Medicină sportivă: ipoteza stresului muscular manifestat prin citokine

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BASIC SCIENCES

Reviews

Cytokine hypothesis of overtraining:

a physiological adaptation toexcessive stress?

LUCILLE LAKIER SMITH

Department of Health, Leisure, and Exercise Science, Appalachian State University, Boone, NC 28608

ABSTRACT

SMITH, L. L. Cytokine hypothesis of overtraining: a physiological adaptation to excessive stress? Med. Sci. Sports Exerc., Vol. 32,

No. 2, pp. 317–331, 2000. Overtraining syndrome (OTS) is a condition wherein an athlete is training excessively, yet performance

deteriorates. This is usually accompanied by mood/behavior changes and a variety of biochemical and physiological alterations.

Presently, there is no global hypothesis to account for OTS. The present paper will attempt to provide a unifying paradigm that will

integrate previous research under the rubric of the cytokine hypothesis of overtraining. It is argued that high volume/intensity training,

with insufficient rest, will produce muscle and/or skeletal and/or joint trauma. Circulating monocytes are then activated by injury-

related cytokines, and in turn produce large quantities of proinflammatory IL-1, and/or IL-6, and/or TNF-, producing systemic

inflammation. Elevated circulating cytokines then co-ordinate the whole-body response by: a) communicating with the CNS and

inducing a set of behaviors referred to as “sickness” behavior, which involves mood and behavior changes that support resolution of

systemic inflammation; b) adjusting liver function, to support the up-regulation of gluconeogenesis, as well as de novo synthesis of

acute phase proteins, and a concomitant hypercatabolic state; and c) impacting on immune function. Theoretically, OTS is viewed as

the third stage of Selye’s general adaptation syndrome, with the focus being on recovery/survival, and not adaptation, and is deemed

to be “protective,” occurring in response to excessive physical/physiological stress. Recommendations are made for potential markers

of OTS, based on a systemic inflammatory condition. Key Words: INTERLEUKIN-1, INTERLEUKIN-6, TUMOR NECROSIS

FACTOR-, ACUTE PHASE PROTEINS, TISSUE TRAUMA

The purpose of this paper is to integrate available

information pertaining to the overtraining syndrome

(OTS) into one paradigm, which will be referred to as

the cytokine hypothesis of overtraining. The following hy-

pothesis is not presented as complete but is advanced in an

attempt to focus future research efforts. For brevity, refer-

ences are generally limited to review articles. The predom-

inant focus of this paper will be on the systemic immune/

inflammatory response. These terms are frequently usedinterchangeably due to their extensive overlap; for concise-

ness, the term systemic inflammation will be used.

Athletes train hard to optimize performance. Inherent in

all training programs is the application of the progressive

overload principle, which implies working beyond a com-

fortable level in order to maximize athletic ability

(26,27,45,91). Unfortunately, there is a fine line between

improved performance and deterioration. When deteriora-

tion in performance occurs in association with an arduous

training schedule, it is referred to as overtraining, staleness,

or burnout (66).

The universal criterion associated with overtraining is a

decrease in performance. However, not all aspects of per-

formance are affected simultaneously nor are they impacted

to the same degree, making prediction and/or interpretationconfusing (66). It is also probable that other signs/symptoms

typically associated with overtraining are evident before a

deterioration in performance. These might include general-

ized fatigue, depression, muscle and joint pain, and loss of

appetite. However, it is the decline in performance fre-

quently associated with an increased volume or load of

training, that captures the attention of the athlete and coach.

A large number of symptoms associated with overtraining,

have been reported in the literature. Fry et. al. (27) have

categorized these according to physiological performance,

psychological/information processing, immunological, and

biochemical parameters (see Table 1). However, there is no

0195-9131/00/3202-0317/0

MEDICINE & SCIENCE IN SPORTS & EXERCISE®

Copyright © 2000 by the American College of Sports Medicine

Submitted for publication January 1999.

Accepted for publication November 1999.

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universally agreed upon cluster of symptoms, and no cluster

that would conveniently describe overtraining associated

with a particular sport, or a particular type of training (such

as aerobic versus anaerobic). For the most part, multiple

symptoms may be present in a variety of combinations, andit is this cluster that is referred to as OTS.

In contrast to overtraining, overreaching is a term used to

imply a temporary deterioration in performance, reflecting the

time period between the application of a exacting stimulus, and

subsequent recovery and adaptation (26,27,45,48,91). In many

training cycles, athletes experience this short-term overreach-

ing as they increase intensity and/or volume but recover rapidly

and improve or maintain performance. However, if the athlete

continues to show a decrement in performance, even with an

appropriate rest/regeneration period, this is most likely OTS.

Since there is a continual risk of imbalance between

training, competition, and recovery, OTS is a common prob-lem (48). Sixty percent of distance runners, 21% Australian

swimmers, and more than 50% of soccer players, have been

classified as overtrained. Presently the only known treat-

ment is a decrease in training volume or in some instances

complete rest. “Once the athlete has developed the full-

blown overtraining syndrome, he or she must rest com-

pletely for anything between 6 to 12 weeks. . .” (64). OTS is

most likely also prevalent amongst recreational athletes, but

has not received the same attention, for obvious reasons.

Existing Theories of OTS

A variety of hypotheses have been proposed to accountfor OTS. A number of these hypotheses remain viable,

whereas others have gained minimal support. It will be

suggested that many of these hypotheses represent pertinent

aspects of the syndrome (45,47,89). For more extensive

information, the reader is referred to excellent reviews

(24,26,27,91).

Several investigators have focused on the role of the

hypothalamus, which results in activation of the autonomic

nervous system (47), and the hypothalamic-pituitary-adre-

nal axis (HPA), as well as involvement of the hypothalamic-

pituitary-gonadal axis (HPG); this results in alterations of

blood catecholamine, glucocorticoid, and testosterone levels

TABLE 1. The major symptoms of overtraining as indicated by their prevalence inthe literature (Reprinted from Fry, Morton, and Keast, 1991)

Physiological performanceDecreased performanceDecreased serum ferritinLowered TIBCMineral depletion (Zn, Co, Al, Mn, Se, Cu, etc.)Increased urea concentrationsDecreased serum ferritinLowered TIBCMineral depletion (Zn, Co, Al, Mn, Se, Cu, etc.)Increased urea concentrationsInability to meet previously attained performance standards or criteriaRecovery prolongedReduced toleration of loadingDecreased muscular strengthDecreased maximum work capacityLoss of coordinationDecreased efficiency or decreased amplitude of movementReappearance of mistakes already correctedReduced capacity of differentiation and correctedReduced capacity of differentiation and correcting technical faultsIncreased difference between lying and standing heart rateAbnormal T wave pattern in ECGHeart discomfort on slight exertionChanges in blood pressureChanges in heart rate at rest, exercise, and recoveryIncreased frequency of respirationPerfuse respirationDecreased body fatIncreased oxygen consumption at submaximal workloadsIncreased ventilation and heart rate at submaximal workloadsShift of the lactate curve towards the X-axisDecreased evening postworkout weightElevated basal metabolic rateChronic fatigueInsomnia with and with night sweatsFeels thirstyAnorexia nervosaLoss of appetiteBulimiaAmenorrhea or oligomenorrheaHeadachesNauseaIncreased aches and painsGastrointestinal disturbances

Muscle soreness or tendernessTendonostic complaintsPeriosteal complaintsMuscle damageElevated C-reactiveRhabdomyolysis

Psychological/information processingFeelings of depressionGeneral apathyDecreased self-esteem or worsening feelings of selfEmotional instabilityDifficulty in concentrating at work and trainingSensitive to environmental and emotional stressFear of competitionChanges in personalityDecreased ability to narrow concentrationIncreased internal and external distractibility

Decreased capacity to deal with large amounts of informationGives up when going gets tough

ImmunologicalIncreased susceptibility to and severity of illnesses, colds, and allergiesFlu-like illnessUnconfirmed glandular feverMinor scratches heal slowlySwelling of the lymph glandsOne-day coldsDecreased functional activity of neutrophilsDecreased total lymphocyte countsReduced response to mitogensIncreased blood eosinophil countDecreased proportion of null (non-T, non-B) lymphocytesBacterial infectionReactivation of herpes viral infectionSignificant variations in CD4: CD8 lymphocytes

TABLE 1.—Continued

BiochemicalNegative nitrogen balanceHypothalamic dysfunctionFlat glucose tolerance curvesDepressed muscle glycogen concentrationDecreased bone mineral contentDelayed menarcheDecreased hemoglobinDecreased serum ironDecreased serum ferritinLowered TIBCMineral depletion (Zn, Co, Al, Mn, Se, Cu, etc.)Increased urea concentrationsElevated cortisol levelsElevated ketosteroidsLow free testosteroneIncreased serum hormone binding globulinDecreased ratio to free testosterone to cortisol of more than 30%Increased uric acid production

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(37). Undoubtedly, there is involvement of these systems in

OTS, since heavy training represents an extreme stress, both

physically and psychologically. However, it will be pro-

posed that activation of these pathways may be a conse-

quence, and not necessarily a primary initiator.

There is substantial evidence demonstrating reductions in

blood levels of the amino acid, glutamine, in OTS (36).

Newsholme’s glutamine theory (62) proposes that reduced

blood glutamine is responsible for the frequently observed

impaired immune response and associated increased rate of

infection seen in OTS, since glutamine is a primary fuel

utilized by lymphocyte cells (69).

Several investigators (44,62) have focused on the reduc-

tion of circulating levels of the amino acid tryptophan

(TRY). Reduced blood levels of TRY have been interpreted

to reflect a greater uptake of this amino acid by the brain.

Tryptophan is the precursor for synthesis of the brain neu-

rotransmitter serotonin. Increased brain levels of serotonin

are believed to result in mood and behavioral changes, such

as inducing sleep and reducing appetite, both behaviors

evident in OTS (44).

The glycogen hypothesis of overtraining (14) has sug-

gested that in response to dramatic increases in training

load, certain athletes are unable to maintain sufficient intake

of calories, in particular carbohydrate, and that this would

result in reduced muscle glycogen, and could account in

part, for feelings of fatigue and reduced performance. Al-

though this phenomenon has been frequently observed in

OTS, this theory has not been substantiated (89).

Foster and Lehman (24) have suggested that the lack of

day to day variation in training, could induce the OTS; this

is referred to as the monotony theory of overtraining. In-

herent in this theory is the assumption that the psychological

monotony can impact on physiological performance. Analternate interpretation for the involvement of monotony in

OTS is that the daily “sameness” of intense training will

impose excessive stress on the musculo-skeletal-joint sys-

tem, thus making the athlete more prone to injury.

At present, there is no all encompassing hypothesis for

OTS. The view presented in this paper will attempt to

integrate the above information into a unifying hypothesis.

To be acceptable, it must account for the diverse physical,

physiological, behavioral, and psychological changes asso-

ciated with OTS. It must also explain how OTS, where

similarities are more striking than differences, occurs in

response to a wide array of training regimens and athleticevents.

Muscle Trauma and Systemic Inflammation

The present hypothesis proposes that trauma to the mus-

cular, skeletal, and/or joint system, is frequently the initiator

of OTS. However, before presenting this argument, it seems

appropriate to discuss the presence of “naturally” occurring,

exercise-related, tissue trauma. It is now widely accepted

that training and competing results in degrees of micro-

trauma to muscle, connective tissue, and/or bones and joints

(87). This type of “injury” will be referred to as adaptive

microtrauma (AMT) and may be regarded as an initial phase

along an “injury continuum.” Contending with this AMT

may require nothing more than an appropriate training pro-

gram that includes rest days, and/or hard and easy work

days, and or cross-training, to allow for recovery.

It is proposed that AMT may be induced via several

mechanisms. It is well documented that the eccentric com-

ponent of a movement will induce tissue trauma (86). Ad-

ditionally, it is suggested that exercise requiring elevated

local metabolic demands, such as high-intensity cycling,

may induce “pockets” of ischemia, resulting in ischemic/

reperfusion injury (1,12). Finally, it is also proposed that

joint structures involved in high volume repetitions, would

induce AMT in these structures (see Fig. 1). The reason for

referring to this microinjury as “adaptive” is that it is widely

believed that AMT results in a mild inflammatory response,

with the final purpose of “healing” (13,50,86). The healing

process may result in an “overshoot” phenomenon and beassociated with an adaptation (13) of muscle, bone, and/or

connective tissue.

Musculo-skeletal-joint trauma/injury, proposed as the un-

derlying cause of OTS, may be induced by a variety of

circumstances. Conceivably, this injury may be due to a

progression from the initial benign AMT-stage, to a sub-

clinical injury in the athlete who is training too hard and too

frequently (2,71,82). Another possibility is a circumstance

involving continued training, before recovery from an acute

injury, which may exacerbate the initial injury (39,81,91).

Kibler and Chandler (39) suggest that relative to overtrain-

ing “the types of injuries identified, range from the overt,that are obvious injuries and will usually prevent perfor-

mance for some period of time, to the subclinical, that

decrease performance but may be seldom recognized.”

As stated previously, the universally accepted sign of

OTS is a decrease in performance (6,27,91). Injury would

undoubtedly compromise performance. A large body of

research demonstrates that even minor muscle trauma, as is

seen after an unaccustomed bout of eccentrics, interferes

with performance (13). Injury impacts locally on factors

such as strength and range of motion, which affects overall

performance. Due to injury “the athlete may modify partic-

ipation, and at times may cause an injury in a distant part of

Figure 1—Schematic diagram of proposed manner by which various

musculoskeletal actions may result in tissue trauma/injury.

OVERTRAINING AND SYSTEMATIC INFLAMMATION Medicine & Science in Sports & Exercise

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the kinetic chain, likely due to abnormal biomechanical

movement patterns” (39).

It has been stated that musculoskeletal overuse injuries

represent a “. . .musculoskeletal manifestation of the over-

training syndrome” (39). This implies first the developmentof OTS and then the inception of injury. However, it is

proposed here, that the injury may be both the initiating and

perpetuating cause of OTS. Many reports suggest the pres-

ence of injury in an overtrained athlete. Such reports include

muscle and joint soreness and tenderness, persistent muscle

soreness that increases with each session, and elevated se-

rum creatine kinase (25,64). More direct evidence has re-

cently been made available by the work of Seene and

colleagues (78), who reported extensive muscle damage in

biopsies of overtrained athletes.

The cytokine hypothesis of overtraining will propose that

repetitive trauma to the musculoskeletal system, due to highintensity/volume training, associated with insufficient rest/

recovery time, is the predominant cause of overtraining. It

will be suggested that many of the physiological, behav-

ioral, and psychological signs and symptoms associated

with OTS could emerge from the presence of an injury.

Additionally, the cytokine hypothesis will attempt to ac-

commodate alternate stressors that may be causal or may

contribute in an additive sense, such as psychological stress

(61) or an acute viral infection (36,75).

Injury, Inflammation, and Cytokines

The proposed connection between injury and OTS is asfollows. Subacute exercise-induced musculoskeletal trauma

will result in the release of local inflammatory factors,

cytokines. With continued high-volume, high-intensity

training and limited rest, typically associated with OTS,

local acute inflammation becomes chronic, and the cyto-

kines released in this process activate circulating monocytes

(46,71). Activated monocytes produce large quantities of

proinflammatory cytokines, resulting in systemic inflamma-

tion. Systemic inflammation is proposed as the central un-

derpinning of OTS (see Fig. 2).

Inflammation is the generalized response of the body to

tissue injury, irrespective of the damaging stimulus. The

primary focus of acute inflammation is healing, a process

crucial to survival. Overt signs and symptoms of inflamma-

tion include swelling, redness, heat, pain, and reduction in

the function of the injured area. However, not all clinical

manifestations are consistently detectable. There are un-

doubtedly variations in the nature and the magnitude of the

inflammatory response (9), dependent upon such factors as

the extent of the injury, the tissue type, and nutritional

status. The present discussion will focus predominantly on

inflammation occurring in response to exercise-induced

muscular-skeletal injury (87).

In response to tissue injury, the body mounts an elaborate,

synchronized response, with extensive amplification at each

step. The overall response is characterized by movement of

fluid, plasma protein, and leukocytes, from the circulation

into injured tissue. Many of the initial events, manifested

within a few hours after injury, are directed toward local

recruitment of specific white blood cells. Neutrophils rep-

resent the first wave of infiltrating cells and play a vital role

in the “clean-up” process. Neutrophils predominate during

the initial phase of acute inflammation but by 24 h are no

longer active (86).

Monocytes form the next line of defense. When these

cells move from the circulation into the tissue, they are

transformed into macrophages. When activated, either as a

circulating monocyte, or as a tissue macrophage, this “com-

plex, powerful and mobile cell,” is capable of secreting over

100 different chemicals and is central to the local and

systemic inflammatory process. In the present paper, focus

will be on activated, circulating monocytes, representative

of a systemic inflammatory response.

Although neutrophils and monocytes are regarded as pri-

mary players in an inflammatory response, coordination of

these cells, as well as amplification of numerous aspects of inflammation, are accomplished by a group of molecules

collectively known as cytokines (84). In recent years, there

has been great interest in this group of inflammatory medi-

ators. Cytokines may be defined as soluble hormone-like

proteins. However, in contrast to hormones, which are syn-

thesized by specific endocrine tissues, cytokines are pro-

duced by a variety of cells such as immune cells, endothelial

cells, and fat-storing cells. Furthermore, their synthesis is

activated by a large array of stimuli including free radicals,

tissue injury, and infectious agents (8,10,80).

Besides involvement in local inflammatory events, cyto-

kines integrate systemic inflammatory events (84). A widevariety of cells, such as lymphocytes, and organs, such as

the liver and the brain, are capable of responding to a

number of different cytokines (30). Cytokines have the

capacity to stimulate surrounding cells (paracrine), or them-

selves (autocrine), which may lead to further cytokine pro-

duction and amplification of a particular response. Thus, the

cellular source and biologic target of cytokines are not

restricted to one cell-type or organ as is often the case with

hormones. Cytokines can be broadly grouped according to

their structure or function, into interlukins (IL), interferons

(INF), tumor necrosis factor (TNF), growth factors, and

chemokines (84). Cytokines are generally regarded as pro-

Figure 2—Schematic diagram of proposed exercise-related events

leading to the development of a systemic immune/inflammatory re-sponse.



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or anti-inflammatory. Proinflammatory cytokines include

interleukin-1 (IL-1), IL-6, IL-8, and tumor necrosis fac-

tor (TNF)-. There are also a number of anti-inflammatory

cytokines whose sole purpose is to regulate this inflamma-

tory network. Some anti-inflammatory cytokines include

IL-4, IL-10, and IL-13, as well as IL-1 receptor antagonist

(IL-1ra).

The cytokines central to the proposed theory of overtrain-

ing are the proinflammatory IL-1, and TNF-. IL-1 and

TNF- are secreted at the onset of an inflammatory cascade

and act locally at the site of injury/infection; they are pleio-

tropic and share many overlapping actions (19). One of their

numerous local functions is activation of endothelial cells of

local blood vessels, which are stimulated to produce diverse

cytokines. Systemically, these proinflammatory cytokines

may act on the liver to regulate the synthesis of acute phase

proteins, and may also act at the level of the hypothalamus,

to initiate the change in the body temperature set-point and

thus assist in the control of fever. There are additional

multiple areas in the higher brain centers, which contain

specific receptor sites for these cytokines (30). Concerning

exercise and the production of IL-1 and TNF-, there are a

number of excellent reviews (5,68,82).

The other cytokine believed to be involved in OTS is

IL-6. IL-6 is generally synthesized after the initial synthesis

of IL-1 and TNF-. It has been regarded as a proinflam-

matory cytokine, but more recently, focus has been on its

anti-inflammatory effects, as it appears to play a role in the

dampening of the inflammatory response (8,19). IL-6 is

inducible in nearly every human cell and tissue type (8).

Numerous factors are capable of stimulating IL-6 expres-

sion, including IL-1 and TNF-. IL-6 appears to modulate

both local and systemic inflammation and immunity. The

magnitude of elevation of IL-6 is related to the degree of tissue injury (8). IL-6 involvement in anti-inflammatory/

immune responses includes synthesis of glucocorticoids,

and certain acute phase proteins that serve as potent anti-

proteases. It also directly inhibits expression of the pro-

inflammatory cytokines IL-1 and TNF-. In addition, it

stimulates macrophage expression of IL-1ra, and soluble

TNF receptor, which binds with IL-1 and TNF, truncating

the response of these two pro-inflammatory cytokines (8).

IL-6 elevations have consistently been reported after in-

tense exercise or exercise-induced muscle injury (73,81). It

appears that muscle cells like myoblasts, satellite cells, and

in vivo regenerating myofibers may produce IL-6 whenactivated in response to muscle injury (70,82).

There is minimal data concerning cytokines and OTS

(36,60,75). An attempt was made by this author to induce a

state of overtraining and measure blood cytokine levels (99).

The exercise protocol failed to induce OTS. However, in a

recent study in our laboratory, with the prime focus being on

changes in the blood cytokine levels in response to exercise-

induced muscle damage, preexercise cytokine values were

determined for eight healthy untrained college males, and

the mean values compared with one subject, inadvertently

found to be suffering from chronic plantar fasciatus. IL-1,

IL-6, and TNF- (pg

ml1

, mean SEM) for the eight

healthy subjects were: 1.3 .1, 1.8 .14, and 1.5 .03,

respectively. Equivalent values for the chronically injured

individual were 6.4, 3.6, and 2.4 pgmL1, respectively,

displaying cytokine levels several-fold greater than age and

activity-matched controls (72).

In addition, two competitive cyclists self-reported as per-

forming well below anticipated levels. They agreed to blood

sampling and to a clinical psychological diagnostic inter-

view. Both participants completed the Beck Depression

Inventory-2 (BDI-II) (7), a widely used assessment for de-

pression. Participant 1 scored 9, indicating extremely mild

symptoms of depression. His blood cytokine levels were:

IL-1 0.09 pgmL1, TNF- 1.5 pgmL1, and IL-6

0.7 mLkg1, all within the normal range of the preexercise

values for healthy males. Participant 2, on the other hand,

scored a 23 on the BDI-II, indicating moderate depression.

Interestingly, his cytokine levels were as follows: IL-6

0.57 pgmL1 was somewhat lower than the mean for age-

matched controls; IL-1 was 6.6 pgmL1, approximately 5

times the level of matched controls, and TNF was 4.5

pgmL1, approximately 3 times the normal level. These

preliminary data suggest a possible interaction between psy-

chological mood state and circulating cytokine levels, an

issue that will be addressed in the following section. Pitfalls

associated with interpreting data from a single subject are

acknowledged.

In summary, although certain cytokines may normally be

present in the circulation in small amounts, there are a

variety of “emergency” circumstances, during which the

pro-inflammatory, as well as additional cytokines are pro-

duced in large quantities. Local production of cytokines, for

example, in injured muscle assists with the development of

a local inflammatory response, subsequent healing, and ter-

mination of inflammation. At times, due to varying circum-stances, increased levels of circulating cytokines will be

evident. They may play a primary role in coordinating

systemic inflammation, engaging the liver, and the central

nervous system. It is suggested that the various signs and

symptoms associated with OTS are a consequence of this

systemic inflammation.

Mood, Behavior, and Cognitive Changes

Associated with OTS

A consistent finding associated with the overtrained ath-

lete is a profound change in global mood/behavior/cognition(61). This pattern varies considerably from athlete to athlete

and may reflect individual heterogeneity or may, in fact, be

related to the type of training (26). For example, “anaerobic”

athletes may tend to experience a greater degree of anxiety/

agitation, whereas endurance athletes may experience a

greater degree of depression (personal correspondence, Dr.

Michael Stone).

Although a reduction in performance is generally consid-

ered an initial sign of OTS, several researchers have sug-

gested that this may be accompanied by, or even preceded,

by mood, behavioral, and cognitive changes (27,64). De-

scriptions of these changes reflect a similar theme: a fa-


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tigued athlete, discouraged and disinterested in training, in

competition, and in life in general. Although there appears

to be consensus regarding psychobehavioral changes ac-

companying overtraining (27,64,91), it is unclear whether

these changes are a consequence of intense training or

precipitate overtraining (29). Morgan et al. (61) have sug-

gested that the symptoms seen in an overtrained athlete, are

remarkably similar to clinical depression (Table 1).

Although the underlying initiator(s) of these psychobe-

havioral changes are not known, several researchers (44,62)

have implicated an increased uptake of tryptophan (TRY)

by the brain, resulting in increased brain serotonin levels.

Serotonin is regarded as a major contributor to mood/be-

havior changes. However, it is suggested here that reduced

circulating levels of TRY may represent part of OTS; a more

global model will now be proposed, based predominantly on

a psychoneuroimmunological (PNI) model (51,57,88).

To understand how physiological changes produced by

high volume training will impact on the psyche, one needs

to focus on the body-mind interaction. Until recently, the

field of PNI, as well as the field of exercise science, has

focused on two major outflow pathways from the CNS, both

activated within the hypothalamus (see Fig. 3) (57). One is

the autonomic nervous system, more specifically the sym-

pathetic nervous system, which results in elevated blood

levels of catecholamines (Fig. 3, Loop A). The other path-

way, the hypothalamic-pituitary-adrenal axis (HPA axis),

leads to the release of cortisol by the adrenal cortex glands

(Fig. 3, Loop B). What has not been stressed until recently,

is the manner in which information is conveyed from the

periphery into the CNS. It seems clear that the brain and

peripheral immune/inflammatory cells form a bidirectional

communication network (Fig. 3, Loop C). In particular,

products of the immune system that are external to the CNS,communicate with the brain (30,57). Cytokines appear to be

the major messenger molecules, in particular the pro-inflam-

matory IL-1, IL-6, and TNF- (8).

Activation of the CNS by these peripheral inflammatory

molecules results in a constellation of behaviors referred to

as “sickness,” “vegetative,” or “recuperative” (18,32,38,57).

This constellation of behaviors generally includes reduced

appetite, weight loss, reduced thirst, reduced libido, depres-

sion, loss of interest, fear, and sleep disturbances. These

behaviors may be initiated by a wide variety of systemic

immune/inflammatory conditions, such as rheumatoid ar-

thritis, chronic fatigue syndrome, as well as in response tosurgery, or to a common cold.

This constellation of sickness behaviors is believed to

have been conserved throughout evolution (32,41) and is

most likely a generalized adaptation to infection and injury,

and may be regarded as an evolved strategy, aimed at

combating infection and injury. These behaviors are there-

fore not regarded merely as reflexive reactions to “illness”,

but rather represent a central motivational state, that assists

the organism in recovery. It has been proposed that the

changes that occur, may function to reduce the energy cost

of behavior so that all available physiological stores can be

directed to more imminent aspects of survival, such as the

production of fever, the reduction of heat loss, and the

activation of the immune/inflammatory systems (57). Cer-

tain behaviors, such as reduced activity, exploration, social

interaction, sexual behavior, and mood, are apparent in this

context. Other behaviors such as reduced feeding, do not fit

as obviously, but might be secondary, for example, to the

conservation of energy, since searching for food and water

in more primitive settings may deplete limited energy re-

serves (32).In addition to research that focuses on the development of

sickness behavior, there now exists an extensive body of

evidence demonstrating a relationship between systemic

cytokines and psychological depression, “numerous intrigu-

ing findings. . .are consistent with the argument that non-

specific immune activation and cytokines are involved in

the etiology or symptomology of depression.” (57). There is

extensive evidence of elevated cytokines in depressed pa-

tients who exhibit significantly higher levels of IL-1 and

IL-6 in culture supernatant of mitogen-stimulated mono-

cytes, when compared with nondepressed controls

(52,54,57); administration of cytokines in the absence of

Figure 3—Loop A and loop B represent the outflow of “information”from the central nervous system (CNS) to the periphery. Loop C

represents the manner by which cytokines convey “information” fromthe periphery to the CNS (inflow) (57). Copyright © 1998 by theAmerican Psychological Association. Reprinted with permission from:

Maier, S. F., and L. R. Watkins. Cytokines for psychologists: implica-tions for bidirectional immune-to-brain communication for under-standing behavior, mood, and cognition. Psychol. Rev. 105:83–107,

1998. Schematic representation of brain-immune system connections.CRH, corticotropin releasing hormone; ACTH, adrenocortico-tropic

hormone; CORT, corticosterone; NE, norepinephrine; E, epinephrine;Enk, enkephlin; SP, substance P; NPY, neuropeptide Y; GH, growthhormone; Mo, macrophages; IL1, interleukin-1; TNF, tumor necrosis

factor; IL6, interleukin-6.



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infection, produces a full syndrome of responses (19); and

when exogenous cytokines are administered to humans, they

often develop a distressed mood state (20,57). Furthermore,

there appears to be a dose-dependent relationship between

level of cytokines and severity of depression (51). Maes (51)

refers to this as the interleukin hypothesis of depression (see

Fig. 4). Both IL-1 (57) and/or IL-6 (8) appear to be involved

in this cyclic process. In addition, there is evidence impli-

cating TNF- in depression and mood/behavioral changes

(57). Thus, it appears that depressed individuals exhibit a

systemic inflammatory-like condition, with elevated serum

cytokines, and conversely, an injured or infected individualexhibits sickness/depressive-like behavior.

Cytokines access the CNS via several routes. They may

directly access brain structures, either using a transport

system to cross the blood brain-barrier, or acting at the level

of circumventricular organs, where this barrier does not

exist (38,77). They may also inform the CNS indirectly via

activation of afferent neurons (57) of the vagus nerve; neural

afferents may activate transcription and translation of cyto-

kines within the central nervous system (18). In the brain,

there are specific receptors for IL-1, IL-6, and TNF that

have a discrete distribution (30). Blocking IL-1 receptors in

the brain can prevent some of the sickness responses toperipheral administration of peripheral cytokines (74). Fur-

thermore, administration of certain cytokines directly into

the brain produces many or all of the sickness responses

(74).

IL-1 and IL-6 receptors in the brain are abundant in the

area of the hypothalamus (30,57). The binding of cytokines

in the hypothalamus results in activation of the hypothalam-

ic-pituitary-adrenal axis (HPA-axis) and sympathetic nuclei,

resulting in increased levels of circulating catecholamines,

and cortisol, the traditional stress hormones (21,51). In-

creased levels of these stress hormones have been consis-

tently associated with mood changes (79) and with OTS

(91). IL-1 and IL-6 may also result in increased activation

of several discrete hypothalamic nuclei, which may account

for many of the sickness-related behavioral changes, includ-

ing hunger, thirst, sleep, reduced libido, and body core

temperature (30,57).

Interleukin receptors, especially IL-1 receptors, are also

abundant in the hippocampal area of the brain (17). The

hippocampus (49) is implicated in learning, memory, and

cognition (16). Thus systemic infection/inflammation may

interfere with cognitive processes, such as loss of attention,

and with certain types of memory (57). Alterations in cog-

nition have been observed in overtrained individuals

(27,64,66). These include: reports of a loss of coordination,

the reappearance of mistakes previously corrected, an in-

ability to concentrate at work, impaired academic ability,

and changes in learning retention. Unlike the other “sick-

ness” behaviors, this does not appear to be adaptive. Maier

and Watkins (57) suggest that the hippocampus is a large

structure that participates in many different functions; dur-

ing illness or injury, certain neurons, usually involved in

learning and memory, are diverted to other more pressing

functions.

The reader has hopefully discerned overwhelming simi-

larities between these physiological, biochemical, cognitive,

and psychological/behavioral signs and symptoms experi-

enced by clinically depressed individuals, by individuals

experiencing “sickness behavior” in response to illness/

injury, and by many overtrained athletes. Although at

present little evidence is available to verify elevated levels

of IL-1, IL-6, and/or TNF- in OTS, results were presented

in a previous section, suggesting an association between

clinical depression and pro-inflammatory cytokine levels, in

an athlete displaying signs and symptoms of overtraining.

Research is needed to explore this postulate. If confirmed,the adoption of such an hypothesis would provide an or-

ganic, physical cause, as the basis for mood, behavioral, and

cognitive changes associated with OTS (88). This approach

would be consistent with new approaches used by psycho-

neuroimmunologists, examining the mind-body connection.

“The division of disease into mental and physical could be

a fundamental flaw in (the) approach. . .to dealing with

mental illness” (88). Such an inappropriate division may

have been propagated in the field of exercise physiology.

Glutamine, Hypercatabolism, and OTS

It has been proposed that intense/long-duration training

may cause a marked decrease in blood levels of the amino

acid glutamine (62,97). Foster and Lehman (24) reported a

decrease in glutamine in overtrained runners, which per-

sisted well into the recovery period, even after performance

has begun to normalize; by comparison, there was an in-

crease in blood glutamine in non-overtrained runners. Row-

bottom et al. (75), using 10 athletes from a variety of sports,

suffering from OTS, surveyed a large range of biochemical,

physiological, and immunological parameters and found

that glutamine was the only parameter consistently reduced.

Keast (36) suggests it is unlikely that reduced levels of

Figure 4 —The interleukin hypothesis of major depression. A sche-matic diagram of the association between psychological depression and

the development of systemic immune/inflammation, as proposed byMaes (51). Reprinted from Prog. Neuro-Psychopharmacol. & Biol. Psychiatry 19, M. Maes. Evidence for an immune response in major

depression: a review and hypothesis, pp. 11–38, 1995, with permissionfrom Elsivier Science.


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glutamine are the prime cause of OTS but that changes in

blood glutamine levels may be indicative of some critical

aspect of metabolism that is at fault and that glutamine

deficit may be an excellent indicator of OTS.

Glutamine is the most abundant amino acid in human

plasma and in the muscle free amino acid pool (97).

Branched chain amino acids and glutamate are taken up by

the muscle, and their carbon skeletons are used for de novo

synthesis of glutamine, with muscle being the most abun-

dant glutamine producing tissue. This high rate of glutamine

synthesis is probably related to the fact that glutamine plays

an important role in human metabolism in many organs. It

is also essential for lymphocyte proliferation and macro-

phage function (69). Because of this latter role, it has been

proposed that decreased circulating levels of glutamine is a

primary factor causing a decline in immune function, fre-

quently associated with OTS (36).

There is undoubtedly an increased need for glutamine

with activation of immune/inflammatory cells. However, a

number of additional associated events place increased de-

mands on blood glutamine levels. The presence of systemic

inflammation, is associated with a catabolic state (11,43,92),

the degree depending on the severity and duration of the

trauma/stress, driven, in part, by several cytokines and glu-

cocorticoids (11,92). This catabolic state is adaptive and

serves a variety of functions (92). Since tissue trauma is

often associated with a reduced food intake, the body is now

required to maintain blood glucose levels for specific organs

such as the brain. The body achieves appropriate blood

glucose levels by up-regulating liver gluconeogenesis. Glu-

tamine and alanine are the primary amino acids released

from the muscle, and are the most important precursors for

gluconeogenesis and the preservation of blood glucose lev-

els (97).An additional amino-acid dependent function during sys-

temic inflammation, is de novo synthesis of large quantities

of inflammatory-related proteins by the liver, the acute

phase proteins, such as C-reactive protein and haptoglobin

(59). Synthesis of these proteins represents a crucial aspect

of an immune/inflammatory response, helping to contain the

potentially lethal amplification of inflammation. Glutamine

is a primary precursor for many of these protein molecules

(59) (see Fig. 5).

Thus, the provision of adequate amounts of amino acid to

support biosynthetic pathways in the liver is crucial, with

transport of amino acids into hepatocytes being a key reg-ulatory event (59). An interplay between numerous cyto-

kines and the classic stress hormones, redirects the flow of

amino acids to the liver. Fischer and Hasselgren (23) re-

ported that IL-6 and TNF- work with glucocorticoids to

stimulate amino acid uptake in human hepatocytes. In hu-

man hepatocytes, both alanine and glutamine transport were

increased significantly by IL-6 and TNF- treatment, com-

pared with control.

This increased requirement for amino acids during hy-

permetabolism is partly satisfied by an augmentation of

muscle proteolysis, the major storage pool of amino acids,

and by a concomitant reduction in muscle anabolism. Ac-

celerated muscle protein degradation would contribute to a

negative nitrogen balance, and this would contribute to the

loss of lean body mass (43,92). The necessary excretion of urinary nitrogen by the kidneys requires an increased urine

output. This, in turn, would stimulate thirst mechanism (59).

All these factors have been associated with illness/trauma

and also with OTS (27,64,91).

Associated with hypercatabolism and injury/infection is a

shift in fuel usage from a typically mixed glucose-fat sub-

strate to the predominant use of fats (92). This adjustment

would support the up-regulation of gluconeogenesis and the

need to preserve blood glucose for specific organs. Stoner

(92) suggests that if an animal survives a serious injury it

may “be condemned to a period of inactivity when it is

unable to forage for food. . .it would make sense to reduce

Figure 5—The movement of amino acids in sepsis and trauma may

also reflect what occurs during overtraining. In sepsis and traumaticinjury, glutamine and other amino acids are released from skeletal

muscle for uptake by tissues involved in the immune response andtissue repair, such as macrophages, lymphocytes, fibroblasts, and theliver. Nitrogen excretion as urea and NH

4

results in negative nitrogen

balance. Adapted from: Marks, D. B., A. D. Marks, and C. M. Smith.Intertissue Relationships in the Metabolism of Amino Acids. In: Basic Medical Biochemistry (1st Ed.). Baltimore: Williams and Wilkins, 1996,

pp. 647.



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the utilization of carbohydrate and use more fat as fuel since

there is much more of it available.” This shift may also

explain the finding of an increased reliance on fat metabo-

lism during submaximal running in OTS (40), as well as

account for excessive fat loss reported in some athletes (91).

In summary, it appears that low blood glutamine and

other OTS-related symptoms could be explained in terms of

a catabolic state related to systemic inflammation. These

symptoms include elevated basal metabolic rate, negativenitrogen balance, decrease in lean body mass and fat mass,

increased uric acid production, increased urination, in-

creased thirst, and fluid intake (64).

Tryptophan and OTS

The central fatigue hypothesis of overtraining proposes

an increased uptake of tryptophan (TRY) by the brain,

resulting in increased brain serotonin levels (44,62). The

rationale for suggesting an increased uptake of TRY is based

on two assumptions. First, there is a decrease in circulating

levels of TRY, suggesting an increased uptake by the CNS.Second, there is a decrease in circulating levels of branched

chain amino acids (BCAA), leucine, isoleucine, and valine,

which normally compete with TRY for the same amino acid

carrier into the brain (85); thus, a decrease in BCAA favors

the entry of TRY into the brain. In the brain, TRY is

converted into the neurotransmitter serotonin. In specific

areas of the brain, serotonin induces sleep, depresses motor

neuron excitability and appetite, and alters autonomic and

endocrine function. Since many of these behavioral changes

have been seen in OTS, as well as changes in serum TRY:

BCAA ratio, Newsholme et al. (62) and Kreider (44) have

suggested that this may be germane to mood and behavioralchanges. However, evidence of increased uptake of TRY

and increased levels of serotonin, although consistently ob-

served in animal research, is inconclusive in human re-

search, possibly due to nonstandardized methodology (28).

It also appears that many of the studies investigating BCAA

and TRP in humans deal more with the acute response to

intense exercise and not OTS (44,96).

The influx of TRY into the brain is certainly dependent on

the TRP-BCAA ratio, but it is also dependent on additional

factors, such as the free and bound plasma concentration.

Normally, tryptophan circulates in the blood with a major

fraction (70–90%) loosely bound to serum albumin (Alb).At the blood brain barrier transport site, Alb is stripped off

and TRP passes though the brain capillaries. The availability

of Alb as a carrier will influence the rate of influx of TRP

into the brain. Since serum albumin concentrations are re-

duced during systemic inflammation (56), this will most

likely reduce the availability of TRY to the CNS.

During systemic inflammation (56), an additional drain

on available TRY may be due to the fact that TRY is used

for leukocyte activity and synthesis of specific inflamma-

tory-related liver proteins. Furthermore, there may be an

associated induction of a major TRP-catabolizing enzyme,

indoleamine 2,3 dioxygenase. Thus, reduced circulating

TRY levels seen during systemic inflammation could be

accounted for by a variety of events (55).

A widely held view in the psychology literature (55) is

that there is correlation between circulating levels of TRY

and brain levels, with low circulating levels reflecting low

availability of TRY in the brain. Reduced brain TRY levels

are consistently associated with depressive symptoms (55).

When comparing normal volunteers with individuals expe-

riencing major-depression, Maes et al. (56) reported a sig-

nificant group difference in: 1) serum TRY levels, with

levels being lower for depressed subjects, and 2) TRY:

BCAA ratio, with the ratio being lower for depressed sub-

jects, implying that both TRY and BCAA were reduced.

They concluded that lowered TRY levels are related to

systemic inflammatory events, evident in clinical depression

(51,55,57). It is proposed here that if circulating TRY is

reduced in OTS, this would reflect a scenario similar to that

seen in clinical depression.

In summary, if serum TRY is reduced in OTS, and OTS

does reflect systemic inflammation, then low serum TRY

levels could be due to reduced availability of the TRY

transporter, Alb, as well as increased usage by leukocytes,

increased uptake by the liver for synthesis of liver proteins,

and increased degradation. Serum TRY may prove to be a

useful marker of immune/inflammatory activation in OTS,

since it correlates well with certain aspects of immune

changes, as well as with the presence of specific acute phase

proteins (55,56).

Acute Phase Proteins, Trace Metals, and OTS

Several researchers have noted changes in various blood

proteins and trace metals in OTS (27,64). These alterations

could be explained by a series of events known collectivelyas the acute phase response (APR), which represents a

crucial aspect of systemic inflammation (9,27,64,98).

Tissue trauma induces local inflammation at the site of

injury, involving factors such as dilation and leakage of

blood vessels, aggregation of platelets and clot formation,

and accumulation of WBCs in the damaged tissue. This

local response is frequently accompanied by a systemic

APR. The overall purpose of the APR is to coordinate

various physiological systems that will assist in dealing with

inflammation; these include the development of fever, re-

cruitment of white blood cells from various sources includ-

ing bone marrow, as well as increases in systemic levels of cytokines. An integral component of the APR is de novo

synthesis of specific proteins by liver hepatocytes (9), the

acute phase proteins (APP). IL-1, IL-6, and TNF-, are

primarily responsible for biosynthesis of these liver pro-

teins, with glucocorticoids acting to enhance their action (8).

The liver proteins that increase in concentration are referred

to as positive APP (94).

Catabolic enzymes and reactive oxygen species released

by phagocytic cells, clear disrupted host tissue in advance of

repair. However, they do not discriminate between healthy

and damaged cells and so aspects of inflammation can lead

to destruction of healthy tissue if uncontrolled. The positive


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APPs represent the primary mechanism for regulating the

inflammatory process (8,9,94). C-reactive protein (CRP) is

a primary APP, which may increase 100–1000 fold (43).

Associated with the increase in the positive APP, is a con-

comitant decrease in negative APP, such as albumin (27).

With regard to OTS, several studies have reported increases

in certain positive APP (64,93,98) and decreases in negative

APP (27).

Intimately associated with the APR and synthesis of APPare changes in blood levels of trace metals (9). During an

infection, plasma iron and zinc concentrations fall, whereas

plasma copper levels are elevated (9). Low plasma iron and

zinc have been reported in OTS (9,27,36).

In summary, it appears that the overtrained athlete shows

changes in certain blood proteins and metals. These changes

mimic an acute phase response, which occurs during a

systemic inflammatory event, with many of these changes

induced by IL-1, IL-6, and TNF-. Changes in positive

APP and negative APP and trace metals in OTS would

support the notion of systemic inflammation.

Muscle Glycogen, Blood Lactate, Insulin

Resistance, and OTS

A number of researchers have reported reduced muscle

glycogen levels in overtrained athletes (89). In a classic

study, Costill et al. (14) had 12 swimmers more than double

their training intensity for 10 d. Eight of the 12 athletes

appeared to cope, whereas four developed signs of OTS;

they had difficulty completing training loads, had signifi-

cantly reduced muscle glycogen levels, consumed 1000

fewer kcal than were needed to match the increased energy

expenditure, and failed to maintain the required carbohy-drate intake. Based on these observations, Costill proposed

the glycogen theory of overtraining (14), suggesting that

reduced muscle glycogen would cause fatigue and result in

a decrement in performance. Furthermore, the low muscle

glycogen levels would result in increased uptake and oxi-

dation of circulating branched chain amino acids (BCAA)

by the muscle. This would reduce the availability of amino

acids for synthesis of central neurotransmitters, resulting in

changes in the nervous system, such as fatigue, which has

been consistently associated with OTS.

The glycogen theory, however, has not been substanti-

ated. Snyder (89) had cyclists increase their training load for2 wk, to meet the criteria for short-term overtraining, but

also increase carbohydrate intake sufficient to maintain

muscle glycogen levels. Although subjects met the criteria

for short-term overtraining, muscle glycogen levels were

normal. They concluded that a mechanism or combination

of mechanisms other than reduced muscle glycogen must be

responsible for the development of overtraining.

Although reduced muscle glycogen might not be causal,

it is frequently observed in overtrained athletes and warrants

attention. It is suggested that excessive stress, including

muscle-related trauma, may result in systemic inflamma-

tion, with elevated pro-inflammatory cytokines (81), mani-

festing the adaptive behavioral mood pattern, “sickness”

behavior (18,32,38,57), discussed previously. A prominent

aspect of this cluster of behaviors is anorexia

(18,32,38,57,77). It is thus proposed that reduced muscle

glycogen levels in OTS may be a consequence of reduced

food intake, mediated by cytokine-induced anorexia.

Directly or indirectly, pro-inflammatory cytokines are

clearly implicated in food intake. Cytokines may act directly

on specific nuclei in the “hunger centers” of the hypothal-amus to suppress food intake in a dose-dependent fashion

(51,53,57). Alternatively, certain interleukins may stimulate

increases in hypothalamic corticotropin releasing factor

(CRF) (19,51,57,77), which suppresses appetite. There is

also mounting evidence that energy and weight dysregula-

tion may be related to IL-1- and TNF--activation of the

ob gene product, leptin, in white adipose tissue (76). A

preliminary study, implicates leptin in overtrained distance

runners (34). In addition to the putative role of cytokines on

food intake, the reduced carbohydrate intake seen in over-

trained swimmers (14) may be a response to conditioned

taste aversions associated with IL-1 and “sickness” behavior(18,32,57).

Aside from the role of cytokines in appetite suppression,

local, subacute muscle injury could interfere with transport

of glucose into the muscle cell and, consequently, muscle

glycogen synthesis. In response to eccentrically induced

muscle damage, postexercise glycogen synthesis is impaired

(15,40). Asp and colleagues (4) found a significant reduc-

tion in the glucose transporter protein, GLUT-4, 1 and 2 d

after eccentrically induced muscle damage. O’Reilly et al.

(65) showed that muscle glycogen stores were markedly

reduced for up to 10 d after eccentric exercise. They sug-

gested that a decreased muscle concentration of GLUT-4protein, possibly due to down-regulation of mRNA by

TNF- (11), would result in decreased transport of glucose

into the muscle, and this in turn would sustain low glycogen

concentrations seen after muscle damaging eccentric exer-

cise (4). Thus local muscle injury, per se, could contribute

to reduced muscle glycogen levels associated with OTS.

In addition to the reduction in GLUT-4 protein and re-

duced glycogen at the level of the muscle, several investi-

gators (3,40) have reported whole-body insulin resistance

associated with muscle injury, most likely mediated by

TNF- (3). Insulin resistance has frequently been reported

as part of the metabolic response to tissue trauma andsystemic infection (92). Insulin resistance, to date, does not

appear to have been tested in the overtrained athlete.

In summary, it is suggested that large volumes of training,

systemic inflammation, and elevated levels of pro-inflam-

matory cytokines, directly and/or indirectly, induce an-

orexia, resulting in a reduced caloric intake. In addition,

local muscle membrane injury and reduced availability of

GLUT-4 glucose transporters in muscle cell membrane,

attenuates movement of glucose into the cell for glycogen

resynthesis. Both factors may contribute to reduced muscle

glycogen synthesis in OTS. Although highly speculative,

if overtrained athletes experience whole-body insulin



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resistance, this too could contribute to reduced glycogen

stores. Finally, it is conjectured that reduced muscle glyco-

gen could in turn account for the “heavy legs” (64) experi-

enced by many overtrained athletes, as well as the reduced

blood lactate levels during both submaximal and maximal

exercise.

Hypothalamic-Related Hormones and OTS

The hypothalamus is a major coordinating center for

neuroendocrine function (79), controlling blood levels of the

stress hormones cortisol, epinephrine, and norepinephrine,

as well as gonadal hormones, such as testosterone and

estradiol. Generally, with an appropriate training stimulus,

the hypothalamic-pituitary axes are stabilized. However,

excessive physiological as well as psychological stress may

lead to an altered hormonal balance; such an imbalance has

been associated with OTS (6,26,27,91), although there is not

complete agreement on this issue (47,95).

Cortisol is generally viewed as a catabolic hormone,

whereas testosterone is anabolic (26,91). Intense, prolongedphysical activity frequently leads to increased blood cortisol

levels and decreased free testosterone. An alteration in the

typical cortisol:testosterone ratio may be associated with the

reported catabolic state in OTS (26,91). Could systemic

inflammation direct these events?

During systemic inflammation, pro-inflammatory cyto-

kines are potent activators of the hypothalamic-pituitary-

adrenal axis (HPA) (77). The effects of IL-1 (35) and IL-6

(67) on the HPA axis have been studied extensively. These

cytokines appear to interact with specific hypothalamic re-

ceptors, resulting in release of corticotropin releasing hor-

mone (CRH) (35,67,77). CRH stimulates release of pituitaryadrenocorticotropin releasing hormone (ACTH), with sub-

sequent release of cortisol from the adrenal cortex. In ad-

dition to the action of cytokines at the level of the hypo-

thalamus, IL-6 may control the release of steroid hormones

by direct action on adrenal cells, and regulate adrenal syn-

thesis of mineralocorticoids, glucocorticoids, and andro-

gens, in a time and dose dependent fashion (67). Thus,

systemic inflammation and elevated cytokines could ac-

count for elevated cortisol levels in OTS (26,27,91).

Reported decreases in testosterone and suppressed repro-

ductive function in OTS (48,90,91) implicate the hypotha-

lamic-pituitary-gonadal (HPG) axis. The controlling hor-mone in this instance is luteinizing-hormone releasing

hormone (LHRH). LHRH controls the pulsatile release of

the pituitary gonadal hormones, luteinizing hormone (LH),

and follicle stimulating hormone (FSH), which in turn in-

duce the release of ovarian estradiol, and testicular testos-

terone (58). In reference to cytokines and reproductive func-

tion, these inflammatory mediators suppress reproductive

function via inhibition of LHRH (58,77,83).

In summary, hypothalamic-related hormonal systems ap-

pear to be altered in OTS, although a clear pattern has not

emerged. However, there is extensive information demon-

strating an interaction between systemic cytokines and the

HPA and HPG axes. Thus, inflammatory cytokines may

account for alterations in reproductive hormones in OTS.

Immune System and OTS

Although not universally accepted (33), anecdotal evi-

dence suggests an increased incidence of illness associated

with OTS (27,36,60,64,68). These include an increased sus-

ceptibility to, and severity of colds, and allergies, flu-like

illness, slow healing of minor scratches, swelling of lymph

glands, reactivation of herpes viral infections, headaches,

and gastrointestinal disturbances (see Table 1).

Reasons for the high incidence of illness in OTS are

unclear (27,36,60,64,68,81). Intuitively, these conditions

are most likely related to impairment of the immune system.

Although immune function appears to be enhanced in re-

sponse to moderate exercise, intense exercise, even one

bout, such as a marathon, might result in immune suppres-

sion (63). Since overtraining is associated with repetitive

bouts of high intensity/volume training, and competing,

often in the absence of adequate rest, it is not unreasonable

to assume a compromised immune system, although much

remains to be learned concerning the influence of overtrain-

ing on the immune system (36,60).

A model that may be relevant to understanding a com-

promised immune system in the overtrained athlete is the

model adopted to explain the high susceptibility to infection,

postsurgery/injury (8,22). Immediately postsurgery/injury,

inflammation is dramatically up-regulated so as to mobilize

cellular and humoral immune mechanisms (8). Frequently,

this early inflammation is hyperinflammatory. As stated

earlier, considerable anti-inflammatory factors are associ-

ated with the up-regulation of inflammation. Anti-inflam-

matory factors are expressed in various “forms” and have avariety of targets. Interleukin-1 receptor antagonist (IL-1ra)

acts specifically to block the action of IL-1 (20); a variety of

soluble serum receptors, such as TNF-receptors, bind and

thus limit cytokine activity (31); hormones, specifically

cortisol, have profound anti-inflammatory action (22,23);

and finally, augmented expression of liver acute phase pro-

teins, such as C-reactive protein, serve as potent anti-in-

flammatory agents (42). Although these anti-inflammatory

effects are necessary to counteract the pro-inflammatory

effects, the ultimate result of prolonged, intense, counter-

regulation is immunosuppression (8). In reference to trauma

patients, Biffl and colleagues (8) have suggested that it isparadoxical that “the hyper-inflammatory response may pre-

dispose the individual to the subsequent development of

immuno-suppression” (see Fig. 6) (8).

A model of early hyperinflammation followed by late im-

munosuppression may be applicable to understanding the im-

mune response of the overtrained athlete (5). Possibly by the

time true overtraining has manifested itself, the athlete has been

exposed to pro-inflammatory cytokines, with associated coun-

terregulatory anti-inflammatory factors, for an extended pe-

riod. Thus, immunosuppression may reflect the body’s highly

developed attempt to contain inflammation through the pro-

duction of endogenous anti-inflammatory molecules (19).


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Theoretical Implications

The stress theory, developed by Selye (79), was based on

the observation that a wide variety of diseases manifest

themselves in a similar physiological fashion, with exten-

sive involvement of the hypothalamic-pituitary-adrenal

axis. The disease process may progress through three stages,

each stage being characterized by a cluster of associated

symptoms. Selye refers to this as the General Adaptation

Syndrome (GAS), with the three stages being the alarm,

resistance, and exhaustion stage. The initial two phases are

considered adaptive and are implicated in adjustments to a

wide variety of psychological and physiological stresses.

However, Selye suggests that the final phase of exhaustionrepresents a breakdown of the adaptive capacity; he reasons

that the organism possesses a limited amount of adaptive

energy and stage 3 represents depletion of these reserves.

Several researchers have suggested that OTS is a mani-

festation of the exhaustion stage of the GAS (24,37,91),

most likely due to excessive physical/physiological stress

related to intense training, with psychological stressors be-

ing additive. It is proposed here that this third stage repre-

sents a generalized response to excessive stress (GRES) and

that this final stage also be viewed as adaptive, but in a more

profound sense, with the focus not being on “improvement”

but more specifically on recovery/survival per se, with the

aim being to regain the homeostatic condition of “wellness.”

It is further proposed that GRES be viewed as a self perpetu-

ating cycle, consisting of a primary stimulus (muscle-related

Figure 6 —A model of immunosuppression, proposed by Biffle et al.

(8). The physiologic response to injury involves an early hyper-inflam-matory response, which is accompanied by a degree of compensatoryanti-inflammatory effect. If the early inflammatory response is exces-

sive, an appropriate persistence of anti-inflammatory compensationwill result in later immunosuppression. Reprinted with permissionfrom: Biffl, W. L., E. E. Moore, F. A. Moore, and V. M. Peterson.

Interleukin-6 in the injured patient. Marker of injury or mediator of inflammation? Ann. Surg. 224:647–664, 1996.

Figure 7—Cytokine theory of overtrain-ing: proposed events leading to, and sus-taining the overtraining syndrome (Sche-

matic diagram under “IMMUNECELLS” is reprinted with permission

from: Biffl, W. L., E. E. Moore, F. A.Moore, and V. M. Peterson. Interleukin-6in the injured patient. Marker of injury or

mediator of inflammation? Ann. Surg.

224:647–664, 1996).



13/15

trauma, psychological stress, and/or a viral infection) that

would result in the activation of circulating monocytes and

the biosynthesis of pro-inflammatory cytokines. These cy-

tokines would in turn coordinate the whole body response,

including the CNS, the liver, and the immune system, at-

tempting to negate the effects of the stressor. If the stressor

persists, then the cyclic, mind-body response will continue

(see Fig. 7). Withdrawal of the egregious stimulus would

probably be the most appropriate means for terminating this

cycle. Withdrawal in this instance implies rest. It is ironic

that despite the wonders of modern medicine, rest may be

the most potent healing agent, universally recommended by

coaches and exercise physiologists. If, however, OTS

proves to be a form of systemic inflammation, drug therapy

such as nonsteroidal anti-inflammatories (22,38), anti-de-

pressants, and anti-cytokine drugs (19), as well as dietary

factors (88), may prove useful adjuncts.

Finally, if this hypothesis proves viable, it will be impor-

tant to guard against overdiagnosing OTS. Selye (79) has

emphasized that the different stages of the general adapta-

tion syndrome are represented by clusters of several symp-

toms and is not represented by one or two manifestations. It

might be important to apply similar thinking to OTS. If an

athlete develops an upper respiratory tract infection (URTI),

as is frequently the case after a marathon (63), this single

event should not be interpreted as overtraining. If however,

an URTI occurs in association with a array of symptoms,

such as changes in sleep patterns, reduced appetite, lethargy,

and depression, this might then be suggestive of OTS. It is

hoped that diagnostic criteria will eventually be established.

Summary

It is suggested that the overtraining syndrome is a re-sponse to excessive musculoskeletal stress, associated with

insufficient rest and recovery, which may induce a local

acute inflammatory response that may evolve into chronic

inflammation and produce systemic inflammation. Part of

systemic inflammation involves activation of circulating

monocytes, which may synthesize large quantities of pro-

inflammatory cytokines, IL-1, IL-6, and TNF-. The cy-

tokines act on the CNS and induce a cluster of motivated

behaviors, commonly referred to as “sickness” behavior

(reduced appetite, depression, etc.), which is conducive to

healing/recuperation. The cytokines also activate the sym-

pathetic nervous system and hypothalamic-pituitary-adrenalaxis, while suppressing activity of hypothalamic-pituitary-

gonadal axis, thus accounting for changes in blood levels of

catecholamines, glucocorticoids, and gonadal hormones.

Pro-inflammatory cytokines also up-regulate liver function,

to maintain blood glucose levels (gluconeogenesis), and to

synthesize inflammatory-related acute phase proteins. Im-

mune-related changes may be related to an immuno-sup-

pression, possibly due to anti-inflammatory factors that ac-

company a pro-inflammatory response, that occurs in

response to tissue trauma.

Thus, if OTS is viewed under the rubric of systemic

inflammation, it is possible to reconcile a variety of previ-ously proposed mechanisms. It is hoped that future research

pertaining to OTS, will examine the role of systemic in-

flammatory markers to test this hypothesis.

This manuscript was supported by a grant from The Procter & Gamble Company.

Thanks to Dr. Joseph Houmard, East Carolina University, foreditorial suggestions. Thank you to Alta Bender, Appalachian StateUniversity, for assistance in developing the graphics. Thank you toDenise Martz-Ludwig, Ph.D. (Psychology), Appalachian State Uni-versity, for administering psychological assessments. I would like tothank the following graduate students from Appalachian State Uni-

versity, for assistance in preparation of this manuscript: Max Shute,Mark Lehmkeul, and Elizabeth Hogen. Address for correspondence: Lucille Lakier Smith, Ph.D., Depart-

ment of Exercise and Sport Science, 371 Ward Sports MedicineBuilding, East Carolina University, Greenville, NC 27858.

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Medicină sportivă: ipoteza stresului muscular manifestat prin citokine

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