Review
Growth hormone and connective tissue in exercise
S. Doessing, M. Kjaer
Institute of Sports Medicine, Copenhagen, Bispebjerg Hospital, Copenhagen NV, Denmark
Corresponding author: Simon Doessing, Institute of Sports Medicine, Copenhagen, Bispebjerg Hospital, Bispebjerg Bakke 23,
2400 Copenhagen NV, Denmark. Fax:145 35 31 27 33, E-mail:
[email protected]
Accepted for publication 21 February 2005
Over the last few years, growth hormone (GH) has become
increasingly popular as doping within different sports.
However, the precise mechanisms behind the ergogenic
(performance enhancing) effects of GH in athletes are still
being debated. Besides a well-documented stimulatory effect
of GH on carbohydrate and fatty acid metabolism, and a
possible anabolic effect on myofibrillar muscle protein, we
suggest a role for GH as an anabolic agent in connective
tissue in human skeletal muscle and tendon. Given the
importance of the connective tissue for the function of
skeletal muscle and tendon, a strengthening effect of GH
on connective tissue could fit with the ergogenic effect ofGH
experienced by athletes.
This review examines the endogenous secretion of GH
and its mediators in relation to exercise. Furthermore, we
consider the effect of endogenous GH and administered
recombinant human GH (rhGH) on both myofibrillar and
connective tissue protein synthesis, thus offering an alternative
explanation for the ergogenic effect of GH. Finally,
we suggest a possible therapeutic role for rhGH in clinical
management of the frequently suffered injuries in the connective
tissue.
The last year’s news media coverage of the abuse of
growth hormone (GH) by professional athletes, and
of the arrests of athletes possessing GH, has brought
full attention onto GH-doping as an increasing
problem in professional sports. Furthermore, several
anecdotal reports from track and field athletes
(Brandt, 2000), bodybuilders (Dickerman et al.,
2000), baseball and American football players
(Smith, 1991; Verducci, 2002) and even high school
students (Rickert et al., 1992) suggests a widespread
abuse of GH, from amateurs to professionals, within
a range of different sports.
Because of the nature of endogenous GH secretion
during exercise (Wallace et al., 2000a) and stress
(Armanini et al., 2002) and because of the amino
acid sequence identity between the majority of endogenous
GH and exogenous recombinant human
GH (rhGH), it is a challenge to document use of
rhGH (Wallace et al., 1999, 2001a; Ehrnborg et al.,
2003), and currently no valid test for proofing rhGHdoping
is available. This fact and a general agreement
in athletic communities that GH possesses
powerful ergogenic (i.e. performance enhancing)
effects, presumably make GH the ‘‘drug of choice’’
for many athletes. This raises the obvious question of
whether there is scientific evidence for effects of GH
on the human body that can explain its postulated
ergogenic effect.
Besides the well-documented stimulatory effect of
GH on carbohydrate (Rosenfalck et al., 2000; Lange
et al., 2002b) and fatty acid metabolism (Lange et al.,
2001a, 2002b) and a possible muscle anabolic effect
(Fryburg et al., 1991; Fryburg & Barrett, 1993; Welle
et al., 1996), a role for GH as an anabolic agent in
connective tissue in human skeletal muscle and
tendon is suggested (Verducci, 2002; Rennie, 2003).
The major role of connective tissue in muscle and
tendon is to provide a matrix for transmission of
force from individual muscle fibers to the bone.
Thus, a strengthened connective tissue would give a
stronger and more strain-resistant muscle and tendon
and this could, in part, fit with the claimed effect of
rhGH on athletic performance. Furthermore, an
anabolic effect of rhGH in connective tissue could
also suggest a potential for rhGH in treatment of
muscle and tendon injuries, which are common
problems in many sports.
The following review will focus on exercise-induced
secretion of GH (and mediators of GH actions)
and effects of GH/rhGH in muscle and tendon
connective tissue during exercise, and thus offer an
alternative explanation for the popularity of rhGHdoping,
and evaluate the potential for the use of
rhGH-supplementation in treatment of sport injuries.
Exercise, GH and connective tissue
Collagen is an important strength-carrying part of
the connective tissue i.e. extracellular matrix (ECM)
Scand J Med Sci Sports 2005: 15: 202–210 COPYRIGHT & BLACKWELL MUNKSGAARD 2005
Printed in Denmark . All rights reserved
DOI: 10.1111/j.1600-0838.2005.00455.x
202
and influences the function of the muscle–tendon
unit, which is constantly challenged during athletic
performance. Exercise has been shown to stimulate
collagen synthesis in the ECM (Langberg et al., 1999;
Miller et al., 2004) and although the precise mechanisms
regulating the increase in synthesis during
exercise are not accounted for, it is based on in vitro
data indicating very likely that the GH/insulin-like
growth factor-I (IGF-I) axis plays an important role
in the regulation of collagen metabolism (Abrahamsson
et al., 1991a, b; Banes et al., 1995).
A more complicated model of GH-endocrinology
has, over the last few years, replaced the traditional
concept of a top–down GH/IGF-I system with GH
at the apex. GH has been shown to have powerful,
IGF-I-independent effect on peripheral tissues
(Izumi et al., 1995; Waters et al., 1999), and furthermore
GH production is also found in extra pituitary
tissues with possible paracrine and autocrine effects
(Waters et al., 1999). Also, the different IGF-I isoforms
identified are now divided into two main
groups. Class-1 isoforms, which are produced locally
in muscle and tendon tissue and presumably act in an
autocrine–paracrine manner, and class-2 isoforms,
produced in hepatocytes with systemic actions on
myocytes and fibroblasts (Harridge, 2003; Hameed
et al., 2004). Finally, the peripheral actions of IGF-I
will be regulated via coupling of IGF-I, IGF-binding
protein-3 (IGFBP-3) and acid-labile subunit (ALS)
into a ternary complex, in a mechanism only partly
understood, and this fact adds further complexity to
the system (Baxter, 1994; Laursen et al., 2000; Borst
et al., 2001).
However, pulsatile endogenous GH secretion from
somatotrophs in the pituitary gland and concomitant
elevation of IGF-I concentrations in target tissues
are closely associated with exercise and is believed to
stimulate fibroblasts to synthesize collagen (Ehrnborg
et al., 2003).
GH and IGF-1 axis during exercise
Pituitary GH secretion and plasma concentrations of
IGF-I ternary complex are affected by several interacting
physiological and endocrinological factors.
Exercise is one of the most potent physiological
stimulators of pulsatile GH secretion (Weltman
et al., 1992; Pritzlaff et al., 1999) and thus increases
the concentration of IGF-I and its binding proteins
(Wallace et al., 1999; Ehrnborg et al., 2003). Factors
such as the training status and age of the individual,
duration and peak intensity of the exercise bout and
the total workload performed will influence not only
the average GH secretion but also the pulsatile
pattern of secretion, which is equally important for
the GH-regulated secretion of IGF-I (Isgaard et al.,
1988; Izquierdo et al., 2001b). Also, vigorous exercise
changes the relative serum concentrations of GHisoforms,
with a more pronounced increase in non-
22 kDa isoform concentration compared with the
22 kDa isoform (Wallace et al., 2001b). The 20 kDa
isoform and other non-22 kDa isoforms have an
extended half-life compared with the 22 kDa isoform,
and it is suggested that vigorous exercise increases
the bioactivity of GH by a change in the concentration
of different GH isoforms (Wallace et al., 2001b;
Nindl et al., 2003). Therefore, differences in exercise
and assay protocols will greatly influence results and
conclusions regarding the GH response to exercise.
Exercise has an acute stimulatory effect on pituitary
GH secretion both in trained athletes (Kjaer
et al., 1988;Wallace et al., 1999; Ehrnborg et al., 2003)
and in recreationally active persons (Kjaer et al.,
1988; Pritzlaff et al., 1999; Wallace et al., 2001a,
2001b). In a study by Ehrnborg et al. (2003), a single
maximal exercise bout performed by competitive
athletes resulted in a fourfold increase in serum
concentrations of total GH and 22 kDa GH isoform.
In active men, an increase in levels of both 22 kDa
GH and in total GH following vigorous exercise is
reported (Wallace et al., 2001a, b), and interestingly,
Pritzlaff et al. (1999) report a linear dose–response
relationship between exercise intensities and serum
level of GH in active male subjects.
Kjaer et al. (1987) investigated the mechanisms
responsible for the regulation of GH secretion during
exercise in healthy male subjects. By varying both the
actual exercise intensity and the perceived exercise
intensity (the latter achieved by weakening skeletal
muscles by curarization) the authors report that the
GH level is closely related to perceived exercise
intensity and not to the actual workload carried
out (Kjaer et al., 1987). These results lead to the
conclusion that GH secretion is regulated via activity
in motor centers in the brain (‘‘central command’’)
that simultaneously stimulate skeletal muscle and
endocrine centers (Kjaer et al., 1987).
In an elegant intervention study, Weltman et al.
(1992) randomized untrained women to one year of
training at either low or high intensity, with a third
group of sedentary control subjects. Compared with
the sedentary and low-intensity training group, the
high-intensity training group exhibited significantly
increased plasma GH, with regard to peak
height, peak area and 24 h GH concentration, but
no changes in the number of GH peaks were observed
(Weltman et al., 1992). These results show
that training increases plasma GH concentration and
suggest that changes in peak GH concentration,
rather than changes in the number of GH peaks,
are important to target tissues. Taken together, there
is a strong positive correlation between vigorous and
chronic exercise and the serum level and pulsatile
secretion of GH (Fig. 1).
Growth hormone and connective tissue in exercise
203
The acute GH response to exercise is blunted
in middle-aged and older individuals, and several
authors report data suggesting that the training
response to exercise in this group is blunted as well
(Hakkinen et al., 1998; Kraemer et al., 1999; Izquierdo
et al., 2001a). This further suggests that with
aging, larger doses of GH may be needed in order to
observe similar doping responses as seen in younger
individuals.
Several studies have demonstrated increased concentrations
of IGF-I, IGFBPs and ALS in relation
to exercise (Wallace et al., 1999; Borst et al., 2001;
Manetta et al., 2002; Ehrnborg et al., 2003). In a
study of 120 competitive athletes, Ehrnborg et al.
(2003) found transient increases in circulating IGF-I,
IGFBP-213 and ALS in response to a maximal
exercise test, and interestingly, serum markers of
collagen synthesis were also increased with exercise
in this study. In 17 trained adult males, similar results
are reported, with transient increased serum levels of
IGF-I, IGFBP-113 and ALS after 30 min of highintensity
exercise (Wallace et al., 1999).
In human and animal studies, resistance training
and mechanical overload increase mRNA expression
of locally produced class 1 IGF-I isoforms in skeletal
muscle (Owino et al., 2001; Hameed et al., 2004). Of
the different class 1 IGF-I isoforms identified in
skeletal muscle, upregulation of the IGF-IEc/mechano
growth factor (MGF) isoform is positively
correlated with mechanical load (Owino et al., 2001;
Hameed et al., 2004). A resistance training period
of five weeks increased MGF mRNA expression
by approximately 200% in a group of elderly men
(Hameed et al., 2004). Furthermore, when training
was combined with rhGH administration, expression
of MGF mRNA increased by approximately 400%,
suggesting an additive effect of rhGH and training
(Hameed et al., 2004). The other IGF-IEa isoform
examined in this study responded to rhGH administration
rather than to exercise, and no additive effect
of rhGH and exercise on IGF-IEa mRNA expression
was observed for that isoform, suggesting that different
class 1 IGF-I isoforms respond differently to
stimuli such as exercise and exogenous rhGH supplementation
(Hameed et al., 2004). Despite a more
pronounced rise in mRNA for MGF in the trained
group receiving rhGH compared with the trained
group not receiving rhGH, there was no difference in
maximal muscle force and volume between groups
(Hameed et al., 2004). This illustrates that the relative
importance of systemic and local IGF-I isoforms
with respect to exercise, GH-level and muscle function
remains to be elucidated.
New perspectives of the physiologic roles of
IGFBPs (the IGFBP superfamily) have been introduced,
including a more complex regulation of
IGF-I bioactivity and IGF-I-independent actions of
IGFBPs in cell growth and metabolism (Rosenfeld
et al., 1999). Comparing trained and previously
untrained individuals, Rosendal et al. (2002) report
that prolonged physical training resulted in increased
IGFBP-3 proteolysis in previously untrained persons
only, suggesting a different training effect on IGFBPs
between trained and untrained persons.
Of the several endocrinological factors known to
regulate GH secretion, some are influenced by exercise
(de Vries et al., 2002, 2003; Kraemer et al.,
2004; Schmidt et al., 2004). In healthy male subjects,
the effect of exercise on the levels of growth hormone-
releasing hormone (GHRH), somatostatin and
GH was investigated (de Vries et al., 2002, 2003). It
was reported that the elevated GH secretion in
response to exercise can partly be explained by an
exercise-induced change in plasma levels of GHRH
and somatostatin (de Vries et al., 2002, 2003).
Growth hormone-releasing protein (ghrelin), on the
other hand, does not seem to be involved in GH
regulation during exercise, and two studies report
that exercise increased GH and IGF-I levels, without
having any effect on the level of ghrelin (Kraemer
et al., 2004; Schmidt et al., 2004) (Fig. 2).
Effect of rhGH supplementation on myofibrillar
muscle protein
The effect of GH on myofibrillar protein anabolism
and muscle strength is controversial. The increase in
muscle mass and strength argued by rhGH-abusers
in athletic and bodybuilding communities and by
several researchers is challenged by scientific controlled
studies reporting no such effect in healthy
individuals. This area has recently been reviewed
(Rennie, 2003) and is briefly summarized in the
following.
There are several studies reporting a positive
correlation between GH supplementation and myo-
36
18
0800 2000 0800
0
36
18
0800 2000 0800
0
[GROWTH HORMONE]
(μg/L)
TIME (CLOCKTIME)
SUBJECT AFTER 1
YEAR OF TRAINING
(a) UNTRAINED SUBJECT (b)
Fig. 1. Twenty-four-hour serum growth hormone (GH)
concentration in a subject at baseline and after 1 year of
training. GH concentration in an untrained female subject
(a), and GH concentration in the subject after 1 year of
regular training at high intensity (b), illustrating that endurance
training at high intensity amplifies the pulsatile
release of GH. Redrawn from (Weltman et al., 1992).
Doessing & Kjaer
204
fibrillar protein synthesis (Cuneo et al., 1991a, b;
Fryburg et al., 1991; Fryburg & Barrett, 1993; Welle
et al., 1996, 1998; Lucidi et al., 2000; Mauras et al.,
2000). Studies of rhGH administration in GHD
children and adults (Cuneo et al., 1991a, b; Lucidi
et al., 1998, 2000; Mauras et al., 2000) and studies of
GHD and animals not fully grown (Daugaard et al.,
1998; Molon-Noblot et al., 1998) uniformly report a
significant effect of GH supplementation on muscle
growth, strength and performance. Furthermore, in
healthy adults and athletes, wholebody measurements
of nitrogen balance (Butterfield et al., 1997)
and whole-body protein synthesis (Mauras, 1995;
Healy et al., 2003) and even specific measurements
of muscle protein synthesis (Fryburg et al., 1991;
Fryburg & Barrett, 1993; Butterfield et al., 1997),
suggest a myofibrillar anabolic effect of GH supplementation.
However, increasing GH level in healthy
subjects via GH supplementation is not necessarily
comparable with a situation in which normalization
of GH level is achieved by GH-treatment in GHD.
Furthermore, whole-body measurements are obviously
not always very conclusive regarding the
local myofibrillar protein. The studies measuring
local human myofibrillar synthesis as a response to
a single GH administration in healthy adult subjects
included relatively few subjects and have lately been
challenged by large, placebo-controlled studies,
examining the effect of long-term GH treatment
(Yarasheski et al., 1992; Lange et al., 2002a). In a
double-blinded study in which 47 healthy elderly men
and women received either placebo or rhGH for a 12-
week-period, no difference in muscle strength, muscle
power and muscle hypertrophy was observed (Lange
et al., 2002a). Moreover, in a study of exercising
young men, no effect of GH on muscle protein turnover,
limb circumferences and muscle mass was reported
(Yarasheski et al., 1992). In agreement with
these results, a study including experienced male weight
lifters showed no effect of rhGH supplementation on
muscle protein synthesis (Yarasheski et al., 1993).
GH stimulates collagen synthesis in connective tissue
In vitro studies of collagen tissue indicate that IGF-I
plays an important role in promoting collagen synthesis
on a cellular level (Abrahamsson et al., 1991a, b;
Banes et al., 1995). In avian tendon fibroblasts, IGFI
supplementation led to a dose-dependent increase
in DNA synthesis, which is indicative of cell division
(Banes et al., 1995). Interestingly, although mechanical
load alone did not increase DNA synthesis, IGFI
and mechanical load, increased DNA synthesis
synergistically (Banes et al., 1995). Moreover, in
rabbit tendon explants the rate of fibroblast cell
division and collagen synthesis, determined via incorporation
of labeled thymidine and hydroxyproline,
respectively, was significantly increased in
medium with rh IGF-I vs medium without rhIGF-I
(Abrahamsson et al., 1991a, 1991b). Thus, IGF-I
promotes collagen synthesis in tendon in vitro.
In vivo studies in animals support in vitro findings
and suggest that GH/IGF-I increases collagen synthesis.
Following Achilles tendon transection in rats,
treatment with local IGF-I injection resulted in a
faster functional recovery compared with controls
(Kurtz et al., 1999). Studies of GH-deficient dwarf
rats showed a significant increase in collagen turnover
in knee tendon and ligaments following 14 days
of rhGH supplementation (Kyparos et al., 2002).
Moreover, GH injection increased mRNA for IGF-I
and collagen in skeletal muscle of dwarf rats (Wilson
et al., 1995).
In patients with clinical conditions of altered GH
activity, the plasma GH/IGF-I level is associated
with pathological changes in connective tissue (Colao
et al., 1998, 1999a, b; Baroncelli et al., 2000; Lange
et al., 2001b; Scarpa et al., 2004). In acromegalic
patients, GH hypersecretion is associated with periarticular
soft-tissue hypertrophy and excess cartilage
synthesis, causing arthropathy (Colao et al., 1998,
1999b; Scarpa et al., 2004). Suppression of circulating
GH and IGF-I levels with somatostatin analogous
is standard medical treatment in acromegalic
individuals (Colao et al., 1998; Colao et al., 2004).
Thus, suppressing the secretion of GH for 6 months
in prior untreated acromegalic patients improved
articular mobility and significantly decreased periarticular
soft-tissue mass and cartilage thickness
Hypothalamus
Pituitary gland
Liver
Skeletal muscle
Blood
stream
CLASS 1
IGF-I
EFFECT OF EXERCISE
ALS
CLASS 2
IGF-1
?
GH
GHRH
IGFBP-3
Fig. 2. Exercise increases the local and systemic concentrations
of molecules responsible for regulating and mediating
the actions of growth hormone (GH). GHRH, growth
hormone-releasing hormone; class 1 IGF-I, local insulinlike
growth factor-I; class 2 IGF-I, systemic insulin-like
growth factor-I; IGFBP-3, IGF-binding protein-3; ALS,
acid labile subunit.
Growth hormone and connective tissue in exercise
205
(Colao et al., 1998, 1999b). These findings strongly
suggest that increasing of GH level for a period of
time, which is often for a period of several years in
late diagnosed acromegalic patients (Colao et al.,
2004), causes excess connective tissue deposition,
which is only partly reversed following 6 months
of GH-suppressing treatment (Colao et al., 1998,
1999b).
In growth hormone-deficient (GHD) children and
adults, hyposecretion of GH and low IGF-I level in
plasma causes a decreased connective tissue deposition
compared with healthy counterparts (Colao
et al., 1999a; Baroncelli et al., 2000; Lange et al.,
2001b). Jensen and colleagues (1991) observed a
significant positive correlation between GH supplementation,
IGF-I level in plasma, and soft-tissue
collagen synthesis in GHD (Jorgensen et al., 1988).
Similar results were found in a study, in which GH
administration to GHD patients exhibited increased
IGF-I, IGFBP and collagen synthesis in soft tissue
and this provides further support for this notion
(Bollerslev et al., 1996). Thus, decreased connective
tissue deposition observed in GHD individuals seems
to be reversible by GH supplementation, again pointing
toward a close positive correlation between the
level of GH and collagen synthesis in connective tissue.
In studies of healthy humans treated with rhGH, a
similar increase in plasma IGF-I level and markers
of whole-body collagen synthesis is observed (Longobardi
et al., 2000; Wallace et al., 2000). In a large
placebo-controlled study, rhGH administration increased
whole-body soft-tissue collagen synthesis
dose-dependently (Longobardi et al., 2000). Moreover,
in a study of healthy active males, comparing
the effect of exercise and rhGH supplementation vs
exercise and placebo, a significantly higher collagen
synthesis was reported in the rhGH group compared
with the control group (Wallace et al., 2000). This
suggests that GH not only has a stimulating effect on
collagen synthesis in GHD humans and animals but
also has a stimulating effect in normo-endocrine
human subjects. A large number of studies report
that systemic GH supplementation increases serum
levels of the IGF-I ternary complex (Lange et al.,
2000; Lange et al., 2001a; Lange et al., 2002a, b).
Recently, Olesen et al. (2004) showed that mRNA
levels of class 1 IGF-I isoforms and IGFBP-3 were
correlated to a concomitant rise in collagen in the
tendon and muscle of exercising rats, suggesting a
role for the IGF-I-ternary complex in mediating
exercise-induced collagen synthesis in tendon and
muscle. This finding is further supported by another
study in rats, reporting elevated IGF-I expression
and increased tendon healing following shock wave
treatment (Kurtz et al., 1999).
A measurement of collagen synthesis is only indicative
of the complete collagen metabolism, and
without any concomitant information on collagen
breakdown, no conclusions regarding overall collagen
metabolism can be made. Unfortunately, no
reliable method for determination of collagen breakdown
is currently available.
Thus, investigations on animals, healthy persons
and patients with altered GH secretion report a close
positive relationship between (1) the level of GH in
plasma, (2) the concentrations of systemic and local
tissue effectors and (3) collagen synthesis in connective
tissue in muscle and tendon.
In conclusion, supraphysiological doses of GH do
not seem to increase synthesis of myofibrillar protein;
however, it is possible that a supraphysiological GH
level has an effect on the connective tissue. A possible
explanation is that the scaffold structure of connective
tissue in skeletal muscle is more ‘‘exposed’’ to
changes in the concentration of hormones in plasma,
and thus, to greater extents than that seen in myofibrillar
protein of skeletal muscle, reacts to increased
concentrations of GH and IGF-I (Fig. 3).
GH-supplementation: ergogenic effect and
perspectives in injury treatment
From the scientific literature it is not obvious why
GH-doping has gained such popularity. There is not
NET SYNTHESIS OF PROTEIN
[GROWTH HORMONE] IN PLASMA
normal range
collagen protein
myofibrillar
protein
GHD
HEALTHY
ACROMEGALIC
GH-DOPING
IN ATHLETES
Fig. 3. The hypothetical relationship between the concentration
of growth hormone (GH) in plasma and the net
synthesis of myofibrillar and collagen proteins: in acromegalic
patients and GH-doped athletes with elevated level of
GH in plasma, the net synthesis of collagen protein is
increased. However, the net synthesis of myofibrillar protein
is not elevated in this group compared with healthy individuals.
GH deficient (GHD) patients have decreased collagen
and myofibrillar protein net synthesis compared with
healthy individuals. There is an increase in both myofibrillar
and collagen protein net synthesis in GHD with treatment
and thus increasing level of GH.
Doessing & Kjaer
206
one single study that provides evidence of improved
athletic performance in healthy individuals as a result
of GH administration, and furthermore, a large
group of controlled studies report no performanceenhancing
effect of rhGH administration in healthy
adults (Yarasheski et al., 1992, 1993; Deyssig et al.,
1993b). It has been argued that the beneficial effect of
rhGH supplementation and the main reason for GH
abuse is because of its lipolytic effect, allowing
athletes to lose weight while keeping their muscle
mass intact (Kraemer et al., 2002; Bidlingmaier et al.,
2003). Others argue that increased muscle size observed
in GH abusers is because of fluid retention
rather than actual increase in contractile protein
concentration, thus creating a false impression of a
stronger muscle (Rennie, 2003). The results from
studies in animals, acromegalic patients and healthy
human subjects presented in this review strongly
suggest a role for GH in maintaining and increasing
the strength of primarily connective tissue in muscle
and tendon. To our knowledge, there is unfortunately
no study investigating the precise effect of GH
on the synthesis of intra-muscular and intra-tendinous
connective tissue, in exercise and non-exercise
conditions in humans.
Tendons heal faster in GH-supplemented animals
(Kurtz et al., 1999), and anecdotal reports from
bodybuilders (http, 2004) and baseball players (Verducci,
2002) suggest that GH prevent tendon and
muscle rupture, especially in those with a concomitant
abuse of anabolic androgenic steroids (AAS).
Tendon and especially the myotendinous junction
are considered a ‘‘weak link in the chain’’ in those
with fast-growing muscles (AAS and/or heavy
strength training) and in athletes training at high
intensities. Thus, it is possible that rhGH supplementation
allows the athlete to train at a higher intensity
and/or reduce the necessary recovery time between
exercise bouts, without running the risk of getting
injured.
Clinical use of rhGH treatment is currently standard
in childhood and adult onset GHD (Cuneo
et al., 1991a; Lucidi et al., 1998, 2000; Mauras et al.,
2000) and in Turner syndrome patients (Gault et al.,
2003). In treatment of burns and bone fractures and
in treatment of intensive care patients, rhGH supplementation
has also been attempted (Suman et al.,
2003; Bach et al., 2004; Carroll et al., 2004). The
effect of GH in connective tissue in humans could be
suggestive for GH treatment after muscle and tendon
injury. However, no studies have, to our knowledge,
investigated the potential of rhGH supplementation
either in injury prevention or in promoting healing of
human muscle and tendon. The lack of such studies
can possibly be explained by ethical concerns regarding
possible side effects of high-dose rhGH administration
or because of concerns of increasing abuse of
ergogenic substances.
Side effects of rhGH administration are an extremely
serious aspect of GH abuse. Observations in
rhGH-supplemented human subjects and acromegalic
patients, including carpal tunnel syndrome and
pitting edema (Lange et al., 2001a), increased
bone growth (Kraemer et al., 2002), myocardial
hypertrophy and cancer (Colao et al., 2004), are
suggestive of the potential risk of rhGH abuse.
Furthermore, because of the high cost of rhGH
(annual costs of up to 36.000 USD according to
bodybuilder-steroid-homepages (Berardi, 2004)), the
use of cadaveric pituitary derived GH is still widespread
on the black market, with abusers running the
hazarderous risk of getting the fatal Creutzfelt–
Jacobs disease (Deyssig & Frisch, 1993a; Ehrnborg
et al., 2000; Dean, 2002). However, extrapolating
observations from studies in human subjects, receiving
relatively small doses of GH, and from acromegalic
patients, with years of elevated GH-level, are
at best indicative for which side effects are to be
expected in abusing athletes. Unfortunately, because
of a lack of communication between physicians and
abusing communities, there is so far very little knowledge
available of the side effects of short- or longterm
GH abuse.
It is concluded that endogenous and exogenous
GH does in fact possess a strong potential for
affecting synthesis of connective tissue during exercise.
At high levels of plasma GH, the effect on
connective tissue synthesis by far exceeds the very
moderate effect on myofibrillar muscle protein and it
is very likely that this effect, in part, can explain the
popularity of GH doping among athletes. Future
research exploring GHs potential as a possible treatment
of muscle and tendon injuries is needed, and
furthermore, experiments in healthy young individuals
and patients with altered GH secretion will
contribute to an increased understanding of the
regulatory role of GH.
Key words: insulin-like growth factor-I, myofibrillar
protein, collagen, doping, performance enhancing.