This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gibney, J. Articles by Sönksen, P. H. Search for Related Content PubMed PubMed Citation Articles by Gibney, J. Articles by Sönksen, P. H.

The Growth Hormone/Insulin-Like Growth Factor-I Axis in Exercise and Sport

Department of Endocrinology and Diabetes (J.G.), Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland; Department of Endocrinology and Diabetes (M.-L.H.), St. James’s Hospital, Dublin 8, Ireland; and Endocrinology and Metabolism Subdivision (P.H.S.), Developmental Origins of Adult Health and Disease Division, School of Medicine, University of Southampton, Southampton, United Kingdom

Correspondence: Address all correspondence and requests for reprints to: Peter Sönksen, East Wing Preshaw House, Preshaw, Upham, Hants SO32 1HP, United Kingdom. E-mail: PHSonksen{at}aol.com

	Abstract

Top Abstract I. Introduction II. Lessons from GH-Deficient... III. The GH-IGF-I Axis... IV. Supraphysiological GH and... V. GH Abuse in... VI. Therapeutic Possibilities... VII. Summary and Conclusions References

 
The syndrome of adult GH deficiency and the effects of GH replacement therapy provide a useful model with which to study the effects of the GH/IGF-I axis on exercise physiology. Measures of exercise performance including maximal oxygen uptake and ventilatory threshold are impaired in adult GH deficiency and improved by GH replacement, probably through some combination of increased oxygen delivery to exercising muscle, increased fatty acid availability with glycogen sparing, increased muscle strength, improved body composition, and improved thermoregulation. In normal subjects, in addition to the long-term effects of GH/IGF-I status, there is evidence that the acute GH response to exercise is important in regulating substrate metabolism after exercise. Administration of supraphysiological doses of GH to athletes increases fatty acid availability and reduces oxidative protein loss, particularly during exercise, and increases lean body mass. Despite a lack of evidence that these metabolic effects translate to improved performance, GH abuse by athletes is widespread. Tests to detect GH abuse have been developed based on measurement in serum of 1) indirect markers of GH action, and 2) the relative proportions of the two major naturally occurring isoforms (20 and 22kDa) of GH. There is evidence that exercise performance and strength are improved by administration of GH and testosterone in combination to elderly subjects. The potential benefits of GH in these situations must be weighed against potential adverse effects.

I. Introduction

II. Lessons from GH-Deficient (GHD) Subjects and Their Response to GH Replacement

A. The effects of GH deficiency and replacement on exercise performance

B. Mechanisms by which GH improves exercise performance in GHD adults

C. Limitations of using GHD adults to study the physiological effects of GH

III. The GH-IGF-I Axis and Exercise in Normal Subjects

A. The acute and long-term effects of exercise on the GH/IGF-I axis

B. The relevance to exercise performance of the GH-IGF-I axis in normal subjects

C. A potential role for GH in adaptation to training

IV. Supraphysiological GH and Exercise Performance

A. Effects of supraphysiological GH administration on the metabolic response to exercise

B. Effects of supraphysiological GH administration on protein metabolism and muscle mass

C. Exercise performance and strength in acromegaly

V. GH Abuse in Sport

A. GH as a putative performance-enhancing agent

B. Tests to detect GH doping by athletes

VI. Therapeutic Possibilities Related to Exercise Performance of Supraphysiological GH Administration

VII. Summary and Conclusions

	I. Introduction

Top Abstract I. Introduction II. Lessons from GH-Deficient... III. The GH-IGF-I Axis... IV. Supraphysiological GH and... V. GH Abuse in... VI. Therapeutic Possibilities... VII. Summary and Conclusions References

 
DEVELOPMENT OF AN assay for human GH (1, 2) was closely followed by the observation that plasma levels of GH increase soon after the beginning of exercise (3). Because of the known anabolic and lipolytic effects of GH and the observation that the exercise-associated increase in GH precedes an increase in circulating free fatty acids (FFAs), it was hypothesized that GH might play an important metabolic role during exercise (4, 5). Further evidence for this notion came from the discovery in the 1980s that exercise capacity and muscle strength are impaired in GH-deficient (GHD) adults and improved by GH replacement (6, 7, 8, 9). Although there is now a large body of literature addressing the effects of the GH/IGF-I axis on exercise and the effects of exercise on the GH/IGF-I axis, the contribution of GH to exercise capacity in normal subjects remains unclear.

Reports of the use of GH by athletes as a performance-enhancing agent (10, 11) predate the introduction of recombinant human GH (r-hGH) by at least 5 yr, and there is an increasing body of evidence that GH abuse represents a significant problem in a number of sports including athletics, swimming, and cycling (12, 13). The likelihood that attaining supraphysiological GH levels improves exercise performance should be considered in the context that although GH is clearly anabolic, there is no evidence that exercise capacity is enhanced by administration of GH to normal subjects (12, 13, 14), and in patients with long-standing endogenous GH excess (acromegaly), muscle strength is usually reduced (15). However, recent metabolic studies provide a plausible mechanistic explanation through which supraphysiological GH administration could lead to short- or-medium-term improvements in exercise performance, and regular seizures of GH from athletes demonstrate an ongoing belief in sporting circles that GH is performance enhancing.

The purpose of this review is, using data from GHD and normal subjects, to address the physiological role of the GH-IGF-I axis during exercise. We will also consider whether available evidence supports an effect of supraphysiological GH administration to enhance exercise performance and strength in athletes, and we will describe recently developed tests to detect GH abuse in sport. Finally, we will review data from studies that have addressed the possibility that administration of supraphysiological doses of GH might improve exercise performance in GH-replete subjects with impaired exercise capacity, including the healthy elderly and the obese.

	II. Lessons from GH-Deficient (GHD) Subjects and Their Response to GH Replacement

Top Abstract I. Introduction II. Lessons from GH-Deficient... III. The GH-IGF-I Axis... IV. Supraphysiological GH and... V. GH Abuse in... VI. Therapeutic Possibilities... VII. Summary and Conclusions References

 
A. The effects of GH deficiency and replacement on exercise performance
In a recent review describing how changes in GH status influence functional capacity and quality of life, the effects of GHD and replacement on exercise performance have been comprehensively evaluated (16). Briefly, maximal oxygen consumption (VO_2max; aerobic capacity or the maximum ability to take in and use oxygen) in GHD adults has been consistently shown to be reduced by estimates ranging from 17 to 27% compared with values predicted for age, gender, and height (6, 8, 17). The effect of treatment with GH to improve exercise performance in GHD adults was demonstrated in some of the first trials of GH replacement to be published, although the doses of GH used in those studies are now known to be supraphysiological. Cuneo et al. (6) demonstrated increases (and normalization compared with predicted values) in VO_2max, maximal power output, and the ventilatory threshold (VeT; lactate threshold) after 6 months of GH replacement in GHD subjects. Notably, the magnitude of the increase in VO_2max was proportionate to the increase in lean body mass (LBM), and after adjustment for changes in LBM or thigh muscle area, did not differ from baseline.

Woodhouse et al. (9) confirmed the finding that GH replacement increased VeT, demonstrated a reduction in fatigue after GH replacement, and provided a plausible explanation as to the mechanism through which this effect occurred. Before GH replacement, VeT occurred at a high percentage of VO_2max because VO_2max was low. Walking required high oxygen consumption relative to VeT (a mean of 83% at normal speeds and a mean of 120% at fast speeds). This effect is likely to lead to fatigue because, compared with normal subjects, the oxygen consumption necessary to carry out daily activities is more likely to exceed VeT, leading to lactate accumulation and limitation of activity. GH replacement increased VeT and also reduced the oxygen cost of walking relative to VeT at normal and fast speeds.

The majority of studies reported to date have demonstrated increased maximum work rate (6, 8, 9, 17, 18, 19, 20, 21, 22, 23) and VO_2max (6, 8, 9, 17, 19) after GH replacement in subjects with both childhood- and adult-onset (AO)-GHD, although statistically significant improvements compared with placebo were not demonstrated in all of these studies (8, 18, 19). One study demonstrated no improvement after GH replacement (24), whereas another demonstrated no difference in the improvement in VeT after exercise training in combination with GH replacement compared with after exercise training alone (25). Some of these studies may have been underpowered to detect between-group differences. The largest study to date addressing exercise performance in response to GH replacement included 55 patients with AO-GHD in a placebo-controlled, crossover study in which GH therapy was individually dosed to obtain an IGF-I concentration within the normal range for age and sex (26). A highly significant effect of GH replacement to increase VO_2max by approximately 6% was observed. The overall body of evidence therefore supports an effect of GH to improve maximum work rate, VO_2max, and VeT, with changes in VO_2max apparently accounted for by increased LBM.

B. Mechanisms by which GH improves exercise performance in GHD adults
The ability to perform exercise requires combustion of metabolic fuels, transforming chemical into kinetic and thermal energy. Glucose is the preferred fuel source for short-term high-intensity activity, whereas FFAs (derived from the circulation or from triglycerides stored in muscle or adipose tissue) become increasingly important during more prolonged activity (27). O₂ delivery to muscles depends upon adequate ventilation and O₂ transport to hemoglobin, circulatory distribution by an adequate cardiac output (CO) and peripheral circulation, dilatation of the muscle capillary network, and extraction of O₂ by the muscle fibers with either storage in myoglobin or immediate combustion. GH could improve exercise performance through increased delivery of substrate and oxygen to exercising muscle, increased fat oxidation with glycogen sparing, increased muscle strength, or a combination of these variables. GH could also improve exercise performance through indirect mechanisms, including changes in body composition or more efficient thermoregulation. These possible effects are demonstrated in Fig. 1.

View larger version (30K): [in this window] [in a new window]   FIG. 1. The effects of GHD (first panel) and GH replacement (second panel) in GHD adults on components of the physiological response to exercise. TG, Triglyceride; IMTG, intramuscular TG.

Independent of effects on preload, GH could also increase cardiac contractility through an anabolic effect on the myocardium, mediated either directly or through increased IGF-I (33). Most (34, 35, 36), but not all (37, 38) studies using echocardiography or equilibrium radionucleide angiography have demonstrated reduced left ventricular (LV) mass and LV ejection fraction (EF) in GHD adults compared with normal subjects. Reports of the effects of GH replacement on cardiac structure and function are inconsistent, but a recent meta-analysis (39) of placebo-controlled trials demonstrated a significant effect of GH replacement to increase left ventricular posterior wall thickness and SV. Of particular importance to this review is evidence from studies using radionucleide angiography that GH enhances the ability of LVEF to increase during exercise, which is necessary to provide adequate blood supply to exercising muscle (40, 41).

The effects of GH on SV and CO must be considered in relation to changes in systemic vascular resistance (SVR) and afterload. As described above, GH replacement increases SV, which in the absence of change in heart rate would be expected to increase mean arterial pressure. However, mean arterial pressure does not change or even decreases (42) after GH replacement, and because it represents the product of CO and SVR, this observation can only be explained by a reduction in SVR. A mechanistic explanation for this effect is provided by a study that demonstrated increased production of nitric oxide, the key mediator of endothelial relaxation, after 3 months of GH replacement (43). To date, no reported studies have addressed whether GH also influences the changes in regional blood flow that occur during exercise.

2. Substrate metabolism.
Hunter et al. (5) reported in 1965 that the exercise-induced increase in GH was followed by an increase in fatty acids and suggested that through its lipolytic effect GH could increase availability of fat as substrate during exercise. Under resting conditions, particularly when fasting, fatty acids are the predominant fuel used by skeletal muscle. Fat oxidation increases in relation to the intensity of exercise up to 65% of VO_2max (45), when it accounts for approximately 50% of energy expenditure, but with increasing intensity of exercise, the reliance on glucose as fuel increases, and the relative oxidation of glucose in relation to fat increases (27). Whether fatty acid availability influences partitioning of substrate oxidation during exercise is unclear, some studies demonstrating increased fat oxidation and reduced muscle glycogen depletion when fatty acid availability is greater (46, 47, 48, 49), and others demonstrating no effect (46, 47, 48, 49, 50, 51).

GH directly stimulates lipolysis through activation of adenylyl cyclase followed by activation of cAMP-dependent protein kinase and phosphorylation and activation of hormone-sensitive lipase (52). Studies in fat cells (53, 54, 55) and in animal models have shown that in addition to its direct lipolytic effect on adipose tissue (demonstrated by stimulation of basal lipolysis), GH also increases lipolysis indirectly by altering the effect of adipocytes to respond to lipolytic factors such as catecholamines.

Raben and Hollenberg (56) in 1959 demonstrated that GH increased plasma FFA in human subjects, and Rabinowitz et al. (57) in 1965 demonstrated that administration of GH enhanced forearm muscle uptake and oxidation of FFA and increased the release of FFA from adipose tissue. GH, administered as a bolus or by infusion, increases circulating levels of glycerol and FFA in GHD and normal subjects after a lag time of 2–3 h (58, 59, 60, 61). Small pulses of GH designed to mimic physiological pulses have been shown to induce a dose-dependent stimulation of lipid oxidation and increase circulating levels of FFA and glycerol (62). Using microdialysis techniques, it has been shown that a physiological GH pulse stimulates lipolysis in both abdominal and femoral adipose tissue, although to a greater degree in abdominal tissue (62). The metabolic effects of GH under resting conditions are summarized in Table 1.

View larger version (21K): [in this window] [in a new window]   FIG. 2. A, Lipolysis estimated from the rate of appearance of glycerol at rest, during exercise, and 30 min after exercise in GHD adults (n = 8) while receiving GH (GH+) and 3 months after discontinuation of GH replacement (GH–). B, Total body, trunk, and nontrunk fat estimated using dual-energy x-ray absorptiometry scanning in GHD adults (n = 8) while receiving GH (GH+) and 3 months after discontinuation of GH replacement (GH–). Results are expressed as percentage change from baseline. *, P < 0.05 for the change from baseline compared with a matched group of GHD adults who continued on GH replacement (data not shown). [Adapted from Ref. 63 with permission. Copyright 2003, The Endocrine Society.]

There is less information available concerning the effects of GHD and GH replacement on glucose kinetics during exercise. Under resting conditions, GH administration results in increased hepatic glucose production, reduced glucose uptake into skeletal muscle, and increased insulin secretion (67, 68, 69, 70, 71, 72, 73). There is increasing evidence that this effect may occur secondary to the lipolytic effect of GH (74). In the study of Gibney et al. (63), plasma glucose levels were greater under resting and exercise conditions during GH replacement, although in the study of Kanaley et al. (64) where a stable isotope glucose tracer was used, there was no discernible effect of GH on the rate of glucose appearance into or disappearance from the circulation. GH replacement did not alter glucose oxidation during exercise in the study of Brandou et al. (65).

In summary (Table 2), therefore, there is strong evidence that GH replacement increases lipolysis, FFA availability, and uptake from the circulation more markedly during exercise compared with resting conditions. There is also preliminary evidence that GH replacement increases whole-body fat oxidation during exercise, although it is not known whether this effect occurs in skeletal muscle or in other tissues. The effects of GH replacement on glucose metabolism during exercise appear to be less marked.

The physiological importance of the anabolic effect of GH is apparent in GHD adults. These effects have been comprehensively documented and reviewed (16, 77, 78) and will not be considered in detail here. Briefly, LBM is reduced in GHD adults by approximately 7–8% compared with age- and gender-matched normal subjects (77, 78, 79), representing similar reductions in extracellular water and body cell mass, the metabolically active component of LBM (80). Skeletal muscle comprises the majority of body cell mass, and studies using computed tomography and magnetic resonance imaging scanning have demonstrated a reduction in cross-sectional skeletal muscle area in GHD adults that is proportional to the reduction in LBM estimated by measurement of total body potassium (81, 82). Reduced muscle mass in GHD subjects is associated with reduced isometric muscle strength (81, 82, 83, 84), whereas some (19) but not all studies have also demonstrated reduced isokinetic strength (81, 83). It remains uncertain whether reduced strength is entirely accounted for by the reduction in muscle mass or whether there is also intrinsic muscle weakness associated with GHD (for review, see Ref. 16).

In contrast to the protein anabolic effect of GH replacement, which occurs within days to weeks of initiation of treatment, the overall body of evidence suggests that long-term but not short-term GH replacement increases and normalizes muscle strength. Cuneo et al. (82) carried out an extensive series of strength tests at the beginning and end of 6 months of GH replacement. Strength increased in most of the nine muscle groups that were studied, but it only reached statistical significance in one of the groups. This study and two other studies of GH replacement, lasting 12 wk and 6 months, respectively (17, 19), may not have been adequately powered to demonstrate a statistically significant effect. However, it is also possible that a detectable increase in muscle strength would require GH replacement of longer duration, and subsequently Johannsson et al. (85) demonstrated this in a 2-yr open-label study. In this study at baseline, compared with a reference population of normal subjects, GHD adults exhibited reductions in isometric and isokinetic muscle strength and local muscle endurance. After 2 yr of treatment with a mean daily dose of 0.62 ± 0.03 mg of GH, isometric and isokinetic strength increased into the normal range, although a reduction was seen in muscle endurance. A later study confirmed that these effects persisted after 5 yr of treatment (86). Like many of the clinical features of GHD, the effect of GH replacement was most pronounced in subjects in whom strength was most abnormal at baseline.

4. Body fat, extracellular water, and thermoregulation.
In addition to reduced muscle mass, other abnormalities of body composition (see Table 3 for summary of effects) and the ability to dissipate excess heat in GHD could contribute to impaired exercise performance. Total body and centrally distributed fat are increased in proportion to the duration of GHD, whereas extracellular water is reduced. The ability to carry out weight-bearing exercise is influenced by the quantity of body fat, which represents a mechanical limitation to exercise. The effect of reduced extracellular water on exercise capacity is less clear but might also be important. Sweating is essential for maintenance of body temperature during exercise, and thus impaired thermoregulation during exercise may also contribute to reduced exercise capacity in GHD. Using pilocarpine iontophoresis, it has been demonstrated that the sweat secretion rate is significantly lower in GHD adults than in appropriately matched control subjects and is increased during GH replacement. Juul et al. (87) demonstrated impaired thermoregulation during heat exposure and exercise in untreated GHD adults compared with normal control subjects. The same group later compared sweating and body temperature during exercise in hot conditions (35 C) in GHD adults who were receiving long-term (4 to 20 yr) GH replacement and normal subjects (88). Despite GH replacement, sweat secretion rates were reduced, body heat storage was increased, and therefore there was a greater increase in core temperature during exercise in GHD subjects. Interestingly, five of 10 GHD patients stopped exercise prematurely because of subjective discomfort and signs of heat exhaustion.

First, studies of exercise physiology in GHD subjects have generally been small and, as detailed in Section II.A, did not all demonstrate significant results using rigorous statistical methods. Although this might reflect type 2 statistical error, the possibility of publication bias must also be considered, i.e., trials showing a positive effect of GH are more likely to be published and ultimately included in meta-analysis.

Second, pharmacological GH replacement with a single sc nightly injection poorly reflects physiological GH production. In normal subjects, GH is secreted in a pulsatile manner, with episodic bursts shortly after the onset of sleep, during exercise, and a few hours postprandially (89). Potential effects of the GH/IGF-I axis on exercise physiology include both a long-term effect of GH secretion with changes mediated by both GH and IGF-I, and as described in detail in Section III.A a short-term effect mediated by the acute GH response to a given bout of exercise. Most of the studies reported above have addressed the medium- to long-term effects of GH replacement, but few have included any attempt to replicate the GH response to exercise.

Third, abnormal findings in GHD subjects must be interpreted in the context that the onset of GHD in adult life is usually secondary to significant pathology, most commonly a pituitary tumor (90). Although there is little information concerning the effects of pituitary neoplasia and its treatment on lifestyle and physical fitness, there is extensive evidence that these are impaired in survivors of other neoplastic diseases (91, 92, 93, 94).

Finally, most AO-GHD patients have other pituitary hormone deficiencies (90). Interpretation of the effects of GHD and GH replacement in this setting is complicated both by interactions between the GH-IGF-I axis and other endocrine axes and by the inherently unphysiological nature of pituitary hormone replacement. In particular, glucocorticoid excess is characterized by similar features as GHD, including reduced protein synthesis, reduced LBM and muscle mass, increased body fat, and impaired exercise capacity (95, 96, 97, 98, 99, 100, 101, 102). Until recently, overreplacement with glucocorticoids was almost universal in glucocorticoid-deficient patients and remains common particularly in patients with hypopituitarism, who are frequently only partially glucocorticoid deficient (103). Studying the effects of GH replacement, while maintaining the same glucocorticoid replacement dose, does not entirely overcome the difficulty of separating the effects of GHD from the effects of glucocorticoid excess because GH replacement, through an effect mediated by IGF-I, inhibits 11ß-hydroxysteroid dehydrogenase-1, which catalyzes the conversion of cortisone to cortisol (104, 105) resulting in a shift in cortisol metabolism favoring inactive cortisone (104, 105). Some of the effects of GH replacement therefore might reflect reduced glucocorticoid exposure, particularly in patients receiving cortisone acetate in whom this effect is more marked compared with hydrocortisone (106).

Interactions between the GH/IGF-I axis and thyroid hormones and sex steroids may also be important. Thyroid hormone replacement in the hypopituitary patient cannot be titrated against serum TSH, the most sensitive index of tissue activity of thyroid hormones, and thus subtle degrees of over- and underreplacement with thyroid hormones likely occur in hypopituitarism. GH, through increased 5'-deiodinase activity, increases conversion of T₄ to metabolically active T₃ (7), and it has been suggested that this effect might underlie some of the metabolic changes observed with GH replacement (107, 108). Untreated testosterone deficiency in males is associated with reduced LBM, increased body fat, and reduced exercise capacity, whereas orally administered estrogen reduces fat oxidation and increases body fat in normal women (109, 110). When administered together, testosterone and GH exert a combined effect on protein anabolism (Fig. 3) and body composition (111, 112), and there is increasing evidence that androgen deficiency might also contribute to the phenotype of hypopituitary women (113).

View larger version (15K): [in this window] [in a new window]   FIG. 3. Percentage leucine oxidation and percentage nonoxidative leucine disposal (NOLD) in hypogonadal GHD subjects at baseline, after treatment with GH alone and GH with testosterone (study 1), and at baseline, after treatment with testosterone alone and GH with testosterone (study 2). *, P < 0.05 vs. baseline. , P < 0.05 vs. baseline and vs. GH only. #, P < 0.05 vs. baseline and vs. testosterone only. [Derived from Ref. 111 . Adapted from J. Gibney et al.: Am J Physiol Endocrinol Metab 289:E266-E271, 2005 (112 ) with permission from The American Physiological Society.]

	III. The GH-IGF-I Axis and Exercise in Normal Subjects

Top Abstract I. Introduction II. Lessons from GH-Deficient... III. The GH-IGF-I Axis... IV. Supraphysiological GH and... V. GH Abuse in... VI. Therapeutic Possibilities... VII. Summary and Conclusions References

View larger version (25K): [in this window] [in a new window]   FIG. 4. The response of serum GH concentrations to exercise of different intensities. LT, Lactate threshold; Control, no exercise; 0.25LT, 25% of the difference between VO2 achieved at lactate threshold and VO2 at rest; 0.75LT, 75% of the difference between VO2 achieved at lactate threshold and VO2 at rest; 1.25LT, 25% of the difference between VO2 achieved at lactate threshold and peak VO2; 1.75LT, 75% of the difference between VO2 achieved at lactate threshold and peak VO2. Values are means ± SE; n = 10 subjects. [Reproduced from C. J. Pritzlaff et al.: J Appl Physiol 87:498–504, 1999 (133 ) with permission from The American Physiological Society.]

The physiological mechanisms through which GH secretion increases during exercise are not known, but changes in body temperature (148), blood lactate levels (130), and pH (149) have all been postulated. Supporting a role of body temperature is the observation that the GH response to exercise is greatly attenuated during exercise in cold conditions (148) and is proportional to core temperature (150). Against an effect of lactate are the observations that infusion of sodium L-lactate does not increase GH secretion (127) (although this experimental model differs significantly from an exercise-induced metabolic acidosis), and as described above there is a linear increase in GH secretion with increased exercise intensity that can be observed before the lactate threshold is reached (133). However, lactate production occurs very early in exercise although it does not increase substantially in blood until the Cori cycle is overwhelmed, and therefore an effect on GH secretion cannot be completely ruled out. There are little data concerning the effect of pH, although one study has demonstrated reduced GH secretion in response to exercise after alkali infusion (149).

Exercise exerts acute effects on other components of the GH/IGF-I axis. GH-binding protein, total IGF-I, IGF binding protein (IGFBP)-3, and acid-labile subunit increase slightly during exercise, whereas IGFBP-1 increases after exercise (151, 152, 153, 154, 155, 156), and free IGF-I does not appear to change during or after exercise (156). These observations are not altered after adjustment for changes in hydration status during exercise (156). IGF-I, IGFBP-3, and acid-labile subunit circulate as a ternary complex, and the observation that all three components increase in parallel with no change in free IGF-I suggests that these effects occur due to mobilization of preformed intact complexes. Consistent with this, IGFBP-3 proteolysis has been shown not to increase during or after strenuous rowing exercise (157). The physiological relevance of these effects is not known, but it has been postulated that the modest increase in IGF-I might enhance postexercise reparative processes, or that increased IGFBP-1 might protect against delayed onset hypoglycemia. There is currently no evidence to support or refute these possibilities.

B. The relevance to exercise performance of the GH-IGF-I axis in normal subjects
The strongest supporting evidence that an intact GH/IGF-I axis exerts a long-term effect on exercise performance comes from studies of exercise physiology in GHD subjects and their response to GH replacement. The findings of these studies and the limitations inherent in their interpretation are discussed in detail under Section II. Whether the acute increase in GH secretion that occurs in normal subjects in response to exercise is also physiologically relevant is not known. In the study of Kanaley et al. (64), acute elevation of GH levels in a pattern similar to the physiological response to exercise increased fatty acid availability during and after exercise at 65% of VO_2max. It is possible that this increase in fatty acid availability would result in glycogen sparing and increased exercise duration. However, because GH does not usually begin to increase until at least 10 min of exercise has elapsed and because, under resting conditions, the maximal lipolytic response to a GH infusion does not occur until approximately 120 min after the infusion has started (60), it is physiologically more likely that GH would exert an effect either during more prolonged low-intensity exercise or in the recovery phase after moderate to high intensity exercise. Consistent with this, Wee et al. (158) demonstrated an increase in lipolysis that reached maximal levels more than 2 h after 20 min of exercise at 70% of VO_2max in healthy subjects, and the magnitude of which correlated with the peak GH response to exercise. In the same study, a similar effect was reproduced under resting conditions using an infusion of GH calculated to mimic the GH response to exercise.

Two alternative approaches to determine the acute effects of GH in normal subjects are to administer an agent that suppresses GH secretion or GH effect, or to correlate the GH response to exercise in normal subjects with metabolic changes during exercise. Chalmers et al. (159), under control conditions and during an octreotide infusion to suppress endogenous GH release, measured plasma metabolites including glucose, glycerol, and FFA during 30 min of exercise at 70% of VO_2max and 90 min of recovery. No significant effect of GH suppression was observed. This study is important because it is the only one to date to use this approach to study the effects of GH/IGF-I on exercise, but a number of limitations must be considered. First, only six subjects were studied. Second, because no tracers were used, no conclusions can be drawn regarding rates of appearance into and disappearance from the circulation. Notably, in the study of Kanaley et al. (64), no statistically significant effects of GH were observed on plasma levels of FFA, despite marked effects on FFA turnover. Finally, results might have been confounded by other metabolic effects of octreotide (160). A similar study using GH receptor antagonists (161), which would be more specific for the effect of GH, and tracer techniques would now be possible and would provide invaluable information.

Pritzlaff et al. (162), in recreationally trained men, studied the response of GH and catecholamines during and after exercise of varying intensity and related these responses to changes in circulating metabolites and substrate oxidation. During exercise, neither glucose oxidation, which was directly proportional to exercise intensity, nor fat oxidation, which remained constant, was influenced by hormonal responses. Fat oxidation after exercise was related to exercise intensity, and although it correlated independently with both the peak GH and peak epinephrine response, using multiple regression analysis, only the peak GH response was found to be an independent predictor. There is evidence, therefore, that endogenous GH secretion exerts an immediate and a delayed effect to increase fatty acid availability after exercise (Fig. 5).

View larger version (9K): [in this window] [in a new window]   FIG. 5. Schematic representation of the possible association between the GH response to exercise and lipolysis. The shaded area represents the components of the lipolytic response to exercise that are probably augmented by the GH response to exercise. Because increased lipolysis during exercise precedes increased plasma levels of GH and because of the delayed effect of a GH pulse to stimulate lipolysis under resting conditions, it is probable that any effect of the acute GH response to exercise on lipolysis occurs in the postexercise period or during very prolonged exercise.

Endurance training over 4 months increases muscle protein synthesis (163), and recently an increase in mixed muscle protein synthesis immediately after endurance exercise has been demonstrated (164). GH secreted in response to exercise could contribute to this postexercise protein anabolic effect either directly or indirectly through increased lipolysis. Studies using animal models have demonstrated that increasing fatty acid availability reduces leucine oxidation (165), and in untrained human subjects, fat oxidation has been shown to correlate negatively with oxidative protein loss (166). Further support for modulation of the anabolic effects of GH through its lipolytic effect comes from a recent study in which an effect of GH to conserve protein during fasting was abolished by administration of the antilipolytic agent, acipimox (167). Administration of acipimox has also been used to demonstrate that GH increases skeletal muscle triglyceride content through its effect on insulin resistance (168). The importance of this is unclear because increased skeletal muscle triglyceride is observed, apparently paradoxically, in both insulin-resistant subjects and endurance-trained athletes (169).

Twenty-four-hour GH secretion rates and plasma IGF-I levels correlate positively with VO_2max and leisure time physical activity (170, 171, 172, 173), whereas long-term exercise training approximately doubles integrated GH concentrations in women when measured on nonexercising days (174). Levels of IGFBP-3 and total and free IGF-I increase after training (172, 175), increased IGF-I levels becoming detectable within 2 wk of commencing training (175) and remaining above baseline for at least 6 months (176). These long-term effects of exercise on the GH-IGF-I axis might also contribute to some of the effects of training, including increased muscle mass and increased CO, although evidence for this is currently lacking.

	IV. Supraphysiological GH and Exercise Performance

Top Abstract I. Introduction II. Lessons from GH-Deficient... III. The GH-IGF-I Axis... IV. Supraphysiological GH and... V. GH Abuse in... VI. Therapeutic Possibilities... VII. Summary and Conclusions References

 
A. Effects of supraphysiological GH administration on the metabolic response to exercise
Administration of supraphysiological GH to normal subjects under resting conditions increases insulin secretion, lipolysis, fatty acid availability, and fat oxidation, and reduces glucose uptake into skeletal muscle (59, 60, 108, 177, 178, 179, 180). More recently, the effects of administration of supraphysiological GH on intermediate metabolism during exercise have also been addressed (Table 5). Lange et al. (181) demonstrated that plasma levels of glucose, glycerol, FFA, and lactate were greater during moderate to high-intensity exercise in trained men after administration of a single dose of r-hGH, 2.5 mg sc, 4 h before exercise. Healy et al. (182) studied glycerol and glucose turnover using stable isotope techniques in endurance-trained athletes before and during 4 wk of r-hGH (0.06 mg/kg·d) administration. r-hGH increased lipolysis and plasma levels of FFA at rest and during and after submaximal exercise (Fig. 6). r-hGH did not influence glucose turnover at rest but increased rates of glucose production and uptake during and after exercise. The findings of these two studies are consistent, although there were important methodological differences. First, the study of Healy et al. addressed the effects of prolonged rather than acute GH administration. Second, the timing of GH administration in the study of Lange et al. resulted in increased GH levels during exercise in contrast to the study of Healy et al. in which GH levels were lower during exercise. Finally, the study of Healy et al. was carried out in the postabsorptive setting, whereas the study of Lange et al. was carried out postprandially. Taken together, the findings of these two studies demonstrate that GH enhances lipolysis during exercise under both postabsorptive and postprandial conditions and that the lipolytic effect of GH during and after exercise does not depend on increased circulating levels of GH during exercise. Despite increased fatty acid availability, there was no effect of GH on fat oxidation during or after exercise in either study or in two other studies in which this was also addressed (183, 184), consistent with the effects of GH on gene transcription in skeletal muscle described in Section II.B.2 (66).

View larger version (21K): [in this window] [in a new window]   FIG. 6. Lipolysis, estimated from the rate of appearance of glycerol (top panel), and oxidative protein loss, estimated from leucine oxidation (bottom panel) at rest and during and after exercise in endurance-trained athletes (n = 6), before and after 4 wk of treatment with GH, 0.066 mg/kg·d. *, P < 0.05 for the change from baseline. [Adapted from Refs. 182 and 190 with permission. Copyright 2003 and 2006, The Endocrine Society.]

Exercise exerts a significant influence on protein metabolism (189). Whole-body and muscle protein breakdown increase during exercise, whereas oxidation of certain amino acids, including leucine, increases during exercise. It is therefore apparent that studies of protein metabolism in the resting state may fail to recognize important changes occurring during or after exercise. Whole-body leucine turnover at rest and during exercise was also reported in the study of supraphysiological GH administration to athletes described under Section IV.B (190). At rest, after 1 wk of r-hGH administration, there was a net reduction in leucine oxidation and a net increase in protein synthesis, changes that were accentuated after 4 wk of r-hGH administration. As previously observed (189, 191, 192, 193), before r-hGH administration, leucine oxidation increased more than 2-fold during exercise. r-hGH administration reduced leucine oxidation during exercise by more than 50%, compared with a reduction under resting conditions of 29% (Fig. 5).

r-hGH administration has been consistently shown to increase LBM in young normal or trained subjects, but it is not known how much of this increase is secondary to protein accretion and how much to increased total body water (TBW) secondary to the antinatriuretic effect of GH (194). Using measurement of skinfold thicknesses, Deyssig et al. (195) demonstrated no change in LBM after 6 wk of treatment with r-hGH, 0.03 mg/kg·d. Using hydrodensitometry and measurement of TBW with dilution techniques, Yarasheski et al. (186) demonstrated an increase in both fat free mass and TBW after 12 wk of treatment with r-hGH, 0.04 mg/kg·d. Crist et al. (196), also using hydrodensitometry, demonstrated an increase in fat free mass and a reduction in percentage body fat after 6 wk of treatment with met-hGH. Healy et al. (190) demonstrated a mean increase in fat-free soft tissue mass of 3.8 kg using dual-energy x-ray absorptiometry scanning. Although this technique, like hydrodensitometry, does not differentiate metabolically active body cell mass from extracellular water, the observed reduction in resting leucine oxidation data would predict a mean increase in body protein of 0.6 kg over 28 d, representing an increase of approximately 5% based on normative data (197).

There is evidence, therefore, that supraphysiological GH administration to trained subjects results in conservation of protein and that this effect is particularly marked during exercise. As described under Section III.B, protein anabolic processes are influenced by fatty acid availability, and therefore it is possible that these effects are secondary to the lipolytic effect of supraphysiological GH. Figure 6 demonstrates the reciprocal relationship between lipolysis and oxidative protein loss demonstrated in the studies of Healy et al. (182, 190). Evidence that changes in body composition after administration of supraphysiological GH are functionally important is considered in Sections V and VI.

C. Exercise performance and strength in acromegaly
Patients with acromegaly represent a useful model to study the chronic effect of GH excess, although the potentially confounding influence of duration of disease, recovery from long-term illness, and the effects of other hormone deficiencies and replacement must be considered. Acromegaly is characterized by marked abnormalities in protein (198) and carbohydrate (199, 200, 201, 202) metabolism and at least late in the disease process, impairments in strength and exercise performance. Protein remodeling in long-standing acromegaly is abnormal in most organ systems, including skeletal muscle, resulting in tissue disorganization and functional impairment, and in some cases cardiomyopathy. Despite an increase in muscle mass, histological examination of muscle fibers reveals a myopathic process, and physical strength is reduced rather than increased (15). Nagulesparen et al. (15) carried out muscle biopsies on 18 acromegalic patients and showed abnormalities in more than half, typically hypertrophy of type 1 fibers and atrophy of type 2 fibers. The degree of abnormality correlated positively with circulating GH levels.

Long-standing acromegaly is also associated with impairment in aerobic exercise capacity and cardiac performance. VO_2max and VeT are reduced in patients with acromegaly, compared with normal subjects, and improve after treatment with octreotide (203). Colao et al. (204) using radionucleide angiography studied cardiac performance during exercise in acromegalic subjects and normal controls. The LVEF response to exercise was reduced in acromegalic subjects and correlated inversely with age and duration of acromegaly. The same investigators later reported that normalization of GH and IGF-I levels after 1 yr of treatment with octreotide was associated with improvement in, but not normalization of, LVEF both at rest and during exercise (205).

Although these findings suggest that long-term GH excess is likely to be detrimental to exercise performance, it should be noted that clinical features of acromegaly are usually present for some years before diagnosis, and that biochemical GH excess precedes the appearance of clinical signs. Although cardiac function is typically found to be impaired in long-standing acromegaly, Fazio et al. (206) have demonstrated that in acromegaly of less than 5-yr duration, certain potentially beneficial components of cardiac function including stroke index and cardiac index are increased, and SVR is reduced. Important differences have also been demonstrated in the acute and long-term effects of treatment of acromegaly. Normalization of IGF-I levels in patients with acromegaly results in an increase in oxidative protein loss (representing net protein catabolism) that is not sustained but a reduction in protein remodeling that is sustained (207). Extrapolating these findings to acute and long-term GH excess would imply an initial anabolic phase (evidence for which is described under Section III.A) followed by a later phase when body protein mass remains stable but when there is a potentially deleterious effect on protein remodeling. It is therefore possible that there is a window in which the potentially beneficial effects of supraphysiological GH predominate, and indeed one of the authors reports such an occurrence in an elite oarsman (P. H. Sönksen, personal communication). A possible mechanism through which these effects might occur is demonstrated in Fig. 7.

View larger version (16K): [in this window] [in a new window]   FIG. 7. Schematic representation of the effects of short-term and long-term GH excess. Question mark indicates a possible, but unproven, short-term effect of supraphysiological GH to increase strength.

	V. GH Abuse in Sport

Top Abstract I. Introduction II. Lessons from GH-Deficient... III. The GH-IGF-I Axis... IV. Supraphysiological GH and... V. GH Abuse in... VI. Therapeutic Possibilities... VII. Summary and Conclusions References

However, to put these unimpressive scientific findings into context, anabolic steroids were widely abused for more than 40 yr (14) before they were definitively shown to increase strength (213), and the pattern of GH abuse by athletes may differ considerably from controlled clinical trials. In particular, there is evidence of an additive effect between testosterone and GH (112), and trials of their combined administration to athletes have not yet been reported. Furthermore, the marginal changes that differentiate winning from losing in high-level sport are unlikely to be detected in classical clinical trials, which are usually statistically powered to distinguish much larger differences. Athletes and coaches, who meticulously monitor their own performance, can detect much smaller changes with different interventions that could not be identified in small or medium-sized clinical trials. This has been demonstrated in secret doctoral theses pertaining to the sports doping program of the German Democratic Republic (214), which became available in the early 1990s after German reunification. In these papers, it is clearly shown that the principal method used by doctors and coaches to evaluate the effects of anabolic steroids was by comparing performance targets in individual athletes when taking and not taking different agents.

B. Tests to detect GH doping by athletes
It is important to detect abuse of GH in the interest of fair competition and also because, as illustrated by the pathophysiological model of acromegaly, long-standing elevation of GH and IGF-I is detrimental to health (215). However, a number of factors complicate GH detection. Exogenous r-hGH and endogenous GH have identical amino acid sequences, making chemical distinction impossible. GH is secreted in a pulsatile manner; is under the influence of stress, exercise, sleep, and food intake (89); and has a very short half-life in the circulation (216), resulting in serum concentrations that vary widely throughout the day and frequently overlap with measurements obtained after exogenous administration of GH. The concentration of GH (like other proteins) in urine varies markedly with exercise and has been previously demonstrated to be insensitive as a marker of either GH administration or acromegaly (217, 218). It is very likely, therefore, that any useful test for GH abuse will involve blood sampling, which represents a major change from the long-established antidoping methods that are based on postcompetition urine tests.

To date, two approaches to detection of GH administration have shown promise. The first approach involves measurement of serum markers of GH action and has largely been developed through the work of the GH2000 and GH2004 projects. Serum levels of IGF-I, IGFBP-2, IGFBP-3, and the bone markers bone-specific alkaline phosphatase, carboxy-terminal propeptide of type I procollagen, carboxy-terminal cross-linked telopeptide of type I collagen, and procollagen type III (PIIIP) were identified in a pilot study (156, 219, 220, 221, 222) as having characteristics potentially useful in detection of exogenous GH administration. These included a clear response to exogenous GH administration, a much smaller response to acute exercise, day-to-day stability within subjects, clear separation between GH and placebo-treated subjects, and persistence of elevated concentrations for many days after the last GH injection. A subsequent double- blind, placebo-controlled trial (DBPCT) demonstrated that 28 d of self-administration of two doses of GH (0.067 and 0.133 mg/kg·d) predictably altered these markers. Notably, plasma levels of bone and connective tissue turnover remained elevated for significantly longer than components of the IGF-IGFBP axis, up to 8 wk after cessation of GH in the case of osteocalcin and PIIIP (219, 221). Reference data from elite athletes in the postcompetition setting were obtained in a cross-sectional study, in which it was demonstrated that after adjustment for the effects of age there was little or no effect of auxological characteristics or the type of sport performed on any of these variables (223). Interestingly, the age-associated decline of plasma IGF-I observed in that study was at least as marked as that previously observed in normal sedentary populations (224, 225, 226), which is highly suggestive that the decline in GH-IGF-I activity is an inexorable feature of the aging process and is not attenuated by maintaining physical fitness (Fig. 8).

View larger version (25K): [in this window] [in a new window]   FIG. 8. Age-dependent change in components of the IGF/IGFBP system in 537 elite male (x) and 276 elite female () athletes. Reference ranges for male (solid lines) and female (dashed lines) athletes are shown. [Reproduced from Ref. 223 with permission. Copyright 2006, The Endocrine Society.

The second potentially useful approach to developing a test for GH abuse involves simultaneous RIA of the natural isoforms and fragments of GH, the two most commonly occurring being 22-kDa GH and 20-kDa GH. Exogenous administration of supraphysiological doses of r-hGH, which consists exclusively of 22-kDa GH, suppresses endogenous GH secretion and therefore increases the ratio in plasma of 22-kDa to 20-kDa GH (228). Preliminary studies evaluating this approach have shown promise (229, 230), although in view of the short half-life of GH in the circulation, this test is only likely to be effective if sampling is carried out within 24 h of the last GH injection. Furthermore, there is a more marked increment in circulating 22-kDa GH compared with 20-kDa GH levels in response to exercise (229), and therefore the sensitivity of the test could be reduced in the postcompetition setting. Pituitary-derived GH consisting of multiple isoforms and fragments is still in circulation, and its use will not be detected. Finally, it must be considered that recombinant 20-kDa GH has also been synthesized, and therefore appropriate combinations of 20- and 22-kDa r-hGH could potentially confound this test. Of note, this test was introduced in the Olympic Games in 2004 and the Winter Olympics in 2006, but no positive tests were recorded.

It must also be considered that in addition to self-administration of GH, other technologies to manipulate the GH/IGF-I axis are emerging. These include gene doping, GH secretagogues, recombinant human IGF-I (r-hIGF-I) and r-hIGF-I/recombinant IGFBP-3 complex. In animals, injection of a recombinant adenoassociated virus genetically manipulated to induce myocyte overexpression of IGF-I induced a 15% increase in muscle mass and a 14% increase in muscle strength without inducing a systemic increase in IGF-I (231). There are few data concerning the effects of r-hIGF-I administration on exercise performance, although one paper demonstrated that a single r-hIGF-I injection to healthy male volunteers 2–4 h before exercise increased SV, CO, and EF, but did not influence exercise duration or VO_2max (232). However, because the effects of GH on these variables appear to be at least partially mediated through increased muscle mass, it is not surprising that a short-term effect would not be detectable.

	VI. Therapeutic Possibilities Related to Exercise Performance of Supraphysiological GH Administration

Top Abstract I. Introduction II. Lessons from GH-Deficient... III. The GH-IGF-I Axis... IV. Supraphysiological GH and... V. GH Abuse in... VI. Therapeutic Possibilities... VII. Summary and Conclusions References

 
In contrast to athletes, in whom GH secretory rates are normal or increased, elderly and obese subjects secrete less GH compared with young subjects with normal body mass index and therefore might be more likely to benefit from GH administration. The first major study to explore the possibility that GH might ameliorate some of the changes in body composition and functional ability that occur with aging was reported by Rudman et al. (233), who demonstrated increased LBM, skin thickness, and bone mineral density, and reduced total body fat after administration of GH for 6 months to older men. However, despite confirming these potentially beneficial changes in body composition, subsequent studies demonstrated little or no improvement in strength or functional ability increase after administration of GH alone (233, 234, 235) or in combination with exercise training (236, 237) to elderly subjects. These disappointing findings might reflect difficulties in determining the most appropriate dosing regime because side effects related to overdosage were common, or alternatively that because production of both GH and testosterone declines with age and because these two anabolic hormones exert an additive effect treatment with either hormone in isolation might be ineffective.

Three recent well-designed studies have addressed the possibility that GH and testosterone in combination might be more efficacious than either hormone alone. In a 26-wk DBPCT, small increases in muscle strength and VO_2max that correlated with increases in LBM were demonstrated in men who were treated with combined GH and testosterone (238). Notably, deterioration in glucose tolerance occurred in a significant number of subjects. A small crossover study compared the effect of administration of testosterone, GH, and combined testosterone and GH in doses chosen to approximate physiological production rates for 1 month each to elderly men (85). Small improvements were seen in some indices of physical function, including walking and climbing stairs, after administration of either hormone alone or in combination, and improvement in balance was seen after treatment with GH alone. The effects of administration of GH and testosterone alone and in combination for 6 months to healthy elderly men were studied in a more recent well-powered DBPCT (239). The dose of GH was titrated to achieve plasma IGF-I levels in the upper half of the normal range, and a transdermal preparation of testosterone was administered daily that resulted in plasma testosterone levels within the normal range. LBM increased with GH alone, whereas there was an increase in muscle mass and a reduction in total body fat after combined treatment. VO_2max also increased significantly in patients who received combined treatment compared with those who received placebo and those who received either treatment alone. Overall, the combined effect of the two hormones was additive rather than synergistic. Of note, all of these studies have been relatively short-term and as described under Section II.B, improvements in strength in GHD adults have only been clearly identified after 2 yr of treatment.

Fewer studies have addressed the effects of GH on physical performance in overweight or obese normal subjects. No additional effect on muscle strength or VO_2max was observed after addition of either GH or IGF-I or a combination of both to a 12-wk program of exercise and weight loss in overweight women, despite increased fat-free mass and reduced total body fat with GH alone or in combination (240). No additional effect of GH on muscle strength or anaerobic power output during jumping was observed in 3-wk study that compared the effect of weight reduction and strength training alone or with the addition of GH (44).

	VII. Summary and Conclusions

Top Abstract I. Introduction II. Lessons from GH-Deficient... III. The GH-IGF-I Axis... IV. Supraphysiological GH and... V. GH Abuse in... VI. Therapeutic Possibilities... VII. Summary and Conclusions References

 
Studies in GHD adults have provided evidence to support the postulate, first made by Hunter and associates more than 40 yr ago, that the metabolic effects of GH might be important in exercise performance. Adult GHD is associated with a decrease in VO_2max that is proportional to the well-documented reduction in skeletal muscle mass, and a decrease in VeT that reflects a reduction in the intensity of exercise that can be carried out aerobically and potentially explains reduced energy levels. DBPCTs have, in general, demonstrated that GH replacement improves exercise performance, probably through a combination of increased delivery of oxygen to exercising muscle, increased FFA availability and fat oxidation, increased muscle mass and strength, reduced body fat and improved thermoregulation. Despite potentially confounding variables including the unphysiological nature of GH replacement, the long-term effects of recovery from serious illness and interactions with other hormonal axes, these observations provide evidence that an intact GH-IGF-I axis is important in maintaining normal exercise capacity.

There is also evidence that the acute GH response to exercise in concert with reduced circulating insulin levels is important in regulating fatty acid availability in the postexercise setting, and it is possible that this effect contributes to the changes in body composition and exercise performance that occur as a result of training. It is also possible that the acute GH response also contributes to the protein anabolic effect of exercise, either directly or through increased fatty acid availability, although this remains unproven.

The effects of administration of supraphysiological doses of GH to subjects with an intact GH/IGF-I axis potentially differ between athletically trained subjects, in whom production of GH and IGF-I is normal or increased, and elderly or obese subjects in whom GH secretion rates are decreased. Administration of supraphysiological doses of GH to athletes increases fatty acid availability and reduces oxidative protein loss at rest and during and after exercise and exerts potentially beneficial effects on body composition. Although there is little scientific evidence that these effects translate to improved performance, GH abuse has been widespread among athletes for more than 20 yr. The two most promising approaches to detection of GH abuse involve measurement of serum markers of GH action and measurement of the relative proportions in serum of the naturally occurring isoforms of GH.

There is preliminary evidence that GH treatment is useful in improving body composition and exercise performance in elderly subjects particularly when used in association with testosterone. In contrast, there is no evidence that GH improves physical performance in obese subjects, although there have been a few studies with small numbers of patients carried out over short duration. It will be important, when considering the role of GH treatment in these or any other subject groups, to balance potential gains with the safety concerns associated with maintaining supraphysiological GH levels.

	Footnotes

 
Disclosure Statement: The authors have nothing to declare.

First Published Online September 4, 2007

Abbreviations: AO-GHD, Adult onset GHD; CO, cardiac output; DBPCT, double-blind, placebo-controlled trial; EF, ejection fraction; FFA, free fatty acid; GHD, GH deficient or GH deficiency; IGFBP, IGF binding protein; LBM, lean body mass; LV, left ventricular; PIIIP, procollagen type III; r-hGH, recombinant human GH; r-hIGF-I, recombinant human IGF-I; SV, stroke volume; SVR, systemic vascular resistance; TBW, total body water; VeT, ventilatory threshold; VO_2max, maximal oxygen uptake.

	References

Top Abstract I. Introduction II. Lessons from GH-Deficient... III. The GH-IGF-I Axis... IV. Supraphysiological GH and... V. GH Abuse in... VI. Therapeutic Possibilities... VII. Summary and Conclusions References

 

1. Glick SM, Roth J, Yalow RS, Berson SA 1963 Immunoassay of human growth hormone in plasma. Nature 199:784–787[CrossRef][Medline]
2. Hunter WM, Greenwood FC 1962 A radio-immunoelectrophoretic assay for human growth hormone. Biochem J 85:39
3. Roth J, Glick SM, Yalow RS, Berson SA 1963 Secretion of human growth hormone: physiologic and experimental modification. Metabolism 12:577–579[Medline]
4. Hunter WM, Fonseka CC, Passmore R 1965 The role of growth hormone in the mobilization of fuel for muscular exercise. Q J Exp Physiol Cogn Med Sci 50:406–416[Abstract/Free Full Text]
5. Hunter WM, Fonseka CC, Passmore R 1965 Growth hormone: important role in muscular exercise in adults. Science 150:1051–1053[Abstract/Free Full Text]
6. Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH 1991 Growth hormone treatment in growth hormone-deficient adults. II. Effects on exercise performance. J Appl Physiol 70:695–700[Abstract/Free Full Text]
7. Jorgensen JO, Pedersen SA, Laurberg P, Weeke J, Skakkebaek NE, Christiansen JS 1989 Effects of growth hormone therapy on thyroid function of growth hormone-deficient adults with and without concomitant thyroxine-substituted central hypothyroidism. J Clin Endocrinol Metab 69:1127–1132[Abstract/Free Full Text]
8. Nass R, Huber RM, Klauss V, Muller OA, Schopohl J, Strasburger CJ 1995 Effect of growth hormone (hGH) replacement therapy on physical work capacity and cardiac and pulmonary function in patients with hGH deficiency acquired in adulthood. J Clin Endocrinol Metab 80:552–557[Abstract]
9. Woodhouse LJ, Asa SL, Thomas SG, Ezzat S 1999 Measures of submaximal aerobic performance evaluate and predict functional response to growth hormone (GH) treatment in GH-deficient adults. J Clin Endocrinol Metab 84:4570–4577[Abstract/Free Full Text]
10. Duchaine D 1983 Underground steroid handbook. 1 ed. Venice, CA: HLR Technical Books
11. Todd T October 15, 1984 The use of human growth hormone poses a grave dilemma for sport. Sports Illustrated; 8–12
12. Jenkins PJ 1999 Growth hormone and exercise. Clin Endocrinol (Oxf) 50:683–689[CrossRef][Medline]
13. Healy ML, Russell-Jones D 1997 Growth hormone and sport: abuse, potential benefits, and difficulties in detection. Br J Sports Med 31:267–268[Free Full Text]
14. Noakes TD 2004 Tainted glory: doping and athletic performance. N Engl J Med 351:847–849[Free Full Text]
15. Nagulesparen M, Trickey R, Davies MJ, Jenkins JS 1976 Muscle changes in acromegaly. Br Med J 2:914–915[Abstract/Free Full Text]
16. Woodhouse LJ, Mukherjee A, Shalet SM, Ezzat S 2006 The influence of growth hormone status on physical impairments, functional limitations, and health-related quality of life in adults. Endocr Rev 27:287–317[Abstract/Free Full Text]
17. Whitehead HM, Boreman C, McIlrath EM, Sheridan B, Kennedy L, Atkinson AB, Hadden DR 1992 Growth hormone treatment of adults with growth hormone deficiency: results of a 13-month placebo controlled cross-over study. Clin Endocrinol (Oxf) 36:45–52[Medline]
18. Beshyah SA, Freemantie C, Shahi M, Anyaoku V, Merson S, Lynch S, Skinner E, Sharp P, Foale R, Johnston DG 1995 Replacement treatment with biosynthetic human growth hormone in growth hormone-deficient hypopituitary adults. Clin Endocrinol (Oxf) 42:73–84[Medline]
19. Degerblad M, Almkvist O, Grunditz R, Hall K, Kaijser L,Knutsson E, Ringertz H, Thorén M 1990 Physical and psychological capabilities during substitution therapy with recombinant growth hormone in adults with growth hormone deficiency. Acta Endocrinol (Copenh) 123:185–193[Abstract/Free Full Text]
20. Jørgensen JOL, Pedersen SA, Thuesen L, Jorgensen J, Ingemann-Hansen T, Skakkebaek NE, Christiansen JS 1989 Beneficial effect of growth hormone treatment in GH-deficient adults. Lancet 1:1221–1225[Medline]
21. Jørgensen JOL, Pedersen SA, Thuesen L, Jorgensen J, Moller J, Muller J, Skakkebaek NE, Christiansen JS 1991 Long-term growth hormone treatment in growth hormone deficient adults. Acta Endocrinol 125:449–453[Medline]
22. Jørgensen JOL, Vahl N, Hansen TB, Thuesen L, Hagen C, Christiansen JS 1996 Growth hormone versus placebo treatment for one year in growth hormone-deficient adults: increase in exercise capacity and normalisation of body composition. Clin Endocrinol (Oxf) 45:681–688[CrossRef][Medline]
23. Vahl N, Jørgensen JO, Hansen TB, Klausen IB, Jurik AG, Hagen C, Christiansen JS 1998 The favourable effects of growth hormone (GH) substitution on hypercholesterolaemia in GH-deficient adults are not associated with concomitant reductions in adiposity. A 12 month placebo-controlled study. Int J Obes Relat Metab Disord 22:529–536[CrossRef][Medline]
24. Rodriguez-Arnao J, Jabbar A, Fulcher K, Besser GM, Ross RJ 1999 Effects of growth hormone replacement on physical performance and body composition in GH-deficient adults. Clin Endocrinol (Oxf) 51:53–60[CrossRef][Medline]
25. Thomas SG, Esposito JG, Ezzat S 2003 Exercise training benefits growth hormone (GH)-deficient adults in the absence or presence of GH treatment. J Clin Endocrinol Metab 88:5734–5738[Abstract/Free Full Text]
26. Bollerslev J, Hallen J, Fougner KJ, Jørgensen AP, Kristo C, Fagertun H, Gudmundsen O, Burman P, Schreiner T 2005 Low-dose GH improves exercise capacity in adults with GH deficiency: effects of a 22-month placebo-controlled, crossover trial. Eur J Endocrinol 153:379–387[Abstract/Free Full Text]
27. Jeukendrup AE 2002 Regulation of fat metabolism in skeletal muscle. Ann NY Acad Sci 967:217–235[Medline]
28. Golde DW, Bersch N, Li CH 1977 Growth hormone: species-specific stimulation of erythropoiesis in vitro. Science 196:1112–1113[Abstract/Free Full Text]
29. Claustres M, Chatelain P, Sultan C 1987 Insulin-like growth factor I stimulates human erythroid colony formation in vitro. J Clin Endocrinol Metab 65:78–82[Abstract/Free Full Text]
30. Kurtz A, Zapf J, Eckardt KU, Clemons G, Froesch ER, Bauer C 1988 Insulin-like growth factor I stimulates erythropoiesis in hypophysectomized rats. Proc Natl Acad Sci USA 85:7825–7829[Abstract/Free Full Text]
31. Vihervuori E, Virtanen M, Koistinen H, Koistinen R, Seppala M, Siimes MA 1996 Hemoglobin level is linked to growth hormone-dependent proteins in short children. Blood 87:2075–2081[Abstract/Free Full Text]
32. Christ ER, Cummings MH, Westwood NB, Sawyer BM, Pearson TC, Sönksen PH, Russell-Jones DL 1997 The importance of growth hormone in the regulation of erythropoiesis, red cell mass, and plasma volume in adults with growth hormone deficiency. J Clin Endocrinol Metab 82:2985–2990[Abstract/Free Full Text]
33. Saccà L, Cittadini A, Fazio S 1994 Growth hormone and the heart. Endocr Rev 15:555–573[Abstract/Free Full Text]
34. Amato G, Carella C, Fazio S, La Montagna G, Cittadini A, Sabatini D, Marciano-Mone C, Sacca L, Bellastella A 1993 Body composition, bone metabolism, and heart structure and function in growth hormone(GH)-deficient adults before and after GH replacement therapy at low doses. J Clin Endocrinol Metab 77:1671–1676[Abstract]
35. Merola B, Cittadini A, Colao A, Longobardi S, Fazio S, Sabatini D, Sacca L, Lombardi G 1993 Cardiac structural and functional abnormalities in adult patients with growth hormone deficiency. J Clin Endocrinol Metab 77:1658–1661[Abstract]
36. Sartorio A, Ferrero S, Conti A, Bragato R, Malfatto G, Leonetti G, Faglia G 1997 Adults with childhood-onset growth hormone deficiency: effects of growth hormone treatment on cardiac structure. J Intern Med 241:515–520[Medline]
37. Shahi M, Beshyah SA, Hacket D, Sharp PS, Johnston DG, Foale RA 1992 Myocardial dysfunction in treated adult hypopituitarism: a possible explanation for increased cardiovascular mortality. Br Heart J 67:92–96[Abstract/Free Full Text]
38. Thuesen L, Jørgensen JOL, Müller JR, Kristensen BO, Skakkebaek NE, Vahl N, Christiansen JS 1994 Short and long-term cardiovascular effects of growth hormone therapy in growth hormone deficient adults. Clin Endocrinol (Oxf) 41:615–620[Medline]
39. Maison P, Chanson P 2003 Cardiac effects of growth hormone in adults with growth hormone deficiency: a meta-analysis. Circulation 108:2648–2652[Abstract/Free Full Text]
40. Colao A, di Somma C, Cuocolo A, Spinelli L, Tedesco N, Pivonello R, Bonaduce D, Salvatore M, Lombardi G 2001 Improved cardiovascular risk factors and cardiac performance after 12 months of growth hormone (GH) replacement in young adult patients with GH deficiency. J Clin Endocrinol Metab 86:1874–1881[Abstract/Free Full Text]
41. Colao A, Di Somma C, Cuocolo A, Filippella M, Rota F, Acampa W, Savastano S, Salvatore M, Lombardi G 2004 The severity of growth hormone deficiency correlates with the severity of cardiac impairment in 100 adult patients with hypopituitarism: an observational, case-control study. J Clin Endocrinol Metab 89:5998–6004[Abstract/Free Full Text]
42. Johannsson G, Sverrisdottir YB, Ellegard L, Lundberg PA, Herlitz H 2002 GH increases extracellular volume by stimulating sodium reabsorption in the distal nephron and preventing pressure natriuresis. J Clin Endocrinol Metab 87:1743–1749[Abstract/Free Full Text]
43. Boger RH, Skamira C, Bode-Boger SM, Brabant G, von zur Muhlen A, Frolich JC 1996 Nitric oxide may mediate the hemodynamic effects of recombinant growth hormone in patients with acquired growth hormone deficiency. A double-blind, placebo-controlled study. J Clin Invest 98:2706–2713[Medline]
44. Sartorio A, Maffiuletti NA, Agosti F, Marinone PG, Ottolini S, Lafortuna CL 2004 Body mass reduction markedly improves muscle performance and body composition in obese females aged 61–75 years: comparison between the effects exerted by energy-restricted diet plus moderate aerobic-strength training alone or associated with rGH or nandrolone undecanoate. Eur J Endocrinol 150:511–515[Abstract]
45. Wolfe RR, Klein S, Carraro F, Weber JM 1990 Role of triglyceride-fatty acid cycle in controlling fat metabolism in humans during and after exercise. Am J Physiol 258:E382–E389
46. Costill DL, Coyle E, Dalsky G, Evans W, Fink W, Hoopes D 1977 Effects of elevated plasma FFA and insulin on muscle glycogen usage during exercise. J Appl Physiol 43:695–699[Abstract/Free Full Text]
47. Dyck DJ, Putman CT, Heigenhauser GJ, Hultman E, Spriet LL 1993 Regulation of fat-carbohydrate interaction in skeletal muscle during intense aerobic cycling. Am J Physiol 265:E852–E859
48. Matzinger O, Schneiter P, Tappy L 2002 Effects of fatty acids on exercise plus insulin-induced glucose utilization in trained and sedentary subjects. Am J Physiol Endocrinol Metab 282:E125–E131
49. Vukovich MD, Costill DL, Hickey MS, Trappe SW, Cole KJ, Fink WJ 1993 Effect of fat emulsion infusion and fat feeding on muscle glycogen utilization during cycle exercise. J Appl Physiol 75:1513–1518[Abstract/Free Full Text]
50. Hargreaves M, Kiens B, Richter EA 1991 Effect of increased plasma free fatty acid concentrations on muscle metabolism in exercising men. J Appl Physiol 70:194–201[Abstract/Free Full Text]
51. Kanaley JA, Cryer PE, Jensen MD 1993 Fatty acid kinetic responses to exercise. Effects of obesity, body fat distribution, and energy-restricted diet. J Clin Invest 92:255–261[Medline]
52. Yip RG, Goodman HM 1999 Growth hormone and dexamethasone stimulate lipolysis and activate adenylyl cyclase in rat adipocytes by selectively shifting Gi 2 to lower density membrane fractions. Endocrinology 140:1219–1227[Abstract/Free Full Text]
53. Marcus C, Bolme P, Micha-Johansson G, Margery V, Bronnegard M 1994 Growth hormone increases the lipolytic sensitivity for catecholamines in adipocytes from healthy adults. Life Sci 54:1335–1341[CrossRef][Medline]
54. Beauville M, Harant I, Crampes F, Riviere D, Tauber MT, Tauber JP, Garrigues M 1992 Effect of long-term rhGH administration in GH-deficient adults on fat cell epinephrine response. Am J Physiol 263:E467–E472
55. Harant I, Beauville M, Crampes F, Riviere D, Tauber MT, Tauber JP, Garrigues M 1994 Response of fat cells to growth hormone (GH): effect of long term treatment with recombinant human GH in GH-deficient adults. J Clin Endocrinol Metab 78:1392–1395[Abstract]
56. Raben MS, Hollenberg CH 1959 Effect of growth hormone on plasma fatty acids. J Clin Invest 38:484–488[Medline]
57. Rabinowitz D, Klassen GA, Zierler KL 1965 Effects of human growth hormone on muscle and adipose tissue metabolism in the forearm of man. J Clin Invest 44:51–61[Medline]
58. Fineberg SE, Merimee TJ 1974 Acute metabolic effects of human growth hormone. Diabetes 23:499–504[Medline]
59. Moller N, Jorgensen JOL, Alberti KGMM, Flyvbjerg A, Schmitz O 1990 Short-term effects of growth hormone on fuel oxidation and regional substrate metabolism in normal man. J Clin Endocrinol Metab 70:1179–1186[Abstract/Free Full Text]
60. Møller N, Jørgensen JOL, Schmitz O, Møller J, Christiansen J, Alberti KG, Orskov H 1990 Effects of a growth hormone pulse on total and forearm substrate fluxes in humans. Am J Physiol 258:E86–E91
61. Laursen T, Jørgensen JOL, Christiansen JS 1994 Metabolic effects of growth hormone administered subcutaneously once or twice daily to growth hormone deficient adults. Clin Endocrinol (Oxf) 41:337–343[Medline]
62. Gravholt CH, Schmitz O, Simonsen L, Bulow J, Christiansen JS, Moller N 1999 Effects of a physiological GH pulse on interstitial glycerol in abdominal and femoral adipose tissue. Am J Physiol 277:E848–854
63. Gibney J, Healy ML, Stolinski M, Bowes SB, Pentecost C, Breen L, McMillan C, Russell-Jones DL, Sonksen PH, Umpleby AM 2003 Effect of growth hormone (GH) on glycerol and free fatty acid metabolism during exhaustive exercise in GH-deficient adults. J Clin Endocrinol Metab 88:1792–1797[Abstract/Free Full Text]
64. Kanaley JA, Dall R, Moller N, Nielsen SC, Christiansen JS, Jensen MD, Jorgensen JO 2004 Acute exposure to GH during exercise stimulates the turnover of free fatty acids in GH-deficient men. J Appl Physiol 96:747–753[Abstract/Free Full Text]
65. Brandou F, Aloulou I, Razimbaud A, Facdou C, Mercier J, Brun JF 2006 Lower ability to oxidize lipids in adult patients with growth hormone (GH) deficiency: reversal under GH treatment. Clin Endocrinol (Oxf) 65:423–428[CrossRef][Medline]
66. Sjögren K, Leung KC, Kaplan W, Gardiner-Garden M, Gibney J, Ho KK 2007 Growth hormone regulation of metabolic gene expression in muscle: a microarray study in hypopituitary men. Am J Physiol Endocrinol Metab 293:E364–E371
67. Cheng JS, Kalant N 1970 Effects of insulin and growth hormone on the flux rates of plasma glucose and plasma free fatty acids in man. J Clin Endocrinol Metab 31:647–653[Abstract/Free Full Text]
68. Metcalfe P, Johnston DG, Nosadini R, Orksov H, Alberti KG 1981 Metabolic effects of acute and prolonged growth hormone excess in normal and insulin-deficient man. Diabetologia 20:123–128[CrossRef][Medline]
69. Rizza RA, Mandarino LJ, Gerich JE 1982 Effects of growth hormone on insulin action in man. Mechanisms of insulin resistance, impaired suppression of glucose production, and impaired stimulation of glucose utilization. Diabetes 31:663–669[Abstract]
70. Sherwin RS, Schulman GA, Hendler R, Walesky M, Belous A, Tamborlane W 1983 Effect of growth hormone on oral glucose tolerance and circulating metabolic fuels in man. Diabetologia 24:155–161[Medline]
71. Davidson MB 1987 Effect of growth hormone on carbohydrate and lipid metabolism. Endocr Rev 8:115–131[Abstract/Free Full Text]
72. Jorgensen JO, Moller N, Lauritzen T, Alberti KG, Orskov H, Christiansen JS 1990 Evening versus morning injections of growth hormone (GH) in GH- deficient patients: effects on 24-hour patterns of circulating hormones and metabolites. J Clin Endocrinol Metab 70:207–214[Abstract/Free Full Text]
73. Hussain MA, Schmitz O, Mengel A, Glatz Y, Christiansen JS, Zapf J, Froesch ER 1994 Comparison of the effects of growth hormone and insulin-like growth factor I on substrate oxidation and on insulin sensitivity in growth hormone-deficient humans. J Clin Invest 94:1126–1133[Medline]
74. Bramnert M, Segerlantz M, Laurila E, Daugaard JR, Manhem P, Groop L 2003 Growth hormone replacement therapy induces insulin resistance by activating the glucose-fatty acid cycle. J Clin Endocrinol Metab 88:1455–1463[Abstract/Free Full Text]
75. Jorgensen JO, Jessen N, Pedersen SB, Vestergaard E, Gormsen L, Lund SA, Billestrup N 2006 GH receptor signaling in skeletal muscle and adipose tissue in human subjects following exposure to an intravenous GH bolus. Am J Physiol Endocrinol Metab 291:E899–E905
76. Fryburg DA, Gelfand RA, Barrett EJ 1991 Growth hormone acutely stimulates forearm muscle protein synthesis in normal humans. Am J Physiol 260:E499–E504
77. Carroll PV, Christ ER, Bengtsson BA, Carlsson L, Christiansen JS, Clemmons D, Hintz R, Ho K, Laron Z, Sizonenko P, Sönksen PH, Tanaka T, Thorne M 1998 Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. Growth Hormone Research Society Scientific Committee. J Clin Endocrinol Metab 83:382–395[Abstract/Free Full Text]
78. de Boer H, Blok G-J, van der Veen EA 1995 Clinical aspects of growth hormone deficiency in adults. Endocr Rev 16:63–86[Abstract/Free Full Text]
79. Salomon F, Cuneo RC, Hesp R, Sonksen PH 1989 The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 321:1797–1803[Abstract]
80. Hoffman DM, O’Sullivan AJ, Freund J, Ho KK 1995 Adults with growth hormone deficiency have abnormal body composition but normal energy metabolism. J Clin Endocrinol Metab 80:72–77[Abstract]
81. Janssen YJ, Doornbos J, Roelfsema F 1999 Changes in muscle volume, strength, and bioenergetics during recombinant human growth hormone (GH) therapy in adults with GH deficiency. J Clin Endocrinol Metab 84:279–284[Abstract/Free Full Text]
82. Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH 1991 Growth hormone treatment in growth hormone-deficient adults. I. Effects on muscle mass and strength. J Appl Physiol 70:688–694[Abstract/Free Full Text]
83. Johannsson G, Grimby G, Sunnerhagen KS, Bengtsson BA 1997 Two years of growth hormone (GH) treatment increase isometric and isokinetic muscle strength in GH-deficient adults. J Clin Endocrinol Metab 82:2877–2884[Abstract/Free Full Text]
84. Rutherford OM, Beshyah SA, Schott J, Watkins Y, Johnston DG 1995 Contractile properties of the quadriceps muscle in growth hormone-deficient hypopituitary adults. Clin Sci (Lond) 88:67–71[Medline]
85. Brill KT, Weltman AL, Gentili A, Patrie JT, Fryburg DA, Hanks JB, Urban RJ, Veldhuis JD 2002 Single and combined effects of growth hormone and testosterone administration on measures of body composition, physical performance, mood, sexual function, bone turnover, and muscle gene expression in healthy older men. J Clin Endocrinol Metab 87:5649–5657[Abstract/Free Full Text]
86. Svensson J, Sunnerhagen KS, Johannsson G 2003 Five years of growth hormone replacement therapy in adults: age- and gender-related changes in isometric and isokinetic muscle strength. J Clin Endocrinol Metab 88:2061–2069[Abstract/Free Full Text]
87. Juul A, Behrenscheer A, Tims T, Nielsen B, Halkjær-Kristensen J, Skakkebæk NE 1993 Impaired thermoregulation in adults with growth hormone deficiency during heat exposure and exercise. Clin Endocrinol (Oxf) 38:237–244[Medline]
88. Juul A, Hjortskov N, Jepsen LT, Nielsen B, Halkjaer-Kristensen J, Vahl N, Jorgensen JO, Christiansen JS, Skakkebaek NE 1995 Growth hormone deficiency and hyperthermia during exercise: a controlled study of sixteen GH-deficient patients. J Clin Endocrinol Metab 80:3335–3340[Abstract]
89. Giustina A, Veldhuis JD 1998 Pathophysiology of the neororegulation of growth hormone secretion in experimental animals and the human. Endocr Rev 19:717–797[Abstract/Free Full Text]
90. Bengtsson B-Å, Abs R, Bennmarker H, Monson JP, Feldt-Rasmussen U, Hernberg-Stahl E, Westberg B, Wilton P, Wuster C 1999 The effects of treatment and the individual responsiveness to growth hormone (GH) replacement therapy in 665 GH-deficient adults. KIMS Study Group and the KIMS International Board. J Clin Endocrinol Metab 84:3929–3935[Abstract/Free Full Text]
91. De Caro E, Fioredda F, Calevo MG, Smeraldi A, Saitta M, Hanau G, Faraci M, Grisolia F, Dini G, Pongiglione G, Haupt R 2006 Exercise capacity in apparently healthy survivors of cancer. Arch Dis Child 91:47–51[Abstract/Free Full Text]
92. McTiernan A 2004 Physical activity after cancer: physiologic outcomes. Cancer Invest 22:68–81[CrossRef][Medline]
93. Ness KK, Baker KS, Dengel DR, Youngren N, Sibley S, Mertens AC, Gurney JG, Body composition, muscle strength deficits and mobility limitations in adult survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 2006 Nov 7 [Epub ahead of print]
94. Schmitz KH, Holtzman J, Courneya KS, Masse LC, Duval S, Kane R 2005 Controlled physical activity trials in cancer survivors: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev 14:1588–1595[Abstract/Free Full Text]
95. Burt MG, Gibney J, Ho KK 2006 Characterization of the metabolic phenotypes of Cushing’s syndrome and growth hormone deficiency: a study of body composition and energy metabolism. Clin Endocrinol (Oxf) 64:436–443[CrossRef][Medline]
96. Rockall AG, Sohaib SA, Evans D, Kaltsas G, Isidori AM, Monson JP, Besser GM, Grossman AB, Reznek RH 2003 Computed tomography assessment of fat distribution in male and female patients with Cushing’s syndrome. Eur J Endocrinol 149:561–567[Abstract]
97. Pirlich M, Biering H, Gerl H, Ventz M, Schmidt B, Ertl S, Lochs H 2002 Loss of body cell mass in Cushing’s syndrome: effect of treatment. J Clin Endocrinol Metab 87:1078–1084[Abstract/Free Full Text]
98. Garrapa GG, Pantanetti P, Arnaldi G, Mantero F, Faloia E 2001 Body composition and metabolic features in women with adrenal incidentaloma or Cushing’s syndrome. J Clin Endocrinol Metab 86:5301–5306[Abstract/Free Full Text]
99. Wajchenberg BL, Bosco A, Marone MM, Levin S, Rocha M, Lerário AC, Nery M, Goldman J, Liberman B 1995 Estimation of body fat and lean tissue distribution by dual energy x-ray absorptiometry and abdominal body fat evaluation by computed tomography in Cushing’s disease. J Clin Endocrinol Metab 80:2791–2794[Abstract]
100. Lamberts SW, Birkenhager JC 1976 Body composition in Cushing’s disease. J Clin Endocrinol Metab 42:864–868[Abstract/Free Full Text]
101. Aloia JF, Roginsky M, Ellis K, Shukla K, Cohn S 1974 Skeletal metabolism and body composition in Cushing’s syndrome. J Clin Endocrinol Metab 39:981–985[Abstract/Free Full Text]
102. Burt MG, Gibney J, Ho KK 2007 Protein metabolism in glucocorticoid excess: study in Cushing’s syndrome and the effect of treatment. Am J Physiol Endocrinol Metab 292:E1426–E1432
103. Agha A, Liew A, Finucane F, Baker L, O’Kelly P, Tormey W, Thompson CJ 2004 Conventional glucocorticoid replacement overtreats adult hypopituitary patients with partial ACTH deficiency. Clin Endocrinol (Oxf) 60:688–693[CrossRef][Medline]
104. Toogood AA, Taylor NF, Shalet SM, Monson JP 2000 Modulation of cortisol metabolism by low-dose growth hormone replacement in elderly hypopituitary patients. J Clin Endocrinol Metab 85:1727–1730[Abstract/Free Full Text]
105. Moore JS, Monson JP, Kaltsas G, Putignano P, Wood PJ, Sheppard MC, Besser GM, Taylor NF, Stewart PM 1999 Modulation of 11ß-hydroxysteroid dehydrogenase isozymes by growth hormone and insulin-like growth factor: in vivo and in vitro studies. J Clin Endocrinol Metab 84:4172–4177[Abstract/Free Full Text]
106. Swords FM, Carroll PV, Kisalu J, Wood PJ, Taylor NF, Monson JP 2003 The effects of growth hormone deficiency and replacement on glucocorticoid exposure in hypopituitary patients on cortisone acetate and hydrocortisone replacement. Clin Endocrinol (Oxf) 59:613–620[CrossRef][Medline]
107. Jorgensen JO, Moller J, Skakkebaek NE, Weeke J, Christiansen JS 1992 Thyroid function during growth hormone therapy. Horm Res 38:63–67[CrossRef][Medline]
108. Moller J, Jorgensen JO, Moller N, Christiansen JS, Weeke J 1992 Effects of growth hormone administration on fuel oxidation and thyroid function in normal man. Metabolism 41:728–731[CrossRef][Medline]
109. Gibney J, Johannsson G, Leung KC, Ho KK 2005 Comparison of the metabolic effects of raloxifene and oral estrogen in postmenopausal and growth hormone-deficient women. J Clin Endocrinol Metab 90:3897–3903[Abstract/Free Full Text]
110. O’Sullivan AJ, Crampton L, Freund J, Ho KKY 1998 Route of estrogen replacement confers divergent effects of energy metabolism and body composition in postmenopausal women. J Clin Invest 102:1035–1040[Medline]
111. Johannsson G, Gibney J, Wolthers T, Leung KC, Ho KK 2005 Independent and combined effects of testosterone and growth hormone on extracellular water in hypopituitary men. J Clin Endocrinol Metab 90:3989–3994[Abstract/Free Full Text]
112. Gibney J, Wolthers T, Johannsson G, Umpleby AM, Ho KK 2005 Growth hormone and testosterone interact positively to enhance protein and energy metabolism in hypopituitary men. Am J Physiol Endocrinol Metab 289:E266–E271
113. Johannsson G, Burman P, Wiren L, Engström BE, Nilsson AG, Ottosson M, Jonsson B, Bengtsson BA, Karlsson FA 2002 Low dose dehydroepiandrosterone affects behavior in hypopituitary androgen-deficient women: a placebo-controlled trial. J Clin Endocrinol Metab 87:2046–2052[Abstract/Free Full Text]
114. Sutton J, Lazarus L 1976 Growth hormone in exercise: comparison of physiological and pharmacological stimuli. J Appl Physiol 41:523–527[Abstract/Free Full Text]
115. Lassarre C, Girard F, Durand J, Raynaud J 1974 Kinetics of human growth hormone during submaximal exercise. J Appl Physiol 37:826–830[Free Full Text]
116. Raynaud J, Drouet L, Martineaud JP, Bordachar J, Coudert J, Durand J 1981 Time course of plasma growth hormone during exercise in humans at altitude. J Appl Physiol 50:229–233[Abstract/Free Full Text]
117. Viru A, Karelson K, Smirnova T 1992 Stability and variability in hormonal responses to prolonged exercise. Int J Sports Med 13:230–235[Medline]
118. Hagberg JM, Seals DR, Yerg JE, Gavin J, Gingerich R, Premachandra B, Holloszy JO 1988 Metabolic responses to exercise in young and older athletes and sedentary men. J Appl Physiol 65:900–908[Abstract/Free Full Text]
119. Zaccaria M, Varnier M, Piazza P, Noventa D, Ermolao A 1999 Blunted growth hormone response to maximal exercise in middle-aged versus young subjects and no effect of endurance training. J Clin Endocrinol Metab 84:2303–2307[Abstract/Free Full Text]
120. Holt RI, Webb E, Pentecost C, Sonksen PH 2001 Aging and physical fitness are more important than obesity in determining exercise-induced generation of GH. J Clin Endocrinol Metab 86:5715–5720[Abstract/Free Full Text]
121. Bunt JC, Boileau RA, Bahr JM, Nelson RA 1986 Sex and training differences in human growth hormone levels during prolonged exercise. J Appl Physiol 61:1796–1801[Abstract/Free Full Text]
122. Wideman L, Weltman JY, Shah N, Story S, Veldhuis JD, Weltman A 1999 Effects of gender on exercise-induced growth hormone release. J Appl Physiol 87:1154–1162[Abstract/Free Full Text]
123. Giannoulis MG, Boroujerdi MA, Powrie J, Giannoulis MG, Boroujerdi MA, Powrie J, Dall R, Napoli R, Ehrnborg C, Pentecost C, Cittadini A, Jørgensen JO, Sonksen PH; GH-2000 Study Group 2005 Gender differences in growth hormone response to exercise before and after rhGH administration and the effect of rhGH on the hormone profile of fit normal adults. Clin Endocrinol (Oxf) 62:315–322[CrossRef][Medline]
124. Kanaley JA, Weatherup-Dentes MM, Jaynes EB, Hartman ML 1999 Obesity attenuates the growth hormone response to exercise. J Clin Endocrinol Metab 84:3156–3161[Abstract/Free Full Text]
125. Veldhuis JD, Liem AY, South S, Weltman A, Weltman J, Clemmons DA, Abbott R, Mulligan T, Johnson ML, Pincus S 1995 Differential impact of age, sex steroid hormones, and obesity on basal versus pulsatile growth hormone secretion in men as assessed in an ultrasensitive chemiluminescence assay. J Clin Endocrinol Metab 80:3209–3222[Abstract]
126. Veldhuis JD, Iranmanesh A, Ho KK, Waters MJ, Johnson ML, Lizarralde G 1991 Dual defects in pulsatile growth hormone secretion and clearance subserve the hyposomatotropism of obesity in man. J Clin Endocrinol Metab 72:51–59[Abstract/Free Full Text]
127. Luger A, Watschinger B, Deuster P, Svoboda T, Clodi M, Chrousos GP 1992 Plasma growth hormone and prolactin responses to graded levels of acute exercise and to a lactate infusion. Neuroendocrinology 56:112–117[Medline]
128. Sutton JR 1978 Hormonal and metabolic responses to exercise in subject of high and low work capacities. Med Sci Sports 10:1–6[Medline]
129. Farrell PA, Garthwaite TL, Gustafson AB 1983 Plasma adrenocorticotropin and cortisol responses to submaximal and exhaustive exercise. J Appl Physiol 55:1441–1444[Abstract/Free Full Text]
130. Felsing NE, Brasel JA, Cooper DM 1992 Effect of low and high intensity exercise on circulating growth hormone in men. J Clin Endocrinol Metab 75:157–162[Abstract]
131. Naveri H 1985 Blood hormone and metabolite levels during graded cycle ergometer exercise. Scand J Clin Lab Invest 45:599–603[Medline]
132. Naveri H, Kuoppasalmi K, Harkonen M 1985 Metabolic and hormonal changes in moderate and intense long-term running exercises. Int J Sports Med 6:276–281[Medline]
133. Pritzlaff CJ, Wideman L, Weltman JY, Abbott RD, Gutgesell ME, Hartman ML, Veldhuis JD, Weltman A 1999 Impact of acute exercise intensity on pulsatile growth hormone release in men. J Appl Physiol 87:498–504[Abstract/Free Full Text]
134. Gray AB, Telford RD, Weidemann MJ 1993 Endocrine response to intense interval exercise. Eur J Appl Physiol Occup Physiol 66:366–371[CrossRef][Medline]
135. Hakkinen K, Pakarinen A 1993 Acute hormonal responses to two different fatiguing heavy-resistance protocols in male athletes. J Appl Physiol 74:882–887[Abstract/Free Full Text]
136. Hakkinen K, Pakarinen A, Alen M, Kauhanen H, Komi PV 1988 Neuromuscular and hormonal responses in elite athletes to two successive strength training sessions in one day. Eur J Appl Physiol Occup Physiol 57:133–139[CrossRef][Medline]
137. Karagiorgos A, Garcia JF, Brooks GA 1979 Growth hormone response to continuous and intermittent exercise. Med Sci Sports 11:302–307[Medline]
138. Kraemer WJ, Fleck SJ, Dziados JE, Harman EA, Marchitelli LJ, Gordon SE, Mello R, Frykman PN, Koziris LP, Triplett NT 1993 Changes in hormonal concentrations after different heavy-resistance exercise protocols in women. J Appl Physiol 75:594–604[Abstract/Free Full Text]
139. Kraemer WJ, Gordon SE, Fleck SJ, Marchitelli LJ, Mello R, Dziados JE, Friedl K, Harman E, Maresh C, Fry AC 1991 Endogenous anabolic hormonal and growth factor responses to heavy resistance exercise in males and females. Int J Sports Med 12:228–235[Medline]
140. Kraemer WJ, Marchitelli L, Gordon SE, Harman E, Dziados JE, Mello R, Frykman P, McCurry D, Fleck SJ 1990 Hormonal and growth factor responses to heavy resistance exercise protocols. J Appl Physiol 69:1442–1450[Abstract/Free Full Text]
141. Raynaud J, Capderou A, Martineaud JP, Bordachar J, Durand J 1983 Intersubject viability in growth hormone time course during different types of work. J Appl Physiol 55:1682–1687[Abstract/Free Full Text]
142. VanHelder WP, Casey K, Goode RC, Radomski WM 1986 Growth hormone regulation in two types of aerobic exercise of equal oxygen uptake. Eur J Appl Physiol Occup Physiol 55:236–239[CrossRef][Medline]
143. Snegovskaya V, Viru A 1993 Elevation of cortisol and growth hormone levels in the course of further improvement of performance capacity in trained rowers. Int J Sports Med 14:202–206[Medline]
144. Hartley LH, Mason JW, Hogan RP, Jones LG, Kotchen TA, Mougey EH, Wherry FE, Pennington LL, Ricketts PT 1972 Multiple hormonal responses to prolonged exercise in relation to physical training. J Appl Physiol 33:607–610[Free Full Text]
145. Wideman L, Consitt L, Patrie J, Swearingin B, Bloomer R, Davis P, Weltman A 2006 The impact of sex and exercise duration on growth hormone secretion. J Appl Physiol 101:1641–1647[Abstract/Free Full Text]
146. Kanaley JA, Weltman JY, Veldhuis JD, Rogol AD, Hartman ML, Weltman A 1997 Human growth hormone response to repeated bouts of aerobic exercise. J Appl Physiol 83:1756–1761[Abstract/Free Full Text]
147. Kanaley JA, Weltman JY, Pieper KS, Weltman A, Hartman ML 2001 Cortisol and growth hormone responses to exercise at different times of day. J Clin Endocrinol Metab 86:2881–2889[Abstract/Free Full Text]
148. Christensen SE, Jorgensen OL, Moller N, Orskov H 1984 Characterization of growth hormone release in response to external heating. Comparison to exercise induced release. Acta Endocrinol (Copenh) 107:295–301[Abstract/Free Full Text]
149. Elias AN, Wilson AF, Naqvi S, Pandian MR 1997 Effects of blood pH and blood lactate on growth hormone, prolactin, and gonadotropin release after acute exercise in male volunteers. Proc Soc Exp Biol Med 214:156–160[CrossRef][Medline]
150. Wheldon A, Savine RL, Sonksen PH, Holt RI 2006 Exercising in the cold inhibits growth hormone secretion by reducing the rise in core body temperature. Growth Horm IGF Res 16:125–131[CrossRef][Medline]
151. Bang P, Brandt J, Degerblad M, Enberg G, Kaijser L, Thorén M, Hall K 1990 Exercise-induced changes in insulin-like growth factors and their low molecular weight binding protein in healthy subjects and patients with growth hormone deficiency. Eur J Clin Invest 20:285–292[Medline]
152. Cappon J, Brasel JA, Mohan S, Cooper DM 1994 Effect of brief exercise on circulating insulin-like growth factor I. J Appl Physiol 76:2490–2496[Abstract/Free Full Text]
153. Koistinen H, Koistinen R, Selenius L, Ylikorkala Q, Seppala M 1996 Effect of marathon run on serum IGF-I and IGF-binding protein 1 and 3 levels. J Appl Physiol 80:760–764[Abstract/Free Full Text]
154. Schwarz AJ, Brasel JA, Hintz RL, Mohan S, Cooper DM 1996 Acute effect of brief low- and high-intensity exercise on circulating insulin-like growth factor (IGF) I, II, and IGF-binding protein-3 and its proteolysis in young healthy men. J Clin Endocrinol Metab 81:3492–3497[Abstract]
155. Suikkari AM, Sane T, Seppala M, Yki-Jarvinen H, Karonen SL, Koivisto VA 1989 Prolonged exercise increases serum insulin-like growth factor-binding protein concentrations. J Clin Endocrinol Metab 68:141–144[Abstract/Free Full Text]
156. Wallace JD, Cuneo RC, Baxter R, Orskov H, Keay N, Pentecost C, Dall R, Rosén T, Jørgensen JO, Cittadini A, Longobardi S, Sacca L, Christiansen JS, Bengtsson BA, Sönksen PH 1999 Responses of the growth hormone (GH) and insulin-like growth factor axis to exercise, GH administration, and GH withdrawal in trained adult males: a potential test for GH abuse in sport. J Clin Endocrinol Metab 84:3591–3601[Abstract/Free Full Text]
157. Dall R, Lange KH, Kjaer M, Jorgensen JO, Christiansen JS, Orskov H, Flyvbjerg A 2001 No evidence of insulin-like growth factor-binding protein 3 proteolysis during a maximal exercise test in elite athletes. J Clin Endocrinol Metab 86:669–674[Abstract/Free Full Text]
158. Wee J, Charlton C, Simpson H, Jackson NC, Shojaee-Moradie F, Stolinski M, Pentecost C, Umpleby AM 2005 GH secretion in acute exercise may result in post-exercise lipolysis. Growth Horm IGF Res 15:397–404[CrossRef][Medline]
159. Chalmers RJ, Bloom SR, Duncan G, Johnson RH, Sulaiman WR 1979 The effect of somatostatin on metabolic and hormonal changes during and after exercise. Clin Endocrinol (Oxf) 10:451–458[Medline]
160. Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ 1996 Octreotide. N Engl J Med 334:246–254[Free Full Text]
161. Veldhuis JD, Bidlingmaier M, Anderson SM, Wu Z, Strasburger CJ 2001 Lowering total plasma insulin-like growth factor I concentrations by way of a novel, potent, and selective growth hormone (GH) receptor antagonist, pegvisomant (B2036-peg), augments the amplitude of GH secretory bursts and elevates basal/nonpulsatile GH release in healthy women and men. J Clin Endocrinol Metab 86:3304–3310[Abstract/Free Full Text]
162. Pritzlaff CJ, Wideman L, Blumer J, Jensen M, Abbott RD, Gaesser GA, Veldhuis JD, Weltman A 2000 Catecholamine release, growth hormone secretion, and energy expenditure during exercise vs. recovery in men. J Appl Physiol 89:937–946[Abstract/Free Full Text]
163. Short KR, Vittone JL, Bigelow ML, Proctor DN, Nair KS 2004 Age and aerobic exercise training effects on whole body and muscle protein metabolism. Am J Physiol Endocrinol Metab 286:E92–E101
164. Sheffield-Moore M, Yeckel CW, Volpi E, Wolf SE, Morio B, Chinkes DL, Paddon-Jones D, Wolfe RR 2004 Postexercise protein metabolism in older and younger men following moderate-intensity aerobic exercise. Am J Physiol Endocrinol Metab 287:E513—E522
165. Tessari P, Nissen SL, Miles JM, Haymond MW 1986 Inverse relationship of leucine flux and oxidation to free fatty acid availability in vivo. J Clin Invest 77:575–581[Medline]
166. Solini A, Bonora E, Bonadonna R, Castellino P, DeFronzo RA 1997 Protein metabolism in human obesity: relationship with glucose and lipid metabolism and with visceral adipose tissue. J Clin Endocrinol Metab 82:2552–2558[Abstract/Free Full Text]
167. Norrelund H, Nair KS, Nielsen S, Frystyk J, Ivarsen P, Jorgensen JO, Christiansen JS, Moller N 2003 The decisive role of free fatty acids for protein conservation during fasting in humans with and without growth hormone. J Clin Endocrinol Metab 88:4371–4378[Abstract/Free Full Text]
168. Krag MB, Gormsen LC, Guo Z, Christiansen JS, Jensen MD, Nielsen S, Jørgensen JO 2007 Growth hormone-induced insulin resistance is associated with increased intramyocellular triglyceride content but unaltered VLDL-triglyceride kinetics. Am J Physiol Endocrinol Metab 292:E920—E927
169. Goodpaster BH, He J, Watkins S, Kelley DE 2001 Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab 86:5755–5761[Abstract/Free Full Text]
170. Eliakim A, Brasel JA, Mohan S, Barstow TJ, Berman N, Cooper DM 1996 Physical fitness, endurance training, and the growth hormone-insulin-like growth factor I system in adolescent females. J Clin Endocrinol Metab 81:3986–3992[Abstract/Free Full Text]
171. Kelly PJ, Eisman JA, Stuart MC, Pocock NA, Sambrook PN, Gwinn TH 1990 Somatomedin-C, physical fitness, and bone density. J Clin Endocrinol Metab 70:718–723[Abstract/Free Full Text]
172. Poehlman ET, Copeland KC 1990 Influence of physical activity on insulin-like growth factor-I in healthy younger and older men. J Clin Endocrinol Metab 71:1468–1473[Abstract/Free Full Text]
173. Weltman A, Weltman JY, Hartman ML, Abbott RD, Rogol AD, Evans WS, Veldhuis JD 1994 Relationship between age, percentage body fat, fitness, and 24-hour growth hormone release in healthy young adults: effects of gender. J Clin Endocrinol Metab 78:543–548[Abstract]
174. Weltman A, Weltman JY, Schurrer R, Evans WS, Veldhuis JD, Rogol AD 1992 Endurance training amplifies the pulsatile release of growth hormone: effects of training intensity. J Appl Physiol 72:2188–2196[Abstract/Free Full Text]
175. Roelen CA, de Vries WR, Koppeschaar HP, Vervoorn C, Thijssen JH, Blankenstein MA 1997 Plasma insulin-like growth factor-I and high affinity growth hormone-binding protein levels increase after two weeks of strenuous physical training. Int J Sports Med 18:238–241[Medline]
176. Koziris LP, Hickson RC, Chatterton Jr RT, Groseth RT, Christie JM, Goldflies DG, Unterman TG 1999 Serum levels of total and free IGF-I and IGFBP-3 are increased and maintained in long-term training. J Appl Physiol 86:1436–1442[Abstract/Free Full Text]
177. Bak JF, Møller N, Schmitz O 1991 Effects of growth hormone on fuel utilization and muscle glycogen synthase activity in normal humans. Am J Physiol 260:E736–E742
178. Copeland KC, Nair KS 1994 Acute growth hormone effects on amino acid and lipid metabolism. J Clin Endocrinol Metab 78:1040–1047[Abstract]
179. Jorgensen JOL, Pedersen SB, Borglum J, Moller N, Schmitz O, Christiansen JS, Richelsen B 1994 Fuel metabolism, energy expenditure, and thyroid function in growth hormone-treated obese women: a double-blind placebo-controlled study. Metabolism 43:872–877[CrossRef][Medline]
180. Møller N, Møller J, Jørgensen JOL, Ovesen P, Schmitz O, Alberti KG, Christiansen JS 1993 Impact of 2 weeks growth hormone treatment on basal and insulin stimulated substrate metabolism in humans. Clin Endocrinol (Oxf) 39:577–581[Medline]
181. Lange KH, Larsson B, Flyvbjerg A, Dall R, Bennekou M, Rasmussen MH, Orskov H, Kjaer M 2002 Acute growth hormone administration causes exaggerated increases in plasma lactate and glycerol during moderate to high intensity bicycling in trained young men. J Clin Endocrinol Metab 87:4966–4975[Abstract/Free Full Text]
182. Healy ML, Gibney J, Pentecost C, Croos P, Russell-Jones DL, Sönksen PH, Umpleby AM 2006 Effects of high-dose growth hormone on glucose and glycerol metabolism at rest and during exercise in endurance-trained athletes. J Clin Endocrinol Metab 91:320–327[Abstract/Free Full Text]
183. Hansen M, Morthorst R, Larsson B, Dall R, Flyvbjerg A, Rasmussen MH, Orskov H, Kjaer M, Lange KH 2005 No effect of growth hormone administration on substrate oxidation during exercise in young, lean men. J Physiol 567:1035–1045[Abstract/Free Full Text]
184. Irving BA, Patrie JT, Anderson SM, Watson-Winfield DD, Frick KI, Evans WS, Veldhuis JD, Weltman A 2004 The effects of time following acute growth hormone administration on metabolic and power output measures during acute exercise. J Clin Endocrinol Metab 89:4298–4305[Abstract/Free Full Text]
185. Horber FF, Haymond MW 1990 Human growth hormone prevents the catabolic side-effects of prednisone in humans. J Clin Invest 86:265–272[Medline]
186. Yarasheski KE, Campbell JA, Smith K, Rennie MJ, Holloszy JO, Bier DM 1992 Effect of growth hormone and resistance exercise on muscle growth in young men. Am J Physiol 262:E261—E267
187. Yarasheski KE, Zachweija JJ, Angelopoulos TJ, Bier DM 1993 Short-term growth hormone treatment does not increase muscle protein synthesis in experienced weight lifters. J Appl Physiol 74:3073–3076[Abstract/Free Full Text]
188. Fryburg DA, Barrett EJ 1993 Growth hormone acutely stimulates skeletal muscle but not whole-body protein synthesis in humans. Metabolism 42:1223–1227[CrossRef][Medline]
189. Rennie MJ, Edwards RH, Krywawych S, Davies CT, Halliday D, Waterlow JC, Millward DJ 1981 Effect of exercise on protein turnover in man. Clin Sci (Lond) 61:627–639[Medline]
190. Healy ML, Gibney J, Russell-Jones DL, Pentecost C, Croos P, Sonksen PH, Umpleby AM 2003 High dose growth hormone exerts an anabolic effect at rest and during exercise in endurance-trained athletes. J Clin Endocrinol Metab 88:5221–5226[Abstract/Free Full Text]
191. Bowtell JL, Leese GP, Smith K, Watt PW, Nevill A, Rooyackers O, Wagenmakers AJ, Rennie MJ 2000 Effect of oral glucose on leucine turnover in human subjects at rest and during exercise at two levels of dietary protein. J Physiol 525:271–281[Abstract/Free Full Text]
192. Bowtell JL, Leese GP, Smith K, Watt PW, Nevill A, Rooyackers O, Wagenmakers AJ, Rennie MJ 1998 Modulation of whole body protein metabolism, during and after exercise, by variation of dietary protein. J Appl Physiol 85:1744–1752[Abstract/Free Full Text]
193. Knapik J, Meredith C, Jones B, Fielding R, Young V, Evans W 1991 Leucine metabolism during fasting and exercise. J Appl Physiol 70:43–47[Abstract/Free Full Text]
194. Hoffman DM, Crampton L, Sernia C, Nguyen TV, Ho KK 1996 Short-term growth hormone (GH) treatment of GH-deficient adults increases body sodium and extracellular water, but not blood pressure. J Clin Endocrinol Metab 81:1123–1128[Abstract]
195. Deyssig R, Frisch H, Blum WF, Waldhor T 1993 Effect of growth hormone treatment on hormonal parameters, body composition and strength in athletes. Acta Endocrinol (Copenh) 128:313–318[Abstract/Free Full Text]
196. Crist DM, Peake GT, Egan PA, Waters DL 1988 Body composition response to exogenous GH during training in highly conditioned adults. J Appl Physiol 65:579–584[Abstract/Free Full Text]
197. Smith R, James WPT 1996 Nutrition. In: Weatherall DJ, Ledingham JGG, Warrell DA, eds. Oxford textbook of medicine. 3rd ed. Oxford, UK: Oxford University Press; 1267–1332
198. Battezzati A, Benedini S, Fattorini A, Losa M, Mortini P, Bertoli S, Lanzi R, Testolin G, Biolo G, Luzi L 2003 Insulin action on protein metabolism in acromegalic patients. Am J Physiol Endocrinol Metab 284:E823—E829
199. Sönksen PH, Greenwood FC, Ellis JP, Lowy C, Rutherford A, Nabarro JD 1967 Changes of carbohydrate tolerance in acromegaly with progress of the disease and in response to treatment. J Clin Endocrinol Metab 27:1418–1430[Abstract/Free Full Text]
200. Moller N, Schmitz O, Jorgensen JO, Astrup J, Bak JF, Christensen SE, Alberti KG, Weeke J 1992 Basal- and insulin-stimulated substrate metabolism in patients with active acromegaly before and after adenomectomy. J Clin Endocrinol Metab 74:1012–1019[Abstract]
201. Foss MC, Saad MJ, Paccola GM, Paula FJ, Piccinato CE, Moreira AC 1991 Peripheral glucose metabolism in acromegaly. J Clin Endocrinol Metab 72:1048–1053[Abstract/Free Full Text]
202. Jap TS, Ho LT 1990 Insulin secretion and sensitivity in acromegaly. Clin Physiol Biochem 8:64–69[Medline]
203. Thomas SG, Woodhouse LJ, Pagura SM, Ezzat S 2002 Ventilation threshold as a measure of impaired physical performance in adults with growth hormone excess. Clin Endocrinol (Oxf) 56:351–358[CrossRef][Medline]
204. Colao A, Cuocolo A, Marzullo P, Nicolai E, Ferone D, Della Morte AM, Petretta M, Salvatore M, Lombardi G 1999 Impact of patient’s age and disease duration on cardiac performance in acromegaly: a radionuclide angiography study. J Clin Endocrinol Metab 84:1518–1523[Abstract/Free Full Text]
205. Colao A, Cuocolo A, Marzullo P, Nicolai E, Ferone D, Florimonte L, Salvatore M, Lombardi G 1999 Effects of 1-year treatment with octreotide on cardiac performance in patients with acromegaly. J Clin Endocrinol Metab 84:17–23[Abstract/Free Full Text]
206. Fazio S, Cittadini A, Biondi B, Palmieri EA, Riccio G, Bone F, Oliviero U, Sacca L 2000 Cardiovascular effects of short-term growth hormone hypersecretion. J Clin Endocrinol Metab 85:179–182[Abstract/Free Full Text]
207. Gibney J, Wolthers T, Burt MG, Leung KC, Umpleby AM, Ho KK 2007 Protein metabolism in acromegaly: differential effects of short- and long-term treatment. J Clin Endocrinol Metab 92:1479–1484[Abstract/Free Full Text]
208. McHugh CM, Park RT, Sonksen PH, Holt RI 2005 Challenges in detecting the abuse of growth hormone in sport. Clin Chem 51:1587–1593[Abstract/Free Full Text]
209. Reiterer W 2000 Positive: an Australian Olympian reveals the inside story of drugs and sport. Sydney, Australia: Pan Macmillan Sydney
210. Sonksen PH 2001 Insulin, growth hormone and sport. J Endocrinol 170:13–25[Abstract]
211. Voet W 2001 Breaking the chain: drugs and cycling; the true story. Fotheringham W, translator. London: Yellow Jersey
212. Berggren A, Ehrnborg C, Rosen T, Ellegard L, Bengtsson BA, Caidahl K 2005 Short-term administration of supraphysiological recombinant human growth hormone (GH) does not increase maximum endurance exercise capacity in healthy, active young men and women with normal GH-insulin-like growth factor I axes. J Clin Endocrinol Metab 90:3268–3273[Abstract/Free Full Text]
213. Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, Bunnell TJ, Tricker R, Shirazi A, Casaburi R 1996 The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 335:1–7[Abstract/Free Full Text]
214. Franke WW, Berendonk B 1997 Hormonal doping and androgenization of athletes: a secret program of the German Democratic Republic government. Clin Chem 43:1262–1279[Abstract/Free Full Text]
215. Nabarro JD 1987 Acromegaly. Clin Endocrinol (Oxf) 26:481–512[Medline]
216. Refetoff S, Sonksen PH 1970 Disappearance rate of endogenous and exogenous human growth hormone in man. J Clin Endocrinol Metab 30:386–392[Abstract/Free Full Text]
217. Flanagan DE, Taylor MC, Parfitt V, Mardell R, Wood PJ, Leatherdale BA 1997 Urinary growth hormone following exercise to assess growth hormone production in adults. Clin Endocrinol (Oxf) 46:425–429[CrossRef][Medline]
218. Saugy M, Cardis C, Schweizer C, Veuthey JL, Rivier L 1996 Detection of human growth hormone doping in urine: out of competition tests are necessary. J Chromatogr B Biomed Appl 687:201–211[CrossRef][Medline]
219. Dall R, Longobardi S, Ehrnborg C, Keay N, Rosen T, Jorgensen JO, Cuneo RC, Boroujerdi MA, Cittadini A, Napoli R, Christiansen JS, Bengtsson BA, Sacca L, Baxter RC, Basset EE, Sonksen PH 2000 The effect of four weeks of supraphysiological growth hormone administration on the insulin-like growth factor axis in women and men. GH-2000 Study Group. J Clin Endocrinol Metab 85:4193–4200[Abstract/Free Full Text]
220. Ehrnborg C, Lange KH, Dall R, Christiansen JS, Lundberg PA, Baxter RC, Boroujerdi MA, Bengtsson BA, Healey ML, Pentecost C, Longobardi S, Napoli R, Rosén T; GH-2000 Study Group 2003 The growth hormone/insulin-like growth factor-I axis hormones and bone markers in elite athletes in response to a maximum exercise test. J Clin Endocrinol Metab 88:394–401[Abstract/Free Full Text]
221. Longobardi S, Keay N, Ehrnborg C, Cittadini A, Rosen T, Dall R, Boroujerdi MA, Bassett EE, Healy ML, Pentecost C, Wallace JD, Powrie J, Jorgensen JO, Sacca L 2000 Growth hormone (GH) effects on bone and collagen turnover in healthy adults and its potential as a marker of GH abuse in sports: a double blind, placebo-controlled study. The GH-2000 Study Group. J Clin Endocrinol Metab 85:1505–1512[Abstract/Free Full Text]
222. Wallace JD, Cuneo RC, Lundberg PA, Rosen T, Jorgensen JO, Longobardi S, Keay N, Sacca L, Christiansen JS, Bengtsson BA, Sonksen PH 2000 Responses of markers of bone and collagen turnover to exercise, growth hormone (GH) administration, and GH withdrawal in trained adult males. J Clin Endocrinol Metab 85:124–133[Abstract/Free Full Text]
223. Healy ML, Dall R, Gibney J, Bassett E, Ehrnborg C, Pentecost C, Rosen T, Cittadini A, Baxter RC, Sönksen PH 2005 Toward the development of a test for growth hormone abuse: a study of extreme physiological ranges of growth hormone dependent markers in 813 elite athletes in the postcompetition setting. J Clin Endocrinol Metab 90:641–649[Abstract/Free Full Text]
224. O’Connor KG, Tobin JD, Harman SM, Plato CC, Roy TA, Sherman SS, Blackman MR 1998 Serum levels of insulin-like growth factor-I are related to age and not to body composition in healthy women and men. J Gerontol A Biol Sci Med Sci 53:M176—M182
225. Yu H, Mistry J, Nicar MJ, Khosravi MJ, Diamandis A, van Doorn J, Juul A 1999 Insulin-like growth factors (IGF-I, free IGF-I and IGF-II) and insulin-like growth factor binding proteins (IGFBP-2, IGFBP-3, IGFBP-6, and ALS) in blood circulation. J Clin Lab Anal 13:166–172[CrossRef][Medline]
226. Landin-Wilhelmsen K, Wilhelmsen L, Lappas G, Rosen T, Lindstedt G, Lundberg PA, Bengtsson BA 1994 Serum insulin-like growth factor I in a random population sample of men and women: relation to age, sex, smoking habits, coffee consumption and physical activity, blood pressure and concentrations of plasma lipids, fibrinogen, parathyroid hormone and osteocalcin. Clin Endocrinol (Oxf) 41:351–357[Medline]
227. Powrie JK, Bassett EE, Rosen T, Jørgensen JO, Napoli R, Sacca L, Christiansen JS, Bengtsson BA, Sönksen PH; on behalf of the GH-2000 Project Study Group 2007 Detection of growth hormone abuse in sport. Growth Horm IGF Res 17:220–226[CrossRef][Medline]
228. Leung KC, Howe C, Gui LY, Trout G, Veldhuis JD, Ho KK 2002 Physiological and pharmacological regulation of 20-kDa growth hormone. Am J Physiol Endocrinol Metab 283:E836—E843
229. Wallace JD, Cuneo RC, Bidlingmaier M, Lundberg PA, Carlsson L, Boguszewski CL, Hay J, Healy ML, Napoli R, Dall R, Rosen T, Strasburger CJ 2001 The response of molecular isoforms of growth hormone to acute exercise in trained adult males. J Clin Endocrinol Metab 86:200–206[Abstract/Free Full Text]
230. Wallace JD, Cuneo RC, Bidlingmaier M, Lundberg PA, Carlsson L, Boguszewski CL, Hay J, Boroujerdi M, Cittadini A, Dall R, Rosen T, Strasburger CJ 2001 Changes in non-22-kilodalton (kDa) isoforms of growth hormone (GH) after administration of 22-kDa recombinant human GH in trained adult males. J Clin Endocrinol Metab 86:1731–1737[Abstract/Free Full Text]
231. Barton-Davis ER, Shoturma DI, Musaro A, Rosenthal N, Sweeney HL 1998 Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function. Proc Natl Acad Sci USA 95:15603–15607[Abstract/Free Full Text]
232. Donath MY, Jenni R, Brunner HP, Anrig M, Kohli S, Glatz Y, Froesch ER 1996 Cardiovascular and metabolic effects of insulin-like growth factor I at rest and during exercise in humans. J Clin Endocrinol Metab 81:4089–4094[Abstract/Free Full Text]
233. Rudman D, Feller AG, Nagraj HS, Gergans GA, Lalitha PY, Goldberg AF, Schlenker RA, Cohn L, Rudman IW, Mattson DE 1990 Effects of human growth hormone in men over 60 years old. N Engl J Med 323:1–6[Abstract/Free Full Text]
234. Papadakis MA, Grady D, Black D, Tierney MJ, Gooding GA, Schambelan M, Grunfeld C 1996 Growth hormone replacement in healthy older men improves body composition but not functional ability. Ann Intern Med 124:708–716[Abstract/Free Full Text]
235. Marcus R, Butterfield G, Holloway L, Gilliland L, Baylink DJ, Hintz RL, Sherman BM 1990 Effects of short-term administration of recombinant human growth hormone to elderly people. J Clin Endocrinol Metab 70:519–527[Abstract/Free Full Text]
236. Taaffe DR, Pruitt L, Reim J, Hintz RL, Butterfield G, Hoffman AR, Marcus R 1994 Effect of recombinant human growth hormone on the muscle strength response to resistance exercise in elderly men. J Clin Endocrinol Metab 79:1361–1366[Abstract]
237. Taaffe DR, Jin IH, Vu TH, Hoffman AR, Marcus R 1996 Lack of effect of recombinant human growth hormone (GH) on muscle morphology and GH-insulin-like growth factor expression in resistance-trained elderly men. J Clin Endocrinol Metab 81:421–425[Abstract]
238. Blackman MR, Sorkin JD, Munzer T, Bellantoni MF, Busby-Whitehead J, Stevens TE, Jayme J, O’Connor KG, Christmas C, Tobin JD, Stewart KJ, Cottrell E, St Clair C, Pabst KM, Harman SM 2002 Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA 288:2282–2292[Abstract/Free Full Text]
239. Giannoulis MG, Sonksen PH, Umpleby M, Breen L, Pentecost C, Whyte M, McMillan CV, Bradley C, Martin FC 2006 The effects of growth hormone and/or testosterone in healthy elderly men: a randomized controlled trial. J Clin Endocrinol Metab 91:477–484[Abstract/Free Full Text]
240. Thompson JL, Butterfield GE, Gylfadottir UK, Yesavage J, Marcus R, Hintz RL, Pearman A, Hoffman AR 1998 Effects of human growth hormone, insulin-like growth factor I, and diet and exercise on body composition of obese postmenopausal women. J Clin Endocrinol Metab 83:1477–1484[Abstract/Free Full Text]

This article has been cited by other articles:

				I. de Glisezinski, D. Larrouy, M. Bajzova, K. Koppo, J. Polak, M. Berlan, J. Bulow, D. Langin, M. A. Marques, F. Crampes, et al. Adrenaline but not noradrenaline is a determinant of exercise-induced lipid mobilization in human subcutaneous adipose tissue J. Physiol., July 1, 2009; 587(13): 3393 - 3404. [Abstract] [Full Text] [PDF]

				S. D. McCormick Evolution of the hormonal control of animal performance: insights from the seaward migration of salmon Integr. Comp. Biol., June 16, 2009; (2009) icp044v1. [Abstract] [Full Text] [PDF]

				J. F. Husak and D. J. Irschick Steroid use and human performance: lessons for integrative biologists Integr. Comp. Biol., May 22, 2009; (2009) icp015v1. [Abstract] [Full Text] [PDF]

				L. Di Luigi, A. E Rigamonti, F. Agosti, M. Mencarelli, P. Sgro, N. Marazzi, S. G Cella, E. E Muller, and A. Sartorio Combined evaluation of resting IGF1, N-terminal propeptide of type III procollagen and C-terminal cross-linked telopeptide of type I collagen levels might be useful for detecting inappropriate GH administration in female athletes Eur. J. Endocrinol., May 1, 2009; 160(5): 753 - 758. [Abstract] [Full Text] [PDF]

				G. Fanciulli, A. Delitala, and G. Delitala Growth hormone, menopause and ageing: no definite evidence for 'rejuvenation' with growth hormone Hum. Reprod. Update, May 1, 2009; 15(3): 341 - 358. [Abstract] [Full Text] [PDF]

				N. Moller and J. O. L. Jorgensen Effects of Growth Hormone on Glucose, Lipid, and Protein Metabolism in Human Subjects Endocr. Rev., April 1, 2009; 30(2): 152 - 177. [Abstract] [Full Text] [PDF]

				W. M. Widdowson and J. Gibney The Effect of Growth Hormone Replacement on Exercise Capacity in Patients with GH Deficiency: A Metaanalysis J. Clin. Endocrinol. Metab., November 1, 2008; 93(11): 4413 - 4417. [Abstract] [Full Text] [PDF]

				K. R. Short, N. Moller, M. L. Bigelow, J. Coenen-Schimke, and K. S. Nair Enhancement of Muscle Mitochondrial Function by Growth Hormone J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 597 - 604. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gibney, J. Articles by Sönksen, P. H. Search for Related Content PubMed PubMed Citation Articles by Gibney, J. Articles by Sönksen, P. H.