BASIC SCIENCES

Reviews

Cytokine hypothesis of overtraining:

a physiological adaptation to
excessive 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. 317331, 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 injuryrelated 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 Selyes 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

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

improved performance and deterioration. When deterioration 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 performance are affected simultaneously nor are they impacted
to the same degree, making prediction and/or interpretation
confusing (66). It is also probable that other signs/symptoms
typically associated with overtraining are evident before a
deterioration in performance. These might include generalized fatigue, depression, muscle and joint pain, and loss of
appetite. However, it is the decline in performance frequently 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

he 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 hypothesis is not presented as complete but is advanced in an
attempt to focus future research efforts. For brevity, references are generally limited to review articles. The predominant focus of this paper will be on the systemic immune/
inflammatory response. These terms are frequently used
interchangeably due to their extensive overlap; for conciseness, 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 comfortable level in order to maximize athletic ability

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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TABLE 1. The major symptoms of overtraining as indicated by their prevalence in

the literature (Reprinted from Fry, Morton, and Keast, 1991)
Physiological performance
Decreased performance
Decreased serum ferritin
Lowered TIBC
Mineral depletion (Zn, Co, Al, Mn, Se, Cu, etc.)
Increased urea concentrations
Decreased serum ferritin
Lowered TIBC
Mineral depletion (Zn, Co, Al, Mn, Se, Cu, etc.)
Increased urea concentrations
Inability to meet previously attained performance standards or criteria
Recovery prolonged
Reduced toleration of loading
Decreased muscular strength
Decreased maximum work capacity
Loss of coordination
Decreased efficiency or decreased amplitude of movement
Reappearance of mistakes already corrected
Reduced capacity of differentiation and corrected
Reduced capacity of differentiation and correcting technical faults
Increased difference between lying and standing heart rate
Abnormal T wave pattern in ECG
Heart discomfort on slight exertion
Changes in blood pressure
Changes in heart rate at rest, exercise, and recovery
Increased frequency of respiration
Perfuse respiration
Decreased body fat
Increased oxygen consumption at submaximal workloads
Increased ventilation and heart rate at submaximal workloads
Shift of the lactate curve towards the X-axis
Decreased evening postworkout weight
Elevated basal metabolic rate
Chronic fatigue
Insomnia with and with night sweats
Feels thirsty
Anorexia nervosa
Loss of appetite
Bulimia
Amenorrhea or oligomenorrhea
Headaches
Nausea
Increased aches and pains
Gastrointestinal disturbances
Muscle soreness or tenderness
Tendonostic complaints
Periosteal complaints
Muscle damage
Elevated C-reactive
Rhabdomyolysis
Psychological/information processing
Feelings of depression
General apathy
Decreased self-esteem or worsening feelings of self
Emotional instability
Difficulty in concentrating at work and training
Sensitive to environmental and emotional stress
Fear of competition
Changes in personality
Decreased ability to narrow concentration
Increased internal and external distractibility
Decreased capacity to deal with large amounts of information
Gives up when going gets tough
Immunological
Increased susceptibility to and severity of illnesses, colds, and allergies
Flu-like illness
Unconfirmed glandular fever
Minor scratches heal slowly
Swelling of the lymph glands
One-day colds
Decreased functional activity of neutrophils
Decreased total lymphocyte counts
Reduced response to mitogens
Increased blood eosinophil count
Decreased proportion of null (non-T, non-B) lymphocytes
Bacterial infection
Reactivation of herpes viral infection
Significant variations in CD4: CD8 lymphocytes

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TABLE 1.Continued
Biochemical
Negative nitrogen balance
Hypothalamic dysfunction
Flat glucose tolerance curves
Depressed muscle glycogen concentration
Decreased bone mineral content
Delayed menarche
Decreased hemoglobin
Decreased serum iron
Decreased serum ferritin
Lowered TIBC
Mineral depletion (Zn, Co, Al, Mn, Se, Cu, etc.)
Increased urea concentrations
Elevated cortisol levels
Elevated ketosteroids
Low free testosterone
Increased serum hormone binding globulin
Decreased ratio to free testosterone to cortisol of more than 30%
Increased uric acid production

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, and
it 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 overreaching 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 problem (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 treatment is a decrease in training volume or in some instances
complete rest. Once the athlete has developed the fullblown overtraining syndrome, he or she must rest completely 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 account
for 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-adrenal axis (HPA), as well as involvement of the hypothalamicpituitary-gonadal axis (HPG); this results in alterations of
blood catecholamine, glucocorticoid, and testosterone levels
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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 proposed that activation of these pathways may be a consequence, and not necessarily a primary initiator.
There is substantial evidence demonstrating reductions in
blood levels of the amino acid, glutamine, in OTS (36).
Newsholmes 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 reduction 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 neurotransmitter 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 suggested 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. Although 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. Inherent in this theory is the assumption that the psychological
monotony can impact on physiological performance. An
alternate 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 system, 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 associated 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 athletic
events.
Muscle Trauma and Systemic Inflammation
The present hypothesis proposes that trauma to the muscular, 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 microtrauma to muscle, connective tissue, and/or bones and joints
(87). This type of injury will be referred to as adaptive
OVERTRAINING AND SYSTEMATIC INFLAMMATION

Figure 1Schematic diagram of proposed manner by which various

musculoskeletal actions may result in tissue trauma/injury.

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 program 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 component of a movement will induce tissue trauma (86). Additionally, 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 be
associated with an adaptation (13) of muscle, bone, and/or
connective tissue.
Musculo-skeletal-joint trauma/injury, proposed as the underlying 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 subclinical 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 overtraining the types of injuries identified, range from the overt,
that are obvious injuries and will usually prevent performance 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 participation, and at times may cause an injury in a distant part of
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Figure 2Schematic diagram of proposed exercise-related events

leading to the development of a systemic immune/inflammatory response.

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 overtraining syndrome (39). This implies first the development
of 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 presence 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 serum creatine kinase (25,64). More direct evidence has recently 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 high
intensity/volume training, associated with insufficient rest/
recovery time, is the predominant cause of overtraining. It
will be suggested that many of the physiological, behavioral, and psychological signs and symptoms associated
with OTS could emerge from the presence of an injury.
Additionally, the cytokine hypothesis will attempt to accommodate 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 as
follows. 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 cytokines released in this process activate circulating monocytes
(46,71). Activated monocytes produce large quantities of
proinflammatory cytokines, resulting in systemic inflammation. Systemic inflammation is proposed as the central underpinning of OTS (see Fig. 2).
Inflammation is the generalized response of the body to
tissue injury, irrespective of the damaging stimulus. The
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primary focus of acute inflammation is healing, a process

crucial to survival. Overt signs and symptoms of inflammation include swelling, redness, heat, pain, and reduction in
the function of the injured area. However, not all clinical
manifestations are consistently detectable. There are undoubtedly 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 represent 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 complex, 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 primary 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 mediators. Cytokines may be defined as soluble hormone-like
proteins. However, in contrast to hormones, which are synthesized by specific endocrine tissues, cytokines are produced 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, cytokines integrate systemic inflammatory events (84). A wide
variety 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 themselves (autocrine), which may lead to further cytokine production 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 prohttp://www.msse.org

or anti-inflammatory. Proinflammatory cytokines include

interleukin-1 (IL-1), IL-6, IL-8, and tumor necrosis factor (TNF)-. There are also a number of anti-inflammatory
cytokines whose sole purpose is to regulate this inflammatory 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 overtraining 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 pleiotropic 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 proinflammatory 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 expression, 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 antiproteases. It also directly inhibits expression of the proinflammatory 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 intense 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 when
activated 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 exerciseinduced 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- (pgml1, mean SEM) for the eight
OVERTRAINING AND SYSTEMATIC INFLAMMATION

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 performing well below anticipated levels. They agreed to blood
sampling and to a clinical psychological diagnostic interview. Both participants completed the Beck Depression
Inventory-2 (BDI-II) (7), a widely used assessment for depression. 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 agematched 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 psychological 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 produced in large quantities. Local production of cytokines, for
example, in injured muscle assists with the development of
a local inflammatory response, subsequent healing, and termination of inflammation. At times, due to varying circumstances, 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 athlete 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 considered an initial sign of OTS, several researchers have suggested that this may be accompanied by, or even preceded,
by mood, behavioral, and cognitive changes (27,64). Descriptions of these changes reflect a similar theme: a faMedicine & Science in Sports & Exercise

321

tigued athlete, discouraged and disinterested in training, in

competition, and in life in general. Although there appears
to be consensus regarding psychobehavioral changes accompanying 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 suggested that the symptoms seen in an overtrained athlete, are
remarkably similar to clinical depression (Table 1).
Although the underlying initiator(s) of these psychobehavioral 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/behavior 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 sympathetic nervous system, which results in elevated blood
levels of catecholamines (Fig. 3, Loop A). The other pathway, 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-inflammatory 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, depression, loss of interest, fear, and sleep disturbances. These
behaviors may be initiated by a wide variety of systemic
immune/inflammatory conditions, such as rheumatoid arthritis, chronic fatigue syndrome, as well as in response to
surgery, 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 therefore 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
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Official Journal of the American College of Sports Medicine

Figure 3Loop 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 from
the periphery to the CNS (inflow) (57). Copyright 1998 by the
American Psychological Association. Reprinted with permission from:
Maier, S. F., and L. R. Watkins. Cytokines for psychologists: implications for bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol. Rev. 105:83107,
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, growth
hormone; Mo, macrophages; IL1, interleukin-1; TNF, tumor necrosis
factor; IL6, interleukin-6.

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

activation of the immune/inflammatory systems (57). Certain 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 reserves (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 intriguing findings. . .are consistent with the argument that nonspecific immune activation and cytokines are involved in
the etiology or symptomology of depression. (57). There is
extensive evidence of elevated cytokines in depressed patients who exhibit significantly higher levels of IL-1 and
IL-6 in culture supernatant of mitogen-stimulated monocytes, when compared with nondepressed controls
(52,54,57); administration of cytokines in the absence of
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Figure 4 The interleukin hypothesis of major depression. A schematic diagram of the association between psychological depression and
the development of systemic immune/inflammation, as proposed by
Maes (51). Reprinted from Prog. Neuro-Psychopharmacol. & Biol.
Psychiatry 19, M. Maes. Evidence for an immune response in major
depression: a review and hypothesis, pp. 1138, 1995, with permission
from Elsivier Science.

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 implicating 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 individual
exhibits 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 cytokines 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 to
peripheral administration of peripheral cytokines (74). Furthermore, 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 hypothalamic-pituitary-adrenal axis (HPA-axis) and sympathetic nuclei,
resulting in increased levels of circulating catecholamines,
and cortisol, the traditional stress hormones (21,51). Increased levels of these stress hormones have been consistently associated with mood changes (79) and with OTS
OVERTRAINING AND SYSTEMATIC INFLAMMATION

(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, including 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 cognition have been observed in overtrained individuals
(27,64,66). These include: reports of a loss of coordination,
the reappearance of mistakes previously corrected, an inability to concentrate at work, impaired academic ability,
and changes in learning retention. Unlike the other sickness 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; during illness or injury, certain neurons, usually involved in
learning and memory, are diverted to other more pressing
functions.
The reader has hopefully discerned overwhelming similarities between these physiological, biochemical, cognitive,
and psychological/behavioral signs and symptoms experienced 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 organic, 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 psychoneuroimmunologists, 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 persisted well into the recovery period, even after performance
has begun to normalize; by comparison, there was an increase in blood glutamine in non-overtrained runners. Rowbottom 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
Medicine & Science in Sports & Exercise

323

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 abundant 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 macrophage 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, frequently 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 demands 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 glucocorticoids (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. Glutamine 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 levels (97).
An additional amino-acid dependent function during systemic 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 regulatory event (59). An interplay between numerous cytokines and the classic stress hormones, redirects the flow of
amino acids to the liver. Fischer and Hasselgren (23) reported that IL-6 and TNF- work with glucocorticoids to
stimulate amino acid uptake in human hepatocytes. In human hepatocytes, both alanine and glutamine transport were
increased significantly by IL-6 and TNF- treatment, compared with control.
This increased requirement for amino acids during hypermetabolism is partly satisfied by an augmentation of
muscle proteolysis, the major storage pool of amino acids,
and by a concomitant reduction in muscle anabolism. Ac324

Official Journal of the American College of Sports Medicine

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

also reflect what occurs during overtraining. In sepsis and traumatic
injury, glutamine and other amino acids are released from skeletal
muscle for uptake by tissues involved in the immune response and
tissue repair, such as macrophages, lymphocytes, fibroblasts, and the
liver. Nitrogen excretion as urea and NH4 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.

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 substrate 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
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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 metabolism 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, negative
nitrogen balance, decrease in lean body mass and fat mass,
increased uric acid production, increased urination, increased 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 behavioral
changes. However, evidence of increased uptake of TRY
and increased levels of serotonin, although consistently observed in animal research, is inconclusive in human research, 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 reduced 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 inflammatory-related liver proteins. Furthermore, there may be an
associated induction of a major TRP-catabolizing enzyme,
indoleamine 2,3 dioxygenase. Thus, reduced circulating
OVERTRAINING AND SYSTEMATIC INFLAMMATION

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 experiencing major-depression, Maes et al. (56) reported a significant 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 subjects, 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 collectively
as 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, recruitment of white blood cells from various sources including 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 proteins, 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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325

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 concomitant 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 APP
are 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 significantly reduced muscle glycogen levels, consumed 1000
fewer kcal than were needed to match the increased energy
expenditure, and failed to maintain the required carbohydrate 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 oxidation 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 substantiated. Snyder (89) had cyclists increase their training load for
2 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 inflammation, with elevated pro-inflammatory cytokines (81), mani326

Official Journal of the American College of Sports Medicine

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 hypothalamus 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 dysregulation 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 overtrained 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 reduction in the glucose transporter protein, GLUT-4, 1 and 2 d
after eccentrically induced muscle damage. OReilly et al.
(65) showed that muscle glycogen stores were markedly
reduced for up to 10 d after eccentric exercise. They suggested that a decreased muscle concentration of GLUT-4
protein, 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 exercise (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 reduced glycogen at the level of the muscle, several investigators (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 and
systemic 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-inflammatory cytokines, directly and/or indirectly, induce anorexia, 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 glycogen could in turn account for the heavy legs (64) experienced 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, prolonged
physical 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 cytokines are potent activators of the hypothalamic-pituitaryadrenal 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 receptors, resulting in release of corticotropin releasing hormone (CRH) (35,67,77). CRH stimulates release of pituitary
adrenocorticotropin releasing hormone (ACTH), with subsequent release of cortisol from the adrenal cortex. In addition to the action of cytokines at the level of the hypothalamus, IL-6 may control the release of steroid hormones
by direct action on adrenal cells, and regulate adrenal synthesis of mineralocorticoids, glucocorticoids, and androgens, in a time and dose dependent fashion (67). Thus,
systemic inflammation and elevated cytokines could account for elevated cortisol levels in OTS (26,27,91).
Reported decreases in testosterone and suppressed reproductive function in OTS (48,90,91) implicate the hypothalamic-pituitary-gonadal (HPG) axis. The controlling hormone 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 induce the release of ovarian estradiol, and testicular testosterone (58). In reference to cytokines and reproductive function, these inflammatory mediators suppress reproductive
function via inhibition of LHRH (58,77,83).
In summary, hypothalamic-related hormonal systems appear to be altered in OTS, although a clear pattern has not
emerged. However, there is extensive information demonstrating an interaction between systemic cytokines and the
OVERTRAINING AND SYSTEMATIC INFLAMMATION

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 evidence suggests an increased incidence of illness associated
with OTS (27,36,60,64,68). These include an increased susceptibility 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 response to moderate exercise, intense exercise, even one
bout, such as a marathon, might result in immune suppression (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 overtraining on the immune system (36,60).
A model that may be relevant to understanding a compromised 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 associated with the up-regulation of inflammation. Anti-inflammatory factors are expressed in various forms and have a
variety 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 proteins, such as C-reactive protein, serve as potent anti-inflammatory agents (42). Although these anti-inflammatory
effects are necessary to counteract the pro-inflammatory
effects, the ultimate result of prolonged, intense, counterregulation is immunosuppression (8). In reference to trauma
patients, Biffl and colleagues (8) have suggested that it is
paradoxical that the hyper-inflammatory response may predispose the individual to the subsequent development of
immuno-suppression (see Fig. 6) (8).
A model of early hyperinflammation followed by late immunosuppression may be applicable to understanding the immune 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 counterregulatory anti-inflammatory factors, for an extended period. Thus, immunosuppression may reflect the bodys highly
developed attempt to contain inflammation through the production of endogenous anti-inflammatory molecules (19).
Medicine & Science in Sports & Exercise

327

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

(8). The physiologic response to injury involves an early hyper-inflammatory response, which is accompanied by a degree of compensatory
anti-inflammatory effect. If the early inflammatory response is excessive, an appropriate persistence of anti-inflammatory compensation
will result in later immunosuppression. Reprinted with permission
from: 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.

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 exhaustion
represents 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 manifestation 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 being additive. It is proposed here that this third stage represents 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 perpetuating cycle, consisting of a primary stimulus (muscle-related

Figure 7Cytokine theory of overtraining: proposed events leading to, and sustaining the overtraining syndrome (Schematic
diagram
under
IMMUNE
CELLS is reprinted with permission
from: 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).

328

Official Journal of the American College of Sports Medicine

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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 cytokines would in turn coordinate the whole body response,
including the CNS, the liver, and the immune system, attempting 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-depressants, and anti-cytokine drugs (19), as well as dietary
factors (88), may prove useful adjuncts.
Finally, if this hypothesis proves viable, it will be important to guard against overdiagnosing OTS. Selye (79) has
emphasized that the different stages of the general adaptation syndrome are represented by clusters of several symptoms 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 response 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 proinflammatory cytokines, IL-1, IL-6, and TNF-. The cytokines 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 sympathetic nervous system and hypothalamic-pituitary-adrenal
axis, while suppressing activity of hypothalamic-pituitarygonadal 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. Immune-related changes may be related to an immuno-suppression, possibly due to anti-inflammatory factors that accompany 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 previously proposed mechanisms. It is hoped that future research
pertaining to OTS, will examine the role of systemic inflammatory 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, for
editorial suggestions. Thank you to Alta Bender, Appalachian State
University, for assistance in developing the graphics. Thank you to
Denise Martz-Ludwig, Ph.D. (Psychology), Appalachian State University, for administering psychological assessments. I would like to
thank the following graduate students from Appalachian State University, for assistance in preparation of this manuscript: Max Shute,
Mark Lehmkeul, and Elizabeth Hogen.
Address for correspondence: Lucille Lakier Smith, Ph.D., Department of Exercise and Sport Science, 371 Ward Sports Medicine
Building, East Carolina University, Greenville, NC 27858.

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