Entries in Unexplained Under Performance Syndrome (4)


Unexplained Underperformance Syndrome

UUPS - unexplained underperformance syndrome - Rod Jaques

The ‘unexplained underperformance syndrome’ (UUPS) is defined as a history of objective loss of performance, without a medical cause and despite two weeks of rest. This definition was arrived at by a group of experts in Oxford in 1999. They chose to call the syndrome UUPS as opposed to ‘over training’ to avoid restricting the cause to training per se.

UUPS is almost exclusively a condition of endurance athletes, commonly occurring after a period of heavy training and competition. There is often a his-tory of frequent minor infections.

Anecdotally it is thought that between 2% and 10% of elite endurance athletes suffer significant episodes of UUPS during their sporting careers. Often the condition occurs insidiously and remains undiagnosed for many weeks. The athlete typically will have sought advice from many quarters and have tried short periods of rest without success. Ideally the diagnosis of UUPS should be one that both athlete and coach agree upon.

Fatigue is the key presenting symptom. This fatigue persists despite rest and leads to underperformance. The athlete may lose motivation and often complains of sore muscles and poor sleep. Sometimes they may experience a loss of libido and appetite. They also often become depressed, and when this is clinically significant, it requires pharmacological treatment. It is often difficult for the athlete to determine whether the depression is the cause or the effect of the UUPS, but in my experience, if you do not treat the depression, you are likely to delay the resolution of the syndrome.

The onset of UUPS may coincide with upper respiratory tract infections, particularly viral. It is common, in taking the patient’s history, to find that they have trained intensively through a viral upper respiratory tract infection, leading to symptoms of fatigue.

Less common symptoms of UUPS include:

  • stiff, sore muscles
  • nocturnal hot sweats
  • minor changes in bowel habit
  • an elevated heart rate at a given intensity of training
  • an elevated resting heart rate.
  • an inability to alter pace at the end of a race.

Sometimes the athlete has difficulty in raising his/her heart rate in exercise and a profound loss of motivation. It is important to stress that none of these symptoms are diagnostic or consistent across all UUPS subjects. Chronic fatigue syndrome is distinct from UUPS in that it is a more severe condition in which sufferers usually cannot even contemplate doing sport, and they recover less quickly.

Despite much ongoing excellent research work, there are as yet no unequivocal diagnostic serological (blood analysis), physiological or psychological markers for UUPS. Observations have included raised stress hormones and reticulocyte (immature red blood cell) counts, increased cortisol to testosterone ratios, raised neutrophil to lymphocyte ratios and lower branch chain amino acids. Some researchers have shown a relative loss of sympathetic neural tone in athletes with UUPS; this is the part of the nervous system which, among other things, increases heart rate. A loss of heart rate variability (HRV) occurs during morning postural testing and this reflects the loss of sympathetic neural tone. This may be useful in monitoring rehabilitation intensity during recovery from UUPS because the loss of HRV can be quantified and recovery thereby monitored.

Mood scores, whilst a helpful psychological tool in confirming the diagnosis, are neither sensitive nor specific. Serological markers may in future help provide a more accurate clinical diagnosis.

UUPS must not be confused with other medical causes of under performance. There is an extremely long list of differential diagnoses for fatigue in athletes, many of which can be excluded by taking a good history and (less importantly) examination of the athlete. Over the last 13 years I have seen 83 cases of athletes presenting with symptoms of UUPS, of which five (6%) had other medical causes. (Some clinicians report higher figures , but this may reflect the fact that many athletes I see have been through a medical screen prior to their consultation with me.) These included two cases of Epstein Barr infection (glandular fever), a Coxsacchie B myocarditis, an iron deficiency anaemia and a non-Hodgkin’s lymphoma. As a consequence of this I regularly perform a full blood count, ferritin, thyroid function test, ESR, urea and electrolytes and other blood tests as indicated by the history and examination. A pre- and post-exercise flow loop spirometry test, if the athlete can manage it, is helpful in the initial battery of tests.

The key to managing UUPS lies in a multi-disciplinary approach by a team of sports specialists, including physician, nutritionist, psychologist and physiologist. An experienced nutritionist should analyse a nutritional diary and the athlete’s carbohydrate ingestion before, during and after exercise. It is important to be able to rule out an eating disorder: the SCOFF questionnaire may be useful(1).

Many athletes with UUPS have coincident social, financial, domestic and career stresses, which a psychologist will need to explore. Physiologists with experience in heart rate variability monitoring can lead athlete and coach through the pulse-dependent rehabilitation that follows, and an early meeting between them is good practice.

The successful resolution of UUPS depends on clear communications between the multidisciplinary team and the athlete, their coach and family. It is really important to give the athlete a clear understanding of what is happening, and to make time to answer their questions throughout treatment and rehab. In my experience, recovery to full training often takes 10 to 15 weeks, during which time there should be regular team meetings, and meetings with the athlete and coach.

Psychological support throughout the whole process is very important to address the concerns of the athlete, family and coach. It is difficult for the athlete to accept that there is no ‘quick fix’ for UUPS and experienced consultation skills are required to address questions on the aetiology of UUPS where our know-ledge is, at best, incomplete. The multidisciplinary team must reflect regularly on the athlete’s clinical status, changing management swiftly when appropriate.

Table 1 Score symptoms
DateFatigueMuscle achesMotivationUpper respiratory tract symptomsOtherTotal
Range 0-10 0-10 0-10 0-5 0-10  
1.02.03 5 5 6 5 8 29
2.02.03 5 6 5 4 6 26
3.02.03 5 6 4 4 5 24
14.02.03 2 1 1 0 1 5

There is no published evidence (to date) that one programme of management of UUPS is better than another. What follows is a pragmatic approach that has been adopted in the south-west region of the EIS, and which is regularly revised. Our strategy is based on symptom scoring and pulse-dependent rehabilitation (PDR). The athlete is asked early to score his/her symptoms in certain key areas (see Table 1). Significant symptoms are scored 1 – 10, less significant symptoms are given less weighting and are scored 1 – 5. Daily totals are collated (high is ‘bad’, low is ‘good’) and used to determine the progression of the PDR programme. We leave one column for ‘other’ symptoms that may be specific to the individual athlete’s history.

The PDR programme is agreed with the athlete and coach, and starts with a few weeks of complete rest, during which time the nutritionist and psychologist work with the athlete. The rate of progress thereafter is governed by improvements in the heart rate during exercise. The physician incrementally increases the volume and intensity of exercise based on heart rate response (see table 2).

Table 2 Pulse-dependent rehab programme for a triathlete
1 Rest
2 Rest
3 HR <120; 20 mins turbo training; 2 days off
4 HR <130; 20-25 mins TT; 2 days off
5 HR< 140; 30 mins TT; alternate days run 20 mins; 1 day off
6 HR < 150; 30 mins TT; run 20-30mins, swim 2k; 1 day off
7 HR 150-160 add short sprints (<10 secs)


In institutes of sport and high performance centres the prevention of UUPS should be high on the agenda. A detailed review of the prevention of UUPS is beyond the scope of this article but the main issue is education of athletes and coaches. Overall attention to the ‘basics’ of sports exercise physiology; periodised training, carbohydrate and fluid replenishment and a holistic approach to athlete-centred training intensity are fundamental to maintaining the good health of the athlete.


  1. 1. Morgan JF, Reid F, Lacey JH, The SCOFF questionnaire: assessment of a new screening tool for eating disorders. BMJ. 1999 Dec 4;319(7223): 1467-8.

Recovery in Training: The Essential Ingredient

By: Jonathan N. Mike, M.S. and Len Kravitz, Ph.D.
From: International SportMed Journal, 2000, Volume 1, Issue 3


Recovery from exercise training is an integral component of the overall training program and is essential for optimal performance and improvement. If rate of recovery is improved, higher training volumes and intensities are possible without the detrimental effects of overtraining (Bishop et al., 2007). While recovery from exercise is significant, personal trainers and coaches use different approaches for the recovery process for clients and athletes. Understanding the physiological concept of recovery is essential for designing optimal training programs. As well, individual variability exists within the recovery process due to training status (trained vs. untrained), factors of fatigue, and a person's ability to deal with physical, emotional, and psychological stressors (Jeffreys, 2005). This article will provide evidence-based research and practical applications on recovery for personal trainers and fitness professionals

What is Recovery?

Bishop et al. (2007) define recovery as the ability to meet or exceed performance in a particular activity. Jeffreys (2005) continues that factors of recovery include 1) normalization of physiological functions (e.g., blood pressure, cardiac cycle), 2) return to homeostasis (resting cell environment), 3) restoration of energy stores (blood glucose and muscle glycogen), and 4) replenishment of cellular energy enzymes (i.e., phosphofructokinase a key enzyme in carbohydrate metabolism). In addition, the recovery is very dependent on specific types of training (see question #1 in the Pertinent Recovery Questions for the Personal Trainer section). Recovery may include an active component (such as a post-workout walk) and/or a passive component (such as a post-workout hydrotherary treatment).

Physiology of Recovery

Muscle recovery occurs during and primarily after exercise and is characterized by continued removal of metabolic end products (e.g., lactate and hydrogen ions). During exercise, recovery is needed to reestablish intramuscular blood flow for oxygen delivery, which promotes replenishment of phosphocreatine stores (used to resynthesize ATP), restoration of intramuscular pH (acid/base balance), and regaining of muscle membrane potential (balance between sodium and potassium exchanges inside and outside of cell) (Weiss, 1991). During post-exercise recovery, there is also an increase in 'excess post-exercise oxygen consumption' (or EPOC). Other physiological functions of recovery during this phase include the return of ventilation, blood circulation and body temperature to pre-exercise levels (Borsheim and Bahr, 2003).

Types of Recovery

The most rapid form of recovery, termed “immediate recovery” occurs during exercise itself. Bishop and colleagues (2007) give an example of a race walker with 1 leg in immediate recovery during each stride. With this phase of recovery, energy regeneration occurs with the lower extremities between strides. As each leg recovers more quickly, the walker will be able to complete the striding task more efficiently.

“Short term recovery” involves recovery between sets of a given exercise or between interval work bouts. Short-term recovery is the most common form of recovery in training (Seiler, 2005). Lastly, the term “training recovery” is used to describe the recovery between workout sessions or athletic competitions (Bishop et al., 2007). If consecutive workouts occur (such as within the same day) without appropriate recovery time, the individual may be improperly prepared for the next training session.

Connection to Fatigue

Fatigue is usually perceived as any reduction in physical or mental performance. However, when discussing various aspects of training, fatigue can be described as failure to maintain the expected force, or the inability to maintain a given exercise intensity or power output level (Meeesen 2006). Bigland (1984) expands that fatigue is any exercise-induced reduction in force or power regardless of whether or not the task can be sustained.

There are two types of fatigue: peripheral and central. Peripheral fatigue during exercise is often described as impairment within the active muscle. The muscle contractile proteins are not responding to their neural stimulation. Depletion of muscle glycogen (for fuel) is thought to be an important factor in peripheral fatigue, especially during prolonged exercise (Jentjens, 2003).
Central fatigue is concerned with the descending motor pathways from the brain and spinal cord. Bishop and colleagues (2008) explain that brain messages may signal reductions or complete cessation of exercise performance. A central fatigue hypothesis suggests that the brain is acting as a protective mechanism to prevent excessive damage to the muscles.

Other Associative Factors of Recovery
Gleeson (2002) elucidates the following related factors involved in the ability of a person to recover.
1) Muscle soreness and weakness
2) Poor exercise performance
3) Decrease in appetite
4) Increased infection
5) Quality and quantity of sleep
6) Gastrointestinal abnormalities
Personal trainers should be aware that these conditions may have an adverse influence on client recovery from exercise.

Pertinent Recovery Questions for the Personal Trainer

1) How Much Rest between Sets? Willardson (2008) describes rest between sets as a multifactorial phenomenon that is affected by several factors (see Figure 1).
However, summarizing previous research, he purposes some specific rest periods (between multiple set training) for the following training protocols.
Muscular endurance training: 30 to 90 seconds
Hypertrophy training: 1 to 2 minutes
Power training: 3 minutes
Muscular strength (for clients less adapted to strength training): 4 to 5 minutes
Muscular strength (for clients well-adapted to strength training): 3 minutes

2) How much rest between sessions? The greater the stress of the workout, the greater the overall muscle recruitment, and the greater the potential for muscle damage and soreness, therefore the need for longer recovery time. Muscle recovery between resistance training sessions for most individuals is also influenced by other types of training performed, such as cardiovascular training, interval sprints and sports conditioning sessions. Rhea (2003) concluded that for untrained individuals and trained individuals a frequency of 3 and 2 days, respectively, per week per muscle group is optimal, which translates to 1-2 days rest between sessions. However, this will vary depending on total volume of resistance training, individual training status, and overall goals (e.g., training for hypertrophy, strength, endurance, etc.).

3) Is there a gender difference in recovery? A gender difference has been shown in fatigue, a factor influencing recovery. Numerous studies have shown fit women have a greater resistance to fatigue than their male counterparts; therefore, fit women are able to sustain continuous and intermittent muscle contractions at low to moderate intensities longer than physically active men (Critchfield and Kravitz, 2008).

4) Do different muscle groups need more rest? Ground based movements such as the deadlift, squat, and overhead press require more rest than smaller muscle groups such biceps, triceps, and forearm flexors. This is due to the increase in motor unit recruitment and larger muscle mass involved with these multi-joint exercises.

5) Can certain supplements aid in the recovery of training? Many supplements have been used to assist in recovery of training. Bloomer (2007) provides evidence on certain antioxidants such as Vitamin C and Vitamin E and their purported affect on attenuating muscle damage, thus enhancing the recovery of training. However, he confirms that these supplements do not eliminate muscle trauma from exercise, only minimize some of the signs and symptoms (e.g., delayed onset damage, inflammation).

6) Does massage therapy affect the recovery process? Weerapong (2005) reported that some studies have shown that massage did in fact reduce delayed onset muscle soreness, while other studies have not realized this effect. However, it should be pointed out that the psychological benefits of massage toward recovery are often quite meaningful to the exercisers.

Bottom Line Message to Trainers

For client's to achieve optimal exercise performance, the personal trainer and fitness professional needs to be proactive in planning recovery into the training program. Although there is no consensus on a central strategy for recovery, monitoring and observing a client's exercise performance will always be most insightful in adjusting and planning for this essential ingredient of training. In addition, educating clients about the importance of recovery (such as proper sleep) may empower them to complete suitable interventions to enhance the process.


Jonathan N. Mike, MS, CSCS, NSCA-CPT, is a doctoral student in the exercise science program in the department of health, exercise, and sports sciences at the University of New Mexico (Albuquerque). He earned his undergraduate and graduate degrees in exercise science at Western Kentucky University (Bowling Green) and has research interests in strength and power performance, exercise and energy metabolism, exercise biochemistry, exercise endocrinology, and neuromuscular physiology.

Len Kravitz, PhD, is the program coordinator of exercise science and a researcher at the University of New Mexico, Albuquerque, where he won the Outstanding Teacher of the Year award. Len was honored with the 2006 Can-Fit-Pro Specialty Presenter of the Year award and chosen as the ACE 2006 Fitness Educator of the Year. He was recently presented with the 2008 Can-Fit-Pro Lifetime Achievement Award.

Bigland-Ritchie B, & Woods J.J. (1984). Changes in muscle contractile
properties and neural control during human muscular fatigue. Muscle and Nerve. 7(9): 691-699.

Bishop, P.A, Jones E., & Woods A.K. (2008). Recovery from training: a brief review.
Journal of Strength and Conditioning Research., 22(3):1015-1024.

Bloomer, RJ. (2007). The role of nutritional supplements in the prevention and treatment of resistance exercise-induced skeletal muscle injury. Sports Medicine. 37(6):519-32.

Borsheim, E & Bahr, R. (2003).Effect of exercise intensity, duration and mode on post-exercise oxygen consumption. Sports Medicine. 33(14):1037-1060.

Critchfield, B. & Kravitz, L. (2008). Fatigue resistance: An intriguing difference in gender. IDEA Fitness Journal 5(6), 19-21.

Gleeson, M (2002). Biochemical and Immunological Markers of Overtraining. Journal of Sports Science and Medicine. 1: 31-41.

Hicks, A.L, Kent-Braun, J., & Ditor, D.S. (2001). Sex differences in human skeletal muscle fatigue. Exercise and Sports Sciences Reviews, 29(3), 109-12.

Jeffreys, I. (2005). A multidimensional approach to enhancing recovery. Strength and Conditioning Journal. 27(5): 78-85.

Jentjens, R, & Jeukendrup, A. (2003).Determinants of post-exercise glycogen synthesis during short-term recovery. Sports Medicine. 33(2):117-144.

Meeusen, R, Watson, P., Hasegawa, H, Roelands, B, & Piacentini, M.F. (2006). Central fatigue: the serotonin hypothesis and beyond. Sports Med. 36(10):881-909.

Rhea, M.R., Alvar, B.A., Burkett, L.N., & Ball S.D. (2003). A meta-analysis to determine the dose response for strength development. Medicine and Science in Sports and Exercise, 35(3):456-464.

Seiler, S. & Hetlelid, K.J. (2005). The impact of rest duration on work intensity and RPE during interval training. Medicine and Science in Sports and Exercise, 37(9):1601-1607.

Weerapong, P., Hume, P.A., & Kolt G.S.N. (2005). The mechanisms of massage and effects on performance, muscle recovery and injury prevention. Sports Medicine, 35(3):235-56.

Weiss, LW. (1991). The obtuse nature of muscular strength: The contribution of rest to its development and expression. Journal of Applied Sports Science Research. 5: 219-227.

Willardson, J.M. (2008). A brief review: How much rest between sets. Strength and Conditioning Journal, 30(3): 44-50.


Overtraining and Chronic Fatigue: The Unexplained Underperformance Syndrome (UPS)

By: Rickard Budgett, GB Team Doctor
From: International SportMed Journal, 2000, Volume 1, Issue 3

All athletes must train hard in order to improve their performance. Some athletes fail to recover from training, become progressively fatigued, and suffer from prolonged underperformance. They may also suffer from frequent minor infections (particularly respiratory infections). This has been called the over training syndrome, burnout, staleness, or sports fatigue syndrome, but in the absence of any medical cause is more accurately called the Unexplained Underperformance Syndrome (UPS). The condition is normally secondary to the stress of training, but the exact etiology and pathophysiology is not known, and many factors other than overtraining may lead to failure to recover from training or competition. Changes in psychological, hormonal, and immune parameters have been shown in these underperforming athletes, some of which may be useful as markers when used on an individual basis. However, the importance of any of these changes, many of which are seen in athletes without UPS when training very hard, is not fully understood.

Athletes normally recover in 6 to 12 weeks with a programme of gentle exercise and regeneration strategies.

Key Points:

  • About 10% of endurance athletes may break down each year (not sprinters).  
  • Redefinition of Unexplained Underperformance Syndrome (UPS): “Persistent performance deficit despite 6 weeks relative rest.”
  • Three main groups of symptoms: frequent infections, mood disturbance, and fatigue.
  • Recovery normally takes 6–12 weeks with a light exercise regime and regeneration strategies.


Despite a hard training program and progressive overload, some athletes fail to improve and their performance may even start to deteriorate. Unexplained underperformance in athletes is a common problem, occurring in around 10– 20% of elite endurance squads, but is rarely seen in sprinters. In the absence of any other medical cause, this has been called the overtraining syndrome, burnout, staleness, “sports fatigue syndrome,” or chronic fatigue in athletes (1–3). The exact etiology and pathophysiology is not known, but the condition is often assumed secondary to the stress of training, or at least due to a failure to recover from training or competition (4). There has been some confusion in the literature on the definition and diagnostic criteria (5).

The term overtraining syndrome implies causation that limits investigations of this problem in athletes. There is confusion as to whether athletes suffering from frequent respiratory infections, depressed mood state, clinical depression, fatigue, or underperformance are all actually overtrained (6). In order to allow researchers and clinicians to investigate the problem, a broader definition was created at a round table discussion in St Catherine’s College, Oxford on April 19, 1999 (7).

The Definition of Unexplained Underperformance Syndrome (UPS)

UPS is a persistent, unexplained performance deficit (recognized and agreed by coach and athlete) despite 2 weeks of relative rest (7). This contrasts with the definition of chronic fatigue syndrome, where symptoms must last at least 6 months (8).

In addition to fatigue and an unexpected sense of effort during training, the following symptoms have been reported in UPS (4, 6, 7, 9): 

  • history of heavy training and competition
  • frequent minor infections
  • unexplained or unusually heavy, stiff, and/or sore muscles
  • mood disturbance
  • change in expected sleep quality
  • loss of energy
  • loss of competitive drive
  • loss of libido
  • loss of appetite

The list of symptoms is included to give a background to the basic definition. If the underperformance can be explained in terms of a major disease, then the diagnosis cannot be made. For this reason, all athletes with a diagnosis of UPS should have a careful history and physical examination. In most cases, it will be the coach and athlete who are best able to measure performance that may be compared to previous weeks, months or years. The performance deficit may be agreed by the sports scientist or sports physician if appropriate ergometer or field tests have been carried out. It may be most appropriate to compare performance to the same stage of previous competition cycles. Relative rest cannot be defined exactly but should involve a significant reduction in training and increase in recovery time, for example, as would occur normally before a major competition.


Figure 1 — Pattern of symptoms in the UPS.  

Endurance athletes present with fatigue and underperformance with secondary changes in mood that is specific to the sport and individual (10). In addition, those runners who suffer from frequent minor infections particularly upper respiratory tract infections (URTI), may form a separate overlapping sub-group (11). Due to these overlapping groups and the confusion of definitions, our definition of unexplained underperformance is broad and all-inclusive. However, it does not include over-reaching or so-called short-term overtraining from which athletes make a full recovery with less than two weeks of relative rest (1).

It is likely that there are several distinct subgroups and that some of these subgroups overlap as represented in Figure 1. 

It would be helpful if researchers and those writing case reports defined exactly which group(s) they were investigating or whether they had included all athletes with persistent unexplained underperformance.

The Normal Response to Training

All athletes must train hard in order to improve. Initial hard training causes underperformance but if recovery is allowed, there is supercompensation and improvement in performance (16). Training is designed in a cyclical way (periodisation) allowing time for recovery with progressive overload. During the hard training / overload period transient symptoms and signs and changes in diagnostic tests may occur; this is called overreaching (5).

There are changes in the profile of mood state (POMS) questionnaire that shows reduced vigour and increased tension, depression, anger, fatigue and confusion (15). Muscle glycogen stores are depleted and resting heart rate rises. The testosterone/cortisol ratio is reduced due to lower testosterone and high cortisol levels. Microscopic damage to muscle also leads to raised creatine kinase levels especially if there is eccentric exercise (17).

All these changes are physiological and normal if recovery occurs within two weeks. Overreaching will occur in most training programs and normally leads to improved performance despite the temporary underperformance and fatigue. The degree of overreaching necessary to enable an athlete to reach his/her maximum performance has been debated amongst coaches, athletes, doctors and sports scientists (6). Many feel that the ability to tolerate and recover from frequent hard training is one of the most important qualities in elite athletes. Nevertheless, it is debatable as to whether those athletes tolerating less training cannot reach the same level as their peers who can tolerate more.

Abnormal Response to Training

If the training is prolonged heavy and monotonous then there is a risk of UPS. Monotonous means lacking in variation or periodization and does not necessarily mean boring. Nevertheless, most athletes will recover fully after two weeks of adequate rest however hard the training. The cyclical nature of most training programs (periodization) allows this recovery and full benefit from hard exercise (16).

Eventually fatigue becomes so severe that recovery does not occur despite two weeks of relative rest. At this stage, a diagnosis of the UPS can be made.


Reported signs are often caused by associated illness and are inconsistent and generally unhelpful in making the diagnosis. Cervical lymphadenopathy is very common. There may be an increased postural drop in blood pressure and postural rise in heart rate, probably related to the underlying pathophysiology (18). Physiological testing may show a reduced V02 max and maximal power output and an increased sub-maximal oxygen consumption and pulse rate, with a slow return of the pulse rate to normal after exercise, and a surprising shift of the lactate curve to the right (15). This is the so-called “lactate paradox”, and has been shown unlikely to be due to glycogen depletion, and may be due to a downregulation of the peripheral adrenoreceptors (4).

Figure 2 — Overtraining or under-recovery, leading to Unexplained Underperformance Syndrome (UPS).  

Prevention and Early Detection

Athletes tolerate different levels of training, competition and stress at different times, depending on their level of health and fitness through the season. The training load must therefore be individualized and reduced or increased, depending on the athlete’s response. Other stresses, such as exams, need to be taken into account (10).

Figure 3 — The cycle of recurrent minor infections.

In practice it is very difficult to distinguish between overreaching and UPS. Researchers have attempted to follow blood parameters, such as hemoglobin, hematocrit and white cell count which alter acutely in exercise and are often low anyway in regularly training athletes due to a dilution effect caused by their increased blood volume. There was hope for urea and creatine kinase but these measure the stress of training and do not predict who will fail to recover. Mood state profiling on a regular basis can give useful guidance (19).

Many runners monitor their heart rate. This is non-specific but does provide objective evidence that something is wrong if the resting pulse is more than 10 beats per minute higher than the athlete’s normal consistent base (20). Other prevention strategies are a good diet, full hydration and rest between training sessions. It is more difficult for athletes who have a full-time job and other commitments to recover quickly after training. Many sports scientists and coaches are advising alternate day hard and light training within the normal cyclical programme (12).

Training intensity and spacing the training are the most important factors in optimizing performance and minimizing the risk of UPS. Morton used a complex mathematical model to optimize periodization of athletic training leading up to a major event such as a marathon. In this, he suggested intensive training on alternate days over a 150-day season, building up over the first two-thirds and tapering over the last third. This was more effective than moderate training throughout the whole year (16).

Many athletes use supplements but these do not seem to offer any protection from chronic fatigue. Trace elements and minerals, such as magnesium, have been investigated but there is no proven link to UPS or chronic fatigue syndrome (5). 


Training and Psychology

Researches have shown a drop in the “lactate: rating of perceived exertion (RPE)” ratio with heavy training (21). Thus for a set lactate level the perceived exertion is higher. This may represent central fatigue, but could be because of glycogen depletion causing lower lactate levels or the “lactate paradox”.

Fry et al (2) tried to induce overtraining by short, near-maximum, high-intensity exercise but failed, suggesting that this is a safe regime. This may be because of the frequent long periods of rest between efforts. This supports our own observations that sprinters and power athletes do not suffer from the UPS (36).

The mood state is most significant if it does not improve during tapering in the lead up to a competition, but unfortunately it may then be too late to prevent underperformance. The advice is therefore to taper and recover regularly through the season to enable regular monitoring of recovery.

At the British Olympic Medical Centre, it has been shown that both performance and mood state improve with five weeks of physical rest. Low level exercise has also been shown to speed recovery from the chronic fatigue syndrome (15).

The profile of mood state (POMS) questionnaire was used on a group of collegiate swimmers in the USA by Morgan (19). Training was increased whenever the mood state improved and reduced whenever the POMS deteriorated. The incidence of burnout, which was previously around 10% per year, reduced to zero (22). 

Hormonal Changes

The role of hormones in the UPS is still not fully understood. Stress hormones, such as adrenaline and cortisol have been shown to rise more in underperforming athletes than in controls. Salivary cortisol levels (reflecting free cortisol levels) in a group of swimmers were significantly higher in stale, underperforming athletes and this correlated with the depressed mood state (23).

A low testosterone:cortisol ratio has been suggested as a marker of UPS, reflecting a change in the balance of anabolism to catabolism. This ratio falls in response to overreaching, so only a very low ratio is useful. In some athletes there is no significant change, despite all the symptoms of UPS (23).

A reduced response to insulin induced hypoglycaemia was demonstrated by Barron and Noakes suggesting hypothalamic dysfunction (24).

Noradrenaline levels have been shown to be higher in fatigued underperforming swimmers than controls, particularly during tapering, but levels were generally proportional to the training stress. There was no change in cortisol levels (25). Plasma catecholamine levels and stress ratings (by questionnaire) were a useful predictor of staleness and a well-being rating questionnaire during tapering predicted performance (26).

The rise in noradrenaline levels and fall in basal nocturnal plasma dopamine, noradrenaline and adrenaline levels has been proposed as a method of monitoring training. These levels correlate with symptoms. There may be a reduction in the sensitivity of beta-adrenergic receptors due to overstimulation, which could lead to undermobilisation of glucose in exercise and explain the lactate paradox (27).

Amino Acids and Central Fatigue

Many of the symptoms seen in underperforming athletes point to a cause within the brain. In 1987, Professor Eric Newsholme from Oxford University proposed a theory of central fatigue involving increased levels of 5HT. The neurotransmitter 5-hydroxytryptamine (5HT, serotonin) has been widely studied, is widespread in the central nervous system, and has been linked to determining tiredness and sleep. The amino acid, tryptophan, the precursor of 5HT, competes with the branched-chain amino acids for entry into the brain on the same amino acid carrier. Transport across the blood brain barrier is the rate-limiting step because the rate-limiting enzyme in 5HT synthesis is non-saturated. Thus a decrease in levels of branched-chain amino acids in the blood, due to an increased rate of utilization by muscle, will increase the ratio of tryptophan to branched-chain amino acids in the bloodstream and favor the entry of tryptophan into the brain. This may result in fatigue originating in the brain. Free tryptophan concentrations are further increased by a rise in plasma fatty acid levels. In endurance activity, free fatty acid concentrations rise and the branched-chain amino acid concentrations fall. In rats, it has been shown that this increases the concentration of 5HT in the hypothalmus and brainstem (28).

A study of runners in the Stockholm marathon showed that those receiving branched-chain amino acids rather than placebo suffered less from a sensation of effort in the second half of the marathon and maintained cognitive function, unlike the controls. The fall in plasma branched-chain amino acids and glutamine levels, associated acutely with hard training and chronically in runners with UPS, may lead to an increase in brain levels of the neurotransmitter 5HT (serotonin) (28,29). This could lead to down-regulation of 5HT receptors and account for many of the symptoms of UPS.

When tested on an isokinetic dynamometer, fatigued athletes did not produce the same concentric power as controls at the higher speeds but there was no difference in eccentric contraction. In addition, during an isometric contraction, superimposed tetanic stimulation increased force output (30). Thus, it seems that athletes with UPS have difficulty in maximally recruiting all muscle fibers when tested in the laboratory and this effect may be due to central fatigue.

5HT re-uptake inhibitors, such as fluoxetine, when given acutely to athletes reduce performance (time to exhaustion) consistent with the widespread effects of HT in the brain. It is possible that the anecdotal improvement of some athletes with these types of antidepressants is either due to the treatment of an undiagnosed depression or due to a slow fall in 5HT-receptor sensitivity.

5HT-containing cells are widespread in the central nervous system, and changes in 5HT receptor levels could account for many of the symptoms of overtraining affecting sleep, causing central fatigue, loss of appetite and inhibiting the release of factors from the hypothalmus which control pituitary hormones (28, 29).

Imunosuppression and Glutamine

There is evidence that moderate regular exercise helps reduce the level of infection in normal individuals. However, intense heavy exercise increases the incidence of infections (11). Upper respiratory tract infections have been shown more likely with higher training mileage and after a marathon (31). A number of factors probably contribute to this apparent immunosuppression, such as raised cortisol levels, reduced salivary immunoglobulin levels and low glutamine levels. Glutamine is an essential amino acid for rapidly dividing cells such as lymphocytes. Low levels of glutamine have been found in chronically fatigued and underperforming athletes, including marathon runners, compared to controls and levels are known to be lower after hard training (32). Thus, in addition to a possible role in Central Fatigue, glutamine may have a role in immunosuppression.

Glutamine intervention studies have been carried out, and there is some evidence that the incidence of infection in endurance athletes after prolonged exercise is reduced after taking glutamine compared to placebo. Recovery from a period of intense training (overreaching) is also quicker (33).

Lowered salivary immunoglobulins, reduced NK cell activity, and changes to the T helper/suppresser cell ratios are just some of the other immune parameters that may contribute to the apparent immunosuppression in many of these athletes (11).


Athletes suffering from prolonged unexplained underperformance (UPS) are different from sedentary individuals with chronic fatigue because they present earlier, they tend to recover more quickly, and there is an opportunity to alter the major stress in their lives (training and competition). Nevertheless, management is similar to any individual with chronic fatigue and requires a holistic approach. Rest and regeneration strategies are central to recovery (1).

At the British Olympic Medical Centre it has been shown that both performance and mood state improve with five weeks of physical rest (15). Low level exercise has also been shown to speed recovery from the chronic fatigue syndrome (34,35).

If told to rest for several weeks athletes are unlikely to comply. Thus they should be given positive advice and told to exercise aerobically at a pulse rate of 120 - 140 beats per minute for 5 to 10 minutes each day, ideally in divided sessions, and slowly build this up over 6 - 12 weeks. The exercise program has to be individually designed and depends on the clinical picture and rate of improvement. The cycle of partial recovery followed by hard training and recurrent breakdown needs to be stopped. It is often necessary to avoid the athlete’s own sport using cross training because of the tendency to increase the exercise intensity too quickly. A positive approach is essential, with an emphasis on slowly building up volume rather than intensity to about one hour per day. Once this volume is tolerated, then more intense work can be incorporated above the onset of blood lactate accumulation (OBLA) (21). 

Very short (less than 10 seconds) sprints / power sessions with at least 3 - 5 minutes of rest are safe and allow some hard training to be done. Athletes can normally add in two to three 30-minute sprint sessions per week after 2 weeks of gentle endurance exercise (36).

There are no trials of regeneration strategies that were widely used in the old Eastern Block countries (30). These include rest, relaxation, counseling and psychotherapy. Massage and hydrotherapy are used and nutrition is looked at carefully. Large quantities of vitamins and supplements are given, but there is no evidence that they are effective. Stresses outside sport are reduced as much as possible. Depression may need to be treated with anti-depressants but normally drugs are of no value, although any concurrent illness must be treated. There is one report of the (prohibited) use of anabolic steroids to treat UPS (37).

Athletes who have been underperforming for many months are often surprised at the good performance they can produce after six to twelve weeks of extremely light exercise. At this point care must be taken not to increase the intensity of training too fast and to allow full recovery after hard parts of their training cycle. We recommend that athletes recover completely at least once a week.


UPS is relatively common in endurance athletes. It is a condition of underperformance with persistent fatigue, and an increased vulnerability to infection leading to recurrent infections in some athletes. Central, peripheral, hormonal and immunological factors may all contribute to the failure of recovery from exercise. The extent to which the stress of hard training and competition leads to the observed spectrum of symptoms is not known and probably very variable in each case.

Optimizing training and careful monitoring of athletes may help prevent UPS. With regeneration strategies and a structured exercise program, symptoms normally resolve in 6–12 weeks.


1. Budgett R. The overtraining syndrome. BMJ 1994;309:4465-4468.

2. Fry RW, Morton AR, Keast D. Overtraining syndrome and the chronic fatigue syndrome. NZ J Sports Med 1991;19:48-52.

3. Lehmann M, Foster C, Keull J. Overtraining in endurance athletes: a brief review. Med Sci Sports Exerc 1993;25:854-862.

4. Lehmann M, Foster C, Gastmann U et al. Definition, types, symptoms, findings, underlying mechanisms, and frequency of overtraining and overtraining syndrome. In: Lehmann M, Foster C, Gastmann U et al., eds. Overload, Performance Incompetence, and Regeneration in Sport. New York: Kluwer Academic/Plenum; 1999:1-6.

5. Budgett R. The overtraining syndrome. Br J Sports Med 1990;24:231-236.

6. Budgett R. Fatigue and underperformance in athletes: the overtraining syndrome. BMJ 1998;32:107-110.

7. Budgett R, Newsholme E, Lehmann M, Sharp C et al. Redefining the overtraining syndrome as the unexplained underperformance syndrome. Br J Sports Med 2000;34:67-68.

8. Royal Colleges of Physicians. Chronic Fatigue Syndrome: Report of a Joint Working Group of the Royal Colleges of Physicians, Psychiatrists and General Practitioners. London: Royal College of Physicians; 1996.

9. Derman W, Schwellnus MP, Lambert MI et al. The “worn-out athlete”: a clinical approach to chronic fatigue in athletes. J Sports Sci 1997;15:341-351.

10. Budgett R. The overtraining syndrome. Coaching Focus 1995;28:4-6.

11. Nieman D. Exercise infection and immunity. Int J Sports Med 1994;15:S131.

12. Fry RW, Morton AR, Keast D. Periodisation and the prevention of overtraining. Can J Sports Sci 1992;17:241-248.

13. Morgan WP, Costill DC, Flynn MG, Raglin DS, O’Connor PJ. Mood disturbance following increased training in swimmers. Med Sci Sports Exerc 1988;20:408-414.

14. Dyment P. Frustrated by chronic fatigue? Phys Sports Med 1993;21:47-54.

15. Koutedakis Y, Budgett R, Faulmann L. Rest in underperforming elite competitors. Br J Sports Med 1990;24:248-252.

16. Morton RH. Modelling training and overtraining. J Sports Sci 1997;15:335-340.

17. Costill DL, Flynn MG, Kirway JP, Houmard JA, Mitchell JB, Thomas R, Park SH. Effects of repeated days of intensified training on muscle glycogen and swimming performance. Med Sci Sports Exerc 1988;20:249-254.

18. Kindermann W. Das Ubertraining-Ausdruck einer vegetativen Fehlsteurung. Deutsche Zeitschrift fur Sportsmedizin 1986;37:138-145.

19. Morgan WP, Brown DR, Fascm Raglin JS, O’Connor PJ, Ellickson KA. Psychological monitoring of overtraining and staleness. Br J Sports Med 1987;21:107-114.

20. Dressendorfer RH, Wade CE, Scaff JH. Increased morning heart rate in runners: a valid sign of overtraining? Phys SportsMed 1985;13:77-86.

21. Synder AC. A physiological/psychological indicator of overreaching during intensive training. Int J Sports Med 1993;14:29-32.

22. O’Connor PJ, Carson Smith J. Using mood responses to overtraining to optimize endurance performance and prevent staleness Flemish J of Sports Med Sports Sci 1999;80(3):14-19.

23. Flynn MG, Pizza FX, Boone JB, Andres FF, Michaud TA, Rodríguez-Zagás JR. Indices of training stress during competitive running and swimming seasons. Int J Sports Med 1994;15:21-26.

24. Barron JL, Noakes TD, Levy W. Smith C, Millar RP. Hypothalamic dysfunction in overtrained athletes. J Clinical Endocrin Met 1985;60:803-806.

25. Hooper SL, Mackinnon LT, Gordon RD, Bachmann AW. Markers for monitoring overtraining and recovery. Med Sci Sports Exerc 1995;27:106-112.

26. Hooper SL, Mackinnon LT. Monitoring overtraining in athletes. Sports Med 1995;20:231-237.

27. Lehmann M, Dickhuth HH, Gendrisch E, Lazar W, Thum M, Kaminski R, Aramendi JF, Peterke E, Weiland W, Keul J. Training-overtraining. A prospective experimental study with experienced middle and long distance runners. Int J Sports Med 1991;12:444-452.

28. Blomstrand E, Hassmen P, Newsholme EA. Administration of branched-chain amino acids during sustained exercise. Eur J Appl Phys 1991;63:83.

29. Blomstrand E, Perrett D, Parry-Billings M, Newsholme EA. Effect of sustained exercise on plasma amino acid concentrations and on 5-hydroxtryptamine metabolism in six different brain regions in the rat. Acta Physiol Scand 1989;136:473.

30. Koutedakis Y, Frishknecht R, Vrbová G, Sharp G, Budgett R. Maximal voluntary quadriceps strength patterns in Olympic overtrained athletes. Med Sci Sports Exerc 1995;27:566-572.

31. Nieman D, Johanssen LM, Lee JW, Arabatzis K. Infections episodes before and after the Los Angeles Marathon. J Sports Med Phys Fitness 1990;30:289-296.

32. Parry-Billings M, Budgett R, Kouttedakis Y et al. Plasma amino acid contrations in the overtraining syndrome: possible effects on the immune system. Med Sci Sports Exerc 1992;24:1353-1358.

33. Castell LM, Poortmans J, Newsholme EA. Does glutamine have a role in reducing infection during intensified training in swimmers. Med Sci Sports Exerc 1996;28:285-290.

34. Fultcher KY, White PD. Randomised controlled trial of graded exercise in patients with chronic fatigue syndrome. BMJ 1997;314:1647-1652.

35. Wearden AJ, Morris RK, Mullis R et al. A randomised, double blind, placebo controlled treatment trial of fluoxetine and a graded exercise programme for chronic fatigue syndrome. Br J Psychiatry 1998;172:485-490.

36. Fry AC, Kraemer WJ. Does short-term near-maximal intensity machine resistance training induce overtraining? J Strength Cond Res 1994;8:188-191.

37. Kereszty A. Overtraining. In: Larson L, ed. Encyclopedia of Sports Science and Medicine. New York: MacMillan; 1971:218-222.


The Unexplained Under Performance Syndrome

By: Kathryn Bistany
From: Corpotential Limited: Fitpro Network.

Could an ‘off day’ actually be an indication of something more serious? This article takes a look at overtraining syndrome (OTS)

We’ve all heard of overtraining, also known as overtraining syndrome (OTS), staleness, chronic fatigue in athletes, sports fatigue syndrome and burnout.1,2

OTS should not be confused with over-reaching which reflects a temporary deterioration in athletic performance or short-term fatigue.3. With sufficient rest, the over-reached athlete should recover and show improvement.2 However if the intensity and duration of training are not reduced, this could lead to OTS. One of the main differences between over-reaching and OTS is in their recovery times. Recovery from over-reaching should take 2-3 weeks whilst OTS recovery could take several months.4.

The exact aetiology of OTS is not fully understood and there is no universal tool to predict its occurrence before it is clinically diagnosed.4 A number of hypotheses have been proposed in an attempt to explain the condition of overtraining syndrome (OTS), however the underlying mechanism(s) remains unclear. Many researchers agree that it is related to a dramatic increase of, or sustained periods of, high volume and/or intensity of training/competition with insufficient time for recovery.2 Yet, some would argue that looking at factors outside the specific training environment, such as relationships between the athlete and the coach, or personal relationships, are important as these could be a significant variable in OTS.1,5

Prevalence of OTS

The prevalence of OTS is difficult to estimate,5 hindered by unsystematic research with large variances in protocols from study to study.5, 6 This has resulted in the very existence of overtraining being questioned.7 A round table discussion was held in 1999 at St. Catherine’s College, Oxford, in an attempt to clarify the diagnostic criteria to be used in the future.1 It was decided to redefine the syndrome as unexplained underperformance syndrome (UPS), defined as ‘a persistent unexplained performance deficit (recognised and agreed by coach and athlete) despite two weeks of relative rest’. This was said to be a broad and all-inclusive definition which does not include over-reaching.

It is postulated that UPS is associated with suppressed immune function. This is associated with increased incidence and severity of upper respiratory tract infections (URTIs). There have also been reports of intestinal upsets, slow wound healing and increased sensitivity to environmental and food allergens. Alteration in immune cell function has also been recorded, which includes suppressed neutrophil function, suppressed lymphocyte count and proliferation, suppressed natural killer cell count and activity and decreased serum, nasal and salivary immunoglobulins.8, 2

Early Markers of UPS

Impaired mood state and subjective complaints are consistently described as sensitive and early markers of UPS and these usually start well before a definitive drop in performance.3 Other signs and symptoms include the following:

Physiological performance:
• decreased performance
• prolonged recovery
• decreased muscular strength
• loss of coordination
• chronic fatigue
• insomnia
• muscle soreness
• loss of appetite

• depression
• general apathy
• emotional instability
• difficulty in concentrating
• fear of competition

• increased susceptibility to illnesses
• allergies
• minor scratches heal slowly
• bacterial infection

• negative nitrogen balance
• depressed muscle glycogen concentration
• mineral depletion i.e. zinc, cobalt, aluminium, selenium, copper elevated cortisol
• low free testosterone

Athletes display different combinations of these symptoms with varying degrees of severity.9, 10, 4,2. Several factors contribute to UPS, including a sudden increase in training volume and/or intensity, heavy competition schedule, lack of periodisation, monotonous training programme, lack of programmed recovery and high self-reported stress levels regardless of whether they are directly related to training.5. Despite the fact that high cortisol has been recorded in some athletes with UPS, very little research is available on how to lower cortisol levels besides rest periods of several months.

Chronic secretions of cortisol need to be addressed as they can lead to the following:
1. A weakening of the immune system, making the athlete more prone to bacterial and viral infections.
2. A depletion of zinc and B6, which are needed to make hydrochloric acid (HCl) in the stomach.
3. An increase of fat in the abdominal area.
4. An increase in protein breakdown, leading to a loss of muscle tone.
5. An inability to heal wounds due to a depletion of zinc.
6. Increased sleep problems.
7. An inability to focus mentally as memory is impaired.
8. An increased possibility of insulin resistance which can lead to diabetes.

Although not all athletes with UPS will present with chronically high levels of cortisol, for those who do, a simple non-invasive saliva test can accurately reflect levels of cortisol. Clinical evidence shows a return to normal function in as little as six weeks or as long as nine months. Certainly more research is needed in this area but for the time being, for athletes showing signs of UPS and after excluding any form of disease or psychological problems, a simple saliva test may be worth considering.

Case Study

A 41-year-old female professional dressage rider and trainer presented with the following:
Lethargy, apathy, loss of appetite as well as an intolerance to numerous foods, tiredness all day and especially after light exercise, anxiety, an inability to concentrate or make decisions, poor memory, palpitations, mood swings and a need to be left alone.

This was affecting her riding and as a result, she was unable to perform the simplest task with her horse, from maintaining her posture to signalling to her horse for him to perform a particular exercise.
She slept whenever she could and kept away from people, feeling unable and unwilling to socialise.
Her blood test showed nothing out of the ordinary and a past history of her training regime did not show any change in training volume with ample recovery time. Her diet history showed that she normally had an excellent appetite and ate a varied diet.

However, in the last 18 months she moved to a new property which needed to be completely renovated and also sold several of her horses and moved to a new stable. All three incidences were highly stressful, each was laden with problems and it appeared she may not have been adapting to the stress.

An Adrenal Stress Index (ASI) test was recommended to ascertain her levels of cortisol (see below). The results showed low noon cortisol levels whilst her afternoon levels dropped below the reference range. This is known as pre-exhaustion or pre-adrenal fatigue. This pattern indicates long-term stress which depletes the adrenal glands caused by an excess cortisol response(11).

After a six-week period, following a protocol of supplements to support the adrenal glands and help balance blood sugar levels, the subject regained her energy, appetite, mental concentration and memory. Her dressage training improved above her own expectations as she was able to multi-task and keep her concentration.

The Adrenal Stress Test

The adrenal stress test is quick, simple and highly reliable. Four saliva samples are collected at four specific times of the day. The vials are sent directly to the laboratory for analysis and results are ready within 5-7 days.

It is important for athletes, coaches and trainers to realise that although adrenal stress is a growing problem, it is not irreversible. Recognising the problem in its early stages will speed up the recovery process, allowing the athlete to resume normal training.

Interestingly, body workers such as massage therapists, osteopaths and physiotherapists may be the first to notice one of the signs of adrenal stress: loss of muscle tone. Assuming there hasn’t been a change in training or any overt signs of any other medical condition or problem, it is hugely important for the nutritionist to get involved at this stage. Dealing with this problem correctly is the difference between the end of an athletic career or simply a learning lesson on the road to peak performance.

Kathryn Bistany

Kathryn Bistany is the Managing Director of Corpotential Limited which provides one-to-one nutritional consultations and group presentations. Kathryn is a qualified and practising sports nutritionist. For more information visit www.corpotential.com or contact 020 8994 3701.


1. Budgett R, Newsholme E, Lehmann M, Sharp C, Jones D, Peto T, Collins D, Nerurkar R, White P. Redefining the overtraining syndrome as the unexplained underperformance syndrome. British Journal of Sports Medicine 2000; 34(1): 67-8.

2. Lakier Smith L. (2003) Overtraining, excessive exercise, and altered immunity: is this a T-Helper-1 versus T-Helper-2 lymphocyte response? Sports Medicine, 33(5): 347-364.

3. Urhausen A & Kindermann W. (2002) Diagnosis of overtraining: what tools do we have? Sports Medicine; 32(2): 95-102.

4. Petibois C, Cazorla G, Poortmans J, Déléris G. (2002) Biochemical aspects of overtraining in endurance sports: a review. Sports Medicine; 32(13): 867-878.

5. Mackinnon L.T. (2000) Overtraining effects on immunity and performance in athletes. Immunology and Cell Biology; 78(5): 502-509.

6. Uusitalo A. (2001) Overtraining: making a difficult diagnosis and implementing targeted treatment. The Physician and Sports Medicine; 29(5): 35-50.

7. Halson SL, Jeukendrup AE. Does overtraining exist?: an analysis of overreaching and overtraining research. Sports Medicine 2004; 34(14): 967-81.

8. Dorshkind K & Horseman ND. Anterior pituitary hormones, stress, and immune system homeostasis. BioEssays 2001; 23(3): 288-94.

9. McKenzie D. (1999) Markers of excessive exercise. Canadian Journal of Applied Physiology; 24(1): 66-73.

10. Lakier Smith L. (2000) Cytokine hypothesis of overtraining: a physiological adaptation to excessive stress? Medicine and Science in Sports and Exercise; 32(2): 317-331.

11. Raber J. (1998) Detrimental effects of chronic hypothalamic-pituitary adrenal axis activation: from obesity to memory deficits. Molecular Biology; 18(1): 1-22.