Endocriene en metabole aspecten van het chronisch vermoeidheidssyndroom
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http://www.cfsresearch.org/cfs/research/abnormalities/25nf.htm
Proefschrift voorgelegd tot het behalen van de graad van Doctor in de Medische Wetenschappen aan de Universitaire Instelling Antwerpen te verdedigen door Greta Moorkens
Antwerpen, 2000
Promotoren: Prof. Dr. I. De Leeuw
Prof. Dr. R. Abs
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PREFACE
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Patients with unexplained chronic fatigue have been described for centuries
in the medical literature, although the terms used to describe the symptom
complex have changed frequently. Most texts and books are written when
workers in the field share and agree on a certain body of knowledge. The
Chronic Fatigue Syndrome (CFS) has not reached that status: pathogenesis
remains uhclear and various mechanisms have been proposed including
infectious, immunological, neurohormonal and psychiatric factors. While
outbreaks of what was very likely CES occurred in the 1930s and were studied
by the US Public Health scientists in the 1950s, it was not until almost
40 years later that substantial progress has been made in defining chronic
fatigue, undertaking and expanding basic clinical research and developing
management strategies for use by clinicians in practice. The 1988 working
case definition of CFS developed by the Centers for Disease Control and
Prevention (CDC) was an important step forward, but it did not effectively
distinguish CFS from other types of unexplained chronic fatigue. Therefore,
in 1993 the COC convened an international chronic fatigue study group that
developed a revised definition of CFS that clearly separates it from cases
of idiopathic chronic fatigue. Conferences on CFS in 1994 (Fort Lauderdale,
Florida), 1995 (Brussels, Belgium), 1996 (San Francisco, California), 1998
(Cambridge, Massachusetts) and 1999 (Brussels, Belgium) helped disseminate
advances in research, but there remains a great deal of uncertainty about
CFS among physicians; their reactions to patients with complaints of chronic
fatigue vary widely: some deny that CFS exists and others are sceptical.
There still is disagreement about whether CFS has an organic component.
The attitude towards CFS is probably due to the vagueness of the term fatigue.
Patients with fatiguing illnesses often do not show external signs of fatigue
and may appear superficially healthy or normal, To date, no reliable
behavioral or physical signs of abnormal fatigue have been established.
In the absence of objective measures, the patient's perception of his or her
fatigue has become the focus of fatigue measures.
Fortunately progress continues to be made in defining CFS, in research as
to its pathophysiology, and also in patient management.
I hope that this thesis can form a contribution to elucidate the puzzle of
the Chronic Fatigue Syndrome.
ACKNOWLEDGEMENTS
----------------
This thesis is respectfully presented to Professor J.Van Steenberge, Rector
of the Universitaire Instelling Antwerpen and to Professor D. W Scheuermann,
Dean of the Faculty of Medical and Pharmaceutical Sciences.
The promotores Professor R. Abs and Professor I. De Leeuw; the members of
the commission, Professor Wi Stevens, ProfessorJ. Denekens and Professor
P. Cosyns have contributed much to improve the manuscript. I am grateful for
their constructive remarks.
I thank Professor T. Dinan and Professor B. Velkeniers for their careful
reading and providing perspectives from their areas of expertise.
The manuscript presented here is a medium to concretize many years of
training, some scientific work and the opportunity to focus on a subject of
my interest with the hope that it may provide new insights. This work
reflects the input of many expertised people (colleagues, nurses,
technicians and others) who were willing to share their time and knowledge
with me, and who I gratefully acknowledge.
Professor I. De Leeuw encouraged me to investigate the role of magnesium
in the problem of chronic fatigue and to start this thesis.
Professor R. Abs was the driving force behind the endocrine part of this
work. He introduced me to and guided me through the interesting field of
human growth hormone. His enthusiasm and his belief in the subject helped
me to persist the daunting combination of clinical activity and the writing
of a thesis.
I specially thank Dr. J. Berwaerts and Dr. B. Manuel y Keenoy for the
teamwork in the writing of publications.
Dr. K. Heyde and Dr. L. Gabricis helped me to investigate sleep patterns
in the population studied.
My special thanks also to Ann Vervaet who helped me with statistical analysis
and to Patrick Vrydaghs for his skilifid support in providing and explaining
hardware and software.
I wish to thank my colleague Dr. H. Wynants for her help in taking over part
of my clinical duties during these last months.
I am much indebted to Professor H. Stuer, Dr. B. Lcroy, Jan Eyskens and
Yolande Deckx for sharing their expertise in the approach of patients with
chronic fatigue.
The support of Karin Peeters, Mieke Smolenacra, Maya Van Ham, Monique Van
Overmeire and Sigrid Wirhaegels at the outpatient clinic of internal
medicine were highly appreciated.
I thank all the patients who volunteered to participate in the studies.
Mention is due to the many others whose collaboration has been essential
during the course of this work Lydi Goffin and the nursing staff of
endocrinolog3jo Van Broeckhoven and the nursing staff of the one-day-clinic,
Jean Pierre Van Waeleghem and the nursing staff of nephrology and our
study-nurse Chris Van den Sande.
I also appreciated the support of the secretarial unit of endocrinology and
the laboratory staff of nuclear medicine.
I'm grateful to D. De Weerdt for the lay-out of this thesis.
I am indebted to all my teachers of the University of Antwerp, who
contributed to my education in medicine and my training, a special thank to
Professor H. Verbraeken who introduced me to the world of internal medicine.
Concentrating ones efforts to improve the care for persons with chronic
fatigue and pain is, in my opinion, a meaningful occupation. I have been
fortunate to receive education and guidance from many admirable persons who
can not all be mentioned. The first ones were my parents who taught me
respect for every individual and the joy to provide care. I am very grateful
to my father and mother for giving me the opportunity to study; both my
parents are a constant source of practical help and caring.
Last but not least I wish to thank my husband, Hans Jacobs, for his loving
patience and his unconditional support. Our three daughters Annemie,
Carolien and Julie taught me that life contains more than professional
activities; I thank them for their patience.
I thank my family and my family-of-friends who make me keep perspective
and with whom I share many treasured memories.
Greta Moorkens
Antwerp, March 2000
TABLE OF CONTENTS
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Abbreviations
CHAPTERS
1. Definitions of The Chronic Fatigue Syndrome and related disorders
2. Aims of the thesis
3. Metabolic and clinical aspects of the Chronic Fatigue Syndrome
3.1. Magnesium deficit in a sample of the Belgian population
presenting with chronic fatigue
3.2. Sleep patterns in CFS and in Fibromyalgia.
4. Endocrine aspects of the Chronic Fatigue Syndrome
4.1. Neuroendocrine disturbances in CFS
4.2. Characterisation of pituitary function in CFS
5. Growth Hormone in the Chronic Fatigue Syndrome
5.1. Secretion of growth hormone in 20 patients with CFS
5.2. Hormonal responses to GHRH and Hexarelin in CFS and
in Fibromyalgia
5.3. Effect of growth hormone treatment in patients with CFS
6. Conclusions and prospects of future research
References
Summary
Samenvatting
ABBREVIATIONS
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AAS atomic absorption spectrophotornetry
ACR American College of Rheumatology
ACTH adrenocorticotropin hormone
AUC area under the curve
EMI body mass index
CDC Centers for Disease Control
CFS chronic fatigue syndrome
CRH corticorropin-releasing hormone
EMG electromyography
EOG electrooculography
FM fibromnyalgia
GH growth hormone
GHD growth hormone deficiency
GI-IRP growth hormone releasing pepride
GHS growth hormone secretagogues
HPA hypothalamic-pituitary-adrenal axis
HT hydroxytryptamine
IGF-I insulin-like growth factor I
ITT insulin tolerance test
LTS latent terany syndrome
mCPP m-chlorophenylpiperazine
Mg magnesium
MS multiple sclerosis
PIFS postinfectious fatigue syndrome
PLMS periodic leg movements of sleep
PRL prolactin
PSG polysomnographic
PTH parathyroid hormone
RBC red blood cell
REM rapid eye movement
REML REM sleep latency
rhGH recombinant human growth hormone
SEI sleep efficiency index
SOL sleep onset latency
SPT sleep period time
SS somatostatin
TIB total time in bed
TSH thyroid stimulating hormone
TST total sleep time
CHAPTER 1: Definitions of The Chronic Fatigue Syndrome and related disorders
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1.1. THE CASE DEFINITIONS OF CFS
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To guide investigators in the field, five definitions of CFS have been
proposed: three from the United States (Holmes et 4, 1988; Schluederberg et
at, 1992; Fukuda et al, 1994), one from Great Britain (Sharpe et al., 1991)
and one from Australia (Lloyd et al, 1990)
1.1.1. The U.S. case definitions
--------------------------------
INITIAL DEFINITION (1988)
-------------------------
The original Holmes, Kaplan, Ganta, et al criteria are as follows:
a case of CFS must flilfill major criteria 1 and 2, plus the following
minor criteria: 6 or more of the 11 symptom criteria and 2 or more
of the 3 physical criteria; or S or more of 11 symptom criteria.
Major criteria
1. New onset of persistent or relapsing, debilitating fatigue or
easy fatigability in a person who has no previous history of
similar symptoms, that does not resolve with bedrest, and that
is severe enough to reduce or impair average daily activity
below 50% of the patient's pretnorbid activity level for a
period of at least 6 months.
2. Other clinical conditions that may produce similar symptoms 3
must be excluded by thorough evaluation.
Minor criteria
Symptoms must have begun at or after the time of onset of increased
fatigability and must have persisted or recurred over a period of at least
6 months. Symptoms include the following:
1. Mild fever or chills: oral temperature 37.5-38.6 0C
2. Sore throat
3. Painful lymph nodes (anterior or posterior cervical or axillary)
4. Unexplained generalized muscle weakness
5. Muscle discomfort or myalgia
6. Prolonged (24 hours or longer) generalized fatigue after levels
of exercise that would have been easily tolerated in the
patient's premorbid state
7. Generalized headaches (different from type headache patient
may have had in premorbid state)
8. Migratory arthralgia (without joint swelling or redness)
9. Neuropsychiatric complaints (one or more of the following:
photophobia, scotomata, forgetfulness, excessive irritability
confusion, difficulty in thiniting or concentrating, depression)
10. Sleep disturbance (hypersoinnia or insomnia)
11. Description of main symptom complex as initially developing
over a few hours to a few days
Physical criteria
-----------------
Physical criteria must be documented by a physician on at least two
occasions, at least one month apart, and include the following:
1. Low-grade fever: oral temperature of 37.6 -38.6 degrees or rectal
temperature of 37.8-38.8 degrees
2. Nonexudative pharyngiris
3. Palpable or tender anterior posterior cervical or axillary lymph
nodes (lymph nodes greater than 2 cm in diameter suggest
other causes; further evaluation is warranted)
SECOND DEFINITION (1992)
------------------------
A second definition of CFS is a modified version of the Holmes, Kaplan,
Gantz, et al. (1988) criteria, using rules developed at the 1991 National
Institute of Allergy and Infectious Disease/National Institute of Mental
Health workshop on CES (as reported in Schluederberg et al., 1992), and
includes the following recommendations:
1. Exclusions from the case definition: psychiatric disorder-psychoses
(psychotic depression, bipolar disorder, schizophrenia, etc);
substance abuse; postinfectious fatigue in which a definite etiology
has been established and the clinical picture is compatible with
ongoing, active infection (inadequately treated)
2. Inclusions in the case definition: fibromyalgia (identified by
established criteria/tender point exam); postinfectious fatigue;
Lyme disease with persistent fatigue after appropriate antibiotic
therapy; brucellosis with persistent fatigue after appropriate
antibiotic therapy; a chronic debilitating fatigue that follows
well-documented cases of acute infectious mononucleosis, acute CMV
(cytomegalovirus)infection and acute adequately-treated toxoplasmosis;
depression, 1 month post onset or 6 months or more before onset;
panic disorder (with or without agoraphobia); generalized anxiety
disorder and somatoform disorder
3. Description of onset and response to therapy
CURRENT DEFINITION (1994)
-------------------------
The third definition of CFS, which is now used by investigators in the United
States, was created by Eukuda et al. (1994). They defined prolonged fatigue
as I month or mote, and chronic fatigue is defined as self-reported persistent
or relapsing fatigue for 6 or more consecutive months.
The following four steps should be included in the assessment
1. A thorough history should be conducted concerning the
medical and psychosocial circumstances at the onset of the
fatigue.
2. A mental status exam should give attention to current anxiety,
self-destructive thoughts, or psychomotorretardation. If there
is evidence of a psychiatric or neurological disorder, there
should be an appropriate psychiatric, psychological, or neuro-
logical evaluation.
3. A physical exam should be conducted.
4. Necessary laboratory tests should be conducted.
Conditions that exclude Chronic Fatigue Syndrome are the following:
1. An active medical condition that explains chronic fatigue (e.g.,
untreated hypothyroidism, sleep apuca, medication side effects)
2. A previously diagnosed medical disorder whose resolution has
not been documented beyond reasonable clinical doubt and
whose continued activity may explain the chronic fatiguing
illness (e.g. unresolved cases of hepatitis B or C)
3. Past or current major depression with melancholic or psy-
chotic features, delusional disorders, bipolar affective
disorder, schizophrenia, anorexia nervosa or bulemia
4. Alcohol or substance abuse within 2 years before the onset of
CFS or at anytime aftenvards
5. Severe obesity (body mass index greater than or equal to 45)
The following are not excluded:
1. Conditions that are defined by symptoms that cannot be
confirmed by diagnostic laboratory tests (e.g., fibromyalgia,
anxiety disorders, somatoform disorders, nonpsychotic or
nonmelancholic depression, neurasthenic)
2. Conditions under specific treatment sufficient to alleviate all
symptoms related to that condition, for example treated and
controlled hypothyroidism
3. Any disease such as Lyme disease or syphilis that was treated
with definitive therapy before the onset of chronic symptomatic
sequelac
4. Any unexplained physical examination finding or laboratory
abnormality that is insufficient to strongly suggest the
existence of an exclusionary condition
After the preceding steps have been completed, a case is then defined as
follows:
(a) CFS is clinically evaluated, unexplained, persistent or relapsing
chronic fatigue that is of new or definite onset (i.e., not
lifelong); the fatigue is not the result of ongoing exertion, is
not substantially alleviated by rest, and results in substantial
reductions in previous levels of occupational, educational,
social, or personal activities.
(b) There must be concurrent occurence of four or more of the
following symptoms, and all must be persistent or recurrent
during 6 or more months of the illness and not predate the fatigue:
* Self-reported persistent or recurrent impairment in short-
term memory or concentration severe enough to cause
substantial reductions in previous levels of occupational,
educational, social, or personal activities
* Sore throat
* Tender cervical or axillary lymph nodes
* Muscle pain
* Multiple joint pain without joint swelling or redness
* Headaches of a new type, pattern, or severity
* Unrefreshing sleep
* Postexertional malaise lasting more than 24 hours
This revised case definition eliminates physical examination criteria and
the following minor criteria symptoms: fever/chills, muscle weakness, and
acute onset.
1.1.2. The British case definition
----------------------------------
A fourth set of criteria comprises the British definition of CFS, proposed
by Sharp; et al (1991). To fulfill their criteria, patients must have met
the following guidelines for CFS:
1. A syndrome characterized by fatigue as the principal symptom
2. A syndrome of definite onset that is not lifelong
3. Fatigue that is severe, disabling, and affects physical and
mental functioning
4. Presence of the symptom of fatigue for a minimum of six
months during which time it was present for more than 50 %
of the time
5. Possible presence of other symptoms, particularly myalgia,
mood, and sleep disturbance
Exclusion of certain patients from the definition as follows:
* Patients with established medical conditions known to produce
chronic fatigue (e.g., severe anemia), who should be
excluded whether the medical condition is diagnosed at
presentation or only subsequently. All patients should have a
history and physical examination performed by a competent
physician
* Patients with a current diagnosis of schizophrenia, bipolar
affective disorder, substance abuse, eating disorder, or proven
organic brain disease. Other psychiatric disorders (including
depressive illness and anxiety disorders)are not nessarily
reasons for exclusion.
In addition, postinfectious fatigue syndrome (PIES) is a subtype of CFS that
either follows an infection or is associated with a current infection
(although whether such associated infection is of etiological significance is
a topic for research).
To meet research criteria for PIFS, patients
(a) must fulfill major criteria for CFS as defined above and
(b) should also fulfill the following additional criteria:
1. There is definite evidence of infection at onset or
presentation(a patient's self-report is unlikely to be
sufficiently reliable)
2. The syndrome is present for at least 6 months after onset
of infection
3. The infection has been corroborated by laboratory evidence.
The British definition also provides specific definitions of the terms used
above. Fatigue is a discrete subjective sensation, and features of fatigue
commonly reported are mental and physical aspects. Mental fatigue is
characterized by lack of motivation and alertness. Physical fatigue is felt
as lack of energy or strength and is often felt in the muscles. The fatigue
must be complained of, it must significantly affect the person's functioning,
it should be disproportionate to exertion, it should represent a clear change
from a previous state, and it must be persistent, or if intermittent, should
be present more than 50 % of the time.
According to the British definition, disability refers to a restriction or
lack of ability to perform an activity in the manner orwithin the range
considered normal for a human being in areas of occupational, social, and
leisure activities. There should be a definite and persistent change from a
previous level of functioning
Finally, the British definition defines myalgia as symptoms of pain or aching
felt in the muscles. Myalgia should be complained of, be disproportionate to
exertion, be a change from a previous state, and should be persistent or
recurrent. Mood disturbances include depressed mood, anhedonia, anxious mood,
emotional lability and irritability. It should be determined whether the
patient's disorder is sufficient to meet operational diagnostic criteria for
major depressive disorder, generalized anxiety disorder, or panic disorder.
These mood disorders should be complained of, should represent a significant
change from a previous state, and should be relatively persistent or
recurrent. Finally, sleep disturbances refer to a subjective report of a
change in the duration or quality of sleep. They include hypersomnia
(increased sleep) or insomnia (reduced sleep). These sleep disturbances,
should be complained of, should not be simply a response to external
disturbances should be a change from a previous state, and should be
persistent.
1.1.3. The Australian case definition
-------------------------------------
Lloyd etal. (1990) proposed an Australian CFS definition: to fulfill the
criteria, patients must have the following symptoms:
1. Chronic persisting or relapsing fatigue of a generalized nature,
exacerbated by minor exercise or causing significant disruption
of usual daily activities, and present for longer than 6 months
2. Neuropsychiatric dysfunction, including impairment of concentration
evidenced by difficulty in completing mental tasks that were easily
accomplished before the onset of the syndrome; new onset of
short-term memory impairment
3. No alternative diagnosis reached by history, physical examinaton,
or investigations over a 6-month period
In order to fulfill criterion 1, the patient must endorse at least one of the
three following items relating to fatigue:
a score of 1 (excessive muscle fatigue with minor activity, prolonged
feeling of fatigue after physical activity),
a score of 2 (moderate or frequent symptoms during the last month
causing major disruption to your usual daily activities) or
a score of 3 (severe or very frequent symptoms during the last
month making you unable to perform your usual daily activities).
In order to fulfill criterion 2, a patient must have a score of 2 or 3 (same
descriptors above) on at least one of two questions related to neuropsychiatric
dysfunction (loss of concentrating ability and memory loss).
1.1.4. Conclusion
-----------------
None of the current definitions have been empirically derived or prospectively
contrasted with one another. However in 1996 A. Komaroff et al. reported
analyses on the 1988 and 1994 CDC criteria. The conclusion was made that all
components of the original and revised CDC working case definition of CFS
discriminate patients with that syndrome from healthy control subjects of the
same age, sex and educational background. Many components of the original
case definition also distinguish patients with chronic fatigue from persons
with Multiple Sclerosis and major depression. A number of other symptoms,
not included as minor criteria in the original or revised CFS case definition
also discriminate patients with chronic fatigue from healthy control subjects,
MS patients and from patients with major depression.
The CDC minor criteria symptoms that are the most succesful discriminators
are myalgias, postexertional malaise, headaches, and an infectious-type group
of symptoms (ie, fever/chills, sore throat, swollen neck glands and swollen
arm glands). Two symp-toms that are not currently considered part of the case
definition of CFS also discriminate patients with chronic fatigue from
controls, MS or depressive patients: anorexia and nausea.
Because interobserver variability in the definition and collection of the
data elements from CFS patients is considerable, it was recommended to
include techniques for collecting data in any future revision of the case
definition.
To date the 1994 Fukuda criteria are widely used although physicians
experienced in the study of chronic fatigue are aware of the limitations.
In this thesis the 1988 CDC criteria were used in the study on magnesium in
chronic fatigue (chapter 3); the 1994 CDC criteria were used in all other
studies from which the data were collected after 1995.
1.2. CFS OVERLAPPING SYNDROMES
-------------------------------
Not all patients with chronic fatigue present the chronic fatigue syndrome.
Non-CFS chronic fatigue or idiopathic chronic fatigue has to be distinguished
from CFS, as are a variety of overlapping syndromes, including fibromyalgia,
spasmophilia or latent tetany syndrome and depression.
Some patients fulfill diagnostic criteria of both chronic fatigue syndrome
and fibromyalgia, other CFS patients show clinical manifestations of
spasmophilia and many CFS patients develop depressive disorders in the cours
of years.
In my own clinical experience, I think it is very important to tell
all his or her diagnoses to a CFS patient in order to explain all
therapeutic possibilities.
1.2.1. Fibromyalgia
------------------------
The clinical characteristics of fibromyalgia consist of widespread pain,
tenderness, fatigue, sleep disturbance, irritable bowel syndrome,
paresthesias, anxiety and similar features.
I used the American College of Rheumatology (ACR) 1990 Criteria for the
classification of Fibromyalgia (Wolfe et al.,1990), realizing well the bias
of palpation (if you palpate with more or less pressure your identification
of fibromyalgia will vary) but all patients were examined by myself.
The ACR criteria are:
1. History of widespread pain
--------------------------------
Definition: Pain is considered widespread when all of the following are
present: pain in the left side of the body, pain in the right side of the
body, pain above the waist and pain below the waist. In addition, axial
skeletal pain (cervical spine or anterior chest or thoracic spine or low back)
must be present. In this definition shoulder and buttock pain is considered
as pain for each involved side. "Low back" pain is considered lower segment
pain.
2. Pain in 11 of 18 tender point sites on digital palpation.
---------------------------------------------------------------
Definition: Pain, on digital palpation, must be present in at least 11 of the
following 18 tender point sires:
Occiput : bilateral, at the suboccipital muscie insertions.
Low cervical : bilateral, at the anterior aspects of the intertransverse
spaces at C5 -C7
Trapezius : bilateral, at the midpoint of the upper borden
Supraspinatus: bilateral, at origins, above the scapula spine near
the medial border
2nd rib : bilateral, at the second costochondral junctions,
just lateral to the junctions on upper surfaces.
Lateral
epicondyle: bilateral, 2 cm distal to the epicondyles.
Gluteal : bilateral, in upper outer quadrants of buttocks in
anterior fold of muscle.
Greater
trochanter: bilateral, posterior to the trochanteric prominence.
Knees : bilateral, at the medial fat pad proximal to the
joint line
Digital palpation should be performed with an approximate force of 4 kg.
For a tender point to be considered "positive" the subject must state that
the palpation was painful. "Tender" is not to be considered painful. For
classification purposes patients were said to have fibromyalgia if both
criteria are satisfied. Widespread pain must have been present for at least
3 months. The presence of a second clinical disorder does not exclude the
diagnosis of fibromyalgia.
1.2.2. Spasmophilia or Latent Tetany Syndrome
--------------------------------------------------
Many parallels are seen between clinical manifestations and dysfunction in
the latent tetany syndrome (LTS) of marginal Mg deficiency and those of CFS,
an observation made in 1992 by Durlach following publication of a small study
that reported low erythrocyte Mg levels in patients with CFS and their
favorable response to a six-week trial of weeldy intramuscular Mg injections
in most of them (Cox et al, 1991). In our own experience, we did not find any
association between Mg deficiency, CFS or FM. However serum Mg level was
significantly lower in the patients with spasmophilia than in the other
patients (Moorkens et al, 1997). Since the early 1960s there has been
recurring evidence that a relative or absolute lack of Mg determines the
neurological conditions known as cryptotetany, latent tetany, hyperventilation
syndrome and spasmophilia. The latter has been referred to as the central
neuronal hyperexcitability syndrome (Durlach et al., 1997; Agnoll et al,
1989).
The subjective symptomatology is at the same time polymorphous and typical.
It consists of general complaints as: morning fatigue, asthenia, sleeping
problems, decrease in appetite, hyperemotionality, anxiety, hypochondria,
depressive tendencies, memory and concentration defects; and of local
complaints as neuromuscular complaints (cramps; acroparesthesias;
periorbitary paraesthesias; cervical, dorsal and lumbar pain; muscular
rigidity), vasomotor complaints (headache; vertigo; visual fatigue),
cardio-vascular complaints (effort dyspnoea, precordialgia, thoracic feeling
of oppression), gastro-intestinal complaints (nausea, aerophagia, swallowing
difficulties, gastric cramps, dyskinesia of the biliary ducts, irritable
bowel), urogenital complaints (bladder dysfunction, dysmenorrhoea,
premenstrual syndrome, frigidity). Spasmophilia is characterized by following
general objective findings : dominance of the orthosympaticus (pupil
dilatation and hypersudation)and local objective findings as neuromuscular
findings (clonus palpebralis, tremor in the limbs, increased reflexes, sign
of Chvostek, sign of Trousseau), vasomotor findings (tendency to syncope,
orthostatic hypotension, Raynaud's syndrome, cold hands and feet),
cardiovascular findings (palpitations, extra-systoles, tachycardia), ructus
as gastrointestinal finding, pulmonary findings (asthmatic dyspnoea,
hyperventilation and sighing) and urogenital findings (vaginism in women;
impotence and ejaculatio praecox in men).
Medically unexplained somatic symptoms are often classified as Hyperventilation
Syndrome but hyperventilation seems a negligible factor in the experience of
spontaneous symptoms. Hyperventilation occurs seldom and seems a consequence
or epiphenomenon of the clinical symptoms rather than a significant contributor
to the onset or severity of it (Hornsfeld et al., 1996).
There is a weak association between hyperventilation and CFS. When present,
hyperventilation is usually related to known causes of respiratory
stimulation such as asthma or panic (Saisch et al, 1994).
1.2.3. Depression
----------------------
The relation of the Chronic Fatigue Syndrome to the syndrome of major
depression is paramount. Neuropsychologic complaints such as concentration
difficulties, memory impairment, sleep disruption and mood disturbance are
almost universal in patients with chronic fatigue syndrome and several
authors (Taerk et al, 1987; Kruesi et al, 1989; Hickie et al., 1995) report
concurrent psychiatric diagnosis in a substantial proportion of patients with
CFS. The high degree of comorbity with depression, is in part, an artefact of
overlapping symptoms: criteria for both disorders list fatigue, sleep
disturbance, psychomotor change, cognitive impairment and mood changes as
characteristic features. Some studies have sought to determine the premobid
rate of psychiatric disorder in patients with CFS and others have compared
CFS patients with subjects suffering from other relevant psychiatric,
neurologic and chronic medical ilnesses (Wood et al, 1994; Wessely, 1993).
Patients with CFS appear to occupy an intermediate status, having more
premorbid and current psychological disorders than patients with medical
illnesses, but less than patients with overt psychiatric disorders. However
the issue of psychiatric or psychological disorder is not accepted in the
majority of my patient population and therefore not all patients described in
this work were examined by a psychiatrist. I am very aware of this
restriction and bias.
1.3. EPIDEMIOLOGICAL DATA ON THE PREVALENCE OF CFS
---------------------------------------------------
1.3.1. Prevalence of CFS In the general population
-------------------------------------------------------
Before considering the epidemiology of CFS, it is neCFSsary to consider what
is known about the chief symptom, chronic fatigue.
There are numerous studies on the prevalence of fatigue, all of which conclude
that it is one of the commonest symptoms encountered in the community (Lewis
& Wessely, 1992). Typical findings are from a British community survey in
which 38 % of the sample reported substantial fatigue, which had been present
for over six months in 18 % (Cox et al, 1987). Most of these fatigued people
neither consider themselves ill, nor consult a doctor (Morrell & Wale, 1976).
Many regard fatigue as 'the norm', or an inevitable consequence of broken
nights, overwork or stress.
Chronic fatigue is thus common, but what about CFS?
The first attempt at a population based study using an operational case
definition came from Lloyd and colleagues in Australia (Lloyd a al., 1990).
Cases were identified using general practitioners as key informants. A point
prevalence of 37 per 100,000 was recorded. However only 25% of those
physicians approached agreed to participate. Ho-Yen and McNamara (Ho-Yen,
1991) achieved a better response rate in their survey of Scottish general
practitioners. They estimated a prevalence of 130 per 100,000, but recognition
of CFS varied. Professional workers remained overrepresented, although this
could still reflect differences in labelling CFS consumed considerable
amounts of medical time. The Center for Disease Control and Prevention (CDC)
attempted to estimate the prevalence of CFS based on surveillance of selected
physicians in four US cities (Anonymous, 1997). The observed prevalence of
CFS were lower than the Australian figures; between 2 to 7 per 100,000.
There was a female excess and a high rate of psychiatric morbidity. All these
studies suggested that CFS is not a common problem in primary care.
However recent studies with systematic case ascertainement report a different
picture. Bates et al. (1993) surveyed an American Ambulatory care clinic.
In keeping with the literature 27% of those attending a primary care clinic
had substantial fatigue lasting more than six months and interfering with daily
life. The point prevalence of CFS according to the various definitions was
0.3 % (CDC-1988), 0.4 % (UK) and 1.0 % (Australia) respectively. To date the
estimated crude point prevalence of CFS ranges from 0.2 % up to 2.6 %
(Wessely, 1998; Reid et al, 2000)
Pawlikowska et al. (1994) reported that among subjects with excessive fatigue,
only 1% believe themselves to be suffering from CFS. This emphasises just how
few of those who could be classified as CFS are labeled as CFS or seek
specialist help and highlights the powerful role of selection bias in
scientific studies, which are almost all based on tertiary care samples of
patients who have frequently made their own diagnosis before seeking
specialist help.
The patient population in this thesis was derived from the outpatient clinic
of internal medicine at the Antwerp University Hospital, all patients were
referred to the clinic by their general practitioner. The reader of this
thesis should keep this important selection bias in mind.
1.3.2. Prevalence of the Chronic Fatigue Syndrome In the
Antwerp University Hospital outpatient clinic of
internal medicine
-------------------------------------------------------------
A cohort of 605 patients (471 females, 134 males; age range 17-59 years)
referred to the outpatient clinic of Internal Medicine at the Antwerp
University Hospital was prospectively evaluated (Fig 1.1.). All patients had
a major complaint of fatigue of at least 6 months' duration. In 21(3%)
patients a wiplash injury formed the start of their medical history of
fatigue, 34 (6 %) patients mentioned an infection as the beginning symptom,
32 (5 %) patients complained of persistent postpartum fatigue. Anamnesis
showed domestic violence in childhood in 12 (2 %) patients, migraine since
childhood in 14 (2 %) patients; 10 (2 %) patients were treated for
juvenile-onset diabetes and 9 (1 %) patients had a history of anorexia
nervosa.
After anamnesis and clinical examination, 39 (6 %) patients fulfilled the
1994 CDC criteria for CFS; 26 (4%) patients fulfilled the 1994 ACR criteria
for Fibromyalgia and 277 (46 %) patients showed a clinical picture of
spasmophilia. Six (1 %) patients fulfilled both the CDC criteria for CFS and
ACR criteria for Fibromyalgia; 96 (16 %) patients fulfilled the CDC criteria
combined with the clinical picture of spasmophilia and 70 (12 %)
Fibromyalgia patients showed a combination with spasmophilia. In 25 (4 %)
patients the triple diagnosis of CFS, FM and spasmophilia could be made and
66 (11 %) patients showed none of those three clinical pictures. After
anamnesis and clinical examination, routine laboratory examination and
chest x-ray were assessed in all patients followed by organ-specific
examinanon. Hyperthyreosis was diagnosed in 2 patients, multiple sclerosis in
5 patients, dermatomyositis in 1 patient, polymyalgia rheumatica in another
patient and adenocarcinoma in the colon descendens in 1 patient. Isolated
ACTH deficiency was diagnosed in 4 patients; diagnosis of narcolepsy was made
in 2 patients. Although the diagnosis of a patient depends greatly on the
biases of the kind of physician patients choose to see and upon which
manifestations the patient percieves to be the most bothersome, these data
show that only 27 % of patients with chronic fatigue fulfill the CDC criteria
for Chronic Fatigue Syndrome, as reported earlier (Swaninck et al, 1991).
Anamnesis and clinical examination often reveal unexpected findings in
patients referred with socalled chronic fatigue syndrome.
CHAPTER 2: AIMS AND SCOPE OF THE THESIS
----------------------------------------
2.1 INTRODUCTION
----------------
During more than 5 years patient data on several aspects of chronic fatigue
syndrome were collected and processed.
Chronologically we started our research assessing, over a time period of two
years, the incidence of magnesium deficit in a very heterogeneous population
of patients with complaints of fatigue of at least one month duration. At
that time the term prolonged fatigue was not used. The heterogenity of the
patient population and the absence of a control group resulted in rather
disappointing condusions.
Publications on adult growth hormone deficiency (AGHD) and the similarity of
clinical symptoms in patients with AGHD and CFS directed us to perform a
pilot study on growth hormone (GH) secretion in CFS patients and healthy
controls and also to treat 20 CFS patients with low nocturnal GH secretion
with recombinant GH.
As we found arguments for impaired GH secretion in CFS we decided to extent
our investigations and we started a study on characterisation of pituitary
function in a large group of CFS patients and controls.
Many CFS patients claim that the fatigue they experience qualitatively
differs from the experience of tiredness or sleepiness. We decided to analyse
retrospectively 70 files of CFS and/or FM patients, taken into account the
biases of retrospective studies and the absence of a control group.
Finally as evidence of impaired GH secretion in CFS was growing, and
publications on impaired GH secretion in fibromyalgia were reported, we
performed a study to further characterise the aberrant behaviour of
GH secretion in CFS and FM patients by observing the GH responses to
stimulating agents in patients and controls.
Making up the table of contents of this thesis, we decided to group the
results of our research in three chapters, respectively on metabolic and
clinical aspects of CFS(chapter 3), hormonal status in CFS (chapter 4) and
emphasis on different aspects of GH secretion in CFS (chapter 5).
2.2. AIMS OF THE THESIS
------------------------
From the definitions and criteria concerning CFS discussed in the previous
introductory chapter it is apparent that CFS remains a vexing problem for
patients and clinicians more than a decade after its formal reintroduction
to the medical world (Holmes et al., 1988)
Despite initial enthusiasm that these definitions would assist in the rapid
identification of a discrete, homogeneous patient population, all of the
clinical descriptions encompassed a collection of individuals who are
heterogeneous in both past history and clinical course.
In the CDC criteria (1988, 1992, 1994), it is of note that the majority of
minor criteria are pain based, reinforcing the fact that diffuse or regional
pain (without accompanying abortnalities in the peripheral tissues) is common
in this condition.
Myalgias, paresthesias, neuromuscular irritability as well as fatigue,
weakness, depression, anxiety and sleep disturbances have long been known to
respond to long term magnesium supplementation (Classen et al., 1986;
Fehlinger, 1990).
The first aim of this thesis is to assess the incidence of magnesium deficit
in patients with chronic fatigue and to identify potential nutritional,
biochemical and clinical correlates to magnesiumdeficit in the study cohort,
as well as to examine the potential for oral magnesium supplementation to
benefit those patients magnesium deficithad been uncovered in. A prospective
observational and interventional study in patients with prolonged and chronic
fatigue was performed over a time period of two years.
Next to fatigue and pain the invalidating complaint of poor sleep in
CFS patients kept our attention. Indeed a great proportion of CFS patients
have complaints of sleep dysfunction starting after illness onset. Poor,
unrefteshing sleep is one of the minor criteria of the 1988 diagnostic
criteria for the diagnosis of CFS. Sleep abnormalities can potentially
explain part of the symptomatology of CFS since postexertional fatigue,
muscle pain and cognitive dysfunction were shown to be consequences of sleep
deprivation. The comorbidity of CFS and FM is known.
The second aim of this thesis is to examine sleep patterns in the Chronic
Fatigue Syndrome and/or Fibromyalgia.
From clinical experience I learned that patients who meet the CDC criteria
for CFS report altered body morphology (often weight gain), reduced muscle
strenght and exercise capacity. We found a striking similarity between the
clinical picture of some patients fulfilling the CFS criteria and those with
adult growth hormone deficiency. Complaints of impaired quality of life,
reduced vitality, and poor general health in the chronic fatigue syndrome are
also distinctive symptoms of adult growth hormone deficiency. Several
biochemical approaches have been studied to define GH deficiency in the adult:
the most widely established criterion is the peak serum GH concentration
achieved during a provocative test, usually the insulin tolerance test (ITT),
or following other pharmacological stimuli (arginine, clonidine or
GH-releasing factor) but, alternatively, a more physiological stimulus (such
as sleep) has been used. Spontaneous circulating levels of IGF-I have been
used in the diagnosis of childhood GH deficiency.
The purpose of our first small study concerning hormonal status in CFS patients
was to examine the secretion of GH in 20 CFS patients. The data of the study
suggested impaired GH secretion in CFS. A review of the literature on
neuroendocrine disturbances in the chronic fatigue syndrome was performed.
Subsequently we examined the pituitary function in a large group of patients.
The third aim of this thesis is to point out the most relevant test for
evaluation of GH metabolism in CFS patients.
Hormonal testing in patients with the chronic fatigue syndrome was performed
not only to compare different GH stimulation tests but also for
epidemiological reasons.
The fourth aim of this thesis is to describe the prevalence of GHD in
patients fulfilling the CDC criteria for chronic fatigue syndrome.
Patients with unexplained chronic fatigue and/or pain have been described for
centuries in the medical literature, although the terms used to describe
these symptom complexes have changed frequently. The currently preferred
terms are chronic fatigue syndrome and fibromyalgia. The diagnostic criteria
of CFS and FM describe the prominent clinical features of the syndromes
without any attempt to identify etiological mechanisms. The symptomatic
overlap of chronic fatigue syndrome and fibromyalgia provoked further
interest in examining the specific neuroendocrine characteristics of patients
with chronic fatigue syndrome and fibromyalgia. Publications on the
pituitary-adrenal function in CFS and FM patients revealed differences
despite clinical overlap. Reports on the GH-IGF-I axis in CFS and FM also
showed conflicting results. To further characterise the hormonal secretion in
CFS and FM patients, we observed the hormonal responses to stimulation.
The fifth aim of this thesis is to assess endocrine evaluation in CFS and
the clinical overlapping syndrome of FM.
Because of the invalidating complaints with long periods of sick leave and
the absence of efficient pharmacologic approach in patients with the chronic
fatigue syndrome, we became interested in the effect of GH replacement in
CFS patients with impaired GH secretion.
The sixth aim of this thesis is to test the effect of growth hormone
treatment in CFS patients.
3.1. MAGNESIUM DEFICIT IN A SAMPLE OF THE BELGIAN
POPULATION PRESENTING WITH CHRONIC FATIGUE
--------------------------------------------------
3.1.1. Introduction
------------------------
Among the manifestations of moderate to severe magnesiumdeficiency, we find
tiredness, muscular weakness, muscular wasting, fasciculations and depression.
These symptoms are often found in patient complaining of longstanding fatigue.
Magnesium is frequently used as an adjuvant in the treatment of a wide
variety of conditions ranging from neuropsychiatric disorder, through
ischemic heart disease and cardiac arrhytmias asthma and diabetes to chronic
fatigue syndrome (Cox et al, 1991). However these conditions are not always
associated with magnesium deficiency and it has not always been clear whether
the beneficial effects of magnesium supplementation were due to the
replenishment of possibly depleted body stores in the above-mentioned
conditions or whether the effect was a pharmacological effect of Mg on energy
metabolism, and which is an effect independent of the state of Mg stores in
these pathologies.
The Physiopathological processes linking Mg status and these disease
processes are still unclear.
In 1997 we published the results of a prospective and inserventional study
in patients with complaints of fatigue of at least 1 month duration. We used
the term chronic fatigue, however this term is no longer correct in the year
2000. The current consensus is that fatigue can be considered as chronic
after six months of illness. There is no particular logic for this division,
but to date it is one of the few non controversial areas in this subject.
The purpose of this study was to assess the incidence of Mg deficienfy over
a time period of two years, using Ryzen's intravenous Mg loadingprocedure
and to identifi potential nutritional biochemical and clinical correlates to
magnesium deficiency in the study cohort, as well as to examine the potential
for oral magnesium supplementation to benefit those patient magnesium
deficienfy had been uncovered in CFS, FM and cryptotetany were identified in
the study cohort using established criteria (CFS- 1988; FM- 1990).
The reader of the following article should keep the above-mentioned remark on
the term chronic fatigue in mind. To date the term prolonged fatigue is used
for the period between 1 month and 6 months of illness. However we preferred
to present the following article in the original version.
Chronic fatigue is a common problem in clinical practice. It is widely
believed that most cases of chronic fatigue seen in primary care practice or
in clinics dedicated to the problem of chronic fatigue, are caused by primary
psychiatric disorders (Barsky, 1981). Various organic conditions also can
produce fatigue: occult malignancies or infections, inflammatory disorders,
anaemia, thyroid disorders, multiple sclerosis, connective tissue disorders
and many other well-defined diseases. Chronic fatigue syndrome, as defined by
the United States Centers of Disease Control case definition (Holmes et al,
1988; Dickinson, 1997), is also a cause of fatigue but is still a
controversial disorder and no characteristic pathophysiology has been
identified.
Chronic fatigue is an integral part of fibromyalgia syndrome, a debilitating
disorder defined by the 1990 American College of Rheumatology Criteria
(Wolfe et al, 1990). There are several views on the predominant construct of
the syndrome: one view, widely held, is that FM is a psychological disorder,
another view holds that it is a muscle disorder. Some support the view that
it is a pain amplification disorder. A fourth view holds tat FM is a
biopsychological disorder (Pillemer, 1994).
A lot of patients with complaints of chronic fatigue also suffer from migraine,
tension type headaches, muscle cramps, irritable bowel syndrome and primary
dysmenorrhea among other dysfunctions. This clinical picture is determined as
spasmophilia or central neuronal hyperexcitability syndrome (Mazzotta et al.,
1996).
Magnesium, next to potassium the second most abundant intracellular cation in
the human body has a widespread metabolic influence on several basic
physiological processes (Brady et al.., 1987). Mg deficit maypresent itself
with varying symptoms from several organs but lasting fatigue and muscle
cramps or muscle pain suggest this diagnosis. A previous study suggested that
patients with CFS suffer from Mg deficit (Cox et al., 1991) but other workers
have failed to substantiate these results (Deulofeu et al., 1991). In the
management of FM, rationale for the use of Mg was reported. This treatment
was based on similarities between mitochondrial abnormalities in FM and
Mg deficiency (Abraham & Flechas, 1992). The role of magnesium in patients
with cryptotetany or spasmophilia has been recorded (Mazzotta et al., 1996).
In order to define groups at high risk of suffering from Mg deficit and also
to study the relationship between dietary Mg intake and Mg status and further
to investigate the feasibility and effect of Mg replenishment we assessed a
prospective study over a period of 2 years and enrolled 97 patients.
Mg status and dietary intakes were studied. Of the first 34 patients diagnosed
as being Mg deficient and accepting Mg supplementation in various forms,
24 returned for a second intravenous Mg loading test and the parameters
measured in the first visit were remeasured
3.1.2. Patients and methods
--------------------------------
97 sequential patients from a larger cohort with complaints of chronic fatigue
for at least the past I month were included in the study. Patients whose
examination or medical record revealed medical conditions associated with
chronic fatigue were excluded, as were patients with certain psychiatric
disorders including schizophrenia, manic depressive ilness and substance
abuse. Patients had not been treated with drugs which can interfere with the
nutritional status of Mg (diuretics, antihypertensive drugs etc). Routine
laboratory tests (hematocrit, blood urea nitrogen, creatinine, glucose, liver
enzymes, total protein, sodium, potassium, calcium, albumin, total and
HDL cholesterol, uric acid, PTH, alkaline phospharase) were performed.
Informed consent was obtained. Chronic fatigue syndrome was diagnosed
according to the 1988 CDC criteria. The two major criteria are disabling
fatigue lasting more than 6 months and exclusion of all other potential causes
of fatigue. Minor criteria include fever, sore throat, lymphadenopathy,
muscle weakness, myalgia, headache, sleep disturbances and neuropsychological
complaints. In order to diagnose a patient as having CFS, the examiner should
find both major and eight of the minor criteria (or six if fever, pharyngitis
or lymphadenopathy are found). The diagnosis of fibromyalgia was based on the
1990 American College of Rheumatology Criteria.: pain must be present in
eleven or more of the 18 specific tender point sites (Wolfe et al., 1990).
A muscle ischaemia test was carried our when the patients had symptoms of
headache, irritable bowel, hypotension, suggesting the diagnosis of
spasmophilia.
Each patient was lying comfortably on a bed in a quiet room that was shielded
from electrical interference. The cuff of a sphygmomanometer was placed on
the right arm and was inflated to a pressure of 270 mmHg. This pressure level
was maintained for 10 mm. From the fifth minute of ischaemia and during 5 min
after the deflation of the cuff, the patient hyperventilated for cycles of
15 s per miii. The EMG machines used were a Saphire (Medelec) and Nicolet
(Viking). The electrical activity in the muscle was recorded with a
concentric needle electrode during the period of ischaemia and for the 5 min
after the blood flow returned to normal. The spontaneous electrical activity
was recorded on photosensitive papet. The test was considered positive when,
after the cuff of the sphygrnomanometer was undone, spontaneous motor unit
discharges in sequences of triplets or multiples were observed for 5 min.
Magnesium deficit was evaluated with a parenteral Mg retention test according
to the guidelines of Ryzen (Ryzen et al., 1985).
0.2 mEq Mg per kg body weight were infused in 5 per cent glucose for 4 h. Mg
was measured in the urine preceding the infusion (preinfusion urine) and
during the 24 h starting with the infusion (postinfusion urine). Mg retention
was calculated according tote following formula
% Mg retention =
100 - (postinfusion 24 h urine Mg - preinfusion 24 h Mg) x 100
--------------------------------------------------------------
total elemental Mg infused
where
preinfusion 24 h Mg=
preinfusion urine Mg concentration x posrinfusion 24 h urine creatinine
-----------------------------------------------------------------------
preinfusion creatunine concentration
total elemental Mg infused = body weight x 0.2 x 12.1
Patients with 20 per cent or more Mg retention were diagnosed as Mg deficient
and those with 50 per cent or more as severely deficient. Magnesium
concentrations were measured by Atomic absorption spectrophotometry (Varian
Spectra- 100 AAS). In the course of their first retention test each patient
was submitted to an extensive dietary anamnesis using the 'dietary history
method' in which consumption during the week and during the weekend were
separated and confirmed by the 'cross-check method'. Quantitative analysis of
energy and nutrient consumption was done using the Nevo 93 (BECEL program
using the Netherlands food tables and the Belgian food tables NUBEL 95).
Patients with a retention of 20 per cent or more of the Mg infused were
considered to be Mg deficient and were asked to take part in a study in which
would be investigated the effect of Mg supplementation at nutritional doses
(aiming at daily intakes of 10mg of Mg/kg body weight) and for periods of
more than 3 months to ensure slow replenishment of Mg body stores. Of the
first 34 patients diagnosed as being Mg deficient and accepting Mg
supplementation, 24 returned for a second intravenous Mg retenton test and
the parameters measured in the first visit were remeasured. The increase in
daily Mg intake was accomplished by either drinking water having higher
concentrations of Mg (in six patients), or adapting the diet so that a higher
proportion of Mg-rich nutrients were ingested (eight patients), or by taking
1 gellule daily containing 200 mg of magnesium oxide (seven patients) or as
an intravenous supplementation of Mg (three patients). The choice of the type
of supplementation was taken by the patient and depended on individual
factors: e.g. patients with elevated body weight and cholesterol levels
avoided the choice of Mg-rich foodstuffs (nuts, chocolates) which are also
rich in fats: or other practical considerations, such as the price of Mg-rich
drinks. Three patients received intravenous supplements because they could
not tolerate (gastrointestinal problems) oral supplementation. For
statistical analysis SPSS version 4.0 was used. Mann-Whitney test for
comparison between groups and Wilcoxon ranksum test for paired comparison
were applied.
3.1.3. Results
--------------
GENERAL CHARACTERISTICS OF THE STUDY GROUP
------------------------------------------
97 patients (25 per cent male and 75 per cent female) with ages ranging from
14 to 73 years (median 38 years) and with a complaint of fatigue lasting for
more than 1 month were enrolled m the study. In the last 33 patients, dietary
anamnesis was not carried out. 47 per cent of the patients retained 20 per
cent or more of the Mg inffised during the parenteral loading test and were
diagnosed as being Mg deficient. 54 per cent presented with a clinical
picture compatible with CFS according to the CDC guidelines. 81 percent had a
positive ischaemic test and 52 percent suffered from fibromyalgia. The
proportion of positive cases for any of these parameters was not affected by
the sex of the patient. Moreover, Mg deficiency was not associated with the
presence of CFS. FM or a nositive ischaemic test, even when scores for the
presence of these three parameters were added. Likewise, per cent of
Mg retention was not significantly different in the groups having or not
CFS, FM or a positive ischaernic test or between male and female patients
(Table 3.1) FM or CFS and cryptotetany were not associated with each other,
but CFS was significantly associated with the presence of FM
(r=7.22, P< 0.007). Blood biochemistryvalues in this study population fell
within the normal ranges.
Parameters of Mg status in the study group before and after the intravenous
Mg retention test are shown in Table 3.2. Per cent of Mg retention after the
intravenous loading test in the whole study population correlated slightly
but significantly positivelywith uric acid (r=0.22, P< 0.046 (87)) and
negatively with albumin (r= -0.23, P< 0.028 (91)) and PTH (r= -0.26,
P< 0.09 (43)). Mg concentration in serum correlated with total cholesterol
(r= 0.29, P< 0.008(82)), ureum (r= 0.24, <0.028(87)), creatinine (r= 0.32,
< 0.003 (88)).
Mg in REC correlated positively with total cholesterol (r=0.31, P< 0.005(83))
and calcium (r= 0.37,P< 0.007(53)), and negatively with alkaline phosphatase
(r= -0.40,<0.5 (49)) and PTH (r= -0.33,<0.035 (42)).
Total daily intake of Mg in the study population averaged 414 +/- 116mg/day
(range 170-777, median 407), or 6.2 +/- 1.9 mg/kg/day (range 2.58-10.44,
median 6.0) and the frequency distribution was normal. About 10 per cent of
daily Mg intake was supplied by fluids, the rest by solid foodstuffs.
Total Mg intake correlated positively with total intakes of calories
(r= 0.45,<0.000), fats (r= 0.29,<0.023), cholesterol (r= 0.38, P< 0.002),
polyunsaturated fats (r= 0.26, P< 0.041) and fibres (r= 0.78,<0.0001 (n=64)).
Multiple regression analysis of all daily dietary intakes showed that 60 per
cent of the variance of daily Mg intake was accounted for by the fibre intake
(partial r= 0.55, P< 0.0005). A further 13 per cent was explained by intakes
of Zn, iron, per cent of calories as proteins (partial r= 0.42, (P< 0.0009),
partial r= 0.16, (P< 0.23), partial r= 0.42, (P< 0.01) resp).
Intake of Mg/kg/day also depends on fibre intake (37 per cent of the variance,
partial r= 0.60, P<0.0000) and on the per cent of calories as proteins (a
further 4 per cent and r= 0.27,<0.03). When expressed as Mg/Kcal, the
dependency is on fibre intake per Kcal (67 per cent of the variance
r= 0.81, P< 0.0000) and on per cent of calories as proteins and zinc
(a further 8 per cent, r of 0.47 and 0.28 resp).
Table 3.1. General patient characteristics in the whole study population
and according to Mg deficit (patients with Mgo retention
>20 per cent are considered as Mg deficient)
----------------------------------------------------------------------------
Whole MG Not MG P
population deficient deficient
(n=93) (n=44) (n=49)
----------------------------------------------------------------------------
Age(yrs)(mean +/- SD) 36 +/- 11 39+/-13 38 +/- 10 us
Body mass index
(Kg/m2)(mean +/- SD) 24 +/- 4 24.5 +/- 5.4 22.6 +/- 3.4 0.004
Sex (% male/% female) 25/75 30/70 20/80 us
Chronic fatigue syndrome
(% yes/% no) 64/46 52/48 56/44 us
Fibromyalgia (% yes/% no) 52/48 44/56 63/37 us
Isohasmic test
(% positive/
% negative) 81/19 84/16 78/22 us
----------------------------------------------------------------------------
Table 3.2. Parameters of Mg status in the whole study population, before
and after the intravenous Mg retention test
----------------------------------------------------------------------------
Parameter (units) Mean SD Median Range n
----------------------------------------------------------------------------
Retention
(96 of infused
Mg retained) 18.7 31.5 19.0 -40 -88 93
Mg plasma
(AAS)
(mmol/L)
before test 0.82 0.09 0.83 0.42-1.02 94
after test 1.03 0.11 1.03 0.72-1.25 61
Mg RBC
(AAS)
(minol/L)
before test 1.98 0.21 1.96 1.56-2.50 94
after test 1.98 0.21 1.96 1.58-2.47 61
Mg urine
(AAS)
(mmol/L)
before test 3.61 2.17 3.04 0.36-13.36 46
after test 4.55 2.23 4.27 1.18-11.84 34
----------------------------------------------------------------------------
Males had significantly higher intakes of Mg (when expressed as total
mg Mg/day. In contrast, mg Mg per g cholesterol was significantly lower in
males). Intakes of calories, fats, cholesterol, per cent of calories in the
form of carbohydrates, of alcohol, of iron, thiamine, phosphorus were also
higher in males, but intake of fruits and vitamin C was lower in males.
Mg intake was related to blood parameters in the following way:
Mg intake/kg/day correlated positively with levels in serum of HDL-Cholesterol
(r=:= 0.31,P<0.017) and negatively with uric acid (r= -0.28, P< 0.026) as
well as with BMI (r=-0.42, P< 0.001).
CHARACTERISTICS OF THE MG DEFICIENT GROUP
-----------------------------------------
BMI was higher in the Mg-deficient group, there being a significant positive
correlation (r= 0.27,P<0.01 and r =0.28, P< 0.007 (n= 93)) between BMI or
weight respectively and per cent of Mg retention.
Mg deficient patients had a significantly lower albumin. Patients with
Mg deficiency did not have significantly different Mg concentrations in serum
or plasma either before or after the Mg infusion. Moreover there was no
significant correlation between per cent of Mg retention and any of the
Mg concentrations measured in serum, plasma or RBC. Only in the small group
having a retention of more than 50 per cent, there was a positive correlation
between the per cent of Mg retention and the increase in plasma Mg due to the
loading test (p= 0.80,P<0.003) as well as with the increase in RBC Mg
(p= 0.72,P<0.013 (Abraham & Flechas, 1992)). Daily dietary intake fats or
fibres, expressed as either total intake or as intake per Kg body weight was
not different in the Mg deficient group and did not correlate with the per
cent of Mg retention during the intravenous loading test nor with any of the
measured Mg concentrations.
CHARACTERISTICS OF THE GROUP WITH CHRONIC FATIGUE SYNDROME
----------------------------------------------------------
Patients with CFS had a tendency for higher RBC Mg concentrations although
concentrations in plasma, serum and urine and Mg retention were not
significantly different from the patients not having CFS. Higher RBC Mg in
CFS patients was still found in both the Mg-deficient and non-deficient
groups. Patients with CFS did not differ in their dietary intakes, except for
ascorbic acid which was significantly higher (199.8 +/- 105.0 vs.
152.3 +/- 71.9, P< 0.042).
CHARACTERISTICS OF THE GROUP WITH FIBROMYALGIA
----------------------------------------------
Patients with FM had a significantly higher increase in RBC Mg after the
intravenous loading test, in contrast to the increase in plasma and serum
Mgwhich was significantlylowen This suggests that the shift of Mg from the
plasma towards the inside of the RBC during the intravenous loading test is
greater in FM patients. Again, this difference was still evident in both the
Mg-deficient and non-deficient groups. Patients with FM also had higher
dietary intakes of ascorbic acid (207.8 +/- 101.7 vs. 144.2+71.1 P<0. 006),
and of Mg when expressed as Mg/Kcal (0.173 +/- 0.054 vs. 0. 144 +/-
0.040,P<0.021), Mg/mg cholesterol (1.86 +/- 0.89 vs. 1.45 +/-O.75,P< 0.053),
Mg/g saturated fat (13.1 +/- 6.4 vs 9.9+3.8 P< 0. 021).
CHARACTERISTICS OF THE GROUP WITH A POSITIVE ISCHAEMIC TEST
-----------------------------------------------------------
Patients with a positive cryptotetany test had significantly lower plasma Mg
before and after the loading but the increase due to the intravenous
loading was not significantly different from the group of patients with a
negative test. Again, the presence of additional Mg deficit did not affect
this difference.
EFFECT OF SUPPLEMENTATION WITH MG
---------------------------------
Of the first 34 patients diagnosed as being Mg deficient and accepting
Mg supplementation for varying intervals and in various forms, 24 returned
for a second intravenous Mg retention test and the parameters measured in the
first visit were remeasured. 33 per cent were male, 54 per cent had CFS,
38 per cent had FM and 88 per cent had a positive ischaemic test. Apart from
a slight overrrepresentation of the males, these proportions are not
significantly different from those in the group of 34 Mg-deficients seen in
the first visit and thus, these 24 patients can be considered as
representative of the Mg-deficient group.
Although 11 patients still had a Mg retention of 20 per cent or more after
supplementation, the mean per cent retention in the group decreased
significantly (Table 3.3.). Only the Mg concentrations in serum (when
measured by the Calmagite method) tended to increase after supplementation,
but Mg concentrations in RBC or changes in Mg concentrations due to the
intravenous loading test were not affected significantly. The 11 patients
remaining Mg deficient even after months of supplementation were classified
as the group of non-responders. In this group of non-responders there was a
higher proportion of males and of patients receiving parenteral Mg supplements
and a lower proportion of patients with diagnosis of CFS, with FM or with
positive cryptotetany test, but these differences did not reach significance
(Table 3.4.). Nor did this group have a significantly higher per cent
retention in the first visit, nor did they differ significantly from the group
which corrected its deficiency after supplementation (responders) as regards
age, BMI, or blood biochemistry valuesb efore or after supplementation.
However, after supplementation, RBCMg in the non-responders tended to decrease
(from 1.987 +/- 0.133 to 1.866 +/- 0.196, paired (P<0.084) so that it became
significantly lower than in the responders (2.06 +/- 0.20, P<0.052)
(Ryzen, et al. 1985). The tendency for an increase in serum Mg after
supplementation was more pronounced in the responders (from 1.97 +/- 0.28 to
2.20 + 0.44 P< 0.063) than in the non-responders (from 2.08 +/- 0.33 to
2.17 + 0.37,P< 0.54).
3.1.4. Discussion
-------------------
We have investigated the Mg status in a group of patients suffering from
chronic fatigue before and after Mg supplementation. Chronic fatigue is a
debilitating complaint and forms an important socioeconomic problem. No
consistent pathognomonic markers can be found. Mg status was assessed by a
parenteral retention test (Cohen & Laor, 1990; Durlach, 1992; Gullestad et
al., 1994) and concentrations in plasma, red blood cells and urine were
measured by atomic absorption spectrometry (AAS). A mean +/- SD of 19 +/- 32
percent retention of the Mg infused in the parenteral test in this group of
patients is comparable to values of 14 per- cent +/- 19 found by Rude (Rude,
1993) in a group of normal subjects and using the same procedure for the
retention test. The frequency distribution of per cent retention was normal.
These results do not support our initial assumption, based on the
literature (Chulton, 1996; Gantz, 1991; Howard et al., 1992) and on the
beneficial effects of Mg therapy in this type of patient, of finding a higher
incidence of Mg deficient individuals amongst patients with a complaint of
chronic fatigue. Mg deficit was diagnosed in patients who retained 20 per
cent or more of the Mg infused in the retention test. Deficit, thus defined,
was present in 47 per cent of this group of patients, who did not differ from
the non-deficient group as regards Mg concentrations. Moreover, there was no
significant correlation between per cent of Mg retention and any of the
Mg concentrations measured. Only in the small group having a retention of
more than 50 per cent, a positive correlation was found between the per cent
of Mg retention and the increase in plasma Mg due to the parenteral test
(p= 0.8, P=0.003) as well as with the increase in RBC Mg (p= 0.72, P= 0.013).
Table 3.3. Effect of suppementation on Mg parameters
---------------------------------------------------------------------------
Parameter (unit) 1st visit 2st visit P
---------------------------------------------------------------------------
Retention
(% of infused
Mg retained) 47 +/- 17 (24) 18 +/- 43 (24) 0.0018
Mg plasma (AM)
(mmol/L)
before test 0.840 +/- 0.083 (21) 0.802 +/- 0.130 (24) NS
after test 1.050 +/- 0.107 (21) 1.049 +/- 0.101 (24) NS
Mg PEG (AM)
(mmol/L)
before test 2.017 +/- 0.220 (21) 1.970 +/- 0.220 (24) NS
after test 2.012 +/- 0.226 (21) 1.993 +/- 0.210 (24) NS
- in plasma Mg
due to test
(mmol/L) 0.210 +/- 0.096 (21) 0.247 +/- 0.112 (24) NS
- in EEC Mg
due to test
(mmol/L) -0.008 +/- 0.078 (21) 0.023 +/- 0.120 (24) NS
----------------------------------------------------------------------------
Table 3.4. Comparison of the general characteristics of the non-responders
and responders. (Non-resnonders are those patients who remained
Mg deficient after Mg supplementation)
----------------------------------------------------------------------------
Age (re) (mean +/- SD) 36.5 +/- 12/3 39A +/- 13.0 NS
Body mass index (Kg/m2)
(mean +/- SD) 26 +/- 6 23 +/- 4 0.18
Sex (% mesa female) 46/54 23/77 NS
Chronic fatigue syndrome
(% yes/ % no) 36/84 69/31 NS
Fibromyalgia
(% yes/% no) 27/73 48/54 NS
Ischaemic test
(% positive/% negative) 73/27 100/0 NS
---------------------------------------------------------------------------
These results support the view that status of total body Mg stores (evaluated
by the retention test, which is known to reflect the state of Mg stores in
bone) is not assessed correctly by measuring of Mg concentrations in plasma,
RBC or urine. From the clinical point of view, this means that individuals
with moderate Mg deficit cannot be identified by solely measuring
concentrations in plasma, RBC or urine because the concentrations are often
normal in individuals where intracellular Mg is depleted, a situation which
is possibly due to the buffering effect of the exchangeable compartment in
bone. In order to identify groups at high risk of Mg deficit, the patients
were divided into groups with diagnosis of CFS, FM and/or positive ischaemic
test. The presence of these conditions was not affected by sex, age, BMI nor
by the presence of Mg deficit. The diagnoses of CFS and FM were associated,
as already described in the literature: FM was present in 67 per cent of the
patients with CFS and only in 32 per cent of the patients without CFS
(P= 0.007). Concerning Mg status in these sub-groups, we can conclude that
CFS is not associated with Mg deficit and Mg concentrations are not lower in
CFS. In FM, increase in plasma Mg after the parenteral test is lower and
increase in RBC Mg higher, suggesting a more intensive shift of Mg into the
RBC during an acute intravenous loading of Mg In patients with a positive
ischaemic test, plasma Mg is lower. These findings were not modified by the
presence or not of Mg deficit, suggesting that CFS, FM or a positive
ischaemic test affect Mg concentrations by mechanisms which are independent
of the Mg body stores. Dietary anamnesis showed a higher daily intake of Mg
in those individuals eating more calories and more fats but, when corrected
for these factors, Mg intake is higher when the diet is rich in fibres or
when a higher percentage of the caloric intake is supplied by proteins. In
their dietary anamnesis 57 per cent of the patients mentioned mild
gastrointestinal disorders which influenced their choice of dietary
ingredients. Nevertheless, Mg intake did not differ in these patients nor was
there any association with the presence of Mg deficit, Daily intake of Mg was
not different in the Mg deficient group and did not correlate with the per
cent of Mg retention during the intravenous loading test nor with any of the
measured concentrations. We can conclude from these data that in this study
group, with relatively healthy eating habits and Mg intake within the range
of recommended daily allowances, Mg status is not directly dependent on
dietary intakes. The Mg deficit present in 47 per cent of the patients was
not due to insufficient intake but other factors such as gastrointestinal
absorption, urinary losses or intercompartmental shifts and turnover rates
should be considered.
Regarding the effect of Mg supplementation on Mg status, 11 patients remained
Mg deficient even after months of supplementation and were classified as
non-responders. These results support the view that Mg concentrations in
plasma and RBC (which did not change after Mg supplements) do not reflect the
state of body stores (which did improve after supplements as seen by the
improvement in mean per cent retention). We could not identify any clinical
factors which could help to identify those patients who do not respond (i.e.
improve Mg stores) to this type of supplementation (i.e. slow replenishment).
3.1.5. Conclusions
------------------
We investigated the relationship between different parameters of Mg status
and dietary Mg intake in a population with chronic fatigue. Although this
study has several limitations (a population which is heterogeneous, small and
drawn from a referral clinic), we can make the following conclusions:
(1) Concentrations of Mg in plasma, RBC or urine did not reflect
status of Mg body stores as measured by an intravenous
retention test. Replenishment of Mg stores by slow supplementation
did not affect these concentrations.
(2) Patients with chronic fatigue or, more specifically, with
confirmed CFS, fibromyalgia or a positive ischaemic cryptotetanic
test, although accompanied by specific alterations in Mg
concentrations and movements, did not have a higher incidence of
Mg deficit. The biochemical parameters found to be altered by the
presence of these syndromes were not affected by the additional
presence of Mg deficit or by supplementation with Mg, pointing
to a lack of association of these conditions with Mg body stores.
(3) Dietary intakes of Mg and other nutrients were acceptable in
this group of patients and were not related to status of Mg
stores or concentrations. Dietary intakes of Mg were related to
intakes of fibres and proteins. Supplementation with Mg in a
group of confirmed Mg-deficient patients was followed by an
improvement in body stores in about half of the patients.
3.2. SLEEP PATTERNS IN THE CHRONIC FATIGUE SYNDROME
AND IN FIBROMYALGIA
----------------------------------------------------
3.2.1. Introduction
---------------------
Sleep complaints are ubiquitous in patients with medical illness. A survey
of outpatients attending hospital clinics indicated that the vast majority
of patients reported sleep disruption concomitant with their condition.
Although sleep related problems among medically illpatients have only begun
to be investigted in the last decade, there is a rapid growing body of
evidence that sleep can be profoundly affected by ill health. Patients with
chronic fatigue syndrome or fibromyalgia report a change in sleep pattern
since the beginning of their medical problem.
During anamnesis on quality of sleep they often respond that they feel as
if they just skimmed below the surface of sleep.
Our interest in the clinical aspect of sleep in the chronic fatigue syndrome
and fibromyalgia motivated us to analyse retrospectivejy 70 files of CFS
and/or FMpatients, consecutively seen at our outpatient clinic of internal
medicine. All the selected patient reported sleep problems and were therefore
referred for polysomnographic examination.
The reader of the following text should keep in mind that the selected files
belong to a tertiary referral cenfre, that analysis of sleep parameters was
done retrospectively and that no controlgroup was investigated. To compare
sleep variables of patients with normal controls, we used normative data
from the literature (Karacan & Williams, 1985)
The chronic fatigue syndrome, as defined by the United States Centers for
Disease Control case definition (Fukuda et al., 1994) is characterized by
generalized incapacitating fatigue of at least 6 months duration and
associated with impaired physical and mental functioning. Fibromyalgia, as
defined by the American College of Rheumatology Criteria (Wolfe et al.,1990),
is characterized generalized pain, localized tender points and chronic
fatigue. Both chronic fatigue syndrome and fibromyalgia patients complain of
nonrestorative sleep : patients awaken tired or unrefreshed with pain and
stiffness. The exact aetiology of both disorders is unknown and various
mechanisms have been proposed including viral, immunological, neuroendocrine
and psychiatric factors (Crofford, 1998; Neeck & Riedel, 1994; Cleare et
al, 1995). The significant overlap of clinical signs in CFS and FM causes
diagnostic problems, and some patients meet both the CFS and FM criteria. We
analysed retrospectively 56 files from CFS and/or FM patients in order to
evaluate similarities and differences in sleep physiology of this overlapping
clinical entities.
3.2.2. Methods
----------------
PATIENTS
--------
The files of seventy CFS and/or FM patients consecutively seen at the
outpatient clinic for chronic fatigue, and referred for polysomnographic
examination on the basis of reported sleep problems were selected.
Thirty-four patients were diagnosed as chronic fatigue syndrome patients
(CFS), twenty-one were fibromyalgia patients (FM) and fifteen patients
fulfilled diagnostic criteria of both chronic fatigue syndrome and
fibromyalgia (CFS+FM). In fourteen files (7 CFS, 4 FM, 3 CFS+FM) an
apnea-hypopnea index over 10 was found. This is a measure for the number of
arousals due to apnoea or hypopnoea and can explain excessive sleepiness and
tiredness, therefore these 14 files were not further investigated in this
report. Fifty-six patient files were included in the study. Characteristics
of the groups studied are shown in Table 3.5.
Table 3.5. Characteristics of the groups studied
----------------------------------------------------------------------
CFS FM CFS+FM
----------------------------------------------------------------------
N 27 17 12
Sex:MF% 18/82 29/71 8/92
Age(yrs)mean+/-SD 39+/-12 35+/-8 38+/-10
BMI (kg/m2) mean +/- SD 24.3 +/- 4.9 24.1 +/- 5.5 24.5 +/- 5.0
Duration of
complaints(yrs) mean+/-SD 6+/-5 4+/-6 7+/-5
----------------------------------------------------------------------
POLYSOMNOGRAPHY
---------------
All 56 subjects were interviewed by a trained clinician on sleep habits and
completed the Beck Depression Inventory. All psychotropic, sedative or
hypnotic medication was discontinued at least 2 weeks before two consecutive
nights in the sleep laboratorywere completed. Polysomnography was recorded
with the MEDILOG sleep analysing computer from Oxford instruments SAC, 847.
Recordings took at least 8 consecutive hours from 11.30 pm. For practical
reasons 18 patients (6 CFS, 10 FM, 2 CFS+FM) had a second night sleep
recording at home using the MEDILOG MR 95 ambulatory monitoring system. From
these 18 patients no second night records on saturation, Periodic Leg
Movement of Sleep or individual golf analysis are available. The registration
included electroencephalography on C4 -A1 and C3 -A2, bilateral
electrooculography (FOG), submentalelectromyography (FMG), EMG of the left
and right anterior tibialis, one lead for precordial electrocardiography,
nasal airflow thoracic and abdominal expansion-bands and pulse oximetry. All
recordings were made to enable conventional sleep staging according to
Rechtschaffen and Kales criteria in epochs of 30 seconds. Quantitative alpha,
beta, sigma and delta waves were recorded as mean counts (= bursts)/min
during REM and stages 1,2,3 and 4. This score indicates the number of times
each waveform appears in a given sleep stage. The following sleep variables
were used for analysis (Table 3.6.): TST, total sleep time calculated as
number of minutes spent asleep; TIB, total time in bed in minutes; SPT, sleep
period time is calculated as TIB minus the time it took to fall asleep and
the time the subject lay awake in the morning; SOL, sleep onset latency
calculated as time in minutes from lights out to the appearance of sigma
waves in stage 2; REML, REM sleep latency calculated as minutes from falling
asleep to first 30-second epoch of REM sleep; I-awake, amount of awake time
in minutes; SEI, sleep efficiency index calculated as total sleep time to
sleep period time (TST/SPT)x1OO; %SPT REM, percentage of rapid eye movement
(REM) sleep during sleep period time; %SPT st1 - 4, percentage of each sleep
stage calculated from SPT. PLMS, periodic leg movements of sleep are sleep-
initiated muscular contractions in the hip, leg, ankle and foot, possibly
followed by partial arousal or awakings. PLMS-recording exists of a minimum
of four bursts on EMG, with a minimum interval of 5 seconds. R-REM, number
of rapid eye movement bursts pro minute of
Table 3.6. Nocturnal polysomnographic data (mean + SD):
-----------------------------------------------------------------------------
CFS CFS FM FM
night 1 night 2 night 1 night 2
-----------------------------------------------------------------------------
TST(min) 314+/-82 360+/-64 321+/-53 365+/-73
TIB(min) 459+/-44 474+/-60 453+/-51 447+/-64
SPT(min) 384+/-75 406 +/-53 397 +/- 60 403 +/-64
SOL(min) 59+/-54 48+/-49 52+/-33 32+/-22
REML(min) 126+/-83 87 +/- 64 133+/-62 105 +/- 64
I-awake(min) 70+/-53 46+/-60 76+/-56 38+/-30
SEI% 82+/-14 89+/-12 82+/-13 91+/-7
%SPT st1 6+/-3 4+/-3 8+/-9 6+/-4
%SPT st2 46+/-9 43+/-14 44+/-12 47+/-17
%SPT st3 9+/-8 10+/-5 10+/-12 10+/-5
%SPT st4 6+/-6 8+/-8 7+/-7 9+/-10
%SPT REM 16+/-8 23+/-13 13+/-6 22+/-9
ast1 cts/min 3.1 +/- 1.6 2.6 +/- 1.6 2.0 +/- 1.4 1.8 +/- 1.5
ast2 2.1 +/- 1.2 2.5 +/- 1.3 1.6 +/- 0.8 1.5 +/- 0.4
actS 1.5 +/- 1.8 1.8 +/- 2.0 1.1 +/- 1.3 1.2 +/- 1.0
ast4 1.4 +/- 1.9 1.4 +/- 2.1 1.4 +/- 1.4 1.1 +/- 0.9
R-REM 2.1 +/- 1.8 1.9 +/- 1.4 3.7 +/- 2.2 3.6 +/- 4.0
number PLMS 8+/-6 5+/-5 10+/-6 9+/-4
mn bursts/PLM 9.4 +/- 7.7 5.9 +/- 4.6 9.8 +/- 7.6 14.5 +/-13.4
mean sat% 96+/-1 96+/-1
mean heart
rate/min 68+/-10 70+/-13 69+/-10 68+/-12
----------------------------------------------------------------------------
Table 3.6. Nocturnal polysomnographic data (mean + SD):
-------------------------------------------------------
CFS+FM CFS+FM
night 1 night 2
--------------------------------------------------------
TST(min) 313+/-66 337+/-73
TIB(min) 457+/-29 448+/-56
SPT(min) 382 +/- 58 388+/-68
SOL(min) 61+/-49 50+/-49
REML(min) 144+/-90 108 +/- 90
I-awake(min) 69+/-53 51+/-68
SEI% 82+/-13 87+/-14
%SPT st1 7+/-3 10+/-10
%SPT st2 48+/-15 44+/-22
%SPT st3 7+/-7 13+/-15
%SPT st4 5+/-8 6+/-10
%SPT REM 15+/-9 19+/-11
ast1 cts/min 3.5 +/- 1.5 3.4 +/- 1.7
ast2 3.0 +/- 1.8 3.8 +/- 1.8
actS 1.8 +/- 2.8 2.2 +/- 3.2
ast4 1.6 +/- 0.7 1.6 +/- 2.0
R-REM 2.9 +/- 2.1 3.0 +/- 2.2
number PLMS 7+/-7 5+/-5
mn bursts/PLM 6.2 +/- 4.0 5.3 +/- 4.1
mean sat% 97+/-2
mean heart
rate/min 71+/-10 68+/-16
----------------------------------------------------------------------------
TST, total sleep time calculated as number of minutes spent asleep;
TIB, total time in bed in minutes;
SPT, sleep period time is calculated as TIB minus the time it took to
fall asleep and the time the subject lay awake in the morning;
SOL, sleep onset latency calculated as time in minutes from lights
out to the appearance of sigma waves in stage 2;
REML,REM sleep latency calculated as minutes from falling asleep to
first 30 -second epoch of REM sleep;
I-awake, amount of awake time in minutes,
SEI, sleep efficiency index calculated as total sleep time to sleep
period time (TST/SPT)x1OO; %SPT
REM, percentage of rapid eye movement (REM)sleep during sleep period time;
%SPTst1 to 4, percentage of each sleep stage calculated from SPT;
ast1-4, alpha waves recorded as mean counts(= bursts)/min during
stage 1,2,3 and 4;
R-REM, number of rapid eye movements bursts pro minute of REM sleep;
PLMS, periodic leg movements of sleep, recording exists of a minimum of
four bursts on EMG, with a minimum interval of 5 seconds;
mean sat%, mean oxygen saturation.
REM-sleep (this can be assumed as a parameter for REM density). To compare
sleep variables of patients with normal controls, we used normative data
from the literature. (Karacan & Williams, 1985; Sloan & Shapiro, 1997)
STATISTICAL ANALYSIS
--------------------
Means and standard deviations were calculated as usual. Qualitative measures
between groups were compared by the CU-Squared test and between groups, a
one-way ANOVA was used. When the zero-hypothesis was rejected, we conducted
a two-tailed, unpaired T-test to define the statistically different groups.
A paired, two-tailed T-test was used to compare within groups between nights.
A P-value P<0.05 (two-sided) was considered as statistical significant.
Correlations between variables were calculated by Pearson's R. The statistical
package Statistica 5.0 for Windows 95 was used.
3.2.3. Results
----------------
An important variability in all sleep parameters was seen in this retrospective
study. All patients showed long periods spend awake and frequent arousals.
Sleep efficiency was low Sleep Period Time and Total Sleep Time were similar
in the three groups. All patients have a long sleep onset latency and a long
REM sleep latency.
Alpha intrusion can be measured by the number of alpha bursts in counts/min,
during a given sleep stage. Significant differences between the 3 groups were
seen in stage 1 and 2 (P< 0.05).
R-REM showed significant differences (P<0.05) between FM patients
(3.7 +/- 2.2 cts/min) and CFS patients (2.1. +/- 1.8 cts/min) during the first
night. A strong correlation between R-REM during first and second night was
seen (r= 0.706).
Mean oxygen saturation and mean heart rate were similar in the three groups.
The groups differed not in Beck Depression inventory scores; all scores were
in the mildly elevated range: 44% of CFS patients, 58 % of FM patients and
40% of patients with CFS and FM showed a score of 15 or highetr.
Although FM patients showed less REM sleep during the first night REM latency
was not the highest in this group.
In both the CFS group and FM group, total sleep time, sleep efficiency index
and stage 4 sleep increased significantly during the second night REM sleep
and slow wave sleep both increased the second night. The CFS+FM patients
showed more superficial (st1 +2)and less slowwave sleep (st3+/-4) during the
first night with considerable improvement during the second night. For this
group an increase in slow wave sleep without difference in REM sleep during
the second night was recorded. The three groups showed a similar number of
periodic limb movements (PLMS) during the first night, with important
decrease of movements in the CFS group and the CFS+FM group during the second
night (Table 3.7.).
Table 3.7. Sleep variables, significant differences between night 1 and 2
---------------------------------------------------------------------------
Mean Mean P-value
night 1 night 2
---------------------------------------------------------------------------
CFS
TST(miun) 314 321 0.006
SEI% 82 89 0.04
%SPTst4 6 8 0.01
number PLM's 8 5 0.05
FM
TST(min) 321 366 0.009
SEI% 82 91 0.0002
%SPTst4 7 9 0.06
CFS+FM
total arousals 63 36 0.04
number PLM's 7 6 0.05
---------------------------------------------------------------------------
3.2.4. Discussion
-------------------
The present study consisted of PSG comparisons between patients with CFS
and/or FM diagnosed according to internationally accepted criteria. The
subjects were selected at the university outpatient clinic for chronic
fatigue on the basis of reported sleep problems. From seventy selected files,
20% revealed an increased apnoea-hypopnoea index; therefore, these 14 files
were rejected from this project. The high number of CFS and/or FM patients
with silent pathological nocturnal breathing proves the usefulness of
polysomnographic study in this population.
The comorbidity of CFS and FM is well known. Earlier (Goldenberg et al., 1990)
values were reported up to 70%; the clinical overlap in this study was 31%.
Over the last 30 years several investigators reported on objective appraisal
of sleep by means of polysomnography in CFS (Morriss et al., 1993; Krupp et
al., 1993; Morehouse & Braha, 1995; Morehouse et al., 1998) and FM patients.
Sleep studies in CFS patients (Fischler et al., 1997) reported subjective
sleep disturbances and occasionally objective disorders as nocturnal apnoeas.
The stage 4 sleep in CFS has been reported to be unaffected (Morriss, et al.
1993) or decreased (Fischler, et at 1997); stages 3 and 4 sleep have
traditionally been referred to as deep or slow wave sleep. It is in slow wave
sleep that restorative processes are thought to occur (Adam, 1980; Oswald,
1980). Alpha intrusion has been reported (Whelton et al., 1988) but not
confirmed (Morehouse et al., 1998; Flaningan et al., 1995) in CFS.
Fibromyalgia has been associated with sleep abnormalities, most frequently in
the form of alpha-delta sleep. In 1975 Moldofsky studied a group of FM patients
and described alpha wave intrusion during their nonrapid eye movement sleep
(NREM) in the majority of the patients. Alpha-delta sleep anomaly in patients
with FM was related to pain, energy and mood (Moldofsky & Lue,1980). Moldofsky
also noted prolonged sleep latencies, increase in stage 1 sleep and a
reduction in slow wave (delta) sleep which was later confirmed (Branco et al.,
1994; Drewes et al., 1995; Home & Shakell, 1991). Lower amounts of REM sleep,
and total sleep time as well as higher number of arousals or awakings, and
long awakings have been described in FM (Shapiro et al., 1993).
In our files we could not confirm the earlier reported decrease in stage 4,
or the decrease in REM sleep in CFS nor in FM patients. Long sleep onset
latency, decreased sleep efficiency and frequent arousals were observed in
all patients. Alpha intrusion was most prominent in the CFS+FM group,
followed by the CFS group. FM patients showed less alpha activity than the
2 other patient groups and this finding was rather unexpected.
We are aware of the limitations of a retrospective study however the
interesting polysomnographic differences between clinical overlapping
entities invite to a prospective study.
4.1. NEUROENDOCRINE DISTURBANCES IN THE CHRONIC fATIGUE SYNDROME:
INDICATIONS FOR A ROLE OF THE GROWTH HORMONE-IGF-I AXIS IN
THE PATHOGENESIS
-----------------------------------------------------------------
4.1.1. Introduction
---------------------
Investigation of the growth hormone (GH)-IGF-I axis in chronic fatigue
syndrome may be indicated for several reasons. Most of the reports regarding
neuroendocrine stimulation tests in CFS point toa disturbed central
serotoninergic (5-HT) function (Beam et al., 1995; Sharpe et al., 1996;
Cleare et al., 1995; Bakheit et al., 1992). Impairment of the hypothalamic-
pituitary-adrenal (HPA) axis activity in CFS and decreased IGF-I levels in
fibromyalgia, which is frequently associated with CFS, are well documented in
the literature (Beam et al., 1995; Cleare et al., 1995; Demitrack et al,
1991; Bennett et al., 1992). CFS patients may clinically not only resemble
glucocorticoid but also GE deficient adult patients (Main et al., 1997). All
these findings may indicate a neuroendocrine pathogenesis of CFS. Up to this
moment only a limited number of studies have examined GH secretion in CFS
(Beam et al, 1995; Sharpe et 4, 1996; Allain et al., 1997; Majeed et al.,
1995; Buchwald et al., 1996). We could wonder about the pathophysiological
basis of a disturbed GH secretion.
4.1.2. Neuroendocrine findings in CFS
---------------------------------------
The reports regarding neuroendocrine testing in CFS primarily deal with the
effects of 5-HT receptor stimulation on prolactin release. In CFS patients
the prolactin response to the 5-HT1A receptor agonist buspirone has been
found to be elevated as compared to controls, which initially was attributed
to an upregulation of postsynaptic 5-1-HT1A receptors (Bakheit et al., 1992).
Since, however, the GH response to buspirone in CFS patients is comparable
to controls, D2 receptor blockade is more likely to be the cause of an
increased prolactin release (Sharpe et al., 1996).
Parallel to the prolactin response to the 5-NT reuptake inhibitor
d-fenfluramine, the ACTH response in CFS patients is reported to be elevated
as compared to controls, which have been interpreted as an indication of an
increased central 5-HT receptor activity (Beam et al., 1995; Cleare et al.,
1995). This may be in accordance with the increased plasma 5 -HIAA lewis
reported in CFS patients (Demnitrack et al., 1992) and the experimental
finding of an increased cerebral 5-NT metabolism in animals at exertion
(Blomstrand et al., 1989; Baily et al., 1993).
Impairment of the EPA axis activity in CFS is generally accepted. This clearly
appears from a reduced 24-hour urinary free cortisol excretion (Demitrack et
al., 1991). Whereas evening plasma ACTH levels are found to be elevated, an
enhanced cortisol response to low-dose tetracosactide and a blunted ACTH
response to CR11 are most compatible with a mild central adrenal insufficiency
as in GRE deficiency (Demitrack et al., 1991). In another study, however, the
ACTH response after administration of d-fenfluramine has been shown to be
enhanced, while the cortisol response remains normal, possibly indicating a
mild primary adrenal insufficiency as well (Beam et al., 1995).
Reports on serum IGF-I levels in CFS have given conflicting results. Buchwald
et al. was not able to demonstrate a difference in IGF-I levels between
CFS patients, patients with fibromyalgia with or without associated CFS, and
normal controls (Buchwald et al., 1996). Allain et al., on the other hand,
reported significantly lower IGF-I levels in CFS patients as compared to
normal controls (Allain et al., 1997). They also demonstrated a significantly
reduced GH response to insulin-induced hypoglycemia, whereas the same group
had reported only a tendency to a lower GH response two years earlier (Beam
et al., 1995). As a matter of fact, decreased IGF-I levels have only been
reported once and a reduced GH response to hypoglycemia twice, with
statistical significance being reached only once. Furthermore, as IGF-I levels
were not related to age (e.g., IGF-I SDS) in neither of the above-mentioned
studies, the conclusions hereby drawn must be considered with prudence.
We recently conducted a study aimed at a further characterisation of
GH secretion in CFS (Berwaerts et al., 1998). For the first time the
nocturnal GH secretion was also examined as a measure of GH deficiency in
adults (Korbonits & Besser, 1996), and because of the possible role of sleep
abnormalities in the pathogenesis of CFS (cfr. infra). Twenty CFS patients
(7 males and 13 females, aged 30-60 years) and a varying number of age-and
sex-matched controls were recruited for the different tests. Serum IGF-I SDS
was significantly lower in CFS patients as compared to controls
(- 0.39 +/- 1.07 vs. 0.33 +/- 0,84, p 0.02). Nocturnal GH secretion in
CFS patients was about half of the secretion in controls (32.4 +/- 18.3
vs. 62.7 +/- 43.7 ug/L/15min (AUC), p= 0.06). However, the peak GH response
to insulin-induced hypoglycemia and to arginine administration did not differ
significantly between CFS patients and controls. These results are arguments
for a main-mined GH secretory capacity of the pituitary, but suggest a
resetting in the framework of the GH secretory pattern.
Majeed et al. demonstrated that the dexamethasone-induced GH release in
patients with CFS or depression is reduced as compared to normal controls
(Majeed et al., 1995). In CFS this response decreased even further after
pretreatment with metyrapone. This has been interpreted as an indication of
a subsensitivity of central type 2 steroid receptors in CFS (Majeed et al.,
1995). Sharpe et al. reported the GH response to buspirone in CFS patients
to be comparable to controls, as opposed to an increased prolactin release
(Sharpe et al., 1996). This may signify that the GH response to 5-HT1A
receptor stimulation is not altered in CFS but does not exclude abnormalities
in the central 5-HT function or other specific 5-HT receptor effects.
4.1.3. Etiologlcal hypotheses concerning the disturbed GH axis activity
-------------------------------------------------------------------------
A first hypothesis puts the disturbed central 5-NT receptor activity forward
as a cause of GH axis dysfunction. 5-NT has been shown to bean important
mediator in the regulation of the HPA axis activity, while the HPA axis
appears to influence significantly the GH axis activity On the other hand,
some experimental data may indicate a direct role of 5-NT in the regulation
of the GH axis activity.
From animal experiments we may assume that the HPA axis is activated by
stimulation of different types of 5-HT receptors, not only at the hypothalamic
but possibly also at the pituitary and adrenal levels (Dinan(a), 1996).
Especially responses to stress, e.g. insulin-induced hypoglycemia, appear to
be mediated by 5-HT receptor activation (Yehuda & Meyer, 1984). Several
studies have been conducted in humans but only a few allow to draw conclusions.
The cortisol response toinsulin-induced hypoglycemia is blunted after
pretreatment with the 5-HT2 receptor antagonists ritanserin and ketanserin
(Prescott et al., 1984; Tepavceci et al., 1995). Cortisol release appears to
be increased after administration of buspirone, the 5-HT1A receptor agonist
ipsapirone and the 5-HT2 receptor agonist mCPP (Lesch et al., 1990; Cowen et
al, 1990; Silverstone et al., 1994). These findings suggest an activation of
the UPA axis in humans through 5-HT1A and 5-HT2 receptor stimulation.
The HPA axis may exert its influence on the GH axis at two different levels:
through CRH or glucocorticoids. In animals the inhibition of GH secretion by
CRH appears to be mediated by an increased somatosratin release (Katakami et
al., 1985). In humans also the GH response to GHRH can be reduced by
concomitant CRH administration (Barbarino et al., 1990). While a CRH
deficiency in CFS may be suspected on the basis of neuroendocrine testing,
the CRH levels in cerebrospinal fluid are reported to be normal in affected
patients (Demitrack et al., 1991). In in titro animal experiments
glucocorticoids appear to alter the GHRH and somatostatin receptor densities
on somatotrophs (Thakore & Dinan, 1994). In humans, both a chronic
glucocorticoid excess,as in Gushing's disease (Smals et al., 1986), and a
chronic glucocorticoid deficiency, as in idiopathic ACTH deficiency (Giustina
et al, 1989), may be associated with a blunted GH response to GHRA. As
previously mentioned, a hypocorticism in CFS is well established (Demitrack
et at, 1991). In addition, the dexamethasone-induced GH release in CFS patients
is reduced, which may indicate a subsensitivity of central type 2 steroid
receptors (Majeed et al., 1995).
A more limited number of data may indicate a direct role of 5-HT in the
regulation of GH axis activity. From rat experiments we may withhold that
during CNS development 5-HT can play much earlier than other neurotransmitters
a role in the regulation of GH secretion (Kuhn & Schanberg, 1981).
GH secretion may be mediated by activation of 5-HT1 receptors in the
hypothalamic nucleus arcuatus, a main location of GURU nerve cell bodies
(Willoughby et al., 1987). A pituitary adenylate cyclase-activating
polypeptide, released from the hypothalamus, may also be involved in the
GH secretion induced by 5-HT receptor stimulation (Yatnauchi et al., 1996).
An alternative mechanism may be the activation of 5-HT receptors (possibly
5-HT2 receptors, as for ACTH secretion) directly at the pituitary level
(Lopez et al., 1986).
Some data suggest that the GH response to a2 -agonists is due to the
activation of a2 -adrenergic heteroreceptors present on 5-HT nerve terminals
in the nucleus arcuatus (Conway et al., 1990; Aulakh et al., 1992). Lastly,
the activity of somatostatin neurons in different parts of the brain also
appears to be modulated by 5-HT (Munoz-Acedo & Arilla, 1996).
In humans not as many studies have been conducted as compared to the testing
of the HPA axis. The GH response to insulin-induced hypoglycemia is blunted
after pretreatment with ritanserin but not ketansetin (Prescott et al., 1984;
Tepavcevi a al., 1995). GH release appears to be increased after
administration of buspirone, the 5-HT1D receptor agonist sumatriptan and
mCPP (Cowen et al., 1990; Silverstone et al., 1994, Anderson & Cowen, 1992;
Bodes et al., 1997). These findings may suggest an activation of the GH axis
through 5-HT1A, 5-HT1D and 5-HT2 receptor stimulation. Regarding CFS, the
GH response to buspirone has been reported to be normal, which may only
signify that the GH response to 5-ET1A receptor stimulation is not altered
(Sharpe et al., 1996).
A second hypothesis highlights CFS as a "stress-related illness" (Chrousos &
Gold, 1992), in which the disturbance of central 5-HT function would occur
as the result rather than the cause of impaired neuroendocrine stress
responses. In this respect, an interrelation between the impaired HPA axis
activity and the increased central 5-HT function has clearly been
demonstrated for CFS, while the role of GH as a "stress hormone" remains
elusive.
The onset and course of CFS appear to be strongly influenced by stress
(Cleare & Wessely, 1996). CFS patients are reported to demonstrate an
inordinate clinical response to psychological stress as compared to normal
controls (Wood er al., 1994). Under these conditions the impaired HPA axis
activity may be attributed to a dysregulation of the neurohormonal stress
response system (Crofford & Demitrack, 1990. This is in contrast to the
development of an overactive HPA axis in major depression (Chrousos & Gold,
1992). The impaired HPA axis activity in CFS can cause symptoms in two ways.
The deficiency in CRH, which is a behaviorally active neurohormone, may be
held responsible for the symptoms of atypical depression, e.g., fatigue,
hypersomnia, hyperphagia (Crofford & Demitrack, 1996). On the other hand,
a glucocorticoid deficiency can induce allergic reactions and inflammation
due to a defective immune counterregulation (Demitrack et al., 1991). Allergy
has indeed been associated with CFS (Straus et al., 1988).
Some data also indicate that the tWA axis activity influences the central
5-HT function, and not only the other way round. After adrenalectomy in rats
the 5-HT metabolism decreases and the 5-HT1 receptor density increases in
the raphe-hippocampal system. These changes can be reversed with corticosterone
administration (de Kloet et al., 1982; de Kloet et al., 1986). In depression
there is an important argument in favor of the overactive HPA axis being the
cause of a decreased central 5-HT function (Dinan(b), 1996). The decreased
prolactin release reported after d-fenfluramine administration in depressed
patients normalizes after pretreatment with ketoconazole (Thakore & Dinan,
1995). By analogs the impaired HPA axis activity in CFS may be considered the
cause of the increased central 5-HT function (Scott & Dinan, 1996). Cleare et
al. provided some evidence for this proposition by comparing neuroendocrine
responses in depression and CFS (Cleare et al., 1995). Whereas baseline
cortisol levels were shown to be increased and prolactin response to
d-fenfluramine reduced in depression, just the opposite was found in CFS.
A strong inverse correlation was reported between prolactin response and
baseline cortisol levels for both CFS and depression. Moreover, these
findings allow to confirm that CFS is associatedwith a neurohormonally
insufficient stress response, as opposed to the excessive stress response
characteristic of major depression (Chrousos & Gold, 1992).
GH is a stress hormone, which is mainly secreted in response to hypoglycemia
and physical activity, and to a lesser extent to psychological stress
(Delitala et al., 1987). After partial hypophy-sectomy in rats, resulting in
a more or less selective GH deficiency, the cerebral 5-HT metabolism
increases and may be reversed with GH administration (Cocchi etal., 1975).
Under GH treatment the 5-HT1 receptor density in rat hypothalamus and
pituitary gland decreases (Popova et al., 1975). These findings could be in
favor of a role of 5-HT in the feedback regulation of GN secretion. On the
other hand, it is possible that there is no clear role for GH in the
development of a stress-related illness, since the GH response to
psychological stress is probably too short in duration and too small in
amplitude for a neurohormonal dysfunction to develop (de In Fuente &
Wells, 1981).
According to a third hypothesis, sleep abnormalities in CFS may impair
GM secretion. This was an additional reason for considering nocturnal
GH secretion in our recent study of GH secretion in CFS (Berwaerts et al.,
1998). Fibromyalgia is generally accepted to be associated with sleep
abnormalities, most frequently in the form of aS-sleep, i.e., intrusion of
a-waves into the normal S-rhythm of the NREM (or stage 4) sleep EEG.
Deprivation of stage 4 sleep in healthy volunteers may lead to a fibromyalgia-
like picture (Moldofsky et al., 1975). CFS may also be associated with sleep
abnormalities: most often subjective sleep disturbances and occasionally
objective disorders as nocturnal apneas. The stage 4 sleep in CFS has been
reported to be unaffected (Morriss et al., 1993) or decreased (Fischler et al.,
1997). Normally, about 70% of GM secretion occurs during stage 4 sleep. This
has formerly been attributed to a decreased somatostatin release due to
cholinergic stimulation during sleep. Presently, an increased GURU release is
also recognized (Van Cauter & Plat, 1996). Moreover, 5-HT may play a role as
neurotransmitter in the regulation of nocturnal GH secretion (Mendelson, 1982).
A deficient nocturnal GH secretion because of sleep abnormalities may
ultimately lead to decreased serum IGF-I levels, as can be demonstrated in
fibromyalgia (Bennett et al., 1992) and in CFS (Bet-waerts et al., 1998).
4.1.4 Conclusion
----------------
The question remains whether the impaired GH secretory function is a primary
or secondary phenomenon in the pathogenesis of CFS (Allain et al., 1997).
Also from a clinical point of view the GN axis dysfunction can comprise both
cause and result of CFS: decreased serum IGF-I levels may be the source of
symptoms, as myalgias in fibromyalgia (Bennett et al., 1992), while decreased
physical activity can result in reduced GH secretion. Future investigations
in CFS patients may need to examine the GH response to selective 5-HT
receptor agonists other than buspirone, and should reconsider the nocturnal
GH secretion, with simultaneous control of sleep stages. A clinical trial
with exogenous GH in CFS patients may also contribute to elucidate the
importance of impaired endogenous GM secretion (Moorkens et al., 1998).
4.2. CHARACTERISATION OF PITUITARY FUNCTION IN THE
CHRONIC FATIGUE SYNDROME WITH EMPHASIS ON
GH SECRETION
---------------------------------------------------
4.2.1. Growth Hormone In the human body
---------------------------------------
PAThOFYSIOLOGY OF GH SECRETION
------------------------------
GH is produced and secreted by somatotrophs in the anterior pituitary gland
and is secreted in pulses that vary in amplitudo and frequency, depending on
factors such as age, body mass, sex, nutritional status, stress and exercise
(Thorner et al., 1990); the amplitude of the pulses is greatest at night.
Because of the pulsatile nature of GN secretion, blood levels of GH should be
measured over a period of 24 hours, which is very impractical in clinical
practice. The integrated 24-hour GH secretion is highest during puberty and
decreases steadily with age thereafter (Zadik et al., 1985).
GH release is controlled by two peptide hormones from the hypothalamus:
Gh-releasing hormone (GHRH) an the inhibitory peptide somatostatin (55).
The production and release of these hypothalamic hormones are modulated by
other hypothalamic factors and incoming neural and endocrine signals. The
external and internal factors influencing GN secretion are summarized in
Fig 4.1.
GH secretion is also regulated by acetylcholine, acting predominantly through
inhibition of somatostatin; dopaminergic stimulation of GH is well accepted
(Frohman & Stachura, 1975).
DIAGNOSIS OF GH DEFICIENCY IN ADULTS
------------------------------------
Growth hormone deficiency has been diagnosed primarly on the basis of
subnormal growth hormone secretion in response to stimuli. The Growth Hormone
Research Society has recommended that the diagnosis be based on a stimulated
serum growth hormone value of less than 3 ug/L per liter during hypoglycemia,
and this value is widely accepted as diagnostic in Europe.
Basal studies used to evaluate GH metabolism in this thesis
-----------------------------------------------------------
GH levels during sleep
----------------------
The mean night-time GH level can be informative of the basal GH secretory
status (Maghnie et al. 1994). In this work nocturnal GH secretion was
assessed by GH peak and area under the curve. However, it is not a practical
approach for clinical diagnostic purposes.
IGF-I
-----
GH secretory status can be assessed indirectly by measuring a peripheral
hormone IGF-I that is dependent upon GH. Serum IGF-I varies with GH secretory
ability, and in general low levels are indicative of GHD; however they are
not diagnostic in individual cases. There is a marked overlap with healthy
subjects and IGF-I depends on factors other than GH secretion (malnutrition,
hepatic disease, thyroid disease, diabetes, renal failure, age and gender).
Dynamic tests used to evaluate GH metabolism in this thesis
-----------------------------------------------------------
ITT
---
Insulin-induced hypoglycemia stimulates GE release via the hypothalamus,
involving a response to the fall in blood sugar as well as the response to
stress. The ITT is contraindicated in patients with evidence of ischaernic
heart disease, epilepsy or unexplained blackouts, in glycogen storage disease
as well as in severe untreated hypoadrenalism because the liverglycogen
stores are depleted and counterregulatory mechanisms restoring blood sugar
towards normal under the influence of adrenaline do not operate efficiently
and promptly. The blood glucose must fall to less than 2.2 mmol/L for an
adequate and reliable hypoglycaemic stimulus to have been present. An insulin
dose of 0.15 U/kg is used. If hypoglycaemia is not achieved, GM deficiency
cannot be diagnosed. In the young mature adult, GH rises normally above
13 ug/L. In the diagnosis of adult GE deficiency 5 ug/L (Hoffman et al.,
1994) and 3 ug/L (Sartorio et al., 1993; Aniato et al, 1993; Holmes et
al., 1994) peak GH concentration are used as cut-off point as the lower end
of the normal range. The specificity and the sensitivity of the ITT test
using the cut-off value of 5 are 100 and 99 % respectively (Hofmann et
al., 1994).
Arginine Test
-------------
Arginine stimulates GH secretion through reduction in somatostatin output
30 g arginine-HCI in 250 ml saline over 30 minutes iv is administered.
Clonidine Test
--------------
Clonidine acts by releasing GHRH. 0.3 mg clonidine po is administered.
GHRH Test
---------
GHRH in a dose of 1 ug/kg body weight is a strong stimulus to test pituitary
GH reserve. It acts directly on the pituitary to stimulate GH synthesis and
release via cAMP-dependent mechanism. It reflects the secretory capacity of
sornatotroph cells and distinguishes pituitary and hypothalamic causes of
GHD; however it cannot discriminate reliably between normal and GHD
individuals and, furthermore, there is great inter- and intra-individual
response variability due to variations in the endogenous somatostatinergic
tone at the time of the test. The combination of an agent which inhibits the
somatostatinergic tone, such as the cholinesterase inhibitor pyridostigmine
or the adrenergic receptor antagonist propranolol, before GHRH produces
greater and more reliable elevation of GH.
GH-Releasing Peptides (GHRPs)
-----------------------------
These six- or seven-amino-acid-residue synthetic peptides and their
pharmacological analogues have marked GH-releasing activity. As an intact
hypothalamic-pituitary unit is needed for the GHRPs to have their effect in
vivo, their use might provide the basis for a dynamic function test for GH.
Further research is needed. We evaluated the response to Hexarelin in
CFS patients.
FACTORS AFFECTING GH SECRETORY STATUS IN ADULTS
-----------------------------------------------
Age
---
Circulating GH levels are age dependent, being highest during puberty and
gradually declining from the age of 20 years. During puberty the elevated
mean GH levels are the result of the marked increases in GH pulse amplitude,
while the decreased GH levels later in life are the results of reduction in
the frequency of GH.
Serum IGF-I levels are also age dependent: IGF-I levels are low in newborns
and gradually increase with age, with peak values observed during puberty.
In adults serum IGP-I levels gradually decline with ageing. For every
10 years in age, the reported decline in mean IGF-I concentration ranges from
7 to 9 % in adult men and from 7 to 13% in adult women.
Sex
---
Gender-related differences in GH secretion are well established:
GH concentration and GH responsiveness to different stimuli are greater in
premenopausal women than age-matched men. Gender differences for IGF-I in
adults are relatively slight.
Obesity
-------
Subnormal spontaneous and stimulated GH levels are characteristic of marked
obesity. With every one unit of extra BMI, there is a 6% loss in GH secretion
rate. The correlation between IGF-I levels and indices of overweight is
doubtful (Iranmanesh et al., 1991)
4.2.2. Characterisation of pituitary function
in 73 patients with Chronic Fatigue Syndrome
-----------------------------------------------------
INTRODUCTION
------------
The clinical picture of the chronic fatigue syndrome (CFS) is characterised
by severe and prolonged fatigue along with a set of non-specific symptoms and
signs. The syndrome has been defined by the Centers for Disease Control
(Fukuda et al., 1994). Despite a considerable overlap in syrnptomatology, CFS
must be distinguished from fibromyalgia in which the pain syndrome is
prominent (Wolfe et al., 1990; Yunus et al., 1994; Crofford et al., 1998).
The estimated crude point prevalence of CFS ranges from 0.2% up to 2.6%
(Wessely, 1998; Reid et al., 2000). The social and economical impact of CFS
is considerable, as it results in physical incapacity with loss in jobs,
broken relationships and financial insecurity (Anderson & Ferrans, 1997).
The debate regarding the aetiology of CFS remains unsettled notwithstanding
competing claims for virologic, immunologic and psychiatric influences
(Chaudhuri et al., 1998). CFS has been proposed to be a stress-related illness
characterised by impaired neuroendocrine stress responses (Crofford &
Demitrack, 1996). Disturbances in the secretion of stress hormones have been
postulated to be at the origin of CFS or to represent at least an element in
the clinical presentation.
The prevailing complaint of fatigue has first directed investigations towards
glucocorticoid metabolism. Abnormalities in the hypothalamic-pituitary-adrenal
axis have been reported in CFS, including a reduced 24-h urinary free cortisol
secretion rate and altered responses to hormonal stimuli (Demitrack et al
1991). A recent study, however, did not support the theory of a low adrenal
reserve (Hudson & Cleare, 1999). No differences in ACTH and cortisol responses
during insulin induced hypoglycaemia were observed between a small group of
CFS patients and healthy controls (Beam et al., 1995).
The recent recognition of a syndrome of growth hormone deficiency (GHD) in
adults (De Boer et al., 1995) has subsequently focussed attention towards
GH function in CFS patients. Complaints of impaired quality of life, reduced
vitality, and poor general health in CFS are also distinctive symptoms of
adult GHD. Until now only a limited number of studies have examined
GH secretion in CFS, giving equivocal or conflicting results. Serum IGF-I
levels in CFS patients have been reported to be decreased (Main et al.,
1997), normal (Buchwald et al., 1996) or increased (Bennett et al., 1997).
GH peak response to insulin induced hypoglycaemia was found reduced in two
studies comprising a small number of patients but reaching statistical
significance in only one (Bean et al., 1995; Allain et al., 1997).
The purpose of the present study was to examine the hormonal characteristics
in a large group of CFS patients. Besides baseline hormonal parameters of
pituitary fbnction, nocturnal secretion of GH, ACTEL and cortisol was
assessed. To investigate the hypothesis that CFS is a stress-related illness,
it was of particular interest to obtain information about GH, ACTH and
cortisol responses to stress provoked during insulin induced hypoglycaemia.
As GH serves to maintain optimal bodycomposition throughout life, body mass
index (BMI) of patients and controls was compared and evaluation of visceral
fat mass by CT scanning was perfurmed.
PATIENTS AND METHODS
--------------------
Patients
--------
The patients with CFS were consecutively recruited from the outpatient clinic
to which they were referred with complaints of longstanding and disabling
fatigue. The cohort consisted of 73 CFS patients (Table 4.1.). They all
fulfilled the 1994 Centers for Disease Control criteria for the diagnosis of
CFS. They underwent medical evaluation, comprising a standardised examination
and a questionnaire on past and current medical problems. Exclusion criteria
were: acute severe illness during the previous six months, pregnancy chronic
liver disease, thyroid dysfunction, hypertension, diabetes mellitus, a
history of malignancy and chronic medication. The average lenght of illness
was 18 months (range 10-29 months). All patients had insidious onset of
complaints, no patient had post-viral onset.
All the patients underwent a psychiatric evaluation before the start of the
study: any co-morbid psychiatric disorder classified according to Diagnostic
and Statistical Manual of Mental Disorders (fourth edition) was an exclusion
criterion. None of the patients included were taken prescribed medication in
the 2 months before study entry
Routine laboratory tests included a complete blood count, erythrocyte
sedimentation rate, 12-factor automated chemical analysis, and liver function
tests. Controls consisted of 21 healthy subjects (Table 4.1.). The women
included, had regular menstrual cycles, the endocrine investigations were
performed in the early follicular phase of menstrual cycle.
Due to the complexity of the tests, not all data were available for all
patients and controls. Analyses were done with all disposable data.
Methods
-------
Serum IGF-I concentration was measured as a parameter of 24-hour GH secretion
in the 73 CFS patients and in the 21 healthy controls. In order to correct
IGF-I for age, the formula was used (Cuneo et al., 1998).
log IGF-I - (5.95 - [0.0197 x age in years])
--------------------------------------------
0.282
Table 4.1. Demographic characteristics of participants
------------------------------------------------------
ITT baseline Nocturnal Arginine Clonidine
prolactin/ GH Secre- stimu- stimu-
TSH/FT4 tion lation lation
----------------------------------------------------------------------
Number M/F 73 (18/86) 29 (9/20) 39 (11/28) 33 (11/22)
Age in years
(mean +/- SD) 36.8 +/- 8.8 39.1 +/- 7.4 38.8 +/- 9.7 40.2 +/- 8.5
BMI in kg/m2
(mean +/- SD) 21.9 +/- 2.5 23.3 +/- 2.9 22.8 +/- 3.0 23.0 +/- 3.0
Controls
--------
Number M/V 21 (9/12) 9 (4/5) 19 (4/15) 6 (1/5)
Age in years
(mean +/- SD) 43.6 +/- 10.7 32.4 +/- 10.7 36.1 +/- 9.2 40.8 +/- 11.0
BMI in kg/m2
(mean +/- SD) 22.4 +/- 2.6 22.3 +/- 1.7 22.4 +/- 1.6 22.6 +/- 1.8
------------------------------------------------------------------------
Nocturnal GH secretion was assessed in 29 CFS patients and 9 age- and
BMI-matched controls (Table 4.1.). Serum GH samples were taken every
15 minutes over an 8 hour period starting at 22h00 in order to ascertain
nocturnal GH peak value and to measure the area under the curve (AUC) as
integrate of the 32 determinations.
GH axis was investigated during an insulin tolerance test (LET) (0.15 U/kg
body weight insulin iv), whereby nadir blood glucose level was less than
2 mmol/L. Serum GH was measured at time 0, 15, 30, 45, 60, and 90 minutes;
BMI was similar in both groups (P= 0.22). Severe GH deficiency was diagnosed
with a value <3 ug/L (Hoffman et al., 1994). An arginine stimulation test
(30 g arginine-HCI in 250 ml saline over 30 minutes iv) was performed in
39 CFS patients and in 19 age- and BMI-matched controls (Table 4.1.).
A clonidine stimulation test (0.3 mg po) was performed in 33 CFS patients
and 6 age- and BMI matched controls (Table 4.1.). Sampling for GH was done
at 0, 30, 45, 60, and 90 minutes. The three different stimulation tests for
GH could be compared in 15 CFS patients.
The tests were performed on separate occasions and in random order with an
interval of at least 7 days.
Nocturnal plasma ACTH and cortisol values were analysed from blood samples
taken every two hours during 8 hours starting at 22.00 h in the previously
mentioned 29 CFS patients and 9 controls. Peak values were evaluated and
area under the curve was measured as integrate of 5 determinations.
Plasma ACTH and serum cortisol concentrations were also measured during ITT
at the same time intervals as GM in all 73 patients and 21 controls. An
adequate response of cortisol was considered when peak value reached 500
nmol/L (Nelson & Tindall, 1978).
Basal serum concentrations for prolactin, ThE and free thyroxin were
determined.
Aliquots for ACTH were taken into cooled heparinised tubes, immediately
centrifuged and plasma was stored at -20o C for later determination. Blood
for IGF-I, GH, cortisol, prolactin, TSH, and free thyroxin was allowed to
clot at 40o C, spun and stored at - 20o C. All measurements were performed
wit commercial radio-immunoassay or immunoradiometric assays. Sensitivity of
IGF-I assay (SMC, Biosource, Fleurus, Belgium) was 9 ug/L; intra-assay
coefficient of variation was 6.1 % at 54 ug/L and 4.7 % at 491 ug/L;
intra-assay coefficient of variation was 9.9 % at 121 ug/L and 9.3 % at
494 ug/L. Sensitivity of GH assay (hGHRIA, Pharmacia & Upjohn Diagnostics,
Belgium) was 0.1 ug/L; inter-assay coefficient of variation was 5.1 % at
0.6 ug/L and 2.9 % at 2.1 ug/L; intra-assay coefficient of variation was
5.6 % at 0.6 ug/L and 4.3% at 2.1 ug/L. Sensitivity of ACTH assay (ACTH
Immunoassay, Nichols Institute Diagnostics, Pads, France) was 0.4 pmol/L;
intra-assay coefficient of variation was 3.0% at 15 pmol/L and 3.2% at
161 pmol/L inter-assay coefficient of variation was 7,8 % at 16 pmol/L and
6.8 % at 158 pmol/L. Normal value for plasma ACTH is 4-22 pmol/L. Sensitivity
of cortisol assay (GammaCoat Cortisol, DiaSorin, Antony, France) was
6 nmol/L; intra-assay coefficient of variation was from 6.6% at 80 nmol/L and
6.8 % at 1300 nmol/L; inter-assay coefficient of variation was 9% at
102 nmol/L and 8.8 % at 1018 nmol/L. Normal value for serum cortisol is
190-660 nmol/L at 08:00 and <140 nmol/L at 24:00. Sensitivity of prolactin
assay (AutoDelfia, Wallac Oy, Turku, Finland) was 0.1 ug/L; intra-assay
coefficient of variation was 1.2 % at 3.2 ug/Land 3.1 % at 110 ug/L;
interassay coefficient of variation was 1.9 % at 3.2 ug/L and 3.1% at
110 ug/L. Normal value for serum prolactin is <20 ug/L. Sensitivity of the
TSH assay (AutoDelfia, Wallac Oy, Turku, Finland) was 0,01 mU/L;
intra-assay coefficient of variation was 11.6 % at 0.05 mU/L and 2.8 % at
17.7 mU/L; inter-assay coefficient of variation was 5.8% at 0.05 mU/L and
2.4% at 17.8 mU/L. Normal value for serum TSH is 0.15 -3,5 mU/L.
Visceral fat mass was assessed by CT scan performed at the L4- L5 level in
17 CFS patients (10 females, 7 males; mean age, 38.9 +/- 7.8 yr; BMI,
23.5 +/- 3.3 kg/m2) and 13 BMI-matched female controls (mean age,
30.9 +/- 6.5 yr; BMI, 22.2 +/- 2.8 kg/m2). Adipose tissue area was determined
by calculating the pixel distribution with attenuation values between -180
and -30 HU (Kvist et al., 1988; van der Kooy & Seiddli, 1993). All CT scans
were performed by the same technician and the scans were analysed blindly by
the same radiologist.
Statistics
----------
Means and standard deviations were calculated as usual. As summary statistics
for the serial measurements, the area under the curve (AUC), peak value and
baseline value were examined. For the comparisons between 2 independent
groups, the Student's t-test or the Mann-Whitney test were employed where
appropriate. Shapiro-Wilk test was used to assess normality Comparison between
3 or more paired groups was done using the Friedman test with the Wilcoxon
Signed Rank test to identify the differences (making due allowance for
multiple testing). The proportion among groups were compared by the
Chi Squared test or Fisher's Exact test. A P value < 0.05 (two-sided) was
considered to as statistical significant. The statistical package SPSS was
used.
RESULTS
-------
Characteristics in GH secretion are shown in Table 4.2.
-------------------------------------------------------
Serum IGF-I concentration and IGF-I SDS in CFS patients were not significantly
different from controls. Two CFS patients (2.7 %) showed an IGF-I SDS <-2,
while none of the control group did. Nocturnal GH peak (P= 0.044) and
nocturnal GH AUC (P=0.045) were significantly impaired in CFS patients
compared to controls (Figure 4.2.). Hypoglycaemia induced Girl peak (P= 0.01)
and GH AUC (p= 0.002) were significantly lower in CFS patients than in
controls (Figure 4.3.). No correlation could be found between GH peak
response and age both in controls (r=0.334; P= 0.14) and CFS patients
(r=0.123; P= 0.30). GH peak response to hypoglycaemia was less than 3 ug/L
in 2 CFS patients (2.7 %) (Figure 4.4.). All controls reached a GB peak value
above 10 ug/L during hypoglycaemia. GH stimulation by arginine or clonidine
did not reveal a significant difference in GH peak and GH AUC between
CFS patients and controls. In the 15 CFS patients whom underwent the three
stimulatory tests, the GH peak valuewas 15.9 +/- 9.1 ug/L after
ITT 7.6 +/- 72 ug/L after arginine, and 4.1 +/- 3.2 ug/L after clonidine.
The GH peak was significantly different between ITT and arginine (P=0.017),
between ITT and clonidine (P= 0.001), but no statistical difference was
found between arginine and clonidine.
Data on the pituitary-adrenal axis are given in Table 4.3.
Table 4.2. GH-IGF-I axis in CFS patients compared to healthy controls
---------------------------------------------------------------------------
CFS group Control group P
mean +/- SD mean +/- SD
(range) (range)
----------------------------------------------------------------------------
IGF-I (ug/L) 187.0 +/- 87.5 175.8 +/- 47.5 NS
(95.0 - 240.0) (95.0 - 240.0)
IGF-I SDS -0.20 +/- 1.02 -0.28 +/- 1.08 NS
(-2.19- 2.44) (-2.44- 1.89)
Nocturnal GH peak (ug/L) 5.4 +/- 3.7 9.0 +/- 5.1 0.044
(0.7- 13.0) (2.3 - 15.0)
Nocturnal GH AUC (ug/L) 34.4 +/- 20.2 87.4 +/- 411 0.045
(6.2.78.7) (12.0-138.3)
Hypoglycaemia induced
GH peak (ug/L) 17.0 +/- 13.1 22.1 +/- 9.8 0.01
(1.8 - 56.0) (10.7- 46.7)
Hypoglycaemia induced
GH AUC (ug/L) 450.0 +/- 361.3 672.3 +/- 393.0 0.002
(32.7-2010.3) (113.0- 1829.7)
Arginine induced
GH peak (ug/L) 9.8 +/- 28.7 9.4 +/- 7.3 NS
(0.3 - 50.0) (2.0 - 32.0)
Arginine induced
GH AUC (ug/L) 461.3 +/- 335.3 503.7 +/- 388.0 NS
(19.0 - 2145.7) (93.0- 1500.0)
Clonidine induced
GH peak (ug/L) 5.8 +/- 5.9 3.3 +/- 1.8 NS
(0.6 . 26.0) (1.2 - 5.3)
Clonidine induced
GH AUC (ug/L) 318.3 +/- 328.0 191.7 +/- 106.0 NS
(40.3 - 1480.0) (65.0- 342.3)
-----------------------------------------------------------------------------
Table 4.3. ACTH-cortisol axis in CFS patients compared to healthy controls
--------------------------------------------------------------------------
CFS group Control group P
mean +/- SD mean +/- SD
(range) (range)
----------------------------------------------------------------------------
Nocturnal ACTH
(pmol/L) 12.2 +/- 6.6 7.5 +/- 4.0 NS
(0.9. 124.6) (1.8 - 16.2)
Nocturnal ACTH peak 12.3 +/- 6.6 (13.7.76.6) NS
(1.8- 29.5) (3.5 - 24.7)
Nocturnal ACTH AUC
(pmoll/L) 45.8 +/- 20.4 44.6 +/- 22.4 NS
(9.7- 88.1) (13.7 - 76.6)
Hypoglycaemia induced
ACTE peak (pmmol/L) 92.0 +/- 56.6 88.0 +/- 51.4 NS
(4.4- 295.6) (7.9 - 205.7)
Hypoglycaemia induced
ACTH AUC (pmol/L) 2985 +/- 1866 2509 +/- 1645 NS
(205 - 7812) (439 - 7240)
Morning cortisol
(nmol/L) 466 +/- 196 425 +/- 165 NS
(138- 994) (163- 911)
Nocturnal cortisol peak
(nmol/L) 387 +/- 139 512 +/- 127 0.021
(50 - 602) (362 - 756)
Nocturnal cortisol AUC
(nmol/L) 1454 +/- 539 1674 +/- 466 NS
(270- 2713) (1143 -2324)
Hypoglycaemia induced
cortisol peak
(nmol/L) 776 +/- 183 809 +/- 213 NS
(638- 1322) (552 - 1297)
Hypoglycaemia induced
cortisol AUC
(nmol/L) 42101 +/- 13703 42286 +/- 12061 NS
(21547- 82303) (25191 - 74934)
----------------------------------------------------------------------------
No statistical differences in basal plasma ACTH and basal serum cortisol
value were found between CFS patients and controls. Nocturnal ACTH peak value
in CFS patients was not different from controls. Conversely, nocturnal
cortisol peak value was significantly lower in CFS patients than in controls
(P= 0.021). ACTH AUC and cortisol AUC during nocturnal sampling were identical
in the CFS group and the control group. Both ACTH peak and cortisol peak
during ITT were similar between CFS patients and controls. Also, ACTH AUC and
cortisol AUC during ITT were comparable for both groups. All CFS patients and
controls achieved a peak cortisol value >500 nmol/L during hypoglycaemia.
Serum prolactin level was significantly higher in the CFS group compared to
the control group: 7.4 +/- 4.7 ug/L vs. 4.4 +/- 1.3 ug/L (P= 0.004). In the
female CFS patients prolactin was also significantly higher than in the
female controlgroup: 7.5 +/-3.6. ug/L vs. 4.7+/-1.3 ug/L (P= 0.009). The
number of male controls was too small to permit statistical analysis. A
modest but significant increase in serum TSH level was also present in
CFS patients: 1.6 +/- 1.0 vs. 1.0 +/- 0.4 mU/L (P= 0.011). Serum free
thyroxin level was not different between CFS patients and controls:
14.9 +/- 3.0 vs. 15.9 +/- 2.9 pmol/L.
A significantly higher amount of visceral fat was found in CFS patients
compared to controls: 86.6 +/- 34.9 cm2 vs. 51.5 +/- 15.7cm2 (P< 0.001).
DISCUSSION
----------
This study confirms the impaired Girl secretory capacity previously reported
in CFS. The strength of our data lies in the large number of CFS patients
enrolled in the study and the extension of the investigation. A significantly
lower nocturnal GH secretion and a significantly lower GH response to ITT
were demonstrated when expressed as peak response and AUC and compared to a
control group. Former studies observing GH responses to hypoglycaemia were
performed in a much smaller group of patients (Bean et al., 1995; Main et
al., 1997). The significantly reduced GH secretion to ITT observed inour
study is obviously too subtle to induce differences in serum IGF-I
concentration or SDS between CFS patients and healthy controls. On the other
hand, IGF-I levels within the normal range do not exclude the diagnosis of
GHD in adults and IGF-I levels below the age-related reference range are only
indicative for GHD. The 2 CFS patients with IGF-I SDS <-2 did not show the
most marked reduction of GH response to ITT It remains unclear if the
specific symptoms accompanying CFS can be related to disturbances in
GH secretion. Indeed, only 2 of 73 CFS patients can be considered having
severe GHD when a GH response to hypoglycaemia less than 3 ug/L is accepted
as diagnostic criterion (Anonymous, 1998). Part of the complaints in CFS may,
however, be due to a diminished central effect of GH as also suggested in
adult GHD (Johansson et al., 1995). Adult GHD has also been associated with
visceral fat accumulation (Dc Boer et al., 1995), a condition that has been
demonstrated here for the first time in association with CFS. Since the
changes in GH secretion are rater subtle, it is unclear if it can be
responsible for this alteration in body composition.
The physiopathological basis for the decreased GH activity in CFS remains
elusive. Insulin induced hypoglycaemia is the longest established test for
determining GH reserve in the adult and is still recognised as the test of
choice. Efforts are made to establish a reliable substitute to ITT, as
variability in GH response even within the same individual is known. A
combined GHRH + arginine test has recently been reported to be as sensitive
as ITT in the diagnosis of adult GHD (Aimaretti et al., 1998) and GH-releasing
peptides might provide the basis for dynamic testing but further research in
this direction is needed (Korbonits & Besser, 1996). Although the mode of
action of hypoglycaemia has not been fully elucidated, a reduction of the
somatostatinergic tone and the involvement of yet unidentified pathways are
proposed (Page et al., 1987). Arginine stimulates GH secretion through
reductionin somatostatin output (Ghigo et al., 1990) and clonidine acts by
releasing GHRH (Katakami et al., 1984). Impairment in GH response in CFS can
only be appreciated during ITT, as no significant differences between
patients and controls are found during arginine and clonidine stimulation.
A difference in stimulatory capacity between arginine and clonidine is also
absent in the 15 CFS patients who underwent the three stimulation tests.
These findings suppose that neither a decrease in GHRH neither an increase in
somatostatin does solely determine the alterations in GH secretion, but that
the interplay between these neuropeptides is possibly influenced by other
factors. The significantly decreased nocturnal GH secretion in CFS may be
related to inadequate withdrawal of somatostatin during slow wave sleep
(Thorner et al, 1990; Holl et al., 1991). Sleep disturbance is indeed often
a prominent symptom in CFS, although its contribution to the syndrome remains
not well-understood (Morriss et al., 1993).
Our study confirmed and extended largely the data regarding 9 CFS patients
all showing normal ACTH and cortisol responses to ITT (Bean et al., 1995).
Moreover, with exception of a significantly lower nocturnal cortisol peak
value in CFS, no differences were found in ACTH morning and nocturnal peak
level, cortisol morning level, and both ACTH and cortisol AUC values during
ITT between CFS patients and controls.
Although basal prolactin levels remained within normal range in our study, a
significantly higher value was found in the CFS group. This is in contrast
with reports showing comparable basal prolactin values in a rather small
number of CFS patients and controls (Bakheit et al., 1992; Cleare et al.,
1995). On the other hand, our data corroborate with the increased prolactin
responsiveness to buspirone and d-fenfluramine in CFS patients observed
before (Bakheit et al., 1992; Cleare et al., 1995; Sharpe et al., 1996;
Sharpe et al., 1997). While in healthy subjects buspirone is capable to
stimulate both prolactin and GH through 5-HT1A receptors, the exaggerated
prolactin secretion in CFS is not paralleled by a pronounced GB increase
(Yatham et al., 1995). This may indicate that the increased prolactin
response to buspirone, in conjunction with the relative hyperprolactinemia
found in our study, is mediated through a deficient dopaminergic system.
Also, the significantly lower response of prolactin to hypoglycaemia in CFS
does not support the hypothesis of an altered 5-HT function (Beam et al.,
1995). In contrast to one other report showing no differences in TSH levels
(Main et al., 1997), our study revealed slightly but significantly higher
TSH levels in CFS patients, although without effecting the secretion of
thyroxin. A decreased dopaminergic environment may also explain this finding.
It has been hypothesised that CFS falls into the spectrum of stress-related
illnesses since physical and emotional stress accentuates the symptomatology.
The hypothalamic-pituitary-adrenal axis is, together with the sympathetic
nervous system, generally considered to play a pivotal role in the
co-ordinated physiological response to stress (Chrousos & Gold, 1992). The
most convenient and only standardised model of acute neuroendocrine stress
is the response of ACTH, cortisol and GH to ITT (Fish et al., 1986). We could
not confirm the presumed incapacity of the pituitary-adrenal axis to react
to stress since none of our patients showed a decreased response to ITT.
A normal ITT does not exclude the possibility that adaptation to chronic
stress is disturbed. Repeated or chronic stressors may contribute to a shift
in the balanced interaction between the different neurotransmitter systems.
The main findings in our study fit into the theory of a reduced dopaminergic
tone in CFS (Bruno et al., 1998). The impaired GH secretion can be explained
accordingly since dopamine acts through reducingthe somatostatinergic tone
(Vance et al., 1987). Both prolactin and TSH secretion are directly inhibited
by dopamine, but are also controlled by somatostatin. However, a decreased
somatostatin tone in CFS can not account for the impaired GH secretion. Our
data provide a rationale for further study of the role played by
neurotransmitters in the symptomatology of CFS. Although interaction between
the different systems may confound definite conclusions, impairment of the
dopaminergic neurotransiwsston may underlie the endocrine disturbances of
CFS.
CHAPTER 5: GROWTH HORMONE IN THE CHRONIC FATIGUE SYNDROME
---------------------------------------------------------
5.1. SECRETION OF GH HORMONE IN 20 PATIENTS
WITH CHRONIC FATIGUE SYNDROME
--------------------------------------------
5.1.1. Introduction
-------------------
Only a limited number of studies have examined the secretion of growth
hormone (GH) in patients with CFS (Bean et al., 1995; Sharpe et al., 1996;
Buchwald et al., 1996; Allain et al., 1997; Majeed et al., 1997). Decreased
(Main et al., 1997), normal (Buchwald et al., 1996) and increased (Bennett A.
et al., 1997) serum levels of IGF-I have been reported. The peak GH response
to insulin induced hypoglycaemia was found to be reduced in two studies
(Beam et al., 1995; Main et al., 1997), but statistical significance was
reached in only one (Main et al., 1997). These findings may indicate
impairment of GH secretory function at the hypothalamic level. In patients
with CFS, the GH secretory response to buspirone (a 5-HT1 A receptor agonist)
has been found to be comparable to that of controls, whereas prolactin
secretion is increased (Sharpe et al., 1996). This may indicate that the
GH response to stimulation of the 5-HT1. A receptor is not altered in
patients with CFS, but does not exclude abnormalities in central 5-HT
function or other specific effects of the 5-HT receptor. The dexamethasone-
induced release of GH in patients with CFS is reduced compared with controls,
and administration of metyrapone does not normalize the response (Majeed et
al.,1995). This may indicate reduced sensitivity of central type 2 steroid
receptors in patients with CFS.
Impaired activity of the hypothalamic-pituitaryadrenocortical (HPA) axis in
patients with CFS and decreased serum levels of IGF-I in fibromyalgia, which
is frequently associated with CFS, are well established (Cleare et al., 1995;
Beam et al., 1995; Demitrack et al., 1991; Bennett et al., 1992). The
symptoms of CFS may therefore not only resemble those of glucocorticoid
deficiency but also those of GH deficiency (GHD) in adults (Allain et al.,
1997).
The purpose of the present study was to examine the secretion of GH in a
group of patients with CFS.
5.1.2. Patients and methods
-----------------------------
Twenty patients with CFS (7 men, 113 women; age range, 30-60 years) were
recruited from the CFS clinic at Antwerp University Hospital. All patients
fulfilled the 1994 Centre for Disease Control criteria for the diagnosis of
CFS (Fukuda et al.., 1994). A structured psychiatric evaluation did not
reveal concomitant major depression in any of the patients, although two
patients had a previous history of depression. A varying number of age- and
sexmatched controls for the different tests were recruited from the nurses
at Antwerp University Hospital. The characteristics of the patient and
control groups are given in Table 5.1. All patients provided written informed
consent, and the study was approved by the Antwerp University Hospital
Ethical Committee.
Table 5.1. Characteristics of the patients with CFS and the control group
-------------------------------------------------------------------------
Patients Controls
Nr Age Gen- Weight BMI Stage 3 Nr Age Gen- Stage 3
(yea- der (kg) (kg/m2) sleep (years) der sleep
rs) (%) (%)
-------------------------------------------------------------------------
1 38 Male 75.0 26.3 8 1 36 Male
2 34 Male 77.5 25.0 0 2 32 Male
3 31 Male 63.5 22.2 0 3 58 Female
4 47 Female 76.0 27.9 27 4 24 Male
5 40 Female 48.5 18.6 5 5 24 Male
6 30 Female 60.5 22.2 0 6 36 Female
7 36 Male 75.5 23.0 16 7 27 Female
8 33 Female 72.5 25.7 5 8 25 Female
9 33 Female 50.0 17.3 0 9 34 Female
10 34 Female 71.0 26.4 10 10 28 Female
11 32 Male 71.0 21.4 0 ------------------------
12 38 Female 62.6 21.6 5 BMI, body mass index.
13 38 Female 68.0 23.3 0
14 38 Female 68.5 27.7 6
15 37 Female 59.8 20.0 2
16 31 Female 80.0 27.3 6
17 38 Female 75.9 27.8 0
18 47 Male 77.0 23.8 0
19 49 Male 52.8 20.6 9
20 60 Female 79.5 26.6 0
-------------------------------------------------------------------------
Endocrine tests consisted of measuring the peak GH response to hypoglycaemia
(<2 mmol/1) induced by insulin (0.15 U/kg i.v.; 12 controls) and to arginine
administration (30 g i.v. over 30 minutes; 20 controls). As secretion of GH
is stimulated at night, and GHD may be more apparent during this time
(Korbonits & Besser, 1996), the nocturnal secretion of GH was measured.
Serum measurements of GH were taken every 15 minutes for 8 hours, and the
area under the curve (AUC) was calculated for the collected blood samples
(10 controls). Concentrations of GH were measured using a commercial
radioimmunoassay kit (Pharmacia & Upjohn, Stockholm, Sweden). IGF-I SDS
values were calculated for each patient, based on age-related reference
values (22 controls). Student's t-test and the Mann-Whitney test were used
for statistical analysis.
5.1.3. Results
----------------
IGF-I SDS values (mean +/- SD) were significantly lower in patients with CFS
compared with controls (-0.39 +/- 1.07 vs 0.33 +/- 0.84; P= 0.02). The mean
AUC values for nocturnal secretion of GH in patients with CFS were
approximately half of those in controls (32.4 +/- 18.3 vs 62.7 +/- 43.7
ug/L/ 15 minutes), although the difference was not statistically significant
(P= 0.06). Patients with CFS did not differ significantly from the controls
in their peak GH response to insulin-induced hypoglycaemia (17.1 +/- 9.6
vs 19.9 +/- 7.6 ug/L) or to arginine administration (8.8 +/- 7.6 vs 9.8
+/- 7.4 ug/L, respectively).
5.1.4. Discussion
-------------------
The data from the present study suggest that spontaneous GH secretion is
impaired in patients with CFS. These patients had significantly lower serum
levels of IGF-I and a tendency for lower nocturnal secretion of GH, although
the latter did not reach statistical significance. On the other hand, no
differences in GH responses to insulin-induced hypoglycaemia or to arginine
administration were demonstrated between the patients and controls. Decreased
serum levels of IGF-I have been reported (Main et ak, 1997), but the present
finding of a normal GH response to hypoglycaemia is in contrast with previous
reports (Beam et al., 1995; Allain et al., 1997). The nocturnal secretion of
GH has not been investigated previously
It is generally acknowledged that patients with CFS have an impaired HPA axis.
Reduced 24-hour urinary exaction of cortisol, elevated plasma levels of
adrenocorticotrophin (ACTH) in the evening, an enhanced cortisol response to
exogenous ACTH and a blunted ACTH response to corticotrophin-releasing
hormone (CRH) are consistent with mild central adrenal insufficiency
(CRH deficiency) (Demitrack et al., 1991). In addition, after administration
of d-fenfluramine in patients with CFS, the ACTH response has been shown to
be enhanced, whereas the cortisol response was normal, possibly indicating
an accompanying mild, primary adrenal insufficiency (Beam et al., 1995).
Most studies involving neuroendoctine stimulation tests in patients with
CFS have focused on the stirnulatory effects (mainly on prolactin release)
of the 5-HT receptor. The prolactin response to buspirone has been found to
be elevated in patients with CFS, which was initially attributed to
up-regulation of postsynaptic 5- HT1A receptors (Bakheit et al., 1992).
However, as the GH response to administration of buspirone is similar in
patients with CFS and controls, the increased release of prolactin is more
likely to be caused by blockade of the D2 receptor (Sharpe et al. 1996).
The increased prolactin and ACTH responses to d-fenfluramine stimulation in
patients with CFS have been interpreted as indicating increased central
5-HT activity (Cleare et al., 1995; Beam et al., 1995). The disturbed
spontaneous secretion of GH in the pathogenesis of CFS may be explained in a
number of ways. Birstly, the increased central 5-HT activity may be a cause
of impaired GH secretory function. Not only has 5-HT been shown to be an
important mediatomin the regulation of the activity of the HPA axis
(Dinan(a), 1996), but the HPA axis also appears to influence the activity of
the GH axis (Thakore & Dinan, 1994).
Other data, however, may indicate a direct role of 5-HT in the regulation
of GH (Conway et al., 1990). Secondly, CFS may be considered a 'stress-
related illness', in which case the disturbed central 5-HT function is a
result rather than a cause of the impaired neuroendocrine stress responses
(Chrousos & Gold, 1992). A relationship between impaired activity of the
HPA axis and increased central S-HT function has been clearly demonstrated
in patients with CFS (Cleare et al., 1995) whereas the possible role of GH
as a 'stress hormone' remains elusive. Finally, by analogy with patients
suffering from fibromyalgia, in which disturbed stage 4 sleep is associated
with decreased serum levels of IGF-I (Bennett a al., 1992), sleep
abnormalities in patients with CFS, although not affecting stage 4 sleep
specifically, may impair the nocturnal secretion of GH.
The question of whether the impaired secretion of GH is primary or secondary
in the pathogenesis of CFS remains unresolved. Decreased serum levels of
IGF-I may be the source of symptoms (e.g. myalgia), whereas decreased
physical activity can result in reduced secretion of GH. Buture
investigations in patients with CFS should re-examine the nocturnal secretion
of GH using a larger control group, and should determine the GH response to
selective 5-HT receptor agonists other than buspirone. Administration of GH
to patients with CFS might also help to elucidate the possible connection
between impaired GH secretion and the syndrome.
5.2. HORMONAL RESPONSES TO GHRH AND HEXARELIN IN
THE CHRONIC FATIGUE SYNDROME AND IN FIBROMYALGIA
------------------------------------------------
5.2.1. Introduction
-------------------------
The chronic fatigue syndrome (CFS), defined byte United States Centers of
Disease Control case definition (Fukuda et al., 1994), and fibromyalgia (FM),
defined by the American College of Rheumatology Criteria (Wolfe et al., 1990),
are both debilitating disorders characrerised by substantial fatigue, diffuse
muscle pain and poor quality of sleep. Aetiology of both diseases is unknown
but disturbed neuroendocrine regulation is one of several possible pathogenic
explanations. The prominent complaint of fatigue has focused most hormonal
studies towards a more profound characterisation of the pituitary-adrenal
axis (Crofford & Demitrack, 1996) and the growth hormone (GH) - insulin-like
growth factor I (IGF-I) axis (Bennett R et al., 1997, Main et al, 1997).
Study of the pituitary-adrenal function in CFS and FM patients revealed
differences and discrepancies despite the clinical overlap between both
disorders. Free cortisol urinary excretion has been described to be normal
(Adler et al., 1999) or decreased in both CFS and FM (Demitrack et al., 1991;
Crofford & Demitrack, 1996; Scott & Dinan, 1998; Griep et al., 1998). When
compared to control subjects, evening ACTH levels were found to be elevated
and cortisol levels reduced in CFS patients (Demitrack et al., 1991), while,
in contrast FM patients showed normal basal ACTH levels and elevated evening
or trough cortisol levels (Crofford & Demitrack, 1996; Crofford, 1998).
Study of the GH-IGF-I axis in CFS and FM also showed conflicting results.
Peak GH response to insulin-induced hypoglycaemia in CFS patients has been
found reduced reaching statistical significance only once (Beam et ad., 1995;
Allain et al., 1997). Serum IGF-I levels in CFS have been reported to be
increased (Bennett A et al., 1997), normal (Buchwald et al., 1996) or
decreased (Main et al., 1997). Serum IGF-I in FM patients have been reported
to be normal (Jacobsen et ad., 1995; Buchwald et al, 1996) or decreased
(Bennett Ret al., 1992; Bennett R et al., 1997; Bennett R et al., 1998).
The functional basis of the disturbances in adrenal function and GH secretion
in some CFS and FM patients remains unknown and no unifying concept to
explain these findings has been proposed so far. To further characterise the
aberrant behaviour of GH secretion in CFS and FM patients, we observed the
responses to GH-releasing hormone (GHRH) and the GE secretagogue (GHS)
Hexarelin, in these patients and compared them to the response in healthy
controls. As the activity of GHS is not fully restricted to GH (Ghigo et
al., 1994), we also determined the ACTH, cortisol, prolactin and
TSH responses.
5.2.2. Patients and Methods
---------------------------
Patients
--------
23 CFS patients (5 men, 18 women) with a mean age of 43.7 yr. (range, 32-57
yr.) and 15 FM patients (2 men, 13 women) with a mean age of 42.1 yr. (range,
31 - 53 yr.) were enrolled in the study. The control group consisted of
6 healthy subjects (6 women) with a mean age 37.8 yr. (range, 36-40 yr).
Body mass index was 23.5 kg/m2 (range, 17.3-27.9 kg/m2) in CFS patients,
22.2 kg/m2 (range, 17.1-27.9 kg/m2 in FM patients, and 23.4 kg/m2 (range,
20.1 -25.5 kg/m2 in controls (P=NS). All subjects were free of any acute
severe illness during the last six months, liver disease, renal disease,
cardiopulmonary disease, diabetes mellitus and pituitary disease.
Study design
------------
GHRLH and Hexarelin stimulation tests were performed after an overnight fast,
the subjeas remaining recumbent throughout the study session. At time 0 min a
bolus of 1 ug/kg hexarein (Pharmacia & Upjohn, Sweden) was administered. The
same experiment was repeated after a washout period of at least 3 days with
1 ug/kg GHRH (Ferring, Germany). Blood samples for measurement of plasma
ACTH, serum cortisol, GE, prolactin, and TSH were drawn every 15 minutes
during 2 hours.
24-hour urinary free cortisol excretion and serum concentration of fT4 and
IGF-I were also determined. In order to correct IGE-I for age, the formula
IGF4 SDS=
log IGF-I - (5.95 - [0.0197 x age in years])
--------------------------------------------
0.282
was used (Cunco et al., 1998).
All samples for hormone measurement were spun at 40 o C, separated and stored
at -20 o C until assayed. The ethics committee approved the study. Written
informed consent was obtained from the patients and controls.
Assays
------
All determinations were performed using commercial RIA and IRMA kits.
Sensitivity of GE assay (hGHRIA, Pharmacia & Upjohn NV Diagnostics, Belgium)
was 0.1 ug/L inter-assay coefficient of variation was 5.1 % at 0.6 ug/L and
2.9 % at 2.1 ug/L; intra-assay coefficient of variation was 5.6 % at 0.6
ug/L and 4.3 % at 2A ug/L
Sensitivity of IGF-I assay (SMC, Biosource Europe SA, Fleurus,Belgium) was
9 ug/L; intra-assay coefficient of variation was 6.1 % at 54 ug/L and 4.7%
at 491 ug/L; intra-assay coefficient of variation was 9.9 % at 121 ug/L and
9.3 % at 494 ug/L.
Sensitivity of ACTH assay (ACTH Immunoassay, Nichols Institute Diagnostics,
Paris, France) was 0.4 pmol/L; intra-assay coefficient of variation was 3.0%
at 15 pmol/L and 3.2% at 161 pmol/L; inter-assay coefficient of variation was
7.8% at 16 pmol/L and 6.8 % at 158 pmol/L. Normal value for plasma ACTE is
4 -22 pmol/L.
Sensitivity of cortisol assay (GammaCoat Cortisol, DiaSorin SA, Antony,
France) was 6 nmol/L intra-assay coefficient of variation was from 6.6 % at
80 nmol/L and 6.8 % at 1300 nmol/L; inter-assay coefficient of variation was
9% at 102 nmol/L and 8.8 % at 1018 nmol/L. Normal value for serum cortisol
is 190 -660 nmol/L at 08:00 and< 140 nmol/L at 24:00.
Sensitivity of prolactin assay (AutoDelfia, Wallac Oy, Turku, Finland) was
0.1 ug/L; intra-assay coefficient of variation was 1.2 % at 3.2 ug/L and
3.1 % at 110 ug/L; inter-assay coefficient of variation was 1.9 % at 3.2
ug/L and 3.1 % at 110 ug/L. Normal value for serum prolactin is<20 ug/L.
Sensitivity of the TSH assay (AutoDelfia, Wallac Oy, Turku, Finland) was
0.005 mU/L; intra-assay coefficient of variation was 11.6 % at 0.05 mU/L and
2.8 % at 17.7 mU/L; inter-assay coefficient of variation was 5.8 % at
0.05 mU/L and 2.4% at 17.8 mU/L. Normal value for serum TSH is 0.15 -3.5 mU/L.
Statistics
----------
The peak serum concentration of GH, ACTH, cortisol, prolactin, and TSH after
administration of GHRH and Hexarelin were used as summary measures for
statistical analysis. We had to rely mainly on non-parametric methods since
serious departures from the assumptions of the parametric methods were found.
Comparison of summary measures between CFS, FM and control group were
therefore assessed by the Kruskall Wallis test with the Mann Whitney test to
identify the differences (making due allowance for multiple testing) when
appropriate. For paired observations, the Friedman test and the Wilcoxon
Signed Rankwere used. Normality was tested by the Shapiro Wilk test. The
proportions among groups were compared by the Chi Squared test Fisher's Exact
test. A P-value< 0.05 (two-sided) was considered as statistically significant.
The statistic package SPSS was used.
5.2.3. Results
--------------------
Baseline hormonal parameters
----------------------------
No statistical difference was found in serum IGF-I level between CFS
(158.3 +/- 57.7 ug/L), FM (153.4 +/- 44.3 ug/L) and controls
(150.0 +/- 34.6 ug/L). Also, no difference was found in IGF-I SDS between CFS
(-0.30 +/- 1.11), FM (-0.47 +/- 1.56) and controls (-0.77 +/- 0.87).
Two CFS patients showed an IGF-I SDS< -2, while none of the FM patients or
controls did. Two other CFS patients showed a GH response less than
3 ug/L during ITT.
No statistical differences between CFS, FM and controls were found in
baseline ACTE, cortisol, GE, prolactin and TSH before administration of
GHRH and Hexarelin.
24-hour urinary excretion of free cortisol showed no statistical difference
between CFS (155.7 +/- 87.0 nmol/d), FM (181.9 +/- 110.0 nmol/d) and
controls (162.3 +/- 14.7 nmol/d). No CFS or FM patient or control had a
urinary cortisol excretion outside the normal range. No CFS or FM patient or
control showed a cortisol response less than 180 ug/L during ITT.
There was no difference in serum free T4 between CFS (14.8 +/- 2.5 pmol/l),
FM (14.7 +/- 1.9 pmol/l) and controls (15.9 +/- 2.0 pmol/l).
GH response to GHRH, and Hexarelin
----------------------------------
Differences in GH peak responses were observed depending on the type of
stimulation test used. In controls GHRH and Hexarelin induced no significant
increase in baseline serum GH. GHRH (P< 0.0O1)and Hexarelin (P< 0.001)
induced in CFS patients a significant increase above baseline values. After
GHRH (P=0.001)and Hexarelin (P= 0.001) a significant stimulation was also
observed in FM patients.
Differences in GH peak responses were observed related to the group of
patients considered. In controls and CFS the difference between GHRH and
Hexarelin was not significant (P=NS). In FM patients, however, a significant
higher GH response to Hexarelin compared to GHRH was observed (P= 0.012).
ACTS response to GHRH and Hexarelin
-----------------------------------
GHRH or Hexarein administration in controls did not generate a significant
increase in baseline plasma ACTH levels. GHRH (P< 0.001)and Hexarelin
(P< 0.001) induced in CFS patients a significant ACTH increase above baseline
values. After GHRH (P= 0.012) and Hexarelin (P= 0.003) administration a
significanr ACTH stimulation was also observed in FM patients, However, both
GHRH and Hexarelin could not produce significant differences in ACTH peak
responses between controls, CFS and FM patients.
In controls, no differences in ACTH peak level were found during GHRH or
Hexarelin administration. In CFS patients, however, a significant higher
response in ACTH peak level (P= 0.031) was found after Hexarelin than after
GHRH. FM patients showed no differences in ACTH peak level after GHRH or
Hexarelin.
Cortisol response to GHRH and Hexarelin
---------------------------------------
GHRH or Hexarelin administration in controls did not cause a significant
increase in baseline serum cortisol levels. GHRH (P=0.018)and Hexarelin
(P= 0.002) induced in CFS patients a significant cortisol increase above
baseline values. After GHRH or Hexarelin administration a significant
stimulation was, however, not found in FM patients. Nevertheless, Hexarelin
administration induced a comparatively similar cortisol peak response in
controls, CFS and FM patients. In contrast, GHRH administration induced a
cortisol peak response which was significantly higher in FM patients than in
controls (P=0.002), while in CFS patients the response was not different
from controls.
In controls, cortisol peak level was similar after GHRH and Hexarelin. In
CFS patients, however, peak cortisol level (P=0.046) was higher after
Hexarelin than after GHRH. FM patients showed no differences in cortisol peak
level after CHRH or Hexarelin.
Prolactin response to GHRH and hexarelin
----------------------------------------
GHRH or Hexarelin administration in controls did not cause a significant
increase in baseline serum prolactin levels. GHRH (P< 0.001) and Hexarelin
(P< 0.001) induced in CFS patients a significant prolactin increase above
baseline values. After GHRH (P= 0.002) and Hexarelin (P= 0.001)
administration a significant prolactin stimulation was also observed in
FM patients. However, GHRH and Hexarelin induced a comparable prolactin peak
response in controls, CFS and FM patients.
In controls, prolactin peak levels were significantly higher after Hexarelin
than after GHRH (P=0.046). Also in CFS patients (P< 0.001) and in FM patients
(P= 0.048), prolactin peak levels were significantly higher after Hexarelin
than after GHRH.
TSH response to GHRH and Hexarelin
----------------------------------
GHRH or Hexarelin administration in controls did not generate a significant
increase in baseline serum TSR levels. GHRH (P=0.001) and Elexarelin
(P= 0.001) induced in CFS patients a significant increase above baseline
values. After GHRH (P= 0.005)and Hexarelin (P=0.012) administration a
significant TSH stimulation was also observed in FM patients. However,
GHRH and Hexarelin induced a comparable TSH peak response in controls,
CFS and FM patients.
In controls, TSR peak levels were significantly higher after Hexarelin than
after GHRH (P= 0.046). In CFS patients and FM patients, TSH peak levels were
similar after Hexarelin and GHRH.
5.2.4. Discussion
------------------------
Despite the magnitude of clinical and public health concerns associated with
FM and CFS, little is known about the underlying pathophysiology.
In this study the effects of GHRH and Hexarelin on GH, ACTH, cortisol,
prolactin and TSH in CFS and FM patients were observed and revealed unexpected
findings. GHRH and Hexarelin induced a similar GH hormone peak in
CFS patients. The more potent GH-releasing effect of Hexarelin compared to
GHRH as reported in other studies (Chigo et al., 1994; Arvar et al., 1995;
Maccario etal., 1995; Arvat et al., 1997; Giusti etal., 1997; Maglinie et
al., 1998) could not be confirmed in our CFS patients or in our controls,
Indeed, only in FM patients Hexarelin acted as a stronger GH-releasing
peptide than GHRH. Growth hormone secretagogues have no structural homology
with GHRH and act via a specific receptor, which has now been cloned and is
present at both the pituitary and hypothalamic level (Sethumadan et al.,
1991; Ghigo et al., 1994; Friboes et al., 1995; Cappa et al., 1995; Howard
et al., 1996; Ghigo et al., 1998), differences in receptor behaviour could
explain the different responses in FM versus CFS patients and controls.
We could not confirm previous reported findings of increased ACTE levels
(Arvat et al., 1997)and increased cortisol levels (Loche et al., 1995;
Giusti et al., 1997; Imbimbo et al., 1994; Massoud et al., 1996) after
Hexardin administration in our female controls. Hexarein showed a higher
ACTH and cortisol response than GHRH in CFS patients. The stimulatory effect
on cortisol seems to be due to the ACTH-releasing activity of GHRPs which in
turn, seems to be dependent on central mechanisms (Ghigo et al., 1997);
blunting of cortisol by GHRH has been described earlier in normal controls
(Friboes et al., 1995) and could explain the different behaviour to GHRH and
Hexarelin but the higher ACTH and cortisol response to Hexarein compared to
GHRH was not seen in FM patients and controls.
Hexarelin showed a significant higher prolactin stimulating effect than GHRH
in CFS and FM patients. The stimulatory effect on PRL seems to include a
direct effect on somatomammotroph cells.
TSH response to GHRH and Hexarelin was similar in CFS patients,
FM patients and controls.
TSH lowering effect, previously reported after administration of
growth-hormone releasing peptide-1 (Laron et al., 1993), was not seen after
Hexarelin administration.
We did not observe differences in IGF-l and urinary free cortisol between
CFS patients, FM patients and controls as reported earlier (Demitrack et
al., 1991; Bennett et al., 1992; Crofford & Demitrack, 1996; Allain et al.,
1997; Bennett R et al., 1997; Scott & Dinan, 1998; Bennett R et al., 1998)
The GH-releasing effect of Hexarelin compared to CHRH was stronger only in
FM patients, suggesting different etiological mechanisms in CFS and FM. We
are aware that the small control group may give less power to detect
differences and that our study has only addressed the effects of Hexarelin
in the acute setting. Human studies (Ghigo et al., 1994) showed Hexarelin to
be active on GH secretion when given IV, SC and P0 route. It was even more
effective and longer lasting than GHRH in healthy volunteers.
Evaluation of therapeutic use of oral GHS in CFS and FM patients could be
useful and may be leading to better understanding the working mechanisms
in this syndromes.
5.3. EFFECT OF GROWTH HORMONE TREATMENT IN
PATIENTS WITH CHRONIC FATIGUE SYNDROME
---------------------------------------------------
3.3.1. Growth hormone treatment In humans
-----------------------------------------
Until recently, GH was only used to treat short statured children with
established GH Deficiency(GHD) and GH replacement therapy was discontinued
when final height was reached. The metabolic effects of GH are now
acknowledged as important, and their significance does not end when final
height is attained.
Symptoms related to GHD
-----------------------
Impaired psychological well-being and quality of life with, poor general
health, impaired self-control, lack of positive well-being, depressed mood,
increased anxiew reduced vitality, reduced energy and impaired emotional
reaction are symptoms that might be related to GHD.
Signs related to GHD
--------------------
GB deficiency in adults causes altered body composition: reduced lean body
mass, reduced extracellular fluid volume, reduced bone mineral density,
reduced muscle bulk, reduced muscle strength, increased body fat and
increased waist: hip ratio. The metabolic consequences of GHD are decreased
plasma HDL- cholesterol, increased plasma LDL-cholesterol, reduced glomerular
filtration rat; reduced renal plasma flow and reduced basal metabolic rate
(De Boer et al., 1995).
Recombinant human growth hormone
--------------------------------
In the following study in CFS patients, recombinant human Growth Hormone
(Genotropin) was provided by Pharmacia & Upjohn.
The active ingredient in Genotropin is somatotropin, which consists of a
191 -amino-acid sequence identical to that found in human growth hormone of
pituitary origin. Genotropin is produced by recombinant DNA technology.
Genotropin is injected subcutanously with a Genotropin Pen. Initially,
patients should be evaluated at one month intervals by means of clinical
observation and measurement of serum insulin-like growth factor I. The dose
of growth hormone should be adjusted as needed to maintain the target value
for serum Insulin-like Growth Factor I.
Effects of GH replacement
-------------------------
Replacement therapy using recombinant human GH hormone in adults with GHD
aims to restore or normalize physiological function. The most important
restoration parameters are : reduction of cardiovascular risk factors,
normalization of body composition, including BMD, improvement in exercise
capacity and improvement in psychological well-being.
5.3.2. Effect of Growth Hormone Treatment in patients
with Chronic Fatigue Syndrome a preliminary study
--------------------------------------------------------------
In the present study, the therapeutic efficacy of GH therapy was evaluated in
patients with CFS, who had nocturnal GH peak levels below 10 ug/L during
stage-controlled sleep.
MATERIALS AND METHODS
---------------------
Patients
--------
In total, 20 patients (7 men, 13 women; age range, 30-60 years) with CFS,
diagnosed according to the 1994 criteria of the Centre for Disease Control,
were recruited from the CFS clinic at the Antwerp University Hospital. All
of these patients had nocturnal peak levels of GH below 10 ug/L (measured in
serum, every 15 minutes, by a commercially available radioimmunoassay [RIA]
kit; Pharmacia & Upjohn, Stockholm, Sweden).
Patients were excluded from the study for the following reasons: pituitary
disease; a maximum GH response of less than 3 ug/L (measured by MA; Pharmacia
& Upjohn); pregnancy; acute severe illness in the last 6 months; liver, renal
or cardiopulmonary disease; diabetes mellitus; hypertension; malignant
neoplasm; a body mass index (BMI) greater than 28 kg/m2 previous GB therapy;
a life expectancy of less than 5 years; hypersensitivity to methyl-cresol;
suspected poor compliance; and chronic medication. Insulin-like growth factor
I (IGF-I) was measured using an RIA (SM-C-MA-CT kit; SMC Biosource Europe),
and the values converted to SDS using the following formula (Burman et al.,
1995; Hew et al., 1996):
log IGF-I - (5.95 - [0.0197 x age in years]).
--------------------------------------------
0.282
Serum lipoprotein(a) (Lp(a)) was measured using an N Latex Lp(a) Reagent
Bebring and Behring BMA nephelometer. Amino adds were determined by automated
v-phtaldehyde derivatization and microdialysis prior to high-performance
liquid chromatography (Cooper et al., 1988). Written informed consent was
obtained from each patient, and the study was approved by the Antwerp
University Hospital Ethical Committee.
Study design
------------
Patients were randomized to receive placebo (n= 10) or GH therapy (n= 10),
6.7 ug/kg/day (0.02 IU/kg/day) (Genotropin®, Pharmacia & Upjohn, Stockholm,
Sweden), for 12 weeks. Following this double-blind treatment period, the
17 patients remaining in the study were given GH therapy at the above dose
for an open period of 9 months. The three patients who withdrew from the
study did so because of lack of motivation (one patient), anxiety (one
patient) and nervousness (one patient). Compliance with the treatment was
excellent in all remaining patients.
Clinical, hormonal and biochemical parameters were assessed at nine clinic
visits during the study period. Body composition was measured using
bioimpedance analysis.
Quality of life was assessed using the Nottingham Health Profile (NHP) and a
specifically designed questionnaire for quality-of-life assessment
GH-deficient adults (QoL-AGHDA).
The paired t-test or Wilcoxon's signed rank test were used when comparing
data from two time points, and repeated-measurement analysis of variance or
Friedman's testwere used when comparing more than two time points. The
results given below are for the 17 patients who completed the 12-month study
period.
RESULTS
-------
No significant changes were seen in weight, muscle strength or skinfold
thickness after 12 months of GH treatment, compared with baseline.
Mean (+/- SD) serum levels of IGF-I increased during 12 months of
GH treatment, from 173 +/- 46 ug/L to 296 +/- 89 ug/L (P <0.001); IGF-I SDS
values also increased, from - 0.45 +/- 1.14 to + 1.43 +/- 1.09 (P< 0.001).
Serum levels of thyrotrophin, free tri-iodothyronine, free thyroxine,
prolactin, cortisol, follicle-stimulating hormone, luteinizing hormone,
testosterone and sexhormone-binding globulin were not significantly different
from baseline after 12 months of treatment Serum Lp(a) levels increased from
26.3 +/- 28.7 ug/dl at baseline to 37.0 +/- 51.9 mg/dl after 12 months of
treatment (P=0.003). The levels of six amino acids (tyrosine, valine,
tryptophane, phenylalanine, isoleucine and leucine) increased significandy
during GH treatment (P< 0.005)
Bioimpedance analysis showed significant increases in fat-free mass (from
49.3 +/- 8.7 kg to 51 +/- 9.7 kg P= 0.006) and total body water (from
35.4 +/- 6.2 litres to 37.0 +/- 7.0 litres; P = 0.003) following 12 months
of treatment, but no significant changes in fat mass (basal, 20.0 +/- 6.3 kg
12 months, 19.2 +/- 7.2 kg) or BMI (basal 23.9 +/- 3.3 kg/m2 12 months,
24.4 +/- 3.5 kg/m2 were observed.
No significant changes were seen in quality-of-life parameters (NHP and
QoL-AGDHA) after GH treatment. However, four patients resumed work after a
prolonged period of sick leave.
During the placebo-controlled period (12 weeks), there were no significant
differences, compared with baseline, in fat mass, fat-free mass, total body
water, BMI or weight.
DISCUSSION
----------
To our knowledge, this study is the first to use GH therapy in patients with
CFS. The administration of GH induced important changes in body composition
in these patients. The significant increases in fat-free mass, total body
water and serum levels of Lp(a) support previous observations in adults with
hypopituitarism or GHD (Weaver etal., 1995; Whitehead etal., 1992;Eden et
al, 1993; Bengtsson B-Act al., 1993). The reason for the increase in levels
of certain amino acids during GH therapy remains unclear.
Although all 17 patients with CFS reported feeling better during GB therapy,
and four patients resumed their professional activities after a long period
of disability no significant improvements were recorded using the NHP and
QoL-AGDHA questionnaires. It is possible, therefore, that these instruments
may not be sensitive enough to evaluate the quality of life of patients with
CFS.
Many questions concerning GH therapy in CFS remain unresolved. Further
studies are neCFSsary to confirm these findings and to investigate the
changes in body composition and metabolism of amino acids in patients with
CFS.
CHAPTER 6: CONCLUSIONS
----------------------
6.1. ANSWERS TO THE AIMS OF THE THESIS
--------------------------------------
The purpose of our first study was to assess the incidence of Mg eficit using
Ryzen's intravenous Mg loading procedure and to identify potential
nutritional, biochemical and clinical correlates to Mg deficit in the study
cohort, as well as to examine the potential for oral Mg supplementation to
benefit those patients in which Mg deficit had been uncovered. A prospective
observational and interventional study in patients with complaints of fatigue
of at least one month duration was performed (we used the term chronic
fatigue as explained in chapter 3). CFS, FM and ctyptotetany were identified
in the study cohort using established criteria.
In the small heterogenous group of patients with prolonged fatigue, chronic
fatigue, chronic fatigue syndrome, fibromyalgia or a positive cryptotetany
test included, over a time period of two years, no higher incidence of
Mg deficit than in controls was observed. Concentrations of Mg in plasma,
RBC or urine did not reflect status of Mg body stores as measured by an
intravenous retention test. Replenishment of Mg stores by slow supplementation
did not affect these concentrations. Dietaryintakes of Mg and other nutrients
were acceptable in our study patients and were not related to status of
Mg stores or concentrations. Oral Mg supplementation improved the level of
Mg body stores in only slightly more than 50 % of patients with Mg deficit.
Patients with cryptotetany presented with slightly lower plasma Mg levels.
CFS was associated with FM in our study cohort.
Tn patients with chronic fatigue syndrome and in fibromyalgia patients,
sleep complaints and related daytime symptoms are frequently found.
Our second study deals with the characteristics of recorded sleep parameters
in CFS patients, FM patients and patients who fulfill diagnostic criteria for
both CFS and FM. Sleep Period Time and Total Sleep Time were similar in the
tree patient groups. Sleep efficiency was reduced, nighttime arousals were
frequent; a long sleep onset latency and a long REM sleep latency were
observed in all patients. A significant higher REM density was observed in
FM patients compared to CFS patients (p<O.O5).
Alpha intrusion was most prominent in the CFS+FM group, followed by the
CFS group. FM patients showed less alpha activity than the 2 other patient
groups and this finding was rather unexpected.
Although significant clinical overlap, patients with chronic fatigue syndrome,
fibromyalgia or patients fulfilling diagnostic criteria of both syndromes
showed different polysomnagraphic findings.
The recent recognition of a syndrome of growth hormone deficiency in adults
(De Boer et al., 1995) has focussed our attention towards GM function in
patients with chronic fatigue syndrome. Complaints of impaired quality of
life, reduced vitality and poor general health in CFS are also distinctive
symptoms of adult GHD.
Insulin induced hypoglycaemia is the longest established test for determining
GH reserve in the adult and is still recognised as the test of choice.
In our third study, we could confirm the fact that ITT is superior to
arginine and clonidine in determining GH reserves not only in a group of
healthy controls but also in CFS patients. Nonetheless, impairment in
GH response in CFS can only be appreciated during ITT, as no significant
differences between patients and controls were found during arginine and
clonidine stimulation. A difference in stimulatory capacity between arginine
and clonidine was also absent in the 15 CFS patients who underwent the three
stimulation tests.
In the third study we also observed a significant impairment of GH response
during insulin induced hypoglycemia in 73 CFS patients and 21 controls.
Diagnosis of severe growth hormone deficiency (GB peak response to
hypoglycaemia less than 3 ug/L) was made in 2 CFS patient (2.7%) and impaired
GH secretion (GB peak response less than 10 ug/L) was diagnosed in another
22 patients (30.1%). A low nocturnal GH secretion in CFS patients was
observed. Serum IGF-I levels showed contrasting results: in a preliminary
study of 20 CFS patients, low IGE-I levels were observed, however we could
not confirm this finding in our group of 73 CFS patients. The clinical
expression of this inadequate GH secretion is not obvious, although the
alteration in body composition may be related to this relative GB deficiency.
Significantly increased prolactin and TSB levels were found when
eompgred to controls.
To further characterise the aberrant behaviour of GH secretion the responses
to GHRH and hexarelin, a growth hormone secretagogue were evaluated in
CFS patients, FM patients and controls: a different GH behaviour after
hexarelin and GHRH administration was seen. The GB-releasing effect of
hexarelin compared to GRRH was stronger in FM patients but not in
CFS patients.
The efficacy of growth hormone therapy was evaluated in patients with
chronic fatigue syndrome who had peak serum GH levels below 10 ug/L during
stage-controlled sleep. Twenty patients were randomized to receive placebo
or GE therapy. Mean serumlevels of insulin-like growth factor I and IGF-I
standard deviation scores, fat-free mass and total body water increased
significantly during GH treatment. Although quality of life, as assessed
using two different questionnaires, did not improve significantly during
GH treatment, four patients were able to resume work after a long period of
sick leave.
6.2. GENERAL CONCLUSION
-------------------------------
The overriding theme of this work is that central neuroendocrine abnormalities
are involved in the chronic fatigue syndrome. Some of the disturbances of the
hypothalamic-pituitary-adrenal axis possibly related to neurotransmitter
dysfunction in CFS were reviewed. Several hypotheses that may explain the
role of a disturbed GH axis activity in CFS were proposed.
A disturbed central 5-HT receptor activity may be the cause of
GB axis dysfunction.
CFS may be considered as a "stress-related illness," in which the disturbed
central 5-HT function is a result rather than the cause of impaired
neuroendocrine stress responses.
Sleep abnormalities in CFS may impair nocturnal GH secretion.
The impaired GH secretion, the relative hyperprolactinaemia and the increased
basal TSH level found in our study can be mediated through a deficient
dopaminergic system.
The GH axis dysfunction can comprise both cause and result of CFS, at this
time however there are more arguments for the impaired GH secretion to be a
secondary phenomenon.
The results of our studies on sleep parameters and the hormonal responses to
GHRH and hexarelin suggest different pathophysiological mechanisms in the
chronic fatigue syndrome versus fibromyalgia.
After examination of many CFS patients and looking at the results of our own
research I want to propose the following synthesis: once CFS develops,
individuals display dysfunction of various components of the stress system,
which can explain the decreased arousal and fatigue, increased pain
perception, and dysautonomia. Hypofunction of the stress system can explain
blunting of hypothalamic-pituitary and growth hormone axes and the sleep
disturbances.
6.3. PROSPECTS OF FUTURE RESEARCH
-----------------------------------------
* Further investigation concerning magnesium balance is
worth-while in a large homogeneous population of
CFS patients since we often observe hypomagnesiaemia
and increased urinary magnesium excretion in CFS patients
with ananinesis of painful muscle cramps.
* Sleep parameters should be investigated in a prospective
study concerning a large population of CFS patients and
compared to FM patients, healthy controls and patients
with depression.
* Neuroendocrine investigations are further required in
order to identify specific adaptations within the
neurotransmitter system in CFS and to determine the
clinical importance of the impaired GH homeostasis.
* Evaluation of therapeutic use of oral GHS in CFS and
FM patients could be useful and may be leading to
better understanding the working mechanisms in this
syndromes.
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SAMENVATTING
------------
Het chronisch vermoeidheidssyndroom (CFS) en de behandelng ervan vormen
momenteel een grote uitdaging voor clinici en onderzoekers. Er is nog steeds
geen consensus omtrent de verschillende definities van CFS, de meting van
vermoeidheid en de behandeing van CFS.
Deze thesis vermeldt enkele aspecten van mogelijke etiopathogenese in de
hoop meer inzicht te krijgen in het chronisch vermoeidheidssyndroom. Naast
metabole en klinische aspecten worden endocrinologische bevindingen, en in
het bijzonder het groeihormoonmetabolisme belcht.
In 1988 werden de diagncstische criteria van het chronisch vermoeidheids-
syndroom opgesteld en gepubliceerd door Holmes en medewerkers (CDC criteria
1988). Momenteel is nog geen algemene diagnostische test beschikbaar en er
is tot op heden geen pathognomonisch teken voor CFS. Het is uitermate
belangrijk onderliggend lijden uit te sluiten alvorens de diagnose van CFS
te weerhouden. De huidige definitie van CFS (Fukuda et al., CDC 1994)
bepaaltdateen patient invaliderende vermoeidheidsklachten moet vertonen
zonder duidelijke oorzaak alsook 4 van de 8 volgende symptomen: spierpijn,
gewrichtspijn, keelpijn, pijnlijke lymfeklieren, cognitieve moeilijkheden,
hoofdpijn, ziektegevoel na inspanning en slaapproblemen.
In het eerste hoofdstuk worden de verschillende definities van het chronisch
vermoeidheidssyndroom beschreven met nadruk op differentiele diagnose en
aanverwante aandoeningen. De doelstellingen van de thesis zijn beschreven in
hoofdstuk 2. De eerste doelstelling is de incidentie van magnesium deficit
te evalueren in een groep personen met klachten van chronisehe moeheid en
ook om een eventuele correlatie tussen magnesium deficit en voeding,
laboresultaten of klinisch beeld aan te tonen.
De tweede doelstelling van de thesis is, slaappatronen van CFS patienten en
Fibromyalgie (FM) patienten te observeren en te vergelijken.
Als derde doelstelling onderzoeken we welke test meest relevant is om
groeihormoonsecretie it evalueren bij patienten met CFS.
De vierde doelstelling van de thesis is om de prevalentie van groeihormoon-
deficientie in CFS patienten te onderzoeken.
De vijfde doelstelling van de thesis is het verder observeren van de
hormonale status in CFS patienten alsook het vergelijken met het overlappend
klinisch beeld van Fibromyalgie.
Tenslotte wordt als zesde doelstelling het effect van therapie met
recombinant groeihormoon in CFS patienten bekeken.
In hoofdstuk 3 wordt een metabool aspect, mn de mogelijke rol van magnesium,
in het probleem 'chronische moeheid' belicht. We tonen de resultaten van een
prospectieve observatie en interventiestudie in een groep patienten met
langdurige en chronische moeheid. De resultaten van deze studie kunnen als
volgt worden samengevat: in onze studiepopulatie bestaande uit patienten met
langdurige en chronisehe moeheid, chronisch vermoeidheidssyndroom,
fibromyalgie of spasmofilie bestudeerd over een periode van twee jaar werd
geen verhoogde incidentie van magnesium deficit waargenomen. Bij patienten
met spasmofilie bleek de magnesiumspiegel in plasma lager. Magnesium deficit
bleek niet in verband te staan met de voedingsgewoonten. Orale magnesium-
supplementen verbeterden de magnesiumwaarden in iets meer dan 50 % van de
patienten met magnesium deficit. Waarden van magnesium in plasma, rode
bloedcellen en urine toonden geen correlatie met het percentage magnesium-
retentie, berekend volgens de methode van Ryzen door middel van intraveneuze
magnesium belastingstest.
In het tweede deel van hoofdstuk 3 worden slaappatronen van en patienten die
voldoen san de diagnostische criteria van beide syndromen geobserveerd en
vergeleken. De 3 patientengroepen toonden gelijkaardige totale slaapperioden
en totale slaaptijden. De slaapefficientie was verminderd en nachtelijk
ontwaken kwam frequent voor. Een lange slaaplatentie en een lange REM-slaap
latentie werden vastgesteld in alle patienten. Een significant hogere
REM-densiteit werd gezien in de fibromyalgiepatienten vergeleken met de
patienten met chronisch vermoeidheidssyndroom (P< 0.05).
In hoofdstuk 4 wordt een overzicht gegeven van de afwijkingen ter hoogte van
de hypothalamus-hypofyse-bijnier-as en de functie van serotonine (5-HT) in
patienten met het chronisch vermoeidheidssyndroom. Er worden 3 hypotheses
geformuleerd over de rol van de gestoorde groeihormoonsecretie in het
chronisch vermoeidiheidssyndroom. Een gewijzigde centrale 5-HT receptor-
activiteit kan een oorzaak zijn van gewijzigde groeihormoonsecretie. Het
chronisch vermoeidheidssyndroom kan echter ook worden beschouwd als een
aan-stress-gecorreleerde ziekte; de gewijzigde centrale 5-HT functie dient
dan eerder te worden beschouwd als een gevolg dan als een oorzaak van
gestoorde neuro-endocriene stressrespons. Slaapsroornissen kunnen, naar
analogie met fibromyalgie, de nachtelijke groeihormoon-secretie in het
chronisch vermoeidheidssyndroom verminderen.
We onderzochten groeihormoonsecretie, ACTH- en cortisolsecretie tijdens
insuline tolerantie test in 73 patienten met chronisch vermoeidheidssyndroom.
In een subgroep van patienten werden arginine en clonidine stimulatietesten
uitgevoerd. De nachtelijke secretie van groeihormoon, ACTH en cortisol werd
eveneens nagekeken. Basale waarden van IGF-I, prolactine, TSH en FT4 werden
gemeten. Viscerale vetmassa werd bepaald door middel van CT-scan. Een
significante vermindering van groeihormoonsecretie tijdens insuline
tolerantie test (P=0.01) en een lage nachtelijke groeihormoonsecretie
(P=0.044) werden vastgesteld in CFS-patienten. Serum IGF-I waarden echter
toonden geen significant verschil met controlepatienten. De klinische
expressie van de verminderde groeihormoonsecretie blijft onduidelijk: de
viscerale vetmassa was significant hoger in CFS-patienten (P<0.O01) en deze
verandering in lichaamssamenstelling kan een gevolg zijn van
groeihormoondeficientie. De nachtelijke piekwaarden voor cortisol waren
lager in CFS-patienten dan in controles doch voor het overige werden geen
afwijkingen in cortisol of ACTH secretie gevonden. De waarden van prolactine
(P=0.004) en TSH (P=0.O11) waren duidelijk hoger in CFS-patienten dan in
controles. De bevindingen van deze studie ondersteunen de hypothese van een
verminderde dopaminerge tonus in chronisch vermoeidheidssyndroom.
Tn hoofdstuk 5 wordt het groeihormoonmetabolisme in chronisch
vermoeidheidssyndroom verder nagekeken. Groeihormoonsecretie werd
geevalueerd in 20 CFS-patientcn. De IGF-1 waarden waren in deze studie
significant lager in CFS-patienten dan in controles. De nachtelijke
groeihormoonsecretie bleek eveneens verlaagd doch er was geen statistische
significantie.
Om de vastgestelde afwijkingen in groeihormoonsecretie verder te onderzoeken
werd het hormonale antwoord op GHRH en Hexareline, een groeihormoon-
releasing-peptide, geevalueerd in patienten met CFS, fibromyalgie en
controles. Naast groeihormoon werden ook ACHT, cortisol, prolactine en TSH
bepaald. Achtendertig patienten en zes controles werden geincludeerd in de
studie. GHRH en Hexareline veroorzaakten geen duidelijke verschillen tussen
CFS, fibromyalgie en controics wat betreft groeihormoon, ACTH, prolactine
en TSH-antwoord. Het hormonale antwoord van cortisol na CHRH was significant
hoger in fibromyalgiepatienten dan in controles. Het antwoord van cortisol
na hexareline was vergelijkbaar in patienten met chronisch vermoeidheids-
syndroom, fibromyalgiepatienten en controles. In controles bleek het
hormonale antwoord na Hexareline en GHRH vergelijkbaar wat betreft
groeihormoon, ACTH en cortisol doch het hormonale antwoord van prolactine
(p=0.046) en TSH (P=0.046) was veel hoger na Hexareline dan na GHRH.
In CFS patienten was het hormonale antwoord van ACHT (P<0.031), cortisol
(P<0.046) en prolactine (P<O.001) significant hoger na Hexareline dan na
GHRH; het hormonale antwoord van groeihormoon en TSH na Hexareline en GHRH
was gelijkaardig.
Bij de fibromya1giepatienten was het hormonale antwoord van groeihormoon
(p=0.012)en prolacrine (P<0.0O1) significant hoger na Hexareline dan na
GHRH; het hormonale antwoord van ACHT en TSH was gelijkaardig na Hexareline
en GHRH.
De studie toonde een zeer sterke groeihormoonrespons na Hexareline ten
opzichte van GHRH in fibromyalgiepatienten, een significant hoger hormonaal
antwoord van ACTH en cortisol in patienten met het chronisch vermoeidheids-
syndroom en een hogere prolactine vrijstelling in patienten met het
chronisch vermoeidheidssyndroom en fibromyalgie na Hexareline dan na GHRH.
De verschillen in hormonaal antwoord na Hexareline en GHRH tussen patienten
met het chronisch vermoeidheidssyndroom en fibromyalgie, suggereren
verschillende etiologische mechanismen in beide syndromen hoewel er klinisch
duideijk overlappende kenmerken zijn.
We onderzochten ook het effect van therapie met recombinant groeihormoon in
patienten met chronisch vermoeidheidssyndroom en lage nachtelijke
groeihormoonspiegels (<10 ug/l). Twintig patienten met chronisch
vermoeiheidssyndroom werden geincludeerd: na een dubbel blinde periode van
12 weken was er een open periode van 9 maanden. Tijdens de studie was er
een belangrijke stijging van IGF-I. De vetvrije massa en de hoeveelheid
lichaamswater stegen significant tijdens de behandeling. Hoewel de
levenskwaliteit objectief niet verbeterde (er werd gebruik gemaakt van
2 vragenlijsten) waren 4 patienten tijdens de studie in staat hun werk te
hervatten na een lange periode van afwezigheid.
In hoofdstuk 6 worden de antwoorden op de doelstellingen van de thesis
geformuleerd.
Er werd geen associatie aangetoond tussen magnesium deficit en het probleem
van chronische moeheid.
Patienten met het chronisch vermoeidheidssyndroom en fibromyalgie tonen
verschillen in slaappatroon.
Insuline tolerantie test is de meest geschikte test voor de evaluatie van
groeihormoonsecretie in patinten met het chronisch vermoeidheissyndroom.
In de studiepopulatie van 73 CFS patienten werd de diagnose van
groeihormoondeficientie gesteld in 2,7 % van de patienten, verminderde
groeihormoonsecretie werd gediagnostiseerd in 30 % van de CFS-patienten
indien 10 ug/l gebruikt wordt als drempelwaarde voor groeihormoonpiek
concentratie.
Er werden verschillen waargenomen in hormonaal antwoord na Hexareline en
GHRH tussen patienten met het chronisch vermoeidheidssyndroom en patienten
met fibromyalgie.
Therapie met recombinant groeihormoon in 20 CFS-patienten induceerde
belangrijke veranderingen in lichaamssamenstelling, IGF-I waarden verhoogden
significant en de patienten voelden zich subjectief beter.
In conclusie wens ik te stellen dat een verminderde groei hormoonsecretie
in patienten met het chronisch vermoeidheidssyndroom werd vastgesteld doch
momenteel heb ik geen argumenten om de verminderde groeihormoonsecretie als
oorzaak van het chronisch vermoeidheidssyndroom naar voor te brengen.
De verminderde groeihormoonsecretie en de verhoogde basale waarden van
prolactine en TSH kunnen passen in een verminderde doparninerge tonus in het
chronisch vermoeidheidssyndroom. Verdere studie van neurotransmitters in het
chronisch vermoeidheidssyndroom is noodzakelijk om de pathofysiologie van
dit syndroom beter te begrijpen.
----[ EOF ]---------------------------[ LICENTI.017 ]---------------------
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