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The goal in training competitive athletes is to provide training loads
that are effective in improving performance. At some stages during
the training process, athletes may experience an unexplainable de-
crease in performance. This might happen when prolonged exces-
sive training takes place concurrent with other stressors and insuf-
cient recovery. This unexplainable performance decrements can
result in chronic maladaptations that can lead to the overtraining
syndrome (OTS). A keyword in the recognition of OTS might be ‘‘pro-
longed maladaptation’’ not only of the athletic performance but also
of several biological, neurochemical and hormonal regulation mech-
anisms. When athletes deliberately use a short-term period (e.g.
training camp) to increase training load, they can experience short-
term performance decrement, without severe psychological or last-
ing other negative symptoms.1,2 This functional over reaching (FO)
will eventually lead to an improvement in performance after recov-
ery. However, when athletes do not sufciently respect the balance
between training and recovery, non-functional over-reaching (NFO)
can occur.1,2 At this stage, the rst signs and symptoms of prolonged
maladaptation such as performance decrements, psychological dis-
turbance (decreased vigour, increased fatigue) and hormonal distur-
bances are present, and the athlete will need weeks or months to
recover. The distinction between NFO and OTS is very difcult and
will depend on the clinical outcome and exclusion diagnosis.
The recent ‘‘consensus statement’’ of the European College of Sport
Science indicates that the difference between NFO and OTS is the amount
of time needed for performance restoration and not the type or duration
of training stress or degree of impairment.1 In essence, it is generally
thought that symptoms of OTS, such as fatigue, performance decline and
mood disturbances, are more severe than those of NFO. However, there
is no scientic evidence to either conrm or refute this suggestion.1 The
distinction between NFO and OTS is most of the time based on ‘‘time
to recover’’. Hence, there is a need for objective, immediately available
evidence that the athlete is indeed experiencing OTS.
Most of the literature agrees that FO, NFO and OTS must be viewed on
a continuum with a disturbance, an adaptation and nally a maladaptation
of the hypothalamic–pituitary–adrenal axis (HPA), resulting in an altered
Diagnosing overtraining in athletes using the two-bout
exercise protocol*
ABSTRACT
Objective. In this work, whether a two-bout protocol can be used
to make an objective, immediately available distinction between
non-functional over reaching (NFO) and overtraining syndrome
(OTS) was studied.
Design. Underperforming athletes who were diagnosed with the
suspicion of NFO or OTS were included in the study. Recovery
of the athletes was monitored by a sports physician to retrospec-
tively distinguish NFO from OTS.
Setting. Sports medicine laboratory.
Participants. The protocol was started and completed by 10 un-
derperforming athletes. NFO was retrospectively diagnosed in
ve athletes, and OTS was diagnosed in ve athletes.
Interventions. A two-bout maximal exercise protocol was used
to measure physical performance and stress induced hormonal
reactions.
Main outcome measurements. Exercise duration, heart rate and
blood lactate concentration were measured at the end of both ex-
ercise tests. Venous concentrations cortisol, adrenocorticotrophic
hormone (ACTH), prolactin and growth hormone were measured
both before and after both exercise tests.
Results. Maximal blood lactate concentration was lower in OTS
compared with NFO, while resting concentrations of cortisol,
ACTH and prolactin concentrations were higher. However, sen-
sitivity of these measures was low. The ACTH and prolactin re-
actions to the second exercise bout were much higher in NFO
athletes compared with OTS and showed the highest sensitivity
for making the distinction.
Correspondence to:
Romain Meeusen, Department of Human Physiology and Sports
Medicine, Faculty of Physical Education and Physical Therapy,
Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium;
rmeeusen@vub.ac.be
Accepted 14 July 2008, published online rst 14 August 2008
* This article was reproduced with permission from the BMJ Group.
It was originally published in the British Journal of Sports Medicine
2010;44:642-648.
R Meeusen,1 E Nederhof,1,2 L Buyse,1 B Roelands,1 G de Schutter,1 M F Piacentini3
1Department of Human Physiology and Sports Medicine, Faculty of Physical Education and Physical Therapy, Vrije Universiteit, Brussel,
Brussels, Belgium
2Center for Human Movement Sciences and University Center for Sports, Exercise and Health, University Medical Center Groningen, Univer-
sity of Groningen, Groningen, The Netherlands
3Department of Human Movement and Sports Science, Istituto Universitario di Scienze Motorie, Rome, Italy
EDITOR`S CHOICE
SAJSM VOL 22 NO. 4 2010 99
Conclusions. NFO might be distinguished from OTS based on
ACTH and prolactin reactions to a two-bout exercise protocol.
This protocol could be a useful tool for diagnosing NFO and OTS;
however, more data should be collected before this test can be
used as the gold standard.
hormonal response to intense training and competition.3–12 When
investigating hormonal markers of training adaptation, it is important to
target specic hormones for their information potential and to synchronise
their sampling in accordance with their response patterns.
The hypothalamus is under the control of several ‘‘higher’’ brain
centres and several neurotransmitters13 known to play a major role
in various neuroendocrine and behavioural functions, for example,
activation of the HPA axis, feeding and locomotion.14 Therefore, the
typical HPA axis-related hormones cortisol, adrenocorticotrophic
hormone (ACTH), prolactin (PRL) and human growth hormone (GH)
were targeted in the present study.
It should be emphasised that, depending on the training status,
the time the hormone measurements are taken (diurnal variation),
urinary, blood and salivary measures create a great variation in the
interpretation of the results. In pathological situations such as in major
depression,15,16 post-traumatic stress disorder,17 and probably also
in OTS,10 the glucocorticoids and the brain monoaminergic systems
apparently fail to restrain the HPA response to stress. Indeed, we
recently showed that a test protocol with two consecutive maximal
exercise tests separated by 4 h may give a good indication of the
HPA response to stress in well-trained and FO athletes relative to
a case of OTS.10 We found a suppression of the HPA response
to the second exercise bout in the OTS athlete as opposed to the
TABLE 1 Demographic data and reported symptoms of the patients
Subject 1 2 3 4 5 6 7 8 9 10
Sex Men Women Men Men Men Men Men Men Women Men
Age 18 17 38 36 31 46 21 35 23 22
Height (cm) 188 163 176 189 185 178 185 187 179
Weight (kg) 78.7 39 64 78 67.9 72.5 68.9 74.8 77.3 62.8
Sport Motor
cross
Distance
running
Distance
running
400 m
running
Distance
running
Triathlon Cycling Race
walking
Swim-
ming
Distance
running
Duration
symptoms
before testing
1 year 1 year At least 3
months
At least 2
months
At least
half a year
2–3 months 6 weeks 2 weeks 2 weeks 5 months
Duration re-
covery after
testing
1 year Several
years
>5 years >3 years No full
recovery
1–2 months max 6
months
approx 12
weeks
1 month 3 months
Performance
decrements
Unable to
complete
training
sessions
Unable to
perform
normal
training
because
of dizzi-
ness
Unable to
perform
normal
training
Unable to
perform
normal
training
Unable to
perform
normal
training
HRmax,<150,
dizziness and
dyspnoea
during uphill
cycling
Unable to
complete
races, bad
recovery
from train-
ing
Unable to
complete
normal
training
and races
Dif-
culty with
speed
training
Unable to
complete
normal
training
and worse
race per-
formance
Fatigue Severe Severe Severe Severe Severe Severe Severe Severe
Muscle sore-
ness
Heavy
legs
Heavy and
painful legs
Muscle
soreness
Hamstring
pain
Heavy up-
per legs
Other symp-
toms
Sleeps
11– 12 h
each night
psycho-
logical
problems
Anorexia Psycho-
logical
problems,
depres-
sion
Gets up
frequently
to urinate,
impo-
tence
Sleeping
distur-
bances
Psycho-
logical
problems
Sleeps
14 h per
day
Difculties
getting up,
gained
5 kg in 5
months
Diagnosis OTS OTS OTS OTS OTS NFO NFO NFO NFO NFO
NFO=non-functional overreaching, OTS=overtraining syndrome
100 SAJSM VOL 22 NO. 4 2010
normal responses. The question can be asked if this method is
also a valuable tool to make a distinction between NFO and OTS.
Therefore, we report the results of 10 patients who were referred to
our laboratory with the diagnosis of suspicion of NFO or OTS.
METHODS
Subjects
Ten patients who consulted a sports physician with complaints of
underperformance and fatigue participated in the present study.
The eight men and two women had an average height and weight
of 181±(8) cm and 68.4±(11.8) kg. All subjects were diagnosed by a
sports physician according to the latest guidelines for overtraining
diagnosis.1,18 A careful history including training history was taken,
completed by a physical examination and a blood draw to rule out
other possible causes for the complaints. Patients were diagnosed
as NFO or OTS retrospectively according to the severity of symp-
toms and the total duration of symptoms and underperformance (ie,
both before and after testing) when no medical explanation for the
condition could be found. It turned out that a cutoff of 1-year total
duration gave a good distinction between NFO and OTS patients.
Demographic data and reported symptoms can be found in table 1.
Data of subject 1 are the same as presented in an earlier publica-
tion.10 All subjects signed informed consent before participation.
Protocol
Two incremental graded exercise tests until exhaustion were per-
formed, with 4 h of rest in between. One hour before each test,
the athletes received a standardised meal (2315 kJ, 73% carbo-
hydrate, 19% protein, 8% fat). Athletes arrived in the laboratory at
07:00 after an overnight fast. The rst blood sample was collected
as they arrived. Immediately after the rst exercise test, the second
blood sample was drawn. The third and fourth blood samples were
drawn before and immediately after the second test. A schematic
overview of the protocol can be found in g 1. Because it is known
that venepuncture increases blood prolactin, going back to base-
line within 30 min, blood was drawn before and after each test (four
punctures) creating the same ‘‘stress’’ in each situation. The study
protocol was approved by the university ethical committee.
Exercise testing
Exercise tests were performed on a cycle ergometer (Lode Excalibur
Sport, Groningen, The Netherlands) or on a treadmill (Ergo ELG 55;
Woodway, Weil am Rhein, Germany) depending on the sport. Tests on
the cycle ergometer started with an initial workload of 80 W (subjects 6
and 7) or 30 W (subjects 4 and 9), the workload was increased by 40
W every 3 min. Tests on the treadmill started at 5.4 km h-1, the speed
was increased with 1.8 km h-1 each 3 min (subjects 1, 2, 3, 8 and 10).
One subject performed the treadmill test with an inclination of 1% (sub-
ject 5). The duration of each test was recorded in seconds. Subjects
wore a heart rate monitor (Polar Accurex Plus, Kempele, Finland) for
determination of maximal heart rate (HRmax) throughout the exercise
tests. After each exercise test, 20 ml of blood was drawn from the right
earlobe to determine maximal blood lactate concentration ([La]max)
with enzymatic analysis (EKF; Biosen 5030, Barleben, Germany).
Fig 1. Schematic overview of the protocol.
Figure 2. Exercise duration, maximal heart rate and maximal
blood lactate concentrations during the rst (grey bars) and the
second (black bars) exercise test for the non-functional over-
reached (NFO) group and the overtraining syndrome (OTS)
group. Data are presented as means (SE).
Table 2 Sensitivity for the detection of OTS and NFO
Measure
Cutoff for
OTS OTS (%) NFO (%)
[La]max rst exercise test <8 mmol l-1 80 50
[La]max second exercise
test
<8 mmol l-1 100 67
[Cortisol]rest >175 mg l-1 80 60
[ACTH]rest >40 ng l-1 80 80
[PRL]rest >50 IU l-1 40 100
Cortisol response to second
exercise test
<200%
increase
80 20
ACTH response to second
exercise test
<200%
increase
100 80
PRL response to second
exercise test
<200%
increase
100 100
GH response to second
exercise test
<1000%
increase
40 40
[ACTH]rest, fasted morning adrenocorticotrophic hormone concentration;
[Cortisol]rest, fasted morning cortisol concentration; GH, human growth hormone;
[La]max, maximal blood lactate concentration; [PRL]rest, fasted morning prolactin
concentration.
SAJSM VOL 22 NO. 4 2010 101
102 SAJSM VOL 19 NO. 4 2007
102 SAJSM VOL 22 NO. 4 2010
Blood analysis
Samples were collected in prefrozen 4.5 ml K3 EDTA vacutainer
tubes (Becton Dickinson Vacutainer System Europe, Plymouth,
UK) and immediately centrifuged at 3000 rpm (Minifuge 2, Heraeus,
Germany) for 10 min, and plasma was frozen at -20˚C until further
analysis. Samples were assayed via RIA for cortisol (DiaSorin, Still-
water, Minnesota, USA), ACTH (Nichols Institute Diagnostics, San
Juan Capistrano, California, USA), PRL (Roche Diagnostics, Man-
nheim, Germany) and GH (Pharmacia & Upjohn Diagnostics, Upp-
sala, Sweden).
Hormonal concentrations were expressed both in absolute
(average (SE)) and relative values. For the relative hormone
concentrations, both pre-test values were set at 100%; both post-
test values were calculated by dividing through the pre-test value
and multiplying by 100%.
Data analysis
Data were analysed using three different methods: visual inspec-
tion, parametric statistics and calculation of sensitivity for both OTS
and NFO detection. Because the sample size was rather small (ie,
maximal 5 for each group), data were rst inspected visually. Para-
metric statistics and sensitivity calculation were used to support
conclusions from visual inspection of the data. For the purpose of
visual inspection, we created graphs with averages and SE for both
the OTS and the NFO groups. When visual inspection gave an in-
dication for group differences, parametric statistical analyses were
performed through ANOVA with repeated measures with one within
subjects factor (post-values for rst and second exercise test) and
one between-subjects factor (NFO or OTS) or through an independ-
ent samples t test. Those analyses were performed in SPSS V.15.0.
Sensitivity was also calculated for these variables by dividing the
number of correct OTS or NFO diagnoses by hormonal analysis by
the total number of OTS or NFO diagnoses according to the consen-
sus statement.1 Sensitivity was presented as a ratio. The denomina-
tor varies because of random missing values.
RESULTS
Exercise testing
Exercise duration, HRmax and [La]max are presented in g 2A, B,
and C. Visual inspection of the data led to the conclusion that there
is no difference in exercise duration and HRmax between the OTS
and the NFO patients. For [La]max, a much lower value was found
for the OTS patients in combination with a larger reduction from the
rst to the second test compared with the NFO patients. However,
parametric analysis did not indicate signicant differences. The main
effect of group gave an F ratio of 2.9 for [La]max and an F ratio <1
for exercise duration and HRmax, showing that almost three times
as much variance is explained by the group membership (ie, OTS vs
NFO) compared with random factors. In addition, sensitivity for OTS
detection with [La]max was high (table 2). With a cutoff of 8 mmol
l-1, four out of the ve OTS patients would have been diagnosed
correctly from the rst exercise test and four out of the four OTS
patients from the second exercise test. Sensitivity for NFO diagnosis
was lower, however (table 2). From the rst exercise test, a correct
diagnostic ratio of two out of four was found, for the second test, two
out of three.
Absolute hormone concentrations
In g 3A–D, absolute hormone concentrations are presented for the
NFO and the OTS groups. Visual inspection of the data led to the
conclusion that resting concentrations cortisol, ACTH and PRL were
higher for OTS patients compared with NFO. However, reactions to
exercise tests did not differ between the groups. Resting hormone
concentrations were tested with independent t tests. Only for ACTH,
the t test gave a value >2 (ie, t8= 2.6; p<0.05), meaning that only for
ACTH, the difference between the groups was more than twice as
large as the SE. Sensitivity of resting cortisol, ACTH and PRL was four
out of ve (cutoff 175 mg l-1), four out of ve (cutoff 40 ng l-1) and two
out of ve (cutoff 50 IU l-1), respectively (table 2). Sensitivity for detec-
tion of NFO was three out of ve, four out of ve and three out of ve
respectively for cortisol, ACTH and PRL, respectively (table 2).
Relative hormone concentrations
Hormonal responses to the two exercise bouts are presented in g
4A–D. Visual inspection led to the conclusion that there are no dif-
ferences in relative cortisol response between the NFO and the OTS
group. ACTH, PRL and GH responses are higher in the NFO group
compared with the OTS group, especially in the second exercise
bout. However, the SE of GH in the NFO group was probably too
large to draw clear conclusions. Indeed, the main effect of group
gave an F ratio of F1,7=1.4 for GH. For ACTH and PRL, F ratios were
F1,7=5.1 and F1,6=14.7, both signicant at p<0.05, conrming larger
responses for the NFO group. Visual inspection led to the conclusion
that this larger response was much more pronounced after the sec-
Figure 3. Cortisol, adrenocorticotrophic hormone (ACTH), pro-
lactin (PRL) and growth hormone (GH) concentrations before
and after the two exercise bouts for the NFO group (solid lines)
and the OTS group (dashed lines). Data are presented as mean
(SE).
Figure 4. Cortisol, ACTH, PRL and GH responses to the two ex-
ercise tests for the non-functional over-reached (NFO) group
(solid lines) and the OTS group (dashed lines). Data are pre-
sented as percentage increase from both baseline values (SE)
of the mean.
SAJSM VOL 22 NO. 4 2010 103
ond exercise bout. Indeed, parametric results pointed in the direction
of an interaction effect between test and group for ACTH and PRL
(F1,7=4.1; p=0.084; F1,6=4.0; p=0.092).
Sensitivity of ACTH and PRL for the detection of OTS was four
out of four and ve out of ve, respectively (table 2; cutoff, 200%
at the second exercise test) and for the detection of NFO was four
out of ve and three out of three, respectively. Sensitivity of cortisol
(cutoff, 200% at the second test) and GH (cutoff, 1000%) for the
detection of OTS was four out of ve and two out of ve, and for the
detection of NFO, one out of ve and two out of four, respectively
(table 2).
DISCUSSION
Results of the present study show that ACTH and PRL responses
to a double maximal exercise bout are sensitive for the diagnosis of
OTS and NFO. Cortisol and GH responses were much less sensitive
measures as were resting hormone concentrations. Maximal lactate
concentrations at both exercise tests showed a high sensitivity for
the detection of OTS, but almost half of the NFO patients did not
reach [La]max of 8 mmol l-1 either.
Subjects
One of the difculties in diagnosing OTS is that this should be based
on ‘‘exclusion criteria’’.1,18 Although, in recent years, the knowledge
of central pathomechanisms of the OTS has signicantly increased,
there is still a strong demand for relevant tools for the early diagnosis
of OTS. By calculating sensitivity for detection of NFO and OTS, a
good indication of the value of the different measures for the diagno-
sis of unexplainable underperformance is obtained (table 2).
Ten patients were referred to the laboratory with a possible
diagnosis of having OTS. Based on the criteria used in the consensus
statement of the ECSS,1 the decision was made to perform a double
maximum test with these athletes. One of the criteria to dene an
athlete as OTS is that recovery from the status will take months, or
even years.1,2 In the present study, an arbitrary cutoff of 1 year was
used. Those patients who needed more than 1 year for recovery
were retrospectively diagnosed with OTS, the others with NFO.
There seemed to be a good distinction between the patient groups
based on this criterion, as the OTS patient with the shortest recovery
time (1) experienced underperformance and other symptoms for
2 years, whereas the NFO patient with the longest recovery time
(10) had NFO for 8 months. In addition, although subjective, there
seemed to be a good parallel with the severity of the symptoms.
Lactate
One almost overall nding, at least in endurance and strength-
endurance athletes having OTS, is a diminished maximal lactate
concentration, whereas submaximal values remain unchanged or
slightly reduced.10,12 This is conrmed in the present study where
OTS patients did not reach maximal lactate concentrations above 8
mmol l-1. Two out of the four NFO patients did not reach [La]max of 8
mmol l-1 at the rst exercise test either (for one patient [La]max was
missing). Thus, although low [La]max has frequently been described
as a diagnostic marker for OTS, from these results, it does not seem
sensitive enough to distinguish OTS from NFO.
Absolute hormone concentrations
Resting hormone concentrations have been a topic of many stud-
ies and discussions. It has been suggested that conicting results
were, at least partly, because of a lack of standardization in both the
way overtraining was measured and in the hormone measurement
protocols used. Results from the present study show that variability
in resting hormone concentrations is also present within groups of
NFO and OTS patients. The arguments for contradictory ndings are
not valid within this study where blood was drawn at the same time
of day always after an overnight fast. However, the diurnal varia-
tion in cortisol cannot be ruled out with this protocol because tests
are separated by 4 h. However, each test was done with the same
protocol and timing so that the data were collected in a standardised
manner. One possible reason why the cortisol levels do not show the
same pattern as ACTH might be because of this diurnal variation.
Therefore, it must be concluded that resting hormone concentrations
are not sensitive enough, at least not to diagnose unexplained un-
derperformance in athletes. It has been suggested that hormonal
reactions to stress tests are more sensitive.1,11
The symptoms associated with OTS, such as changes in emotional
behaviour, prolonged feelings of fatigue, sleep disturbances and
hormonal dysfunctions are indicative of changes in the regulation
and coordinative function of the hypothalamus.8,19 Previous
studies have shown different results for stress-induced hormonal
responses.6,20,21 Results from a previous study10 and the present
study show that contradictory ndings cannot solely be explained by
different measurement methods and/or denitions used. From gs 3
and 4, it is clear that hormonal responses to one single exercise bout
are not sensitive enough to distinguish NFO from OTS.
Relative hormone concentrations
The only measures that accurately distinguished NFO from OTS
were increases in ACTH and PRL concentrations after a second
maximal exercise bout. The OTS athletes showed a very small or
no increase in ACTH and PRL concentrations after the second exer-
cise bout; the NFO athletes showed very large increases. This is a
conrmation of our previous studies with this protocol.10 ,22 The use
of two bouts of maximal exercise to study neuroendocrine variations
showed an adapted exercise-induced increase of ACTH, PRL and
GH to a two-exercise bout.10
The fact that GH did not perform as well as both other pituitary
hormones in the present study could be the result of the large inter-
individual variation in the NFO group. One of the NFO athletes had
a very low resting value before the second exercise test and showed
an increase of 12 000%. Cortisol concentrations after the second
exercise test seem also quite good markers for OTS but poor when
it comes to distinguish NFO from OTS. Although almost all OTS
athletes showed a reduced increase in the response of cortisol to
the second exercise bout, almost none of the NFO athletes showed
an overshoot (table 2). This result is similar to earlier ndings.10,22
In an earlier study, we found that in order to detect signs of OTS
and distinguish them from normal training responses or FO, this
method may be a good indicator not only of the recovery capacity
of the athlete but also of the ability to normally perform the second
bout of exercise.10 The test could, therefore, be used as an indirect
measure of hypothalamic– pituitary capacity. It was hypothesised
that on the NFO–OTS continuum, a hypersensitivity of the pituitary
is followed by an insensitivity or exhaustion afterwards.10,22 Results
from the present study conrm this hypothesis. The NFO athletes
showed a very high response to the second exercise bout, at least in
ACTH and PRL, whereas the OTS athletes showed suppression.
There are two other studies that have measured prolactin in
relation to overtraining. Lehmann et al23 showed that an increase
in training volume, rather than intensity, led to more symptoms
associated with overtraining. They also observed a close-to-
signicant exercise-induced decrease in plasma prolactin in the
104 SAJSM VOL 22 NO. 4 2010
increased intensity group but no change because of increased
volume. Budgett et al24 observed a more marked plasma prolactin
response to a neuroendocrine challenge in athletes with unexplained
underperformance syndrome. They also observed a higher resting
plasma prolactin in unexplained underperformance syndrome
athletes than healthy controls. These authors also state that prolactin
could prove useful in monitoring the individual response to training
and recovery.
Behind the seemingly uniform acute hormonal response to
exercise, explaining the disturbance to the neuroendocrine system
caused by OTS is not that simple. There are several similarities with
other intensive and chronic stress situations. There is compelling
evidence for the involvement of HPA axis abnormalities in chronic
stress situations such as post-traumatic stress disorder17 and
depression25 and probably also during NFO and OTS. In chronic
stress situations, the number of ACTH and cortisol secretion pulses
is increased, which is also reected in elevated urinary cortisol
production.25
Chronic stress and the subsequent chronic peripheral
glucocorticoid secretion plays an important role in the desensitisation
of higher brain centre response during acute stressors because it
has been shown that in acute (and also chronic) immobilisation, the
responsiveness of hypothalamic corticotrophin-releasing hormone
(CRH) neurons rapidly falls.26 These adaptation mechanisms
could be the consequence of changes in neurotransmitter release,
depletion of CRH and/or desensitisation of hypothalamic hormonal
release to afferent neurotransmitter input.26 Indeed, concentrations
of CRH are elevated, the number of CRH-secreting neurons in the
limbic brain regions is increased and the number of CRH binding
sites in the frontal cortex is reduced secondary to increased CRH
concentrations following chronic stress.25
Another very important brain area that mediates, and in
turn is affected by the stress response, is the hippocampus.27
The consequences of impaired regulation of cortisol secretion
are manifold, ranging from effects in peripheral tissues (eg,
osteoporosis) to changes in the central nervous system.28 Most of
the effects seen in chronic stress situations can be explained by
the occupation of the two glucocorticoid receptors in the brain. In
normal situations, the mineralocorticoid receptor will be occupied,
whereas the glucocorticoid receptor has lower afnity for the natural
ligand corticosterone (cortisol) than the mineralocorticoid receptor
and is extensively activated only after stress and at the peaks of
the circadian rhythm. One of the main functions of glucocorticoid
receptors is to normalise brain activity some hours after an organism
has been exposed to a stressful event and to promote consolidation
of the event for future use.25,28 To this purpose, corticosteroids feed
back in precisely those circuits that are initially activated by the
stressor and are enriched in glucocorticoid receptors: limbic forebrain
neurons and the paraventricular nucleus of the hypothalamus.
When stress is chronically induced, as in NFO and OTS, two
specic mechanisms could occur: rst, when corticosteroid levels are
chronically too high, a hypersensitivity of the receptors will occur, this
can lead to a disinhibition of CRH producing neurons, which in turn
will lead to an intensied release of ACTH (as seen in the second
exercise bout in the NFO athletes). When the chronic stress situation
continues and glucocorticoid receptors are chronically activated
(which occurs in post-traumatic stress disorder17 and depression),25
a blunted ACTH response to CRH will occur.28
From the data mentioned previously, it can be concluded that
in NFO and OTS, the neuroendocrine disorder is a hypothalamic
dysfunction rather than a malfunction of the peripheral hormonal
organs29 and that the distinction between NFO and OTS can be
characterised by hypersensitivity versus insensitivity of glucocorticoid
receptors. The interactive features of the periphery and the brain
could be translated into possible immunological, psychological and
endocrinological disturbances.
Competing interests: None.
Re f e r e n c e s
1. Meeusen R, Duclos M, Gleeson M, et al. Prevention, diagnosis and the
treatment of the Overtraining Syndrome. Eur J Sport Sci 2006;6:1–14.
2. Nederhof E, Lemmink KAPM, Visscher C, et al. Psychomotor speed: pos-
sibly a new marker for overtraining syndrome. Sports Med 2006;36:817–
28.
3. Keizer H. Neuroendocrine aspects of Overtraining. In Kreider R, Fry AC,
O’Toole M, eds. Overtraining in sport 1998:145–68. Champaign (IL): Hu-
man Kinetics.
4. Lehmann M, Foster C, Keul J. Overtraining in endurance athletes: a brief
review. Med Sci Sports Exerc 1993;25:854–62.
5. Lehmann M, Foster C, Dickhuth HH, et al. Autonomic imbalance hypoth-
esis and overtraining syndrome. Med Sci Sports Exerc 1998;30:1140–5.
6. Lehmann M, Gastmann U, Baur S, et al. Selected parameters and mecha-
nisms of peripheral and central fatigue and regeneration in overtrained
athletes. In: Lehmann M, Foster C, Gastmann U, Keizer H, Steinacker
J, eds. Overload, performance incompetence, and regeneration in sport.
New York: Kluwer Academic/Plenum, 1999:7–25.
7. Lehmann M, Petersen KG, Liu Y, et al. Chronische und erscho¨pfende
Belastungen im Sport—Einuss von Leptin und Inhibin. [Chronic and ex-
hausting training in sports—inuence of leptin and inhibin] Dtsch Z Sport-
med 2001;51:234–43.
8. Meeusen R. Overtraining, indoor & outdoor. Vlaams tijdschrift voor Sport-
geneeskunde & Sportwetenschappen 1998;19:8–19.
9. Meeusen R. Overtraining and the central nervous system, the missing
link? In:Lehmann M, Foster C, Gastmann U, Keizer H, Steinacker J, eds.
Overload, performance incompetence, and regeneration in sport. New
York: Kluwer Academic/ Plenum publishers, 1999:187–202.
10. Meeusen R, Piacentini MF, Busschaert B, et al. Hormonal responses in
athletes: the use of a two bout exercise protocol to detect subtle differ-
ences in (over)training status. Eur J Appl Physiol 2004;91:140–6.
11. Urhausen A, Gabriel H, Kindermann W. Blood hormones as markers of
training stress and overtraining. Sports Med 1995;20:251–76.
12. Urhausen A, Gabriel H, Weiler B, et al. Ergometric and psychological
ndings during overtraining: a long-term follow-up study in endurance
athletes. Int J Sports Med 1998;19:114–20.
13. Meeusen R, De Meirleir K. Exercise and brain neurotransmission. Sports
Med 1995;20:160–88.
14. Wilckens T, Schweiger U, Pirke K. Activation of 5-HT1C-receptors sup-
presses excessive wheel running induced by semi-starvation in the rat.
Psychopharmacology 1992;109:77–84.
15. Dishman R. The norepinephrine hypothesis. In: Morgan WP, ed. Physical
activity & mental health. Washington: Taylor & Francis, 1997:199–212.
16. Porter R, Gallagher P, Watson S, et al. Corticosteriod–serotonin interac-
tions in depression: a review of the human evidence. Psychopharmacol-
ogy 2004;173:1–17.
17. Liberzon I, Taylor S, Amdur R, et al. Brain activation in PTSD in response
to traumarelated stimuli. Biol Psychiatry 1999;45:817–26.
18. Uusitalo ALT. Overtraining. Making a difcult diagnosis and implementing
targeted treatment. Phys Sportsmed 2001;29:35–50.
What is already known on this topic
• The diagnoses NFO and OTS must be made based on an
exclusion diagnosis. The most important marker to distinguish
NFO from OTS is duration of recovery, which is only known
retrospectively.
• Athletes with NFO or OTS show a disturbed functioning of
the hypothalamic–pituitary–adrenal (HPA) axis, which parallels
disturbances in other stress-related syndromes.
What this study adds
• The two-bout exercise protocol seems a useful tool for pro-
spectively diagnosing underperforming athletes, with an over-
shoot of adrenocorticotrophic hormone (ACTH) and prolactin
(PRL) after the second exercise bout in NFO athletes and a
suppression in OTS.
• A possible explanation for the difference is hypersensitivity of
glucocorticoid receptors in NFO versus insensitivity in OTS.
SAJSM VOL 22 NO. 4 2010 105
19. Armstrong L, VanHeest J. The unknown mechanisms of the overtraining
syndrome. Clues from depression and psychoneuroimmunology. Sports
Med 2002;32:185–209.
20. Fry AC, Kraemer WJ, Ramsey LT. Pituitary–adrenal–gonadal respons-
es to highintensity resistance exercise overtraining. J Appl Physiol
1998;85:2352–9.
21. Rietjens GJWM, Kuipers H, Adam JJ, et al. Physiological, biochemical
and psychological markers of strenuous training-induced fatigue. Int J
Sports Med 2005;26:16–26.
22. Nederhof E, Zwerver J, Brink M, et al. Different diagnostic tools in non-
functional overreaching. Int J Sports Med 2008;29:590–7.
23. Lehmann M, Gastmann U, Petersen KG, et al. Training-overtraining: per-
formance, and hormone levels, after a dened increase in training volume
versus intensity in experienced middle- and long-distance runners. Br J
Sports Med 1992;26:233–42.
24. Budgett R, Hiscock N, Arida RM, et al. The effects of the 5-HT2C ago-
nist mchlorophenylpiperazine on elite athletes suffering from unexplained
underperformance syndrome (overtraining). Br J Sports Med. Published
Online First 4 July 2008. doi:10.1136/bjsm.2008.046425
25. Holsboer F. The corticosteroid receptor hypothesis of depression. Neu-
ropsychopharmacology 2000;23:477–501.
26. Cizza G, Kvetnansky R, Tartaglia M, et al. Immobolisation stress rapidly
decreases hypothalamic corticotropin-releasing hormone secretion in
vitro in the male 344/N Fischer rat. Life Sci 1993;53:233–40.
27. Bremmer D. Does stress damage the brain? Biol Psychiatry 1999;45:797–
805.
28. Joels M, Kvarst H, DeRijk R, et al. The coming out of the brain mineralo-
corticoid receptor. Trends Neurosci 2008;31:1–7.
29. Kuipers H, Keizer H. Overtraining in elite athletes. Sports Med 1988;6:79–
92.
