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It seems that there is a lot of debate if growth factors causing cancer growth or not. It seems that there is a lot of difference between Igf-1 inside the cell and when it is active outside the cell.
this is the read from growth factors in tendon repair :
Carcinogenesis
Growth Factors act on cell surface receptors, do not enter the cell, and do not
cause DNA mutation. There is no plausible mechanism by which GF result in
neoplastic development, and there have been no reports of this in the literature.6,22
Effect on Serum Growth Factor levels
Recent research by Banfi’s group in Italy47 looked at the potential systemic
effects of locally administered PRP. This group found that a locally administered
injection of PRP (4 patella tendons, 1 elbow) led to a fall in the Serum Concentration
of Epidermal Growth Factor (EGF). There was no statistically significant difference
in the concentration of VEGF, measured at 30mins, 3hrs and 24hrs post-injection
wheras other GF were not measured. A limitation of this study unfortunately was its
small size (n = 5), but the implication is that locally administered PRP will impact on
systemic levels of GF, but in a negative manner.
The use of GF methods and conflict with the WADA code
In the United Kingdom, the use of autologous blood products containing
growth factors entered the public arena when a Premiership Football Club Sports
Physician made enquires to the National anti-doping organisation (UK Sport) and
WADA regarding the legality of their use in sport50. The question asked forced
WADA to consider their position on both the use of autologous blood injections and
any autologous product which contains growth factors.
The response from WADA was quite clear, that the use of either of these techniques is
prohibited under the terms of the Prohibited List51(see figure 1). The use of ABI as
described above was considered prohibited under section M148 while the use of any
autologous product which contains GF was prohibited under Section S2. This section
specifically mentions Growth Hormone (GH), Insulin-like Growth Factor-1 (IGF-1),
and Mechano-Growth factor (MGF) as prohibited (see figure one).
Insulin-like Growth Factor-1 content of PRP:- therapy versus doping
Insulin-like growth factor-1 (IGF-1) is a 7.5kDa polypeptide, structurally similar to
Insulin49. It induces proliferation, differentiation and hypertrophy of multiple cell
lines, in particular skeletal muscle, and has an additional role of facilitating Glucose
entry into skeletal muscle cells 24, 49.
IGF-1 is secreted as the result of a hypothalamic-pituitary-liver axis. The
Hypothalamus secretes Growth Hormone-releasing hormone (GHRH), which
stimulates the Pituitary to release Growth Hormone (GH), which in turn stimulates the
Liver to release IGF-124. Like most endocrine systems, the system is controlled by
negative feedback, thus in normal individuals, exogenous administration of IGF-1 will
Downloaded from bjsm.bmj.com on 19 November 2007
11
lead to suppression of the axis. Whereas GH secretion is pulsatile, with greatly
varying levels in a 24hour period, serum IGF-1 levels are relatively stable within a
24hour period meaning a serum IGF-1 level is now the favoured test for Acromegaly
or Growth Hormone Deficiency52.
IGF-1 circulates in the serum 99% bound to a carrier protein Insulin-like Growth
Factor Binding Protein-3 (IGFBP-3). Only 1% of serum IGF-1 is ‘free’ IGF-1 (fIGF-
1), and it is the free portion which is believed to exert the biological effects, upon
binding to the IGF-1 receptor (IGF-1R)52. IGF-1 has a serum half-life of 10 minutes
(t½ 10mins) when unbound to IGFBP-353, and it is in this unbound form that IGF-1 is
administered within PRP. In contrast, the IGF-1/IGFBP-3 complex has a much longer
half-life of 16 hours (t½ 16hrs)53.
IGF-1 has at least three Isoforms, namely:- IGF-1Ea, IGF-1Eb and IGF-1Ec. IGF-
1Ea is the circulating form of IGF-1 released from the Liver, whereas IGF-1Ec, also
known as Mechano-growth factor (MGF) is the tissue isoform released from skeletal
muscle cells, and is believed to exert exclusively autocrine/paracrine actions24.
The different isoforms have slightly different biological actions. IGF-1Ea is known to
stimulate terminal differentiation of muscle cells into myotubes, and promote stemcell
mediated muscle regeneration, whereas MGF is damage sensitive, controls local
tissue repair, and is more potent than IGF-1Ea at causing hypertrophy24. MGF is
rapidly degraded in the serum24.
These varying biological actions of IGF-1 isoforms are important since IGF-1 derived
from PRP (IGF-1Ea) which is used for therapeutic purposes may not have the same
performance enhancing implications as skeletal muscle derived IGF-1Ec (MGF).
Serum IGF-1 levels vary greatly between individuals, and are dependent on genetic
influences and nutritional status, however a typical value of 300ng/ml (range 94-506)
is seen in 17-20 year old adults and 250ng/ml (range 117-358) in 21-30 year olds55. In
order to achieve such physiological levels, Children with Laron syndrome, a rare form
of GH resistance typified by very low levels of natural IGF-1, are given exogenous
IGF-1 in doses of 160mcg (micrograms) per day for many months54,55. Contrast this
with a typical dose of a single locally administered PRP injection in the treatment of
elbow extensor tendinopathy – 3mls of PRP containing ~ 100ng/ml of IGF-1 (total
dose 300ng)7 and there is a demonstrable 5 x 102 fold difference in even a single dose.
It is also important to mention that exercise has some effect on circulating levels of
IGF-1. Berg et al56 studied changes in serum IGF-1 in relation to acute bouts of
exercise. This group demonstrated a 27% increase in serum IGF-1 following 10mins
of moderate exercise in healthy adults, corresponding to changes of 10-28mcg/l. This
was likely to be IGF-1 released from skeletal muscle. The implication of this being
that it would be difficult to differentiate changes in serum IGF-1 as a result of
exercise, from changes caused by exogenous administration.
Thus there appear to be several compelling reasons to believe it would be unlikely
that PRP would be a potent ergogenic aid:
• The unbound IGF-1 has too short a half-life to be able to exert systemic effects
(10 minutes versus 16 hours).
Downloaded from bjsm.bmj.com on 19 November 2007
12
• The isoform IGF-1Ea found in PRP is not the isoform principally responsible
for skeletal muscle hypertrophy (IGF-1Ec/MGF).
• The doses of IGF-1 in PRP are sub-therapeutic in terms of producing systemic
anabolic actions by a factor of 500 (300 nanograms versus 160 micrograms).
A recent IOC Medical Commission Consensus Statement on the use of Growth Factor
technologies in therapy appears to welcome further research in the field “to ensure
these therapies are optimised” and, “to ensure athlete/patient safety”. We would
welcome such assertions also, though the statement by the IOC somewhat contradicts
the WADA Code which prohibits all use of Growth Factors therapies in elite sport57.
Notwithstanding these concerns expressed by WADA, it is possible to apply to a
WADA approved Anti-Doping Organisation for a Therapeutic Use Exemption to
utilise these techniques for specific clinical indications, in elite athletes. Given the
obvious difficulties associated with detection of these techniques and the bureaucratic
delays the TUE process entails, it is unclear whether this approach has been widely
utilised. Indeed, the only research known to have been conducted on professional
athletes makes no mention of any anti-doping concerns47. The authors would strongly
support the use of this approach in order for WADA to develop awareness of the
current clinical utility of these techniques.
Figure 1: Selected Sections of the 2006 WADA Prohibited List (WADA 2007)
S2 Hormones and Related Substances
The following substances, including other substances
with a similar chemical structure or similar biological
effect(s), and their releasing factors, are prohibited:
1. Erythropoetin
2. Growth Hormone (GH), Insulin-like
Growth Factors (eg. IGF-1), Mechano
Growth Factors (MGFs)
3. Gonadotrophins
4. Insulins
5. Corticotrophins
• M1 Enhancement of Oxygen Transfer
• The following are prohibited:
a. Blood doping, including the use of autologous,
homologous or heterologous blood or red blood cell
products of any origin.
Conclusion:
Medical technology continues to advance at a furious pace. The use of Growth
Factors promises to herald a new era of accelerated healing of injured tissues, and is
already commonplace in many fields of medicine. The technology is still in its
infancy with respect to soft tissue injuries, and the precise mechanisms of action, and
Downloaded from bjsm.bmj.com on 19 November 2007
13
optimum therapeutics need to be developed. The use of Platelet-rich plasma promises
to become a powerful therapeutic modality for use in muscle, tendon and ligament
injury in the future, but at present its use is considered a doping violation under the
WADA code, so research and treatment is restricted to non-elite sportspersons. In the
future an ironic dichotomy may exist whereby the general public will be able to
benefit from state of the art medical technology utilising growth factors, but elite
athletes will be excluded because of doping restrictions. The World anti-doping
agency and International Olympic committee must work with scientists to allow
athletes to benefit from the best medicine available in a both a safe and fair
environment.
What is already known on this topic
• Growth factors mediate tissue repair following injury
• Various techniques have been developed to deliver increased concentrations of
growth factors to sites of injury, including Autologous Blood Injections and
Platelet-Rich Plasma
• Robust data of clinical efficacy is lacking
• The use of growth factors is prohibited by the WADA Anti-Doping Code
What this study adds
• Growth factor technologies have the potential to accelerate healing in soft
tissue injury
• The debate of therapeutic
this is the read from growth factors in tendon repair :
Carcinogenesis
Growth Factors act on cell surface receptors, do not enter the cell, and do not
cause DNA mutation. There is no plausible mechanism by which GF result in
neoplastic development, and there have been no reports of this in the literature.6,22
Effect on Serum Growth Factor levels
Recent research by Banfi’s group in Italy47 looked at the potential systemic
effects of locally administered PRP. This group found that a locally administered
injection of PRP (4 patella tendons, 1 elbow) led to a fall in the Serum Concentration
of Epidermal Growth Factor (EGF). There was no statistically significant difference
in the concentration of VEGF, measured at 30mins, 3hrs and 24hrs post-injection
wheras other GF were not measured. A limitation of this study unfortunately was its
small size (n = 5), but the implication is that locally administered PRP will impact on
systemic levels of GF, but in a negative manner.
The use of GF methods and conflict with the WADA code
In the United Kingdom, the use of autologous blood products containing
growth factors entered the public arena when a Premiership Football Club Sports
Physician made enquires to the National anti-doping organisation (UK Sport) and
WADA regarding the legality of their use in sport50. The question asked forced
WADA to consider their position on both the use of autologous blood injections and
any autologous product which contains growth factors.
The response from WADA was quite clear, that the use of either of these techniques is
prohibited under the terms of the Prohibited List51(see figure 1). The use of ABI as
described above was considered prohibited under section M148 while the use of any
autologous product which contains GF was prohibited under Section S2. This section
specifically mentions Growth Hormone (GH), Insulin-like Growth Factor-1 (IGF-1),
and Mechano-Growth factor (MGF) as prohibited (see figure one).
Insulin-like Growth Factor-1 content of PRP:- therapy versus doping
Insulin-like growth factor-1 (IGF-1) is a 7.5kDa polypeptide, structurally similar to
Insulin49. It induces proliferation, differentiation and hypertrophy of multiple cell
lines, in particular skeletal muscle, and has an additional role of facilitating Glucose
entry into skeletal muscle cells 24, 49.
IGF-1 is secreted as the result of a hypothalamic-pituitary-liver axis. The
Hypothalamus secretes Growth Hormone-releasing hormone (GHRH), which
stimulates the Pituitary to release Growth Hormone (GH), which in turn stimulates the
Liver to release IGF-124. Like most endocrine systems, the system is controlled by
negative feedback, thus in normal individuals, exogenous administration of IGF-1 will
Downloaded from bjsm.bmj.com on 19 November 2007
11
lead to suppression of the axis. Whereas GH secretion is pulsatile, with greatly
varying levels in a 24hour period, serum IGF-1 levels are relatively stable within a
24hour period meaning a serum IGF-1 level is now the favoured test for Acromegaly
or Growth Hormone Deficiency52.
IGF-1 circulates in the serum 99% bound to a carrier protein Insulin-like Growth
Factor Binding Protein-3 (IGFBP-3). Only 1% of serum IGF-1 is ‘free’ IGF-1 (fIGF-
1), and it is the free portion which is believed to exert the biological effects, upon
binding to the IGF-1 receptor (IGF-1R)52. IGF-1 has a serum half-life of 10 minutes
(t½ 10mins) when unbound to IGFBP-353, and it is in this unbound form that IGF-1 is
administered within PRP. In contrast, the IGF-1/IGFBP-3 complex has a much longer
half-life of 16 hours (t½ 16hrs)53.
IGF-1 has at least three Isoforms, namely:- IGF-1Ea, IGF-1Eb and IGF-1Ec. IGF-
1Ea is the circulating form of IGF-1 released from the Liver, whereas IGF-1Ec, also
known as Mechano-growth factor (MGF) is the tissue isoform released from skeletal
muscle cells, and is believed to exert exclusively autocrine/paracrine actions24.
The different isoforms have slightly different biological actions. IGF-1Ea is known to
stimulate terminal differentiation of muscle cells into myotubes, and promote stemcell
mediated muscle regeneration, whereas MGF is damage sensitive, controls local
tissue repair, and is more potent than IGF-1Ea at causing hypertrophy24. MGF is
rapidly degraded in the serum24.
These varying biological actions of IGF-1 isoforms are important since IGF-1 derived
from PRP (IGF-1Ea) which is used for therapeutic purposes may not have the same
performance enhancing implications as skeletal muscle derived IGF-1Ec (MGF).
Serum IGF-1 levels vary greatly between individuals, and are dependent on genetic
influences and nutritional status, however a typical value of 300ng/ml (range 94-506)
is seen in 17-20 year old adults and 250ng/ml (range 117-358) in 21-30 year olds55. In
order to achieve such physiological levels, Children with Laron syndrome, a rare form
of GH resistance typified by very low levels of natural IGF-1, are given exogenous
IGF-1 in doses of 160mcg (micrograms) per day for many months54,55. Contrast this
with a typical dose of a single locally administered PRP injection in the treatment of
elbow extensor tendinopathy – 3mls of PRP containing ~ 100ng/ml of IGF-1 (total
dose 300ng)7 and there is a demonstrable 5 x 102 fold difference in even a single dose.
It is also important to mention that exercise has some effect on circulating levels of
IGF-1. Berg et al56 studied changes in serum IGF-1 in relation to acute bouts of
exercise. This group demonstrated a 27% increase in serum IGF-1 following 10mins
of moderate exercise in healthy adults, corresponding to changes of 10-28mcg/l. This
was likely to be IGF-1 released from skeletal muscle. The implication of this being
that it would be difficult to differentiate changes in serum IGF-1 as a result of
exercise, from changes caused by exogenous administration.
Thus there appear to be several compelling reasons to believe it would be unlikely
that PRP would be a potent ergogenic aid:
• The unbound IGF-1 has too short a half-life to be able to exert systemic effects
(10 minutes versus 16 hours).
Downloaded from bjsm.bmj.com on 19 November 2007
12
• The isoform IGF-1Ea found in PRP is not the isoform principally responsible
for skeletal muscle hypertrophy (IGF-1Ec/MGF).
• The doses of IGF-1 in PRP are sub-therapeutic in terms of producing systemic
anabolic actions by a factor of 500 (300 nanograms versus 160 micrograms).
A recent IOC Medical Commission Consensus Statement on the use of Growth Factor
technologies in therapy appears to welcome further research in the field “to ensure
these therapies are optimised” and, “to ensure athlete/patient safety”. We would
welcome such assertions also, though the statement by the IOC somewhat contradicts
the WADA Code which prohibits all use of Growth Factors therapies in elite sport57.
Notwithstanding these concerns expressed by WADA, it is possible to apply to a
WADA approved Anti-Doping Organisation for a Therapeutic Use Exemption to
utilise these techniques for specific clinical indications, in elite athletes. Given the
obvious difficulties associated with detection of these techniques and the bureaucratic
delays the TUE process entails, it is unclear whether this approach has been widely
utilised. Indeed, the only research known to have been conducted on professional
athletes makes no mention of any anti-doping concerns47. The authors would strongly
support the use of this approach in order for WADA to develop awareness of the
current clinical utility of these techniques.
Figure 1: Selected Sections of the 2006 WADA Prohibited List (WADA 2007)
S2 Hormones and Related Substances
The following substances, including other substances
with a similar chemical structure or similar biological
effect(s), and their releasing factors, are prohibited:
1. Erythropoetin
2. Growth Hormone (GH), Insulin-like
Growth Factors (eg. IGF-1), Mechano
Growth Factors (MGFs)
3. Gonadotrophins
4. Insulins
5. Corticotrophins
• M1 Enhancement of Oxygen Transfer
• The following are prohibited:
a. Blood doping, including the use of autologous,
homologous or heterologous blood or red blood cell
products of any origin.
Conclusion:
Medical technology continues to advance at a furious pace. The use of Growth
Factors promises to herald a new era of accelerated healing of injured tissues, and is
already commonplace in many fields of medicine. The technology is still in its
infancy with respect to soft tissue injuries, and the precise mechanisms of action, and
Downloaded from bjsm.bmj.com on 19 November 2007
13
optimum therapeutics need to be developed. The use of Platelet-rich plasma promises
to become a powerful therapeutic modality for use in muscle, tendon and ligament
injury in the future, but at present its use is considered a doping violation under the
WADA code, so research and treatment is restricted to non-elite sportspersons. In the
future an ironic dichotomy may exist whereby the general public will be able to
benefit from state of the art medical technology utilising growth factors, but elite
athletes will be excluded because of doping restrictions. The World anti-doping
agency and International Olympic committee must work with scientists to allow
athletes to benefit from the best medicine available in a both a safe and fair
environment.
What is already known on this topic
• Growth factors mediate tissue repair following injury
• Various techniques have been developed to deliver increased concentrations of
growth factors to sites of injury, including Autologous Blood Injections and
Platelet-Rich Plasma
• Robust data of clinical efficacy is lacking
• The use of growth factors is prohibited by the WADA Anti-Doping Code
What this study adds
• Growth factor technologies have the potential to accelerate healing in soft
tissue injury
• The debate of therapeutic
