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.
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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).
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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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