mediators Inflamm. Epub 2009 Jan 11
  9. Brenner I, Shek PN & Zamecnik J, et al. Stress hormones and the immunological responses to heat and exercise. Int J Sports Med 1998 Feb; 19 (2): 130-43
  10. Claman HN. Corticosteroids as immunomodulators. Ann N Y Acad Sci 1993 Jun 23; 685: 288-92
  11. Besedovsky HO, Del Rey A & Sorkin E. Antigenic competition between horse and sheep red blood cells as a hormone-dependent phenomenon. Clin Exp Immunol 1979 Jul; 37 (1): 106-13
  12. Bakir S, Mori T, Durand J, et al. Estrogen-induced vasoprotection is estrogen receptor dependent: evidence from the balloon-injured rat carotid artery model. Circulation 2000 May 23; 101 (20): 2342-4
  13. Mealy K, Robinson B, Millette CF, et al. The testicular effects of tumor necrosis factor. Ann Surg 1990 Apr; 211 (4): 470-5