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Abstract and Figures

Growth hormone is essential for normal linear growth and the attainment of an adult mature height. It also plays an important role in cartilage growth and the attainment of normal bone mass. There is only one rheumatic disorder, namely acromegaly, in which abnormalities of growth hormone production play a major etiologic role. However, there is increasing appreciation that suboptimal growth hormone secretion, leading to a state of adult growth hormone deficiency, may occur in the setting of chronic inflammatory disease, chronic corticosteroid use, and fibromyalgia. Therefore, the evaluation and effective management of growth hormone oversecretion and undersecretion is relevant to practicing rheumatologists.
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Growth Hormone in
Musculoskeletal Pain States
Robert Bennett, MD, FRCP
Oregon Health & Science University, Department of Medicine (OP09),
3181 SW Sam Jackson Park Road, Portland, OR 97201, USA.
Current Pain and Headache Reports 2005, 9:331–338
Current Science Inc. ISSN 1531–3433
Copyright © 2005 by Current Science Inc.
Growth hormone (GH) secretion is pulsatile because of a
tonic inhibition by the hypothalamic secretion of somato-
statin in conjunction with a pulsatile secretion of GH
releasing hormone (GHRH) [1•]. Serum GH levels are
usually undetectable between pulses. There are approxi-
mately 10 pulses of GH secretion per day, lasting approxi-
mately 90 minutes, and separated by approximately 128
minutes. Peak GH secretory activity occurs within an hour
after the onset of deep sleep. Exercise, physical activity,
and sepsis are associated with increased GH secretion.
In general, women have an increased daily integrated
growth hormone secretions compared with men. However,
men have an increased pulsatility compared with women.
This is thought to be an important determinant to linear
growth, as the tissue response to GH appears to be deter-
mined by the pulsatility of GH secretion rather than the
absolute amount of GH that is secreted. Peak serum GH
concentrations are 4.3 ± 0.7 ng/mL at night and 2.7 ± 0.5
ng/mL during the day. The critical actions of GHRH and
somatostatin in controlling GH and its secretion are also
influenced by several other factors. For instance, serotonin,
dopamine, enhanced α
-adrenergic tone, and gamma-
aminobutyric acid (GABA) receptor stimulation all lead to
an increase in GH secretion. Whereas GH itself, insulin-like
growth factor 1 (IGF-1), enhanced β-adrenergic tone and
IGF-1, and cortisol all inhibit GH secretion. Furthermore,
several drugs, fasting, estrogen levels, and exercise, all
modulate GH production. GH secretion is lower in elderly,
postmenopausal, and obese patients, and estrogen replace-
ment improves GH secretion.
In 1996, this classical view of GH secretion was compli-
cated by the identification and cloning of an endogenous
GH secretagogue receptor. This is structurally different
from the receptor for GHRH and its ligand, ghrelin was
discovered in 1999. Ghrelin is a 28 amino acid peptide
produced by endocrine cells within the stomach that
increases appetite and stimulates GH secretion. Ghrelin
secreting cells have also been reported in the intestine,
pancreas, hypothalamus, and testis. There is an inverse
relationship between body weight and plasma ghrelin
levels. However, its precise role in modulating the pulsatile
release of GH is not yet fully elucidated. It is increasingly
evident that ghrelin has other actions, which include
increased gastric motility and acid secretion, stimulation of
endocrine and exocrine pancreatic function, modulation
of the pituitary gonadal axis, and stimulation of slow
wave sleep. Ghrelin levels are reduced by approximately
80% after total gastrectomy and to a lesser extent by gastric
bypass surgery. So far the only rheumatic disorder that has
been studied, in regards to ghrelin, is fibromyalgia. In a
report on 19 patients with fibromyalgia and 14 healthy
controls there was no significant difference in plasma
ghrelin levels [2].
Physiology and Actions of Growth Hormone
and Insulin-like Growth Factor 1
Growth hormone has multiple actions, which serve to
promote linear growth, increase muscle mass, and reduce
fat stores. These actions are due in part to direct effects of
GH, but most are mediated through the effects of IGF-1
(Table 1). With increased availability of supplemental
GH therapy it has become increasingly apparent that
GH has subtle but important effects on the general sense
of well-being.
Growth hormone acts by binding to a specific receptor
in the liver leading to the production and secretion of IGF-1
(Fig. 1). The GH receptor is a 70 kd protein which is dimer-
Growth hormone is essential for normal linear growth
and the attainment of an adult mature height. It also plays
an important role in cartilage growth and the attainment
of normal bone mass. There is only one rheumatic dis-
order, namely acromegaly, in which abnormalities of growth
hormone production play a major etiologic role. However,
there is increasing appreciation that suboptimal growth
hormone secretion, leading to a state of adult growth
hormone deficiency, may occur in the setting of chronic
inflammatory disease, chronic corticosteroid use, and
fibromyalgia. Therefore, the evaluation and effective
management of growth hormone oversecretion and
undersecretion is relevant to practicing rheumatologists.
332 Fibromyalgia/Myofascial Pain
ized by interaction with GH. Then a complex second signal-
ing cascade that involves phosphorylation through various
protein kinases follows. Mutations of the GH receptor are
associated with partial or complete GH insensitivity and
growth failure (eg, Laron dwarfism).
Insulin-like growth factor 1 is a small protein of
molecular weight 7647 kd that is secreted into the blood
under the control of GH. Some 75% of IGF-1 is secreted
by the liver, the other 25% is synthesized into peripheral
tissues resulting in autocrine and paracrine responses. It
is 99% protein-bound to one of six IGF binding proteins
(IGFBPs). These function to transport IGF and control
access to extra-vascular spaces. IGFBP-3 has the highest
affinity for IGF-1 and is the most abundant of the
binding proteins, however, it is usually fully saturated.
The second most abundant binding protein, IGFBP-2
accounts for the greatest changes in the levels of free
IGF-1. The levels of IGF binding proteins are positively
influenced by the magnitude of GH secretion and
reduced by deficiency states of testosterone, estrogen,
and thyroxine.
The blood levels of IGF-1 vary greatly over the lifespan.
Peak values are reached in early puberty (300–500 ng/mL)
and fall rapidly to approximately 40% of the peak value by
age 20 and decline after age 20 by approximately 3 ng/mL
per year. Twin studies have indicated that approximately
40% of an individual's IGF-1 is related to undefined genetic
factors. Nutritional status significantly affects blood IGF-1
levels. For instance, a 7-day fast decreases the IGF-1 level by
approximately 50%. Disorders associated with malnutri-
tion such as renal failure, severe liver dysfunction, and
chronic inflammatory disorders such as Crohn's disease
also result in reduced IGF-1 levels. There is a strong inverse
correlation between GH secretion and obesity, especially
intra-abdominal fat deposits. However, there is often a
paradoxical effect of obesity on IGF-1 levels, as in some
obese patients the IGF-1 level is normal whereas in others it
may be elevated or depressed. This discrepancy between
GH secretion and IGF-1 levels is probably because of
increased levels of IGFB-3 in obese patients.
Oversecretion of Growth Hormone
Oversecretion of GH in children leads to gigantism and
acromegaly in adults. This is not a common condition, its
prevalence is approximately 40 per million. Acromegaly
(from the Greek akron = extremity and megale = great)
becomes clinically evident when there is an increasingly
disproportional enlargement of distal skeletal structures
such as the jaw, hands, feet, nose, and ears.
Articular disorders
The prevalence of joint problems in untreated acromegalic
patients is nearly 100%. However, with earlier recognition
and more effective treatment these figures have decreased
to less than 50%.
Before the typical clinical picture of acromegaly
emerges, some patients present to rheumatologists
with a poorly defined joint pain and morning stiffness,
which may be mistaken for an early inflammatory arthritis
(Table 2). This joint discomfort is because of a dispropor-
tionate expansion of cartilage—causing "tight joints."
Over the course of time the joint capsule enlarges with a
resulting hypermobility, which causes joint instability [3].
The thickened cartilage in acromegaly is mechanically
dysfunctional and becomes fissured and ulcerated leading
to a secondary osteoarthritis that is often enhanced by
joint laxity [4••]. Joint effusions are uncommon and when
present in the synovial fluid it is typified by a low leukocyte
count, as in osteoarthritis. In some patients synovial hyper-
trophy is prominent, but this is because of increased
amounts of fibrous tissue and fat in the synovium
rather than synoviocyte hyperplasia. The most commonly
involved joints are hands, hips, knees, and shoulders.
Axial involvement is common with symptoms of neck and
Table 1. Actions of growth hormone and insulin-
like growth factor 1
Stimulation of protein synthesi
Mobilization of stored fat
Retention of sodium, phosphate, and water
Maintains blood glucose by suppressing insulin
Inhibits proteolysis
Inhibits apoptosis
Enhances the effects of stimulating hormones such as
Stimulates differentiation and proliferation of chondrocytes
Stimulates the differentiation and proliferation of
muscle cells
Increases glomerular filtration rate
Decreases blood glucose
Stimulates wound healing
TSH—thyroid-stimulating hormone; ACTH—adrenocorticotropic
Figure 1. Pathways of growth hormone and insulin-like growth factor
1 secretion. Solid lines are stimulatory pathways and dashed lines
are inhibitory pathways. GH—growth hormone; GHRH—growth
hormone releasing hormone; IGF-1–insulin-like growth factor 1.
Growth Hormone in Musculoskeletal Pain States • Bennett 333
back pain [5]. Diffuse idiopathic skeletal hyperostosis has
been reported to occur in 20% of acromegalic patients [6].
Temporomandibular pain, usually because of maloc-
clusion, occurs in approximately one-third of patients. An
important clue in differentiating acromegalic arthritis from
classical osteoarthritis is the clinical finding of pronounced
joint crepitus and hypermobility in acromegalic patients.
Another clue, which occurs in most cases of advanced
acromegaly, is the finding of a visible enlargement of the
costochondral junctions. This is sometimes referred to as
the "acromegalic rosary."
Soft tissue overgrowth is a prominent feature of acro-
megaly and results in thickened digits, bursal enlargement,
and hypertrophy of joint capsules. Bony thickening of the
distal ungula tufts, seen in approximately 60% of patients,
can produce an appearance of pseudo clubbing. Other
common symptoms are excessive sweating, peripheral
neuropathy, impotence, headaches, and visual field defects.
Acromegaly is often complicated by other endocrine
disorders such as hypothyroidism and diabetes mellitus.
Elevated levels of GH and IGF-1 have been reported in
patients with hypermobility syndrome without any other
features of acromegaly [7]. It has also been reported that
the course of knee osteoarthritis is influenced by IGF-1
levels, in that higher levels are associated with more osteo-
phytes [8]. However, another study failed to find any sig-
nificant relationship between age-adjusted IGF-1 levels
and radiologic progression of knee osteoarthritis [9].
Carpal tunnel syndrome, which is frequently bilateral,
occurs in approximately 30% of patients with acromegaly.
This is because of hyperplasia of the flexor tendons and
synovial edema. Medical or surgical reduction of the IGF-1
level leads to a rapid resolution of median nerve compres-
sion symptoms.
Peripheral neuropathy occurs in approximately 50% of
patients with acromegaly [10]. Its cause is complex but in
some cases appears to be a result of segmental demyelina-
tion without obvious axonal degeneration [11]. Histologi-
cally an irreversible hypertrophy of Schwann cells is seen
in advanced cases. In some acromegalic patients this is
a major cause of morbidity which is not benefited by
normalization of GH levels. In some patients an associated
diabetes mellitus contributes to the neuropathy.
A distinctive "acromegalic myopathy" has been
described in a small number of patients [12]. This might
seem paradoxical in view of the anabolic actions of GH on
muscle. Muscle biopsies have shown a hypertrophy of
type 1 fibers with an atrophy of type 2 fibers. Electron
microscopy has revealed abnormal looking mitochondria,
inclusion bodies, and infiltration of glycogen granules
[13]. The molecular basis of acromegalic myopathy is
now thought to be related to an upper regulation of
a muscle wasting factor called myostatin [14]. This
molecule is a member of the transforming growth factor-
beta (TGF-beta) superfamily.
Bone metabolism is influenced directly and indirectly by
GH/IGF-1 with a resulting increased rate of bone turnover.
Depending upon the severity and duration of acromegaly,
this increased bone turnover is not always associated with
structurally sound bone formation and this can result in
widely varying problems. For example, some studies have
reported osteoporosis and increased vertebral fractures
and other studies have reported increased bone density
in acromegalic patients. Furthermore, hypogonadism is a
common accompaniment of severe acromegaly, and proba-
bly contributes to reduced bone mineral density (BMD) in
that subset of patients.
Diagnosing acromegaly
The diagnosis of acromegaly is based on the typical clinical
features in conjunction with a consistently elevated IGF-1
level [15•] (Fig. 2). The levels of GH itself are also elevated,
but this is a less reliable screening test as the measurement
of GH is subject to more variation because of pulsatile
secretion. It is important to remember that IGF-1 levels
vary significantly with age, with the highest levels being
seen in early puberty. Thus, an IGF-1 level that would be
normal in puberty could be indicative of a GH secreting
pituitary adenoma in a 70-year-old.
As in other functional tumors, there is no feedback
inhibition of GH secretion from pituitary adenomas and
this forms the basis for the confirmatory glucose load test.
In normal individuals, the serum GH concentrations fall
to 2 ng/mL or less within 2 hours after ingestion of 50 to
100 g glucose. In patients with acromegaly the post-glucose
levels of GH are greater than 2 ng/mL.
Management of acromegaly
As there are many subtle variables influencing the treatment
algorithm for acromegaly, a close working relationship
Table 2. Clinical features of growth
hormone excess
Joint involvement
Cartilage hyperplasia
Synovial proliferation
Secondary osteoarthritis
Joint hypermobility
Capsular thickening
Bursal enlargement
Muscle involvement
Muscle enlargement
Proximal weakness
Muscle cramping
Nerve involvement
Carpal tunnel syndrome
Palpable peripheral nerves
Peripheral neuropathy
Other problems
Raynaud's phenomena
Dorsal kyphosis
Neck and back pain
334 Fibromyalgia/Myofascial Pain
between an endocrinologist and an experienced neuro-
surgeon is essential. There are several therapeutic options in
managing patients with acromegaly, with the overriding
aim of reducing the serum level of IGF-1 to normal range
for the patient’s age and sex.
In general, small adenomas (< 10 mm in diameter)
can be excised through the transsphenoidal route without
significantly compromising the secretion of other pituitary
hormones. Large adenomas can seldom be removed
entirely, and the goal of surgery is to remove enough tissue
to maximize the results of nonsurgical therapy. Potential
complications of surgery include meningitis, cerebrospinal
fluid rhinorrhea, central diabetes insipidus, and other
pituitary hormone deficiencies.
There are several drugs that inhibit GH secretion
or its action that have proven to be useful in managing
symptoms of acromegaly that cannot be totally cured
by surgery. The most widely used medications are the
somatostatin analogues octreotide and lanreotide which
are given by intramuscular injection. Because they have
a long half-life (2 hours versus 2 minutes) they are more
effective than naturally occurring somatostatin. In general
somatostatin analogues are well tolerated but approxi-
mately one-third of patients have nausea, abdominal
discomfort, bloating, loose stools, and fat malabsorption.
These problems become less severe with ongoing therapy.
In some acromegalic patients a reduction of the IGF-1 level
may be achieved by the use of dopamine agonists such
as cabergoline. The advantage of these is that they can
be given orally.
Undersecretion of Growth Hormone
Undersecretion of GH gives rise to pituitary dwarfism
in children and the syndrome of adult GH deficiency
(AGHD) in adults. This latter problem is of relevance
to rheumatologists as there are several scenarios in which
they may encounter AGHD. The experience of rheuma-
tologists in this respect is very different from that
of an endocrinologist in that the cause of deficient GH
secretion is usually because of a disordered pituitary or
its adjacent structures. Thus, the common causes of AGHD
in an endocrinology practice are a pituitary tumor, surgical
resection of the tumor, or pituitary radiation (approxi-
mately 75% of cases), an adjacent tumor (eg, cranio-
pharyngioma—approximately 15% of cases), infiltrative
disorders (eg, sarcoidosis, hemochromatosis—approxi-
mately 1% of cases), and Sheehan's syndrome (approxi-
mately 0.5% of cases). In a rheumatology practice the
cause of AGHD deficiency is seldom because of pituitary
disease itself, but results from a dysregulation of the hypo-
thalamic hormones controlling the pituitary secretion of
GH or a peripheral insensitivity to GH.
The syndrome of adult growth hormone deficiency
There has been increasing realization over the past 10 years
that the secretion of GH is not only important in promoting
normal linear growth and an adult stature, but is also impor-
tant in the attainment of an optimal hormone milieu in
adults. Deficiency of GH in adults is now well accepted to
cause a distinctive syndrome known as AGHD [16••,17]. In
large part, this burgeoning awareness of AGHD has been
because of the increasing availability of GH supplementa-
tion, from the use of DNA recombination technology, and
its beneficial effects in GH deficiency in adults.
As might be predicted from the actions of GH
(Table 1), the most obvious clinical features of AGHD
are changes in body composition resulting in a decreased
muscle mass and increased total body fat (Table 3). The
fat accumulation is preferentially intraabdominal, a distri-
bution that has been associated with dyslipidemia, insulin
intolerance, hypertension, and some malignancies (breast
and colon). It has been hypothesized that the predilection
for intraabdominal fat deposition in AGHD is because of
relative hypercortisolism—as a result of increased activity
of 11-hydroxysteroid dehydrogenase (the enzyme that
converts inactive cortisone to active cortisol).
A major factor contributing to reduced life expectancy
in AGHD is the additive effect of several consequences
Figure 2. Radiograph of a hand in moderately advanced acromegaly
showing a mixture of joint space enlargement and degenerative changes.
Growth Hormone in Musculoskeletal Pain States • Bennett 335
deleterious to cardiac function [18]. These include a
reduced left ventricular ejection fraction, stroke volume
and cardiac index (a result of reduced left ventricular wall
thickness), and the atherogenic lipid profile. Therefore it is
not surprising that patients with AGHD, from whatever
cause, have a twofold increase in cardiovascular related
mortality and a threefold increase in cerebrovascular
related mortality [17].
Rheumatologists are used to hearing their patients
complain of increase fatigability. In inflammatory rheumatic
disorders there is an increasing awareness that, in part, the
fatigue results from increased levels of proinflammatory
cytokines. Nowhere is this more evident than in the dramatic
improvements in fatigue that patients experience when
placed on anti-tumor necrosis factor (anti-TNF). Other
causes of fatigue that rheumatologists often consider, are
depressive illness, anemia of chronic inflammation, decondi-
tioning, and drug side effects. To this list should be added the
syndrome of AGHD.
The cause of fatigue in AGHD probably results from an
accumulation of several factors, such as a reduced cardiac
index, a reduction in maximal oxygen uptake, reduced
muscle strength, reduced red cell blood volume, reduced
plasma volume, and an array of psychosocial difficulties.
These latter include a significantly reduced overall quality
of life, low self-esteem, poor socioeconomic achievement,
dysthymia, and reduced vitality [16••].
Diagnosis of adult growth hormone deficiency
Because GH has a very short half-life and is secreted in a
pulsatile manner, mainly at night and after vigorous exercise,
the measurement of a single GH level is a useless exercise.
The most stringent test for GH deficiency is to measure GH
levels every 10 to 20 minutes to obtain an integrated 24-hour
GH profile. As this is impractical outside the research setting,
the recommended screening test for AGHD is the measure-
ment of an IGF-1 level. The levels of IGF-1 (which have a
half-life of approximately 22 hours) are stable throughout
the day with minimal diurnal variation and thus measure-
ment of an IGF-1 level does not require the subject to be in
fasting state. A low IGF-1 level, age-adjusted, is a very specific
indicator of AGHD. However its sensitivity is poor, especially
in the setting of pituitary disease. In this situation there are
often coexistent endocrine deficiencies as part of a syndrome
of panhypopituitarism, which provides initial diagnostic
clues. The sensitivity of IGF-1 levels for diagnosing AGHD in
the setting that most rheumatologists are likely to encounter
(ie, hypothalamic dysregulation or peripheral insensitivity
to GH) has not been rigorously studied. Unfortunately,
nonpituitary AGHD is not recognized by most insurance
companies in the United States as they require "confirma-
tion" of GH deficiency with a GH stimulation test. These
tests were initially developed in the pediatric population and
basically assess the pituitary’s ability to secrete GH under
conditions of maximal stimulation. Currently the most
widely used GH stimulation test involves the oral adminis-
tration of arginine (an amino acid that inhibits hypo-
thalamic somatostatin tone) concurrently with intravenous
GH releasing hormone (GHRH) at a dose of 1 ng/kg. GH
levels are measured every 30 minutes over the next 2 hours.
A single GH level greater than or equal to 5 ng/mL is consid-
ered indicative of normal pituitary function. As the problem
in rheumatologic causes of AGHD is not at the level of the
pituitary, most patients with conditions such as rheumatoid
arthritis, chronic corticosteroids usage, and fibromyalgia will
be shown to have a normal pituitary secretion of GH in
response to this test and are thus ineligible for supplemental
GH therapy through most insurers.
Corticosteroid induced growth hormone deficiency
Rheumatologists are very familiar with the stunting of
linear growth that occurs in children on chronic cortico-
steroid therapy [19]. The reasons for this stunting are
complex and still not fully worked out. To date, two
major abnormalities have been reported: 1) a suppression
of the transcription of GH receptor messenger RNA
(mRNA) with a resultant down regulation of GH stimu-
lated synthesis of GH receptor and IGF-1 receptor, and
2) a reduced production of local IGF-1 (ie, inhibited
paracrine secretion), a key determinant of chondrocyte
proliferation and endochondral ossification. There are
several persuasive studies, regarding children on chronic
corticosteroid therapy, that have reported a normaliza-
tion of linear growth after treatment with recombinant
human GH [20]. Therefore, GH therapy should be
considered a potentially important adjunctive therapy in
children with steroid responsive rheumatic disorders that
cannot be weaned off their medication. However, supple-
mental GH should be used with caution in patients with
systemic lupus erythematosus as there are two case
reports of significant disease flares.
Table 3. Clinical features of adult growth
hormone deficiency
Clinical features of
adult GH deficiency
Improved by GH
Increased abdominal fat Yes
Reduced muscle mass and strength Yes
Reduced cardiac capacity Yes
Reduced blood volume Yes
Cold intolerance Probably
Impaired exercise capacity Yes
Thin, dry skin Yes
Reduced sweating Yes
Reduced bone mineral density Yes (delayed effect
after 1 year)
Psychosocial dysfunction Yes
Atherogenic lipid profile Probably
Increased atherosclerosis Not known
Reduced life expectancy Not known
GH—growth hormone.
336 Fibromyalgia/Myofascial Pain
Inflammation induced growth hormone deficiency
Inflammatory cytokines, in general, acutely stimulate the
secretion of GH. Paradoxically, chronic inflammation is
often associated with stunted growth. Reduced linear
growth has been well described in juvenile rheumatoid
arthritis and inflammatory bowel disease. The reasons for
this are not entirely clear, but ongoing research indicates
that chronic inflammation reduced the expression of GH
responsive genes [21]. For instance, TNF-alpha, and IL-6
down regulate the expression of mRNA for the GH receptor
on hepatocytes, thus causing a state of GH insensitivity.
Clinically GH unresponsiveness should be suspected in
patients with normal elevated GH levels who have low or
normal IGF-1 levels. Evaluation of the GH/IGF-1 axis in
patients with adult onset rheumatoid arthritis has not been
extensively studied, but two studies have reported a sub-
optimal GH response to GHRH [22] and insulin-induced
hypoglycemia in rheumatoid patients [23], whereas
another study reported a normal GH/IGF-1 axis [24].
There are no good studies to indicate a beneficial effect of
supplemental GH in inflammation induced GH deficiency.
This might be expected if the problem is mainly a GH
insensitivity state.
Bone mass and growth hormone deficiency
Growth hormone and IGF-1 are essential for linear growth
and the achievement of an adult bone mass. Bone mass
increases steadily through childhood, peaking in the mid-
20s and subsequently declines throughout life. Linear
growth results from a proliferation and differentiation of
chondrocytes at the epiphyseal growth plates through
the effects of GH directly and indirectly through IGF-1,
which directly stimulates proteoglycan synthesis [25].
The accumulation of bone mass results from the iterative
process of bone remodeling with bone resorption by
osteoclasts and new bone formation by osteoblasts. GH
and IGF-1 stimulate osteoclasts differentiation and activity
thus promoting bone resorption. They also stimulate
osteoclast proliferation and activity to promote bone
resorption. This results in an overall increase of bone
remodeling leading resultant reduction in BMD [26] which
can be improved with supplemental GH therapy [27].
There has naturally been an interest as to the potential role
of the GH/IGF-1 axis in postmenopausal osteoporosis. In
one placebo-controlled study in postmenopausal women,
GH supplementation on top of hormone replacement
therapy and calcium/vitamin D, increased bone mineral
content by 14% [28]. Considering the current cost of
supplemental GH therapy ($600–$1200 per month) and
the ready availability of effective alternatives, there is
little enthusiasm for using GH in the management of post-
menopausal osteoporosis. This situation may change as
oral GH secretogogues become available. A recent study
evaluated the individual and combined effects of MK-677
(an experimental oral GH secretogogue) and alendronate
on BMD and biochemical markers of bone formation [29].
MK-677 plus alendronate increased BMD at the femoral
neck 4.2% versus 2.5% for alendronate alone. However, a
similar additive, enhancement of BMD was not seen at the
lumbar spine or total body.
Fibromyalgia and growth hormone deficiency
A possible link between AGHD in fibromyalgia was
reported in 1992, based on the theory that fibromyalgia
patients may have impaired GH production because of the
alpha-delta sleep anomaly [30]—stages three and four of
nonREM sleep are a prime time for GH secretion [31].
Several subsequent studies have supported a disordered
GH/IGF-1 axis in fibromyalgia [32–37] and some other
studies have not [38–41]. Most of the negative studies have
been underpowered. When IGF-1 levels were measured
in a cohort of 500 fibromyalgia patients, there was a
very significant reduction compared with healthy controls
(P = 0.0000001) [42•]. A subsequent 9-month placebo-
controlled therapeutic trial in fibromyalgia patients, with
low IGF-1 levels, reported a significant clinical benefit [43].
Paiva et al. [44] has reported an impaired GH response to
the stress of exercise to volitional exhaustion, the GH
response was normalized after the patients had taken
pyridostigmine (an acetyl cholinesterase inhibitor that
reduces hypothalamic somatostatin tone by stimulation of
cholinergic pathways). McCall-Hosenfeld et al. [41] have
reported a similar impairment of GH secretion to the stress
of hypoglycemia. The latter article found a correlation of
increasing body mass index with an impaired GH response
to hypoglycemia, whether this is the cause of the impair-
ment or a result of GH deficient patients having increased
fat stores is not known. The current hypothesis is that
a subset of fibromyalgia patients (approximately 30%)
developed AGHD because of a stress induced increase in
corticotropin releasing factor, which in turn stimulates
hypothalamic somatostatin tone [45–47].
In the early stages of oversecretion of GH, before the
obvious appearance of acromegaly, symptoms of diffuse
polyarticular pain may mimic the early stages of an inflam-
matory arthritis. In a subset of patients there are myopathic
and neuropathic presentations. As the course of acromegaly
progresses, joint laxity and dysregulated chondrocyte prolif-
eration production results in osteoarthritic changes.
The syndrome of AGHD is increasingly recognized as a
cause of fatigue, dysthymia, and increased mortality as a
result of dyslipidemia. Rheumatologists will encounter this
syndrome in some patients on chronic corticosteroids with
long-standing inflammatory arthritis and fibromyalgia.
There is an increasing experience with using GH to mini-
mize growth retardation in children on corticosteroids for
management of inflammatory rheumatic disorders.
Growth Hormone in Musculoskeletal Pain States • Bennett 337
References and Recommended Reading
Papers of particular interest, published recently, have been
highlighted as:
Of importance
•• Of major importance
1.• Giustina A, Veldhuis JD: Pathophysiology of the neuroregula-
tion of growth hormone secretion in experimental animals
and the human. Endocr Rev 1998, 19:717–797.
A classic review on the regulation of GH and IGF-1.
2. Otero M, Nogueiras R, Lago F, et al.: Ghrelin plasmatic levels
in patients with fibromyalgia. Rheumatol Int 2003.
3. Dons RF, Rosselet P, Pastakia B, et al.: Arthropathy in acromegalic
patients before and after treatment: a long-term follow-up
study. Clin Endocrinol (Oxf) 1988, 28:515–524.
4.•• Lieberman SA, Bjorkengren AG, Hoffman AR: Rheumatologic
and skeletal changes in acromegaly. Endocrinol Metab Clin
North Am 1992, 21:615–631.
A very comprehensive account of the musculoskeletal findings
in acromegaly.
5. Scarpa R, De Brasi D, Pivonello R, et al.: Acromegalic axial
arthropathy: a clinical case-control study. J Clin Endocrinol
Metab 2004, 89:598–603.
6. Altomonte L, Zoli A, Mirone L, et al.: Growth hormone secretion
in diffuse idiopathic skeletal hyperostosis. Ann Ital Med Int
1992, 7:30–33.
7. Denko CW, Boja B: Growth hormone, insulin, and insulin-
like growth factor-1 in hypermobility syndrome. J Rheumatol
2001, 28:1666–1669.
8. Schouten JS, Van den Ouweland FA, Valkenburg HA, Lamberts
SW: Insulin-like growth factor-1: a prognostic factor of knee
osteoarthritis. Br J Rheumatol 1993, 32:274–280.
9. Hochberg MC, Lethbridge-Cejku M, Scott WW, Jr., et al.: Serum
levels of insulin-like growth factor in subjects with osteo-
arthritis of the knee. Data from the Baltimore Longitudinal
Study of Aging. Arthritis Rheum 1994, 37:1177–1180.
10. Jamal GA, Kerr DJ, McLellan AR, et al.: Generalized peripheral
nerve dysfunction in acromegaly: a study by conventional
and novel neurophysiological techniques. J Neurol Neurosurg
Psychiatry 1987, 50:886–894.
11. Dinn JJ, Dinn EI: Natural history of acromegalic peripheral
neuropathy. Q J Med 1985, 57:
12. Pickett JB, Layzer RB, Levin SR, et al.: Neuromuscular compli-
cations of acromegaly. Neurology 1975, 25:638–645.
13. Cheah JS, Chua SP, Ho CL: Ultrastructure of the skeletal
muscles in acromegaly—before and after hypophysectomy.
Am J Med Sci 1975, 269:183–187.
14. Lee SJ, McPherron AC: Myostatin and the control of skeletal
muscle mass. Curr Opin Genet Dev 1999, 9:604–607.
15.• Kim HJ, Kwon SH, Kim SW, et al.: Diagnostic value of serum
IGF-I and IGFBP-3 in growth hormone disorders in adults.
Horm Res 2001, 56:117–123.
A useful primer on the clinical relevance of measuring IGF-1 and its
binding proteins.
16.•• Cook DM, Ludlam WH, Cook MB: The adult growth hormone
deficiency syndrome. Adv Intern Med 2000, 45:297–315.
An excellent topical review of the clinical and biochemical features
of AGHD.
17. Rosen T, Wilhelmsen L, Bengtsson BA: Altered lipid pattern
explains increased cardiovascular mortality in hypopituitary
patients with growth hormone deficiency. Clin Endocrinol
(Oxf) 1998, 48:525–526.
18. Shahi M, Beshyah SA, Hackett D, et al.: Cardiac function and
structure in growth hormone deficiency. Br Heart J 1991,
19. Zak M, Muller J, Karup PF: Final height, armspan, subischial
leg length and body proportions in juvenile chronic arthritis.
A long-term follow-up study. Horm Res 1999, 52:80–85.
20. Mauras N: Growth hormone therapy in the glucocortico-
steroid-dependent child: metabolic and linear growth effects.
Horm Res 2001, 56(Suppl 1):13–18.
21. Bergad PL, Schwarzenberg SJ, Humbert JT, et al.: Inhibition of
growth hormone action in models of inflammation. Am J
Physiol Cell Physiol 2000, 279:C1906–C1917.
22. Templ E, Koeller M, Riedl M, et al.: Anterior pituitary function
in patients with newly diagnosed rheumatoid arthritis. Br J
Rheumatol 1996,
23. Demir H, Kelestimur F, Tunc M, et al.: Hypothalamo-pituitary-
adrenal axis and growth hormone axis in patients with
rheumatoid arthritis. Scand J Rheumatol 1999, 28:41–46.
24. Rall LC, Walsmith JM, Snydman L, et al.: Cachexia in rheuma-
toid arthritis is not explained by decreased growth hormone
secretion. Arthritis Rheum 2002, 46:2574–2577.
25. Schalkwijk J, Joosten LA, van den Berg WB, et al.: Insulin-like
growth factor stimulation of chondrocyte proteoglycan
synthesis by human synovial fluid. Arthritis Rheum 1989,
26. Geusens PP, Boonen S: Osteoporosis and the growth
hormone-insulin-like growth factor axis. Horm Res 2002,
58(Suppl 3):49–55.
27. Nilsson AG: Effects of growth hormone replacement therapy on
bone markers and bone mineral density in growth hormone-
deficient adults. Horm Res 2000, 54(Suppl 1):52–57.
28. Landin-Wilhelmsen K, Nilsson A, Bosaeus I, Bengtsson BA:
Growth hormone increases bone mineral content in post-
menopausal osteoporosis: a randomized placebo-controlled
trial. J Bone Miner Res 2003, 18:393–405.
29. Murphy MG, Weiss S, McClung M, et al.: Effect of alendronate
and MK-677 (a growth hormone secretagogue), individually
and in combination, on markers of bone turnover and bone
mineral density in postmenopausal osteoporotic women.
J Clin Endocrinol Metab 2001, 86:1116–1125.
30. Bennett RM, Clark SR, Campbell SM, Burckhardt CS: Low levels
of somatomedin C in patients with the fibromyalgia syndrome.
A possible link between sleep and muscle pain. Arthritis Rheum
1992, 35:111 3 111 6 .
31. Davis KD, Hutchison WD, Lozano AM, et al.: Human anterior
cingulate cortex neurons modulated by attention-demanding
tasks. J Neurophysiol 2000, 83:3575–3577.
32. Ferraccioli G, Guerra P, Rizzi V, et al.: Somatomedin C (insulin-
like growth factor 1) levels decrease during acute changes
of stress related hormones. Relevance for fibromyalgia.
J Rheumatol 1994, 21: 1332–1334.
33. Riedel W, Layka H, Neeck G: Secretory pattern of GH, TSH,
thyroid hormones, ACTH, cortisol, FSH, and LH in patients
with fibromyalgia syndrome following systemic injection of
the relevant hypothalamic-releasing hormones. Z Rheumatol
1998, 57(Suppl 2):81–87.
34. Landis CA, Lentz MJ, Rothermel J, et al.: Decreased nocturnal
levels of prolactin and growth hormone in women with
fibromyalgia. J Clin Endocrinol Metab 2001, 86:1672–1678.
35. Leal-Cerro A, Povedano J, Astorga R, et al.: The growth hor-
mone (GH)-releasing hormone-GH-insulin-like growth
factor-1 axis in patients with fibromyalgia syndrome. J Clin
Endocrinol Metab 1999, 84:3378–3381.
36. Griep EN, Boersma JW, de Kloet ER: Altered reactivity of the
hypothalamic-pituitary-adrenal axis in the primary fibro-
myalgia syndrome. J Rheumatol 1993, 20:469–474.
37. Griep EN, Boersma JW, de Kloet ER: Pituitary release of growth
hormone and prolactin in the primary fibromyalgia syndrome.
J Rheumatol 1994, 21:2125–2130.
38. Buchwald D, Umali J, Stene M: Insulin-like growth factor-I
(somatomedin C) levels in chronic fatigue syndrome and
fibromyalgia. J Rheumatol 1996, 23:739–742.
39. Dessein PH, Shipton EA, Joffe BI, et al.: Hyposecretion of adrenal
androgens and the relation of serum adrenal steroids, sero-
tonin and insulin-like growth factor-1 to clinical features in
women with fibromyalgia. Pain 1999, 83:31 3 –319.
40. Jacobsen S, Main K, Danneskiold-Samsoe B, Skakkebaek NE:
A controlled study on serum insulin-like growth factor-I
and urinary excretion of growth hormone in fibromyalgia.
J Rheumatol 1995, 22:1138–1140.
338 Fibromyalgia/Myofascial Pain
41. McCall-Hosenfeld JS, Goldenberg DL, Hurwitz S, Adler GK:
Growth hormone and insulin-like growth factor-1 concen-
trations in women with fibromyalgia. J Rheumatol 2003,
42.• Bennett RM, Cook DM, Clark SR, et al.: Hypothalamic-pituitary-
insulin-like growth factor-I axis dysfunction in patients with
fibromyalgia. J Rheumatol 1997, 24:1384–1389.
A study of 500 fibromyalgia patients and controls.
43. Bennett RM, Clark SR, Walczyk J: A randomized, double-blind,
placebo-controlled study of growth hormone in the treat-
ment of fibromyalgia. Am J Med 1998, 104:227–231.
44. Paiva ES, Deodhar A, Jones KD, Bennett R: Impaired growth
hormone secretion in fibromyalgia patients: evidence for
augmented hypothalamic somatostatin tone. Arthritis Rheum
2002, 46:1344–1350.
45. Bennett RM: Adult growth hormone deficiency in patients
with fibromyalgia. Curr Rheumatol Rep 2002, 4:306–312.
46. Neeck G, Riedel W: Hormonal pertubations in fibromyalgia
syndrome. Ann N Y Acad Sci 1999, 876:325–338; discussion
47. Katakami H, Arimura A, Frohman LA: Involvement of hypo-
thalamic somatostatin in the suppression of growth hormone
secretion by central corticotropin-releasing factor in conscious
male rats. Neuroendocrinology 1985, 41:390–393.
... Most of these actions are stimulated by insulin-like growth factor-1 (IGF-1) rather than GH itself. GH also promotes the secretion of IGF-1 from the liver by binding to the specific receptor [8]. IGFs are bound to circulating binding proteins (IGFBPs) and act on growing bones [9]. ...
... IGFs are bound to circulating binding proteins (IGFBPs) and act on growing bones [9]. Hypersecretion of GH causes gigantism in children and acromegaly in adults, while hyposecretion of GH causes pituitary dwarfism in children and adult GH deficiency (AGHD) in adults [8]. GH and IGF-1 levels are associated with musculotendinous collagen expression [10]. ...
... Hypersecretion of GH results in connective tissue hyperplasia [7]. Thus, hypersecretion of these hormones may affect every part of the musculoskeletal system; it may cause neck and back pain and can mimic rheumatological disorders with joint involvement and morning stiffness [8,11]. This condition is caused by the disproportional enlargement of joint cartilage and increased deposition of fibrous tissue and fat in the synovium [8,12]. ...
Background Growth hormone deficiency is a well-known clinical entity that is usually treated with somatotropin (growth hormone). Growth hormone has some frequent side effects such as intracranial hypertension, lymphedema and diabetes mellitus. Case presentation We report the case of a 14-year-old girl with a history of wrist pain and clumsiness. Magnetic resonance imaging revealed de Quervain tenosynovitis. The patient had a history of using growth hormones for 12 months. We conservatively managed the patient with corticosteroid injections and oral nonsteroidal anti-inflammatory drugs and followed the course. However, the conservative treatment methods failed, and we recommended surgery, which was rejected. She was given nonsteroidal anti-inflammatory drugs and was followed up for 2 years, at the end of which her visual analog scale had decreased from 80 to 50. Conclusions To the best of our knowledge this is the first case of de Quervain tenosynovitis related to somatotropin treatment. Physicians should consider the possibility of musculoskeletal side effects after somatotropin treatment.
... Both growth and post-injury tissue repair are influenced by the GH signaling cascade (Lanning and Carter-Su, 2007;Rosenfeld and Hwa, 2009). In addition, there have been a few recent reports that patients with growth hormone deficiency (GHD) often have a resting pain in their limbs (Cimaz et al., 2001;Bennett, 2004). ...
... Reports show that GHD can be associated with pain (Bennett, 2004;Cuatrecasas et al., 2010;Cimaz et al., 2001). We found that developing GHRHr −/− mice display mechanical and heat hypersensitivity in an age-related fashion ( Fig. 1-3). ...
... Male GHRHr−/ − did eventually display mechanical hypersensitivity by P14. Although to our knowledge, no sex specific effects of GHD are well-documented regarding pain, reports do indicate that GH may be a strong modulator of sensory function during early stages of life (Liu et al., 2017;Bennett 2004;Cimaz et al. 2001;Devesa et al., 2017). Results of our current report support this notion as by P21, GHRHr−/− mice did not display any evoked hypersensitivity like P7 and P14 animals (Figs. ...
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Injury during early postnatal life causes acute alterations in afferent function and DRG gene expression, which in addition to producing short-term sensitivity has the potential to influence nociceptive responses in adulthood. We recently discovered that growth hormone (GH) is a key regulator of afferent sensitization and pain-related behaviors during developmental inflammation of the skin. Peripheral injury caused a significant reduction in cutaneous GH levels, which corresponded with the observed hypersensitivity. However, it has yet to be determined whether GH deficiency (GHD) is sufficient to drive peripheral sensitization in uninjured animals. Here, we found that systemic GHD, induced by knockout of the GH release hormone receptor (GHRHr), was able to induce behavioral and afferent hypersensitivity to peripheral stimuli specifically during early developmental stages. GHD also produced an upregulation of many receptors and channels linked to nociceptive processing in the DRGs at these early postnatal ages (P7 and P14). Surprisingly, P21 GHRHr knockouts also displayed significant alterations in DRG gene expression even though behavioral and afferent hypersensitivity resolved. These data support previous findings that GH is a key modulator of neonatal hypersensitivity. Results may provide insight into whether GH treatment may be a therapeutic strategy for pediatric pain.
... Ghrelin, the endogenous ligand for the GH secretagogue receptor, has been reported to have antinociceptive effects. Disturbance of the GH/IGF-1/ghrenlin paracrine axis has been linked to painful conditions such as fibromyalgia and inflammatory and rheumatic diseases [3][4][5][6][7][8]. Treatment with GH for fibromyalgia and chronic lower V C 2019 American Academy of Pain Medicine. ...
... GH/IGF-1 axis abnormalities have been associated with several rheumatic diseases [4]. A review of the literature suggested that serum GH levels are elevated in patients with osteoarthritis (OA), rheumatoid arthritis (RA), and diffuse idiopathic skeletal hyperostosis but not in patients with gout, pseudogout, or systemic lupus erythematosus [8]. ...
Objective: Growth hormone (GH) and GH-related signaling molecules play an important role in nociception and development of chronic pain. This review aims to examine the potential molecular mechanisms through which GH-related signaling modulates sensory hypersensitivity in rodents, the clinical pharmacology of GH, and the clinical evidence of GH treatment for several common pain syndromes. Methods: A search was conducted using the PUBMED/MEDLINE database, Scopus, and the Cochrane library for all reports published in English on GH in pain management from inception through May 2018. A critical review was performed on the mechanisms of GH-related signaling and the pharmacology of GH. The levels of clinical evidence and implications for recommendations of all of the included studies were graded. Results: The search yielded 379 articles, of which 201 articles were deemed irrelevant by reading the titles. There were 53 reports deemed relevant after reading abstracts. All of these 53 articles were retrieved for the analysis and discussion. Conclusions: Dysfunction of the GH/insulin-like growth factor 1 (IGF-1)/ghrelin axis was linked to hyperalgesia and several common clinical pain syndromes. Low levels of GH and IGF-1 were linked to pain hypersensitivity, whereas ghrelin appeared to provide analgesic effects. Pretreatment of GH reversed mechanical and thermal hypersensitivity in an animal model of inflammatory pain. Clinical trials support GH treatment in a subgroup of patients with fibromyalgia syndrome (level of evidence: 1B+) or chronic lower back pain syndrome (level of evidence: 2C+).
... Coincide with this study; treatment with 2 mg/kg HGH stimulates the cartilage growth and higher cartilage thickness in rabbits [6]. In addition, GH defeats inflammatory pain through the role of IGF-1 by overcoming the inflammation and prostaglandin which have a role as the pain mediator [1,3]. In other studies, the healing of the cartilage was generated after the intra articular injection of GH [9,16,8]. ...
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Recombinant human growth hormone (rHGH) which plays an important role for remodeling of bone has an effect on cartilage differentiation and regeneration, as well. Herein, we reviewed human growth hormone and its roles on cartilage. We discussed different roles on growth, regeneration, inflammation, cell maturation, and mitotic activity. These findings provide proof of principle that therapeutics based on rHGH can improve treatment for numerous disorders.
... Injection of GH as a single agent does not have mechanical ef fect or local antiinflammatory effect at the joint 8,16) . The effect of GH in overcoming inflammatory pain is through the indirect role of cortisol and IGF1 which suppress the inflammatory process and prostaglandin that act as the pain mediator 14,17) . The assessment of pain scale in this study was highly dependent on the observer. ...
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Purpose: Up to now, there is no feasible solution for stopping or reversing the degenerative process of osteoarthritis (OA). Our study evaluated the effect of intra-articular injection of growth hormone (GH) in OA-induced rabbit knees compared to hyaluronic acid (HA) and placebo. Materials and methods: A total of 21 male, skeletally mature, New Zealand rabbits received an intra-articular type II collagenase injection for OA induction. Two weeks later, the rabbits were randomized into three groups based on the weekly intra-articular injection to be received: GH, HA, and saline. Injections were done for three consecutive weeks. Evaluation was done at 8 weeks after treatment, clinically using the lameness period, macroscopically using the Yoshimi score and microscopically using the Mankin score. Results: The shortest period of lameness was found in the GH group (15.9±2.12 days), compared to the HA group (19.4±1.72 days) and placebo group (25.0±2.94 days). There was a statistically significant difference in macroscopic scoring between groups (p=0.001) in favor of the GH group. There was also significant difference in the microscopic score between groups (p=0.001) also in favor of the GH group. Conclusions: Intra-articular injection of GH showed better clinical, macroscopic and microscopic results as compared to HA and placebo.
... It was shown that prolonged systemically applied GH therapy improves overall symptomatology, including the number of tender points in fibromyalgia patients (Bennett et al., 1998). It was also suggested that bone and muscle deficiencies may result in resting pain through GH deficiency (Bennett, 2004). Overall, a majority of clinical studies indicate that GH increase directly leads to severe pain, while few reports imply that GH shortage resulted in abnormalities indirectly affecting resting pain. ...
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Clinical and basic research on regulation of pituitary hormones, extra-pituitary release of these hormones, distribution of their receptors and cell signaling pathways recruited upon receptor binding suggests that pituitary hormones can regulate mechanisms of nociceptive transmission in multiple orofacial pain conditions. Moreover, many pituitary hormones either regulate glands that produce gonadal hormones (GnH) or are regulated by GnH. This implies that pituitary hormones may be involved in sex-dependent mechanisms of orofacial pain and could help explain why certain orofacial pain conditions are more prevalent in women than men. Overall, regulation of nociception by pituitary hormones is a relatively new and emerging area of pain research. The aims of this review article are to: (1) present an overview of clinical conditions leading to orofacial pain that are associated with alterations of serum pituitary hormone levels; (2) discuss proposed mechanisms of how pituitary hormones could regulate nociceptive transmission; and (3) outline how pituitary hormones could regulate nociception in a sex-specific fashion. Pituitary hormones are routinely used for hormonal replacement therapy, while both receptor antagonists and agonists are used to manage certain pathological conditions related to hormonal imbalance. Administration of these hormones may also have a place in the treatment of pain, including orofacial pain. Hence, understanding the involvement of pituitary hormones in orofacial pain, especially sex-dependent aspects of such pain, is essential to both optimize current therapies as well as provide novel and sex-specific pharmacology for a diversity of associated conditions.
... Serotonin plays an important role in the process of deep sleep, central and peripheral mechanisms of pain. In favour of the hypothesis of central serotonin deficiency may serve as evidence of declining transportation of its predecessor – tryptophan and reducing its metabolite 5-hydroxyindole acetic acid in the blood plasma of patients with fibromyalgia[Suleymanova G.P., et al., 2011;Tabeeva G.R., et al., 2000;Bennett R.M., 2004;Blotman F., Branco J., 2007]. The role of various neurotransmitters in the pathogenesis of FM are simultaneously involved in modulating pain mechanisms and in the regulation of sleep (norepinephrine, dopamine, histamine, GABA, and others.)[Russel ...
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Pain is a concept that is clinically and pathogenetically complex and heterogeneous. It varies in intensity, localization and subjective manifestations (shooting, pressing, pulsating, pricking, cutting, aching, etc.), can be permanent or periodic, which is largely due to localization and what causes it. Some well-recognised types of pain include muscle or joint-muscle pain. An example of this type of pain is fibromyalgia, a rheumatic disease of unknown etiology, is characterized by generalized muscle weakness and painful palpation in limited areas of the body, designated as trigger points. Effective methods of treatment of patients with this disease have not yet been developed. Some medications allow the patient some form of short-term relief, however, even this is not always the case. Using a complex approach, which involves a wide range of laser therapy methods, it allows the human body to restore itself and any abnormalities in the functioning of various organs and systems, which, as well as providing direct analgesia, ensures the elimination of the causes of the disease. In addition, laser therapy methods are simple and safe, and unlike analgesics do not cause side effects, as well as there being no contraindications. Laser illumination doesn’t only affect one link of the painful reception, but essentially the whole hierarchy of mechanisms in the appearance of pain. Due to this, the curative effect persists for a long period of time. This “versatility” predetermines the exceptional effectiveness of laser therapy, all while using adequate techniques and appropriate equipment. Laser therapeutic devices in the LASMIK series have a frequency of up to 10.000Hz, and a unique set of laser emitting attachments and nozzles. These are the most suitable for implementing methods of pain management. The book is intended for specialists in rehabilitation, rheumatologists, traumatologists, general practitioners and physiotherapists.
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Background The hemophilic arthropathy was caused by repeated joint bleeding, which resulted in joint synovium hyperplasia, cartilage damage and bone deformity. Extracorporeal shockwave treatment (ESWT) is a non-invasive treatment with high safety and has been widely used in the treatment of various musculoskeletal conditions. This study was aimed to evaluate the safety of ESWT in hemophilic arthropathy of the knee. Methods This is a prospective single blind randomized control study conducted between 2019/08/01 and 2020/07/31. Hemophilia and Von Willebrand disease patients were enrolled and randomized for extracorporeal shock wave therapy to the left or right knee joint and energy-free sham therapy to the other knee joint at the 1st and 2nd month after prophylactic coagulation factor administration. As safety evaluation, hemophilia joint health score (HJHS), knee score scale (KSS), visual analog scale (VAS) and ultrasound (HEAD-US) were checked at the beginning, 1st, 2nd, 3rd and 6th month. Knee MRI was examined at the beginning and 6th month. Results HJHS score of the knee receiving real ESWT did not elevate in 9 patients (75%). KSS demonstrated neither significant improvement nor deterioration after ESWT. VAS declined after two sessions of ESWT. Ultrasound and MRI showed no breakthrough joint bleeding nor progression of previously existed effusion and hemarthrosis. Conclusion ESWT might be a safe treatment for hemophilic arthropathy once prophylactic coagulation factors are adequately administrated before ESWT. Further well-controlled study enrolling more hemophilia patients might be needed for the effectiveness of ESWT on these patients.
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Growth hormone (GH) and insulin growth factor 1 (IGF1) are implicated in nociceptive processing; it has been reported that the latter participates in neonatal inflammatory nociception. In the target article, the authors propose that local inflammation evoked by carrageenan administration in mice produces a decrease in the local GH levels and an increment of IGF1 receptors type 1 expression, this produces behavioral nociception and peripheral sensitization that can be prevented by GH systemic administration pretreatment.
Cutaneous inflammation alters the function of primary afferents and gene expression in the affected dorsal root ganglia (DRGs). However specific mechanisms of injury-induced peripheral afferent sensitization and behavioral hypersensitivity during development are not fully understood. Recent studies in children suggest a potential role for growth hormone (GH) in pain modulation. GH modulates homeostasis and tissue repair after injury, but how GH effects nociception in neonates is not known. To determine if GH played a role in modulating sensory neuron function and hyper-responsiveness during skin inflammation in young mice, we examined behavioral hypersensitivity and the response properties of cutaneous afferents using an ex vivo hairy skin-saphenous nerve-dorsal root ganglion (DRG)-spinal cord preparation. Results show that inflammation of the hairy hindpaw skin initiated at either postnatal day 7 (P7) or P14 reduced GH levels specifically in the affected skin. Furthermore, pretreatment of inflamed mice with exogenous GH reversed mechanical and thermal hypersensitivity in addition to altering nociceptor function. These effects may be mediated via an upregulation of insulin-like growth factor 1 receptor (IGFr1) as GH modulated the transcriptional output of IGFr1 in DRG neurons in vitro and in vivo. Afferent-selective knockdown of IGFr1 during inflammation also prevented the observed injury-induced alterations in cutaneous afferents and behavioral hypersensitivity similar to that following GH pretreatment. These results suggest that GH can block inflammation-induced nociceptor sensitization during postnatal development leading to reduced pain-like behaviors, possibly by suppressing the upregulation of IGFr1 within DRGs.
Objective: Assessment of growth disturbances in adults with a history of juvenile chronic arthritis (JCA). Material and Methods: Sixty-five subjects, 52 premenopausal females and 13 males with a mean age (range) of 32.2 years (22.3–49.4) participated. Mean age at disease onset was 5.7 years (0.8–15.8) and mean disease duration was 12.4 years (0.4–32). The follow-up time ranged from 18.7 to 46.9 years with a mean of 26.4 years. For each participant standard deviation scores (z-scores) for final height, delta-height (the difference between observed and expected height), armspan, subischial leg length and sitting height ratio, were calculated. Results: The study group as a whole did not exhibit linear growth impairment. The categorical distribution of heights differed significantly from a expected distribution in a healthy population (p < 0.001). A height z-score < –2 SD was present in 10.7&percnt; of the study group, of whom all had polyarticular course of JCA. Polyarticular and systemic course of JCA (versus pauciarticular) (p = 0.022), systemic steroid treatment (p = 0.006) and Steinbrocker functional class II–IV (vs. I) in 1979 (p = 0.043) were variables associated with reduced delta-height. In linear regression analyses, disease severity defining variables were statistically significant predictors of reduced final height and armspan. 27&percnt; of the study subjects had significantly reduced arm span (p < 0.001). Subischial leg length and body proportions (sitting height ratio) were normal. Conclusion: Our findings suggest that functionally impaired polyarticular and systemic JCA patients treated with systemic steroids may be at an increased risk of developing reduced final height and armspan. Disease control achieved by an aggressive therapeutic approach, if possible with a minimal use of systemic steroids, may reduce growth impairment in JCA.
The symptomatology characterizing fibromyalgia (FM) comprises three systems: the musculoskeletal system with widespread muscular pain, neuroendocrine disorders, and psychological distress including depression. Though the most prominent symptom of FM is pain in defined points of the musculoskeletal system, the numerous other somatoform and psychological disorders suppose a common primary disturbance which we consider to originate within higher levels of the central nervous system. Recent studies of the entire endocrine profile of FM patients following a simultaneous challenge of the hypophysis with corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone, growth hormone-releasing hormone, and luteinizing hormone-releasing hormone support the hypothesis that an elevated activity of CRH neurons determines not only many symptoms of FM but may also cause the deviations observed in the other hormonal axes. Hypothalamic CRH neurons thus may play a key role not only in “resetting” the various endocrine loops but possibly also nociceptive and psychological mechanisms as well.
Objective: To examine the relationship between serum levels of insulin-like growth factor 1 (IGF-1) and osteoarthritis (OA) of the knee. Methods: Serum IGF-1 levels were compared in 162 male and 101 female subjects age > or = 20 stratified by presence of radiographic changes of OA of the knee. Results: Mean serum IGF-1 levels were significantly lower in subjects with knee OA; however, after adjustment for age-related changes in IGF-1 levels, these differences were no longer significant. Conclusion: These data fail to support the hypothesis that serum IGF-1 levels are reduced in subjects with OA of the knee independent of the known age-related changes in these levels.
To study the hormonal perturbations in FMS patients we injected sixteen FMS patients and seventeen controls a cocktail of the hypothalamic releasing hormones: Corticotropin-releasing hormone (CRH), Thyrotropin-releasing hormone (TRH), Growth hormone-releasing hormone (GHRH), and Luteinizing hormone-releasing hormone (LHRH) and observed the hormonal secretion pattern of the pituitary together with the hormones of the peripheral endocrine glands. We found in FMS patients elevated basal values of ACTH and cortisol, lowered basal values of insulin-like growth factor I (IGF-I) and of triiodothyronine (T-3), elevated basal values of follicle-stimulating hormone (FSH) and lowered basal values of estrogen. Following injection of the four releasing-hormones, we found in FMS patients an augmented response of ACTH, a blunted response of TSH, while the prolactin response was exaggerated. The effects of LHRH stimulation were investigated in six FMS patients and six controls and disclosed a significantly blunted response of LH in FMS. We explain the deviations of hormonal secretion in FMS patients as being caused by chronic stress, which, after being perceived and processed by the central nervous system (CNS), activates hypothalamic CRH neurons. CRH, on the one hand, activates the pituitary-adrenal axis, but also stimulates at the hypothalamic level somatostatin secretion which, in turn, causes inhibition of GH and TSH at the pituitary level. The suppression of gonadal function may also be attributed to elevated CRH by its ability to inhibit hypothalamic LHRH release, although it could act also directly on the ovary by inhibiting FSH-stimulated estrogen production. We conclude that the observed pattern of hormonal deviations in FMS patients is a CNS adjustment to chronic pain and stress, constitutes a specific entity of FMS, and is primarily evoked by activated CRH neurons.
Purpose: The cause of fibromyalgia (FM) is not known. Low levels of insulin-like growth factor 1 (IGF-1), a surrogate marker for low growth hormone (GH) secretion, occur in about one third of patients who have many clinical features of growth hormone deficiency, such as diminished energy, dysphoria, impaired cognition, poor general health, reduced exercise capacity, muscle weakness, and cold intolerance. To determine whether suboptimal growth hormone production could be relevant to the symptomatology of fibromyalgia, we assessed the clinical effects of treatment with growth hormone. Methods: Fifty women with fibromyalgia and low IGF-1 levels were enrolled in a randomized, placebo-controlled, double-blind study of 9 months' duration. They gave themselves daily subcutaneous injections of growth hormone or placebo. Two outcome measures--the Fibromyalgia Impact Questionnaire and the number of fibromyalgia tender points-were evaluated at 3-monthly intervals by a blinded investigator. An unblinded investigator reviewed the IGF-1 results monthly and adjusted the growth hormone dose to achieve an IGF-1 level of about 250 ng/mL. Results: Daily growth hormone injections resulted in a prompt and sustained increase in IGF-1 levels. The treatment (n=22) group showed a significant improvement over the placebo group (n=23) at 9 months in both the Fibromyalgia Impact Questionnaire score (P <0.04) and the tender point score (P <0.03). Fifteen subjects in the growth hormone group and 6 subjects in the control group experienced a global improvement (P <0.02). There was a delayed response to therapy, with most patients experiencing improvement at the 6-month mark. After discontinuing growth hormone, patients experienced a worsening of symptoms. Carpal tunnel symptoms were more prevalent in the growth hormone group (7 versus 1); no other adverse events were more common in this group. Conclusions: Women with fibromyalgia and low IGF-1 levels experienced an improvement in their overall symptomatology and number of tender points after 9 months of daily growth hormone therapy. This suggests that a secondary growth hormone deficiency may be responsible for some of the symptoms of fibromyalgia.
Electron microscopic examination of the skeletal muscles in a patient with acromegaly and marked elevation of the serum growth hormone reveals altered mitochondria (pleomorphism, elongation, matrical pallor, and cristae abnormalities), glycogen granules infiltration, inclusion bodies, and vesicular dilatations. Nine months after surgical removal of the pituitary tumor, the serum growth hormone levels were markedly diminished. A repeat examination of the skeletal muscle shows that the previous ultrastructural changes in the muscles are related to the growth hormone levels.
Seventeen consecutive acromegalic patients were evaluated for evidence of neuromuscular dysfunction and followed for 1 year after hypophysectomy. Before treatment, four patients had both a myopathy and the carpal tunnel syndrome, five had myopathy alone, four had carpal tunnel syndrome alone, and four had neither. The myopathy was caracterized by mild, strictly promixal weakness and flabbiness of muscles; electromyography revealed typical myopathic abnormalities, but serum enzymes and muscle biopsy usually were normal. The presence of myopathy or the carpal tunnel syndrrome could not be correlated with the magnitude of growth hormone elevation or any secondary endocrine derangement, but myopathy was associated with a longer duration of acromegaly. Carpal tunnel symptoms usually improved in the first 6 weeks after hypophysectomy, while myopathy improved more slowly and sometimes was detectable 1 year later.