NUTRITION & ERGOGENIC AIDS

Growth Hormone, Exercise, and Athletic

Performance: A Continued Evolution of Complexity
William J. Kraemer,1,2 Courtenay Dunn-Lewis,1 Brett A.Comstock,1 Gwendolyn A.Thomas,1 James E.Clark,1 and
Bradley C. Nindl 3
1
Human Performance Laboratory, Department of Kinesiology, 2Department of Physiology and Neurobiology,
University of Connecticut, Storrs, CT; 3Military Performance Division, The U.S. Army Research Institute of
Environmental Medicine, Natick, MA

KRAEMER, W.J., C. DUNN-LEWIS, B.A. COMSTOCK, G.A. THOMAS, J.E. CLARK, and B.C. NINDL. Growth
hormone, exercise, and athletic performance: a continued evolution of complexity. Curr. Sports Med. Rep., Vol. 9, No. 4,
pp. 242Y252, 2010. Growth hormone (hGH) presents pleiotropic effects in many tissues encompassing a diverse range of physiological
actions. Its complexity as a family of hormones with different isoforms and different somatotroph molecular functions continues to
challenge the status quo of our understanding of its release, function, and signaling. Owing to the fact that the majority of the literature
has viewed hGH from the perspective of the primary 22 kD monomer, further investigation is needed as to the influence and biological
activity of other aggregate and splice variant isoforms that are released into circulation. Its role over the life span and with supplementation
yields equivocal results with more study needed. Testing for the use of hGH has progressed, and the first positive test was recently
documented. Understanding of pituitary function and physiology will remain complex until the use of a broader range of analytical
techniques, including assays, becomes mainstream.

INTRODUCTION
Within the scope of physiological function, the extensive
and interconnected nature of hormonal relationships, the
complex web of molecular signaling pathways, and the vast
families of genetic interactions have made the study of a sin-
gle hormone’s role daunting at best. Deciphering the results
and physiological meaning of one study often can take years,
require new technology or analytical methods, and require
additional data. While simplistic dismissals for the relative
physiological importance of hormonal roles are more palat-
able, they can obviate the evolution of our understanding and
serve to minimize the appreciation for each molecule’s role in
our complex and integrated biology. A complete picture only
emerges with complete and comprehensive analysis.
The complexity of the endocrine system is best understood
through the endocrine model. The endocrine model is based
Address for correspondence: William J. Kraemer, Ph.D., FACSM, Professor, Human
Performance Laboratory, Department of Kinesiology Unit 1110, 2095 Hillside Road,
University of Connecticut, Storrs, CT 06269 (E-mail: William.Kraemer@uconn.edu).
1537-890X/0904/242Y252
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upon the basic tenet that perturbations within the physio-
logical system lead to a cascade of events to restore equili-
brium. The upper regulatory elements provide an integrated
stimulus to all downstream physiological systems and induce
adaptations (Fig. 1). Environmental conditions, age, sex, psy-
chological status, nutritional status or intake, and the spe-
cific nature of an exercise stimulus are the primary drivers of
this process. The integration of adaptations to any exercise or
training program is a confluence of these daily signals over
time. The dramatic demands on metabolism, cellular repair,
and tissue remodeling have made exercise a popular context
in which to study the endocrine model and hormones such
as human growth hormone (hGH). Of utmost importance,
however, is the proper use of appropriate analytical techniques
and context in doing so.
In this article, we examine a small portion of the evolving
paradigm of hGH with regard to exercise and in the con-
text of analytical techniques used to study it. A biological
description of the regulation and action of hGH will be dis-
cussed. While many essential aspects of 22 kD hGH regu-
lation and its action are understood and will be detailed, the
larger physiological context for growth hormone is, in some
senses, still in its infancy. We will discuss how the use of
the radioimmunoassay (in most research since the 1960s) has
focused research predominantly on the 22 kD monomer of
hGH. A host of other biochemical detection systems that

242

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Figure 1. The upper regulatory elements play a major role in creating
the integrated stimuli that is then supported or translated downstream to
signaling effects at the gene level.
detect the rich and diverse nature and function of other hGH
isoforms, including bioassays, have been neglected for some
time. As a result, the potential importance of all isoforms of
hGH to both aerobic and resistance exercise has not been
developed fully and will be discussed. As a final example of
our need for improved analytical techniques, the modern
misconceptions and abuse of exogenous recombinant growth
hormone (rGH) in multiple populations will be detailed
briefly. Throughout this discussion, the importance of uti-
lizing a broader set of analytical techniques to encompass
the complex nature of all growth hormone isoforms will be
emphasized.
SEQUENCE OF PHYSIOLOGICAL EVENTS IN GROWTH
HORMONE RELEASE AND REGULATION
The factors involved in the stimulation of 22 kD growth
hormone monomer secretion are well known (Fig. 2). A set
of upstream regulatory elements surrounding a specific exer-
cise protocol (68) stimulates the release of growth hormone
releasing hormone (GHRH) from the hypothalamus into the
hypophyseal portal system. GHRH binds with its receptors in
the anterior pituitary, leading to the synthesis and release of
hGH from their site of production in the somatotrophs of the
pituitary into the circulation. Correlations in the response of
exercise-induced plasma norepinephrine and hGH levels
could suggest that catecholamines drive hGH responses to
exercise (82). This basic GHRH model of hGH synthesis and
release follows a general endocrine model.
At the same time, the stimulation of hGH may be com-
plicated with an additional pathway. Ghrelin is associated
with stimulation of hunger and is produced in the human
stomach, the epsilon cells of the pancreas, and the arcuate
nucleus of the hypothalamus (53). The discovery of ghrelin as
an endogenous ligand for the hGH secretagogue receptor
(GHSR) in the anterior pituitary gland demonstrated its
ability to stimulate hGH release at the anterior pituitary (34).
Although subsequent research has shown that ghrelin directly
stimulates growth hormone-releasing neurons in the arcuate
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nucleus, ghrelin does not appear to be a major factor in the
exercise-induced hGH response (8). Nonetheless, it is of in-
terest that hGH may be stimulated both directly by GHRH
or indirectly (through increased GHRH or increased release)
by ghrelin.
The regulatory restriction of hGH production and release
from anterior pituitary somatotrophs is accomplished through
both inhibition and negative feedback. The primary inhib-
itor of hGH secretion is somatostatin [also referred to as
growth hormone inhibiting hormone (GHIH) or somato-
tropin release inhibiting factor (SRIF)] released from the
periventricular nucleus. Negative feedback also arises from
circulating hGH and insulin-like growth factor-1 (IGF-1, the
peripheral hormone for hGH). Thus blood concentrations of
hGH are controlled by somatostatin and through negative
feedback by hGH and IGF-1.
Like the stimulation pathways, the concept of regulatory
control also is continuing to evolve based on inherent dif-
ferences in the release patterns and contents of somatotrophs
(26,28) (Fig. 3). Band 1 somatotrophs show low granularity
and contain small molecular weight hGH molecules (e.g.,
22 kD). Band 2 cells have much greater granularity and a
different cell surface charge, and they contain binding pro-
teins and aggregates of hGH (e.g., 44 kD, dimers, homo-
and heterodimeric, tri- to pentameric, and growth hormone
binding protein-bound monomeric). An afferent feedback
loop from skeletal muscle to the hypothalamic-pituitary axis
influences the amount of so-called bioactive, large-molecular
weight hGH released, indicating that band 2 cells predom-
inantly were affected (51). Interestingly, reductions in band
2 content of pituitary cells also have been noted with expo-
sure to microgravity with little change in band 1 contents
(28). It therefore seems that a regulatory system for hGH
may exist within the pituitary gland.
PHYSIOLOGICAL ACTIONS OF GROWTH HORMONE
While the most dramatic visible action of growth hormone
occurs with the development of linear bone growth in child-
hood, hGH plays several important roles during exercise in
adulthood. Growth hormone exhibits pleiotropic effects in
many tissues encompassing such diverse physiological actions
as growth, reproductive function, immune function, osmo-
regulation, endocrine function, and neural function. The
various forms (variants, aggregates) of hGH circulate to target
tissues and interact with receptors to create additional hor-
monal signal events to the cells, such as peripheral production
of IGF-1. The classic ‘‘somatomedin hypothesis’’ states that
hGH exerts its primary effects by stimulating IGF-1 secretion
from the liver which then mediates somatogenic effects in
peripheral tissues, although it appears that direct effects of
hGH occur independent of IGF-1 upregulation (67).
The pulsatile release of growth hormone from the anterior
pituitary is an important aspect of growth hormone action.
Growth hormone pulses are released episodically throughout
the day and the majority is released nocturnally. Original
work by Isgaard et al. (30) and Maiter et al. (49) in rodent
models reported that growth hormone administered in a pul-
satile manner had a much more potent effect on both liver
IGF-1 and bone IGF-1 than continuous infusion (even when
Growth Hormone, Exercise, and Athletic Performance 243
Figure 2. In response to upper regulatory stimulation, human growth hormone (hGH) is released from different types of somatotrophs (band 1 or band 2)
that give rise to different types and concentrations of secretory products (22 kD or aggregates of higher molecular weight isoforms) in the blood. These
secretory products provide signals to the receptor components (including the growth hormone binding proteins). This produces a signal pathway of events
that leads to gene expression and acute homeostatic function. Repeated stimuli help to signal chronic adaptations to the integrated response from the
upstream regulatory elements.

the continuous infusion was five times greater). Conversely,
recent work in humans has suggested that continuous growth
hormone administration in humans is responsible primar-
ily for augmenting hepatic and muscle IGF-1 while pulsa-
tile growth hormone administration augments adipose tissue
lipolysis. Hence, the pulsatile release of growth hormone and
pattern of exposure to peripheral tissues determines growth-
promoting and metabolic effects in a pattern- and tissue-
specific fashion (75).
One key action of hGH is its impact on the metabolism of
substrates such as protein. Growth hormone is thought to
increase net muscle protein synthesis indirectly by facilitating
amino acid transport and availability via both endocrine and
locally produced IGF-1. Direct effects on muscle synthesis,
unrelated to protein metabolism, also are under investigation
(11). This anabolic impact of hGH helps to facilitate the
body’s exercise responses, but the impact on substrates is not
restricted to protein alone.
While often ignored, one of the most potent effects of hGH
is its lipolytic actions. hGH increases lipolysis by several
mechanisms, including 1) potentiating the sensitivity (via
activation of A-adrenergic receptors) of adipose tissue to other
lipolytic hormones (i.e., catecholamines); 2) stimulating the
primary fat breakdown enzyme (i.e., hormone-sensitive li-
pase); and 3) inhibiting fat storage enzymes (i.e., fatty acid
synthase and acetyl-CoA carboxylase). Through these ac-
tions, hGH ‘‘diverts’’ nutrients away from adipose tissue and
toward other peripheral tissues. The mobilization of fatty acids
during exercise is thought to accommodate the increase in
energy demands of the body.
Growth hormone’s impact on carbohydrate metabolism
causes a net elevation of circulating glucose concentrations

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Figure 3. The organization and biosynthesis of human growth hor-
mone (hGH) in the pituitary is related to the production of different hGH
isoforms, from the 22 kD to splice variants (e.g., 20 kD) to larger molecular
weight aggregates. All are organized and stored for release into the cir-
culation through a microtubular transport system. Release into the peri-
ventricular area also allows for last-minute, posttranslational processing of
hGH prior to being released into circulation.
(in excess, this may have a diabetogenic effect). It increases
gluconeogenesis at the liver, decreases glucose uptake into
adipose tissue and skeletal muscle, and decreases utilization of
glucose. Recent studies suggest that this may occur not by
changes in receptor levels at the plasma membrane (as pre-
viously believed) but by impairing the ability of the GLUT-4
receptor itself to transport glucose (65).
Figure 4. The rat tibial line bioassay. Hypophysectonized rats are injected with human samples and sacrificed. Weight gain is measured. A silver nitrate
stain is used to allow for the measurement of tibial epiphyseal plate growth at set time points to measure bioavailability of growth hormone in the sample.
Larger widths indicate higher human growth hormone (hGH) concentrations on a standard curve. (Courtesy of Dr. Wes Hymer, The Pennsylvania State
University, University Park, PA).
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GROWTH HORMONE DETECTION SYSTEMS
The responses to and adaptations of circulatory concen-
trations of growth hormone (for example, hGH) to exercise
and training have been studied extensively over the past 45 yr.
Interestingly, as described by Hymer et al. (27), the view of
this hormone has been documented primarily through the use
of various immunoassays (e.g., EIA, RIA) based on their re-
duced costs, assay duration, complexity, and/or sensitivity in
comparison to other assays (Table 2). One weakness of the
immunoassays, however, is that they essentially quantify the
22 kD monomer, the fundamental 191 amino acid product of
the hGH1 gene (9). While it is possible that the 22 kD mo-
nomer is the primary hGH molecule interacting with target
receptors, a paradox exists as the 22 kD does not interact with
all target receptors (27). Unfortunately, these immunoassays
often have been used to the exclusion of bioassays, which mea-
sure concentrations of other hGH isoforms.
The differences in the assays used have a significant impact
on both research findings and their interpretation. Different as-
says signal different target end points of interaction and there-
fore produce divergent values for both the magnitude and
response of hGH to exercise or physiological stimuli (13,14,29).
Once released from the anterior pituitary, the measured con-
centration of hGH in the blood via aggregate detection (i.e.,
tibial line rat assay or bioactive hGH) can be more than a
1000-fold greater than the concentration of 22 kD hGH that
is measured by immunoassay (13,29) (Table 1). The principle
of growth hormone pulsatility has been shown to exist in im-
munoreactive samples but it has not been reported with other
assays measuring the splice variants, aggregate, or bioactive
forms. It is clear that the complexity of pituitary function and
Growth Hormone, Exercise, and Athletic Performance 245
 TABLE 1. Estimated proportions of growth hormone forms in
plasma 15 min after secretion.
Monomeric Dimeric Oligomers Fragments
22 kD Noncovalent Noncovalent 30 kD (variable)
-Free (24%) -22 kD (14%) -22 kD (7%) 16 kD (variable)
-Bound (24%) -20 kD (5%) -20 kD (1%) 12 kD (variable)
20 kD -Acidic (1.5%) -Acidic (1%)
-Free (6.5%) Disulphide Disulphide
-Bound (2.5%) -22 kD (6%) -22 kD (3%)
Acidic -20 kD (2%) -20 kD (0.5%)
-Acidic (0.6%) -Acidic (1%)
Non S-S linked
covalent (1%)
While this provides an instantaneous view, it does not reflect the
perturbations due to pulsatility, exercise, and other factors. [Adapted from
Bauman G. Acta. Paediatr. Scand. 1990. Copyright * 1990. Used with
permission.]
the larger context of hGH cannot and should not be reduced
to the study of the 22 kD monomer alone.
One prominent bioassay that provides important insights
into hGH responses is the rat tibial line bioassay. This assay was
developed by Greenspan et al. (18) in 1949 and has been used
in our laboratory with exercise (18,39,51). Growth hormone
concentration differences are determined by the width of the
uncalcified growth plate in hyposectomized rats injected with
human samples (13,27,29) (Fig. 4). Papkoff and Li (60) indi-
cate that rat weight gain bioassays were the primary hGH
detection assay up to the 1960s despite various disadvantages.
Bioassays still allow for more information as to the specific re-
ceptor end point interactions (as 22 kD has low reactivity in
the assay) (14,27). Other bioassays (IM-9 lymphocyte cell line,
3T3-F422A adipocyte) have been used to quantify hGH,
but not all in exercise research (14,27). The rat tibial line
assay, therefore, is one important alternative to current im-
munoassay technology.
Several other types of assays have been used in exercise
research. The immunofunctional assay has been used to
determine the hGH molecules in which both epitopes were
available for binding and dimerization (73,74). It has been
shown that such signals of hGH are expected to be lower in
concentration and also correlate highly to the monoclonal
radioimmunoassay in response to exercise (58). The NB-2
node lymphoma assay is a lactogenic assay typically used for
determination of large molecular weight prolactin concen-
trations, but hGH concentrations also can be determined (14).
From our laboratory, it appears to have a different concentra-
tion signal than the immunoassay response patterns (34a).
Similarly, the use of mass spectrometry and a 2D-PAGE
method have been used to identify some of the hGH variants
as part of a potential strategy to determine ergogenic use of
hGH in athletics (33). Each of these assays might very well
offer a further dimension to exercise research examining hGH
response and adaptations.
As a final point, our picture remains incomplete, in part,
because not every assay has been used with exercise. One set
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of salient examples is related to the available cell proliferation
assays that have been used to measure hGH signal in a blood
sample. Roswall and colleagues (63) developed the assay using
cells from a mouse myeloid leukemia cell line that is trans-
fected with a full length receptor and then incubated with test
samples. The 3H-thymidine uptake into DNA was then used
as the measure of hGH activity. Wada et al. (79) also used a
similar approach to measuring hGH activity of certain var-
iants using Ba/F3-hGHR cells with the intent to gain under-
standing of the direct biological effects and hGH impact.
However, to date these cellular proliferation approaches have
not been used to examine exercise responses and may present
an opportunity for new discoveries in this area.
Our understanding of hGH has evolved over the past sev-
eral years based on the results we have been able to obtain
from the different types of hGH assays. Over 100 molecular
weight forms and two growth hormone binding proteins now
have been detected in the blood (3,4,27,45). Growth hor-
mone now appears to be more of a super-family of hGH iso-
forms and variants (56,59). The complexity of the anterior
pituitary cell system, growth hormone isoforms, and targeted
function has been described by Hymer et al. (27) and reflects
the very challenging and dynamic nature for understanding
anterior pituitary function. Investigations that take advantage
TABLE 2. Various methods to assay growth hormone samples in blood.
Test Type of Tests or Description of Single Test
In vivo bioassay Hypophysectonized rats injected with human GH
(bioactive) samples; measure weight gain and tibial epiphyseal
plate growth at set time points to measure
bioavailability of GH in the sample
Immunoassay RIA
EIA or ELISA: two forms, monoclonal or polyclonal
-Use specific monoclonal test for 22 kD and 20 kD
variant of GH to evaluate for doping
Immunofunctional
Receptor assay Radioreceptor assay
-Liver
-Lymphocyte
In vitro bioassay NB2 assay: lactogenic response of the NB2 node
lymphoma cells
Mass spectrometry Evaluation of pI, an indication of the molecular weight
of the GH protein. Isolates from samples to establish
percentages of each protein that is separated out
based on mass spectrometry reading
Biomarkers of GH IGF-1 via RIA
IGFBP via polyclonal EIA
Procollagen III propeptide (P-III-P) via monoclonal
EIA or via RIA
Cell proliferation 3H-thymidine uptake into DNA
assays
Ba/F3-hGHR cell line
EIA/ELISA, enzyme immunoassay; GH, growth hormone; IGF, insulin-
like growth factor; IGFBP, insulin-like growth factor binding protein; P-III-P,
procollagen III propeptide; RIA, radioimmunoassay.
www.acsm-csmr.org
of the wide variety of assays available will provide a clearer
and richer understanding of the physiological complexity of
hGH. These assays may have novel stories and may expand
the scope of our understanding of hGH behavior in the
human body.
EXERCISE RESPONSES
The potent impact of exercise on the release of hGH into
circulation was first documented by Hunter et al. (25) in
1965. Over time, a paradigm for the responses of hGH to both
aerobic and resistance exercise has developed, including some
appreciation for the influence of the upper regulatory ele-
ments. However, studies into hGH forms other than 22 kD
have suggested that there is more to the picture that has yet to
be uncovered. Taken as a whole, the research that has been
done with growth hormone’s response and exercise clearly
suggests that our knowledge of hGH has been restricted by our
preference for specific types of assays. This pattern will be
examined for both aerobic and resistance exercise.
Aerobic Exercise
Research into hGH and aerobic exercise historically has
been an attempt to better understand the metabolic roles of
hGH in energy production and its responses to exercise
intensities (%V̇O2max). Substantial research in the area, par-
ticularly recent investigations by Weltman and Veldhuis, has
provided a strong understanding of the interaction between
acute and chronic aerobic exercise and hGH release, as well as
the influences of gender, age, and adiposity (85). At the same
time, immunoassays have been the preferred analytical tool
for much of our current knowledge in this area.
The acute relationship of hGH to aerobic exercise is well-
characterized. The relationship of growth hormone to aerobic
exercise time is direct and positive; the rate of growth hor-
mone release increases at or close to the onset of aerobic
exercise and peaks at or close to its cessation (7,61,76,83,84,86).
Growth hormone concentration also increases linearly (in
a dose-response relationship) with aerobic exercise intensity
(61,62,71,85). Upper regulatory elements do impact the
stereotyped response. Kanaley et al. (32) demonstrated that
time of day did not influence the acute exercise response of
hGH, but response magnitudes and pulse characteristics po-
tentially were confounded by nutrition, sleep, prior exercise
patterns, and body composition. Elevated adiposity suppresses
hGH, including the response of hGH to aerobic exercise
(31,85). Older individuals have blunted responses of growth
hormone to the acute exercise, which may start at middle age
and progress (71,85,87). In addition, intensity, sex, adrenal
hormonal influences, nutritional intakes, and metabolic fac-
tors all impact this exercise response (71).
With chronic training, reductions in the hGH response
may be seen. Within 3 wk of chronic aerobic training, there
appears to be a down-regulation of exercise-induced hGH
release (21,85). When performed at the level of the lactate
threshold or above, chronic training may increase total 24-h
hGH on both days with and days without training (84).
There appears to be no chronic training impact in older in-
dividuals or in obese individuals in the absence of weight loss
(85). While down-regulation does appear to occur, it may not
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be at a significant level in all individuals or may require a
higher stimulus for some.
Although the relationship of hGH to aerobic exercise
seems clear, other research in this area helps to reiterate
the importance of bioassays. With submaximal cycle exercise
(65% V̇O2max), much of the plasma contains non-22 kD
isoforms during recovery (78). Rubin et al. (63) assayed
plasma at 90% and 100% V̇O2max and showed that higher
plasma concentrations of hGH were observed if the plasma
was reduced with glutathione to break down bonds within
oligomeres. Such data again point to the importance of al-
ternative analysis techniques to develop the larger context of
response patterns.
Resistance Exercise
The potential role of hGH in the repair and remodeling of
skeletal muscle and connective tissue has lead to the study of
hGH responses to acute resistance exercise. Research interest
began in the 1980s, and more attention was given to this
modality in the 1990s and onward. Before the understanding
of the importance of the acute program variables (or do-
mains), research into hGH responses did not take such factors
(such as gender, metabolic demands, rest period lengths,
intensity, amount of tissue activation, volume of exercise, and
choice of exercise) into account. However, once the impor-
tance of these domains was understood, the acute exercise
response patterns of growth hormone in the subsequent
studies began to account for the acute program domains. All
of these factors contributed to the response patterns of hGH
when examining it from an immunoassay signal detection
viewpoint (38,41).
An early research study suggested the importance of acute
program variables (or domains) such as intensity (68). In an
initial study by Vanhelder et al. (78), seven sets of leg lifts at
85% of the subject’s 7 repetition maximum increased growth
hormone concentrations in the blood. When the load was
reduced to one third of the intensity, no changes occurred.
The concept that not all resistance training protocols were
the same started to gain momentum at this point. Soon, the
impact of upstream regulatory elements in the workout design
on the hGH response was demonstrated. In 1990, Kraemer
and colleagues (37) demonstrated for the first time that rest
period lengths, intensity, and volume of work were all
potentially modifying factors when examining hGH responses
with heavy resistance exercise in men and later in women
(35) using immunoassays. Shorter rest periods stimulated
dramatically greater hGH responses to the resistance exercise
protocol and, as has been shown previously, women during
the follicular phase of the menstrual cycle had higher resting
growth hormone concentrations then men (36). The poten-
tial influence of metabolic signals (with shorter rest and
greater total work) may well have influenced the hGH
responses observed in these initial studies of the acute resist-
ance exercise response patterns (15,16). Häkkinen et al. (19)
eloquently validated the influence of total work by demon-
strating dramatically higher growth hormone concentrations
with 10 sets at 10 RM compared with 20 sets of 100% of 1
RM. Nindl et al. (57) showed that the pulse characteristics
were affected by acute heavy resistance exercise at different
times of the day. Different burst and output amounts followed
Growth Hormone, Exercise, and Athletic Performance 247
exercise versus control resting conditions over 16 h (including
sleep). The complexity of the physiological response of hGH to
the acute program variables, therefore, clearly was demon-
strated.
In 2000, McCall et al. (51) published data suggesting that
hGH responses might be different if viewed from the per-
spective of a bioassay, opening the door to more complexity in
both the regulatory roles and potential influences of higher
molecular weight isoforms in biological actions. In 2001,
Hymer et al. (29) investigated acute exercise in women dur-
ing the early follicular phase of the menstrual cycle. He and
colleagues showed that the rat tibial line bioassay resulted
in much higher values of hGH pre- and postexercise (six
sets of 10 RM in Smith-machine squat exercise). However,
the values were unchanged by exercise stress, even when
fractionated into different molecular weight fractions. Con-
versely, increases in concentrations were observed concom-
itantly with the use of immunofunctional assays and the
monoclonal RIA, which was higher than the polyclonal RIA.
When total samples were reduced with glutathione, an in-
crease in hGH signal was detected, again suggesting that
disulfide-linked hormone aggregates/fragments are released
into the circulation after the exercise regimen used in this
study. Such data also suggested that the exercise response
differed by assay perspective, reflecting the potential inherent
complexity of anterior pituitary somatotroph function. Bio-
assays therefore have helped to show that the response of hGH
to exercise is not limited to 22 kD.
Resistance training and its impact on hGH adaptations
remain in a state of uncertainty because of a number of up-
stream regulatory elements. Aging can impact the magnitude
of the response, but results are equivocal as to the changes in
response to a resistance exercise stressor (typically, no changes
have been reflected in resting values with training) (41,50).
One study examining the role of 6 months of resistance training
in women who were tested in the early follicular phase of the
menstrual cycle demonstrated even more complexity as hGH.
Results differed by training time, acute exercise response, pro-
gram used, assay type, and assay molecular weight fraction. This
showed that typical single radioimmunoassay of the 22 kD
molecules could not provide a complete understanding of
adaptation; even monoclonal and polyclonal assays showed
some differentiation (39). Interestingly, the whole body heavy
periodized group was the only group to demonstrate increases
after 6 months of training in their postexercise value for the
high molecular weight fraction of growth hormone as mea-
sured by the rat tibial line bioassay. Another study examining
these same assays showed strikingly few differences between
assays with the use of oral contraceptives (40). It is clear that a
variety of variables related to hGH adaptations are still under
investigation.
The significance of aggregates is another area of particular
interest in this line of research. One study often lost in this
area of study was the finding that stronger women have been
shown to have higher concentrations of growth hormone as
measured by the rat tibial line bioassay but not RIA. This may
suggest that physical characteristics of stronger women in the
untrained state are reflected in this aggregate concentration
(42). This could relate back to the sophisticated processing of
growth hormone in the somatotrophs and the regulation of
248 Current Sports Medicine Reports
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band 1 and band 2 type cells. Furthermore, the regulation
of the aggregate formation on the somatotrophs (potentially
by heat shock proteins and chaperone proteins) may be crit-
ical in this molecular organization. Investigations into hGH
aggregates that look into their significance should be exam-
ined with proper assay techniques.
EXOGENOUS GROWTH HORMONE FOR ANTIAGING
AND PERFORMANCE
Overview
Prior to the 1980s, exogenous growth hormone was limited
to either human and monkey sources. The synthesis of rGH
in the 1980s dramatically increased its availability and
allowed for the treatment of a broader range of medical con-
ditions. In concert with the medical implications, this
development created an availability of rGH that would allow
for its use in otherwise healthy individuals. While availability
was no longer a concern, legal considerations became more
relevant. Unlike most medications in America, hGH only is
approved by the U.S. Food and Drug Administration for a
discrete set of medical conditions and cannot be prescribed for
off-label. The prescription of rGH for any other purpose is a
felony punishable by up to 5 yr in prison, fines, or both.
Despite this classification, off-label use of rGH appears to
continue in individuals concerned with improvements in
body composition, sports performance, or the effects of aging.
The off-label use of growth hormone appears to be prom-
inent in two primary populations: those interested in antiag-
ing and those interested in athletic performance. After 40 yr
of age, individuals may expect to lose 5% of their muscle mass
every 10 yr. While controversial, sarcopenia, or the decline in
muscle mass with age, is a natural extension of frailty and is
associated with osteoporosis. While the lay public may not be
acutely aware of such factors, they may be concerned with
age-associated frailty, decreased independence, and increased
rates of illness, disability, and death. The potential for a de-
crease in these risks may be the cause of the use of rGH in
individuals. On the other end of the spectrum, for many elite
athletes, any potential to improve performance is worthwhile,
regardless of consequences (68). In both cases, the attraction
of rGH to healthy populations is based on its perceived abil-
ity to improve muscle mass, decrease fat stores, and improve
energy regulation.
While still an area of controversy, rGH has been shown to
increase uptake and decrease protein oxidation at both the
local and central level in healthy individuals (64). Clinically,
rGH increases total body water, decreases body fat, and may
increase fat-free mass in hGH-deficient patients (70). How-
ever, whether those or any results in the literature are relevant
in practice with healthy populations is a matter of some
debate. In some research, increases in fat-free mass could be
attributed to fluid retention and increases in connective tissue
(rather than increases in muscle) (22).
One issue with the use of rGH is that, once again, it chiefly
is available in the 22 kD form. Given the diverse functions of
hGH in the human body, the differential patterns of release
seen in acute exercise, and the presence of a broad variety of
isoforms within the human body, it is likely that the isoforms
do have physiological significance in terms of their function.
www.acsm-csmr.org
Growth hormone isoforms do not interact in the same way
with all growth hormone receptors. Indeed, the 22 kD form
does not interact strongly with the rat tibial line assay (15). In
addition, athletes are unlikely to take growth hormone in
isolation; much of the time, the concurrent use of anabolic
steroids or, at minimum, nutritional supplements limits the
applicability of research to athletes (23).
The safety of rGH is another issue of debate. Preliminary
studies in mice produced no changes in tumor incidence,
longetivity, or survival (70). However, the transfer of any
results to humans cannot be generalized. Importantly, the
impact of the use of one isoform of growth hormone, the
22 kD version as is marketed with rGH, to the exclusion
of all other isoforms cannot be anticipated. In the meta-
analysis conducted by Liu et al., side effects in the short-term
protocols were common and appeared to be related to salt and
water balance at the kidney. These effects included increased
sweating, edema, joint pain, and carpal tunnel syndrome.
Importantly, the elevation of plasma glucose in response to
growth hormone is a concern in older populations in terms
of the risk for diabetes (47).
Efficacy
The antiaging effects of rGH are not understood well. In
the animal model, a reduction in the activity of the growth
hormone/IGF-1 axis results in an increase in lifespan. This
trend also has been seen with caloric restriction, which is
associated with a decrease in IGF-1 (although this is neither
considered to be safe nor advised in humans). At the same
time, some animal studies have shown an increase in mor-
tality when the growth hormone/IGF-1 system was compro-
mised (70,54). Liu et al. (47) reviewed the use of rGH in older
populations. In older adults, short-term hGH use may increase
lean body mass; however, improvements in strength or quality
of life are not observed widely. The combined use of testos-
terone and hGH only increased lean body mass (6), and rGH
and resistance exercise did not increase muscle mass beyond
resistance exercise alone (77). However, resistance exercise
alone may be an effective method of addressing sarcopenia. In
sum, the research on the use of rGH to combat aging is
unclear and, in some ways, contradictory at this stage (54).
In 2008, Liu et al. completed a systematic review of 44
articles from 27 unique studies related to rGH for perfor-
mance enhancement. The 303 total subjects had an average
age of 27 yr (46). On average, the daily dose administered was
5 to 10 times higher than the dose administered clinically
(36 mcgIkgj1Idj1). The review unfortunately was limited by
the available body of knowledge. Recreational athletes com-
pleted short-term studies that did not reflect the usage of elite
athletes in terms of time, dosage, and use of other substances.
Particularly in the areas of strength and exercise capacity,
there is little research available. Additionally, the studies were
not sensitive enough to detect the minute differences that
distinguish first place from last in elite competition.
Despite the limitations in the available research, the results
of Liu et al. (46) indicated an increase in lean mass (2.1 kg),
no significant change in body mass, and a statistically insig-
nificant decrease in fat mass (j0.9 kg). In two studies evalu-
ating strength changes, no significant differences were seen
despite interventions of 42 and 84 d. Results from work on
Volume 9 Number 4 July/August 2010
c c
Copyright © 2010 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
metabolism indicated a slight resting preference for fat over
carbohydrate. Respiratory exchange ratios did not change, but
higher plasma free fatty acid and glycerol concentrations
combined with trends toward higher lactate levels indicated
that hGH supplementation may have influenced lipolysis.
Measures such as an increased heart rate with exercise could
suggest a decrease in work capacity.
A small number of studies do point to a more promising
impact from rGH. A carefully controlled 6-d study of 0.058
IUIkgj1Idj1 rGH on regular but abstinent steroid users
demonstrated strong results (17). Total protein, albumin, and
free thyroxine, and thyroid-stimulating hormone significantly
decreased while IGF-1 increased. Fat-free mass, peak V̇O2,
peak power, and strength increased and fat mass decreased.
A very recent 6-wk study examining recreational athletes
also showed positive effects of rGH as an ergogenic aid.
Meinhardt et al. (52) demonstrated that growth hormone
(2 mgIdj1 subcutaneously) in men and women, growth hor-
mone and testosterone (250 mgIwkj1 intramuscularly), or
combined treatments in men resulted in expected hormonal
changes as well as increased sprint performance, decreased fat,
and increased lean tissue mass. However, these speed changes
were not maintained after 6 wk of non-use. Thus, while the
majority of research shows little effect of rGH on performance,
the concept also is evolving as more research is done. From
their article, the authors stated:
‘‘First, body cell mass at baseline was correlated with all
measures of physical performance. Second, growth
hormone significantly reduced fat mass, increased lean
body mass through an increase in extracellular water, and
increased body cell mass when given with testosterone.
Third, growth hormone led to statistically significant
improvements in sprint capacity that were not
maintained after a 6-week washout period in a pooled
group of men and women, and the improvements were
greater when growth hormone was coadministered with
testosterone to men. Finally, changes in body cell mass
did not correlate with improvement in sprint capacity,
except when growth hormone was coadministered with
testosterone.’’
One effect worth discussion is the potential for hGH and
IGF impact on connective tissue. The synthesis of collagen,
an aspect of connective tissue associated with its strength, is
stimulated by exercise (44). Populations deficient in hGH
exhibit lower connective tissue deposition and show signs of
recovery in this aspect with treatment. The converse also is
true in conditions with excess hGH such as acromegaly
(10,11). A number of animal and human studies demonstrate
strong relationships between plasma growth hormone (or
IGF), the effectors of collagen synthesis at both the local and
systemic level, and both tendon and muscle synthesis of col-
lagen (10,11). IGF-1 promotes collagen synthesis, including
increased cell proliferation and protein synthesis, in the rabbit
tendon (1) and increases recovery from anterior cruciate liga-
ment (ACL) injuries in the rat (43). Hasen et al. (20) docu-
mented decreased bioavailability of IGF-1 and inhibited
collagen synthesis in response to exercise with women tak-
ing oral contraceptives (20). Healthy trials in humans
have shown increased whole-body collagen synthesis and/or
Growth Hormone, Exercise, and Athletic Performance 249
turnover (81), including a dose-dependent response (48) and
higher synthesis in an rGH-supplemented exercise group than
a placebo group in healthy active men (80); 50 mcg of rGH
increased collagen I mRNA and tendon collagen protein syn-
thesis 3.9-fold in younger healthy individuals, although this
was not impacted by moderate exercise (10). However, con-
clusions to be drawn from these data remain speculative (11).
In sum, the available research connecting rGH to antiaging
or performance-enhancing effects remains limited. Doessing’s
laboratory has continued research into effects on connective
tissue, but warned in the 2005 review that without a measure
of connective tissue breakdown, results must be viewed with
scrutiny (11). The conclusion of Liu et al. (46) was that any
claim on performance enhancement was premature and that
its use was associated with common side effects. In concert, a
statement by the Growth Hormone Research Society after an
international conference on the use of growth hormone in
older adults suggested that until more research was completed,
the use of rGH in older populations could not be recom-
mended (70). The complexity of growth hormone and its use
as a therapeutic drug or ergogenic aid requires further study
and validation of the salient hypotheses (23,54).
DETECTING RGH USE IN ATHLETES
rGH presents a unique testing challenge on a number of
levels. One factor motivating the use of rGH in athletes is
that to date no test for it has been proven legally (70). Urine
testing, often the preferred method of sampling in athletes, is
not possible with growth hormone. Growth hormone is
present at levels of less than 0.1% in urine and is highly var-
iable in terms of excretion (5). Blood measures must be used
when testing for growth hormone; this necessitates the inva-
siveness of blood testing and its political ramifications. How-
ever, the tests currently available are limited.
It is extremely difficult to accurately determine rGH doping
(12,23,24,55,65,66,69,71,72). While many substances may
be detected simply by supra-physiological levels in the blood,
the pulsatile release of growth hormone, its fast half-life in
the body, and its natural fluctuations due to sleep, stress, and
exercise, prevent the use of any testing modality based on
blood concentration alone. Circadian and ultradian rhythms
of secretion must be tracked to obtain accurate measurements
because hGH is secreted in a pulsatile manner; the peak for
a normal individual may appear to be no different than con-
centrations observed in an active rGH user. As hGH is
released in response to various stresses (exercise and psycho-
somatic stress included), testing at pre- and postcompetition
potentially may confound test results due to stress-induced
increases in hGH.
In addition to the fundamental challenges with growth
hormone, the blood testing itself presents a number of chal-
lenges. rGH is comprised exclusively of the 22 kD isoform and
has an amino acid sequence identical to it. There are no dif-
ferentiating aspects to the molecular sequence of synthetic
growth hormone from the 22 kD isoform that would other-
wise allow for its detection (5). Growth hormone, regardless
of the source, is metabolized rapidly; even individuals who are
doping may have undetectable levels of rGH. The fitness
level of the athlete, gender, ethnicity, age, nutrition status,
250 Current Sports Medicine Reports
Copyright © 2010 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
and recent athletic performance all may alter the results of the
growth hormone doping tests. Further, circulating binding
proteins and cross-reactivity may exacerbate confounding
factors (24).
The push for testing has resulted recently in positive test
results in a British rugby league player and a desire of major
sporting leagues in the United States (Major League Baseball,
National Football League) to institute rules for testing players
for rGH doping. The test for rGH use, as detailed by Saugy
et al. (65) and Stow et al. (71), is a two-part analysis of growth
hormone and growth hormone-related peptide biomarkers
obtained from a blood sample. The first aspect is referred to
as the isoform approach and the second is referred to as the
marker approach.
The isoform approach is a test of the ratio of the 22 kD
isoform (the isoform used in rGH) with other isoforms. Any
dramatic increase in the ratio of the 22 kD isoform to the
other isoforms could suggest the use of rGH in body. The
use of a recombinant assay to detect the 22 kD isoform with
a pituitary assay to measure other isoforms helps to deter-
mine this ratio. This test cannot account for pituitary-derived
growth hormone (which would have natural ratios of all
isoforms) or the natural variations in isoforms that occur with
developing adolescents. Another weakness of this test is that
a short window of time V probably at about 24 h after in-
jection V is required for accurate results. This suggests that
unannounced off-season tests would be more effective.
The second part of the test, the marker approach, relies on
the factors released in response to growth hormone in the
human body that may be detected up to 84 d after rGH
administration. Growth hormone-related biomarkers within
the same sample, IGF-1 and P-III-P, are analyzed. The results
are compared with normative values for gender, ethnicity, and
athletic training status (55). To our knowledge, while neither
this test nor the isoform approach have been validated in a
court of law, some suggest that a complimentary approach
utilizing both could present some degree of validity (5). De-
spite their weaknesses, they have been validated by the World
Anti-Doping Agency (WADA) and used in multiple Olym-
pic Games (5).
It has been suggested that pharmaceutical companies add a
marker to rGH to reduce the difficulty of doping tests. How-
ever, such an approach would not help with the identification
of so-called gene doping. This potential for the addition of
genes to the human body to produce these hormones, a pos-
sibility already tested in animals (2), would present a further
and incredible obstacle for testing.
CONCLUSION
To date, no testing modality has been challenged legally
and established to address the use of rGH in sport. The use
and abuse of rGH in both athletic and older populations
continues despite side effects, the relative paucity of data
suggesting benefits, and the unknown impact of the long-term
use of the 22 kD form of growth hormone to the exclusion of
other isoforms in healthy populations. While we have exam-
ined the evolving paradigm of hGH with regards to exercise,
the apparent misunderstandings concerning the true physio-
logical role of hGH in the community suggest that this
www.acsm-csmr.org
examination will not be complete without further inves-
tigations into the varied nature of hGH isoforms, variants,
and aggregates. It is the opinion of the authors that the con-
tinued development of the larger physiological context and
the nature of growth hormone can and should be achieved
through the use of a broader range of assay technologies used
to partial out the evolving complexities of pituitary function
from its somatroph origin, transport, binding, and targeting
of hGH in the human body with exercise and cellular and
tissue adaptations.
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