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  • 1. Journal of Exercise Physiologyonline (JEPonline) Volume 12 Number 6 December 2009 Managing Editor Tommy Boone, PhD, MPH Editor-in-Chief Jon K. Linderman, PhD Review Board Todd Astorino, PhD Julien Baker, PhD Tommy Boone, PhD Eric Goulet, PhD Robert Gotshall, PhD Alexander Hutchison, PhD M. Knight-Maloney, PhD Len Kravitz, PhD James Laskin, PhD Derek Marks, PhD Cristine Mermier, PhD Chantal Vella, PhD Ben Zhou, PhD Official Research Journal of the American Society of Exercise Physiologists (ASEP) ISSN 1097-975 GH-IGF Axis & ADL Review Growth Hormone Therapy in Health and Disease. Could GH and IGF-I Combination Therapy Combat the Somatopause? MICHAEL GRAHAM1,3 , PETER EVANS2 , BRUCE DAVIES3 , NON THOMAS4 , JULIEN BAKER3,5 1 The Newman Centre for Sport and Exercise Research, Newman University College, Birmingham, UK 2 Royal Gwent Hospital, Newport, Gwent, Wales, UK, 3 University of Glamorgan, Pontypridd, Wales, UK 4 Centre for Child Research, Swansea University, Swansea, UK 5 Division of Sport, Faculty of Engineering and Science, University of the West of Scotland, Paisley Campus, Paisley, UK. ABSTRACT Graham MR, Evans P, Davies B, Thomas NE, and Baker JS. Growth Hormone Therapy in Health and Disease. Could GH and IGF-I Combination Therapy Combat the Somatopause? JEPonline 2009;12 (6):1-24. Recombinant human growth hormone (rhGH) has allowed investigations of the role of GH and identified the effects of rhGH replacement in GH-deficiency (GHD). Both obese and elderly subjects with low insulin like-growth factor-I (IGF-I) levels have functional GHD. Administration of rhGH to elderly subjects with low IGF-I levels results in reversal of changes associated with GHD. These changes are similar to those shown in adults with GHD with rhGH replacement. RhGH replacement in the elderly and obese has been compromised by side effects, due to hypersensitivity. Doses are required to be titrated to individual needs. Insulin like growth factor-I (IGF-I) mediates some of the metabolic actions of GH and has both GH-like and insulin-like actions. Both GH and IGF-I have a net anabolic effect enhancing whole body protein synthesis improving anthropometry in GHD. Both hormones have been used in catabolism and have been effective in counteracting the protein wasting effects of medicines such as glucocorticoids. IGF-I may be an appropriate combination agent to use in conditions where carbohydrate metabolism is impaired. The pendulum of research has progressed towards IGF-I and it may be possible that the two can be used together to treat the sarcopenic effects of the somatopause, with an application for use in obesity? Key Words: Anthropometry, Exercise, Peptide Hormones, Performance. 1
  • 2. GH-IGF Axis & ADL TABLE OF CONTENTS Review......................................................................................................................1 TABLE OF CONTENTS.....................................................................................................................2 Disclaimer...........................................................................................................................................23 Physiological Aspects Genetic elements normally determine the ability of the somatotroph cells in the anterior pituitary to synthesize and secrete the polypeptide, human growth hormone (GH). The development of somatotrophs is determined by a gene called the Prophet of Pit-1 (PROP1), which controls the development of cells of the Pit-1 (POU1F1) transcription factor lineage. Pit-1 binds to the growth hormone promoter within the cell nucleus, developing somatotrophs and growth hormone transcription. When it is translated, 70-80% of the GH is secreted as a 191-amino-acid, 4-helix bundle protein and 20-30% as a less abundant 176-amino-acid form (1, 2). Hypothalamic-releasing and hypothalamic-inhibiting hormones acting via the hypophysial portal system and acting directly on specific somatotroph surface receptors, control the secretion of GH, which is then secreted into the circulation in a pulsatile manner (3). Growth hormone releasing hormone (GHRH) induces the synthesis and secretion of GH and somatostatin suppresses the secretion of GH. Growth hormone is also controlled by ghrelin, a growth hormone secretagogue–receptor ligand (4) that is synthesized mainly in the gastrointestinal tract. In healthy persons, the GH level is usually < 0.2 μg.L-1 throughout most of the day. There are approximately 10-12 intermittent bursts of GH in a 24 hour period, mostly at night, when the level can rise to 30 μg.L-1 (3). Aging is associated with decreased secretion and GH declines at 14% per decade (5). GH action is mediated by a GH receptor, which is expressed mainly in the liver and is composed of dimers that change conformation when occupied by a GH ligand (6). Cleavage of the GH receptor provides a circulating GH binding protein (GHBP), prolonging the half-life and mediating the transport of GH. Janus kinase 2 (JAK2) tyrosine kinase binds to the GH receptor, once activated by GH. Both the receptor and JAK2 protein are phosphorylated, and signal transducers and activators of transcription (STAT) proteins bind to this complex. STAT proteins are then phosphorylated and translocated to the nucleus, initiating transcription of GH target proteins (7). Intracellular GH signalling is suppressed by suppressors of cytokine signalling. GH induces the synthesis of peripheral insulin-like growth factor I (IGF-I) (8) and endocrine, autocrine and paracrine IGF-I induces cell proliferation and is thought to inhibit apoptosis (9). IGF-binding proteins (IGFBP) and their proteases regulate the access of ligands to the IGF-I receptor affecting its action. Levels of IGF-I are at their peak during late adolescence and decline throughout adulthood, duplicating the activity of GH (10). IGF-I levels usually reflect the secretory activity of growth hormone and are one of a potential number of markers for identification of GH-deficiency (GHD), excess (acromegaly) or rhGH administration in sport (11). In conjunction with GH, IGF-I has varying differential effects on protein, glucose, lipid and calcium metabolism (12) and therefore body composition. Direct effects result from the interaction of GH with its specific receptors on target cells. In the adipocyte, GH stimulates the cell to break down triglyceride and suppresses its ability to uptake and accumulate circulating lipids. Indirect effects are mediated primarily by IGF-I. Many of the growth promoting effects of GH, are due to the action of IGF-I on its target cells. In most tissues, IGF-I has local autocrine and paracrine actions, but the liver actively secretes IGF-I and its binding proteins, into the circulation. 2
  • 3. GH-IGF Axis & ADL Growth Hormone Deficiency (GHD) Recombinant human growth hormone (rhGH) development has resulted in investigations of the role of GH in adulthood as well as childhood and the effects of GH replacement in the GHD adult (A- OGHD) and in the GHD child (C-OGHD). Severe GHD developing after linear growth is complete but before the age of 25 years should be treated with rhGH. Treatment should continue until adult peak bone mass has been achieved (13). A-OGHD causes reduced lean body mass (LBM) (14, 15, 16) increased fat mass (FM), especially abdominal visceral adiposity, (14, 15, 16, 17, 18) reduced total body water (19) and reduced bone mass (20, 21, 22). There is also reduced strength, exercise capacity, (23, 24, 25) cardiac performance and an altered substrate metabolism (26, 27, 28, 29, 30). This leads to an abnormal lipid profile (31, 32, 33, 34) predisposing to the development of cardiovascular disease (CVD). Side-Effects of GH Replacement The most common side effects following administration arise from sodium and water retention. Dependent oedema, or carpal tunnel syndrome; can frequently occur within days (35). Arthralgia, can occur in any joint, but there is usually no evidence of effusion, inflammation, or X-ray changes (14). Muscle pains can also occur. GH administration is documented to result in hyper-insulinaemia (36) which may increase the risk of CVD. GH induced hypertension and atrial fibrillation have both been reported, but are rare (14, 17). There have also been reports of cerebral side effects, such as encephalocele (14) and headache with tinnitus (17) and benign intra-cranial hypertension (37). Cessation of GH therapy is associated with regression of side effects in most cases (37). GH Excess (Acromegaly) GH excess results in the clinical condition known as acromegaly. This condition occurs as a consequence of a pituitary tumour. Acromegalics have an increased risk of diabetes mellitus, hypertension and premature mortality due to CVD (3, 17). Treatment was originally surgical, via a trans-sphenoidal resection of the pituitary, or hypothalamo-pituitary radiotherapy. Today use of the somatostatin analogue; octreotide and the GH receptor anatagonist; pegvisomant are the treatments of choice, either after inadequate surgery, radiation or both (13). Effects of GH Replacement on Quality of Life Decreased psychological well-being has been reported in hypopituitary patients despite pituitary replacement with all hormones but growth hormone (38). A-OGHD reduces psychological well-being and quality of life (QoL) (39). The quality of life (QoL) and mental state was shown to improve, after GH administration for six months, in adults with GHD after completing the Nottingham Health Profile and the Psychological Well-being Schedule (40). There has been an increasing interest in hormone replacement therapy to improve health and QoL of older men with age-related decline in hormone levels (41). Despite adequate adrenal, thyroid or sex hormone replacement therapy, A-OGHD patients complain of attention and memory disabilities. RhGH treatment, demonstrated a beneficial effect on attention performance, in A-OGHD when treated for at least 3 months (42). Six months of GH substitution in C-OGHD patients resulted in improved memory functioning, both for long-term and working memory. Brain functional magnetic resonance imaging showed activations during the working memory task in prefrontal, parietal, motor, and occipital cortices, as well as in the right thalamus and anterior cingulate cortex. Decreased activation in the ventrolateral prefrontal cortex was observed after rhGH treatment, indicating decreased effort and more efficient recruitment of the neural system involved (43). Effects of GH on Anthropometry & Performance 3
  • 4. GH-IGF Axis & ADL RhGH administration has therapeutic value as a replacement therapy for GHD adults increasing lean body mass (LBM) and reducing total and visceral fat, which may be delayed by up to 12 months (24, 25, 44, 45). Absolute maximal oxygen uptake (VO2max) increased in A-OGHD after 6 months replacement therapy (23, 25, 46), after 12 months therapy (47) and after 36 months therapy, but reversed following cessation (46). RhGH treatment increased LBM and results were sustained after 5 years in A-OGHD (48). After five years of rhGH replacement therapy, there is little observable difference between C-OGHD and A-OGHD groups in any variable body composition or isometric or concentric knee extensor strength, knee flexor strength, or left-hand grip strength (49). Five years of rhGH replacement therapy in elderly adults with A-OGHD, normalised knee flexor strength (98-106% of predicted) and improved, but did not fully normalise, knee extensor strength (90-100% of predicted) nor handgrip strength (80- 87% of predicted) (50). When rhGH was given in conjunction with prednisone, it counteracted the protein catabolic effects of prednisone and resulted in increased whole body protein synthesis rates, with no effect on proteolysis (51). The clearance of leucine into protein was increased after 2 and 7 days of rhGH treatment in Cushing’s syndrome (52). This was consistent with rhGH stimulating the availability of amino acid transporters. However, when large therapeutic doses of rhGH are used in the treatment of cachexia, in human immunodeficiency (HIV) wasting syndrome, diabetic symptoms occur relatively more quickly than development of lean body mass (53, 54). RhGH infusion over 24 hours causes a net glutamine release from skeletal muscle into the circulation and increased glutamine synthetase messenger-ribonucleic acid (mRNA) levels (55). This possibly compensates for reduced glutamine precursor availability, post-trauma, in hyper-catabolic trauma patients, which can account for its anti- catabolic effects. RhGH treatment improved absolute VO2max during exercise tolerance tests in children with cystic fibrosis (56). This presumably resulted from the combined effects of GH on the muscular, cardiovascular, and pulmonary capacity. RhGH treatment induced LBM gains in HIV- associated wasting, and improved sub-maximal measurements, but not VO2max (57). The stimulation of lipolysis by rhGH is its principle protein-conserving mechanism (58). Muscle protein breakdown increased by 50% confirmed by skeletal muscle biopsies from the vastus lateralis performed at 6-monthly intervals during 18 months of rhGH treatment. Myostatin mRNA expression was significantly inhibited to 31% of control by GH. The inhibitory effect of GH on myostatin was sustained after 12 and 18 months of GH treatment. These effects were associated with significantly increased lean body mass at 6 months, 12 months, and 18 months and translated into significantly increased aerobic performance, determined by VO2max at 6 months and 12 months (59). The diminution of GH & IGF-I with age, would appear to be one of the fundamental mechanisms whereby rhGH administration affects an individual. Initial research experimented on athletes using biosynthetic methionyl hGH (met-hGH), consisting of 192 amino-acids, as opposed to recombinant hGH (191 amino acids). Met-hGH was administered for 6 weeks in 8 well-trained exercising adults (22-33 years) trained with progressive resistance exercise and significantly decreased body fat and significantly increased LBM (60). It was thought that rhGH administration would benefit elderly men, decreasing adiposity and increasing LBM (principally muscle), but strength was not increased (61, 62). Acute administration of rhGH in normal healthy humans in the post-absorptive state, significantly increases forearm net balance of amino acids (63). The effects were claimed to have occurred through the stimulation of protein synthesis rather than decreased protein breakdown. Increased LBM has not yet been translated into increased strength or power. The administration of rhGH appears to cause no further increase in muscle mass or strength, than that provided by resistance training in any 4
  • 5. GH-IGF Axis & ADL healthy young athletes (60, 64, 65, 66, 67) or indeed in healthy middle aged elderly men (68). There has been no substantial evidence that it can increase strength in healthy men and women greater than sixty years of age (69).RhGH administration did not enhance the muscle anabolism associated with heavy-resistance exercise in 16 men (21-34 years) for 12 weeks (64). Skeletal muscle protein synthesis in 7 young (23 years) healthy experienced male weight lifters before and at the end of 14 days of subcutaneous rhGH administration (65). RhGH treatment of 8 healthy, non-obese males (23.4 years) for a period of six weeks, had no effect on maximal strength during concentric contraction of the biceps and quadriceps muscles (66). RhGH administration for 16-weeks, did not increase muscle strength over resistance exercise training (75-90% max strength) in 8 healthy, sedentary men (67 years) with low serum IGF-I levels (68). RhGH administration for 6 months in 26 healthy elderly men (75 years) with well-preserved functional ability, but low baseline IGF-I levels, significantly increased LBM (by 4.3%). However, there were no significant differences seen in knee or hand grip strength or in systemic endurance (70). There was no improvement in physical or performance characteristics, assessed by cycle ergometry and VO2max assessment, following rhGH administration in young males (28.3 years) for seven days (71). RhGH, administration for one month, significantly improved performance in “stair climb time” in 10 healthy older men (68 years) (72). A single rhGH dose in 7 highly trained men (26 years) who performed 90 min of bicycling for 4 hours prevented two subjects from completing the exercise protocol. It significantly increased plasma lactate and glycerol as well as serum non-esterified fatty acids (NEFA) which may have compromised exercise performance. RhGH had no signifcant effect on the VO2max which remained unaltered until exhaustion (73). Plasma glucose was, on average, 9% higher during exercise after rhGH administration. This suggests that any benefits of exercise in terms of increased glucose tolerance, in elderly subjects, would appear to be negated by rhGH use. RhGH significantly increased the myosin heavy chain (MHC) 2X isoforms, which may be regarded as a change into a younger MHC composition, possibly induced by the rejuvenation of systemic IGF-1 levels (74). However, rhGH had no effect on isokinetic quadriceps muscle strength, power, cross- sectional area (CSA), or fibre size. Resistance training (RT) and placebo caused substantial increases in quadriceps isokinetic strength, power, and CSA; but these RT induced improvements were not further augmented by additional rhGH administration. In the RT and GH group, there was a significant decrease in MHC 1X and 2X isoforms, whereas MHC 2A increased. RT, therefore, appeared to overrule the changes in MHC composition induced by GH administration alone (74). RhGH and sex steroids were administered to healthy aged men and women, (65-88 years) for 26 weeks, and showed that rhGH with or without sex steroids increased VO2max in men, but not women (75). RhGH exerts an anabolic effect both at rest and during exercise in endurance-trained athletes, measuring whole body leucine turnover (76). Plasma levels of glycerol and free fatty acids and glycerol rate of appearance (Ra) at rest and during and after exercise increased during rhGH treatment. Glucose Ra and glucose rate of disappearance (Rd) were greater after exercise during rhGH treatment compared with placebo. Resting energy expenditure and fat oxidation were greater under resting conditions during rhGH treatment (76). Any effect on exercise performance was undetermined. Nine men (23.7 years) completed six, 30-min randomly assigned bicycle ergometer exercise trials at a power output midway between the lactate threshold and peak oxygen consumption. Subjects received an rhGH infusion, followed by a 30-min exercise trial (77). There were no significant condition effects for total work, caloric expenditure, heart rate response, the blood lactate response, or ratings of perceived exertion response (RPE). However, acute GH administration resulted in lower VO2max without a drop-off in power output, which was considered energy efficient. There was no increase in strength in 20 physically active and healthy individuals of both genders (10 men and 10 5
  • 6. GH-IGF Axis & ADL women), mean age 25.9 years, who received rhGH for 1 month. IGF-I significantly increased by 134%, body mass significantly increased by 2.7%, LBM significantly increased by 5.3%, total body water significantly increased by 6.5%, extracellular water (ECW) significantly increased by 9.6% and body fat significantly decreased by 6.6% (78). The interaction of GH and 11ßhydroxysteroid dehydrogenase (11ßHSD1 and 11ßHSD2) has been suggested in the pathogenesis of central obesity. After 6 weeks rhGH, 11ßHSD1 significantly decreased. After 9 months rhGH, 11ßHSD2 significantly increased. Between 6 weeks to 9 months glucose disposal rate increased and visceral fat mass decreased. Changes in 11ßHSD1 activity correlated with body composition and insulin sensitivity in 30 men (48-66 years) with abdominal obesity. However, the authors considered that the data could not support the hypothesis that long- term (9 months) metabolic effects of GH are mediated through its action on 11ßHSD 1 and 2 (79). Plasma levels of glycerol and free fatty acids increased at rest and during exercise during rhGH administration for 4 weeks, in 6 trained male athletes. This had the effect of increasing resting energy expenditure and fat oxidation and increased glucose production and uptake after exercise (80). The relevance of these effects for athletic performance is as yet unknown, but one cannot exclude that enhancement is possible. It is possible that the dosages and subject numbers used by researchers have been too low to achieve the results that are still anecdotally claimed to be the result of self-administration. It was many years before researchers accepted that androgenic anabolic steroids (AAS) could increase muscle mass and strength in adult males (81). However, effects of rhGH have also been studied at greater than physiological dosages, and although these may well have been below the dosages abused in sport, they have still resulted in serum concentrations of IGF-1 that are at least twice normal (65, 68). There have been significant physiological effects: increased lipolysis, altered carbohydrate metabolism, activation of the renin-angiotensin system, and water retention. When rhGH was given to severely GHD subjects, both protein synthesis and protein degradation increased with a net anabolic effect (12). Another explanation for the lack of evidence of increased strength in apparently healthy individuals is that rhGH has been reported to have anabolic effects on bone and collagen metabolism (82, 83) and the collagenous components of skeletal muscle and connective tissue elements of skin may also present as new lean body mass. A small increase in visceral protein and collagen could equate to an increased positive nitrogen balance. This effect on connective tissue would not necessarily make the muscle generate greater strength or power, which would be advantageous to athletes. Current evidence would appear to contradict an ergogenic effect of rhGH on the strength healthy human muscle. Effects of GH on Blood Pressure The research on the effects of rhGH on blood pressure (BP) has involved its replacement in GHD. In a large cohort of GHD adults the prevalence of treated hypertension was found to have increased (32). In younger GHD adults, the systolic BP (SBP) was found to be lower, but increased by rhGH replacement (84). Short term, placebo-controlled rhGH trials of 4-12 months’ duration in GHD have demonstrated anabolic effects of rhGH on cardiac structure (15, 85) and beneficial effects on SBP (86) but no change in diastolic BP (DBP) (16, 85). A significant increase in body sodium, but not plasma volume nor blood pressure in GHD adults was shown in rhGH replacement in physiological dosages and supraphysiological dosages for 7 days (35). The renin-angiotensin-aldosterone system has been demonstrated to be one of the systems responsible for the antinatriuretic effects of GH increasing plasma volume and extracellular fluid (87). Studies have also demonstrated a reduced diastolic BP in men and women as an effect of reduced peripheral vascular resistance (88, 89). 6
  • 7. GH-IGF Axis & ADL Further studies have found a significant increase in SBP and DBP after 12 months, but not 6 months, of supraphysiological rhGH administration, but only to the level of the controls (90). Such data would suggest that among other reasons, the BP response also has a dosage related action over different time intervals (90). An improvement in systolic cardiac function during exercise has also been demonstrated during rhGH administration in GHD, suggesting a direct inotropic and chronotropic action by GH on the heart muscle (91). GHD leads to a reduced mass of both ventricles and to impaired cardiac performance with low heart rate (hypokinetic syndrome). These alterations are particularly evident during physical exercise and provide an important contribution to the reduced exercise capacity of GHD patients. The consequences of GHD are more relevant if the disorder starts during early heart development. Cardiac dysfunction is also susceptible to marked improvement by rhGH (92). Attempts have been made by research enthusiasts to extrapolate the anabolic effects of GH in GHD, to individuals in a state of senescence (75) and also to the exercising athlete, in combination with AAS (93). Few significant effects have been recorded on BP in athletes, who were either aggressive users of AAS (93) or non-substance users (76). Effects of GH on Heart Rate No alteration was recorded in the heart rate, using physiological dosages, three times per week in GHD for six months (15). An increase was recorded in heart rate at rest in GHD following daily replacement therapy with physiological dosages of rhGH (35, 90). Cardiovascular morbidity and mortality are increased in the GH excess condition of acromegaly. Both GH and IGF-I excess induces a specific cardiomyopathy. Concentric biventricular hypertrophy and diastolic dysfunction can occur in such individuals ending in heart failure if untreated (94). Resting, but not maximal heart rate was significantly higher, in early-onset growth hormone excess, prior to treatment with the GH antagonist octreotide. Following treatment, a significant reduction in the resting and maximal heart rate, with no amelioration of the elevated peak BP was demonstrated (95). Maximal heart rate differences have not been recorded in healthy athletes, who have administered rhGH (77). An acute single dose of rhGH at 65% VO2max was reported in males to significantly increase heart rate compared with placebo (73). An inverse correlation of nitric oxide (NO) levels with GH and IGF-I has been shown, in excess growth hormone disease states (96). This suggests that reduced levels of platelet NO linked to GH excess may contribute to vascular alterations affecting heart rate and endothelial dysfunction. Effects of GH on Haemoglobin and Packed Cell Volume Erythropoietin (Epo), the primary regulator of erythropoiesis and GH/IGF systems share similar receptors and pathways. Epo receptor activation seems to exert its effect by inhibiting apoptosis rather than by affecting the commitment of erythroid lineage, although the mechanism by which this occurs is unclear (97). Foetal and early postnatal erythropoiesis are dependent on factors in addition to Epo and the likely candidates are GH and IGF-I (98). GHD patients do not necessarily have anaemia, but have haematopoietic precursor cells in the lower normal range, and rhGH replacement therapy over a period of 24 months has a marked effect on erythroid and myeloid progenitor precursor cells, but negligible effects on peripheral blood cells in GHD (99).Haemoglobin (Hb) levels were shown to be decreased in children with GHD compared with age-corrected norms (100). Hb concentration in children with short stature was positively correlated with relative body height and with serum IGF-1 levels, but not with the concentrations of Epo (101). Treatment with rhGH accelerated growth significantly and elevated Hb and serum IGF-1. When GHD is associated with multiple pituitary hormone deficiencies there are pathological influences on erythropoiesis which are not corrected until rhGH treatment is started, indicating a permissive role of GH in haematopoiesis (102). 7
  • 8. GH-IGF Axis & ADL Erythropoiesis is impaired in adult GHD and rhGH therapy has been shown to stimulate erythropoiesis and the significantly increased plasma volume and total blood volume may contribute to increased exercise performance (103). Arterial Pulse Wave Velocity in Pathological GH States The potential mechanisms accounting for any abnormality on Arterial Pulse Wave Velocity (APWV) in GHD or GH excess may result from a direct IGF-I-mediated effect via attenuated or increased production of NO. Qualitative alterations in lipoproteins have been described in GHD adults (104), resulting in the generation of an atherogenic lipoprotein phenotype, which would contribute to endothelial dysfunction. Growth hormone deficiency Increased oxidative stress exists in GHD adults, which may be a factor in atherogenesis and reduced by rhGH therapy’s effects on oxidative stress (105). Endothelial dysfunction exists in GHD adults (106), which is reversible with GH replacement (107). Patients with GHD, with increased risk of vascular disease, have impaired endothelial function (assessed by flow-mediated dilatation of the brachial artery) and increased augmentation index (AIx ) compared with controls. Replacement with rhGH resulted in improvement of both endothelial function and AIx , without changing BP (108). Administration of rhGH for 3 months corrected endothelial dysfunction in patents with chronic heart failure (109). Endothelial dysfunction in GHD is reversed in renal failure by rhGH therapy (110). Renal failure induces growth hormone resistance at the receptor and post-receptor level, which can be overcome by rhGH therapy. Growth hormone excess Acromegaly is associated with changes in the central arterial pressure waveform, suggesting large artery stiffening. This may have important implications for cardiac morphology and performance as well as increasing the susceptibility to atheromatous plaque formation . Large artery stiffness was reduced in surgically “cured” acromegaly (GH < 2.5mU.L-1 ) and partially reversed after pharmacological treatment of active disease (111). GH on Inflammatory Markers of Cardiovascular Disease (CVD) There have been suggestions of an association between certain inflammatory markers of CVD and GHD. Human peripheral blood, T cells, B cells, natural killer (NK) cells and monocytes express IGF-I receptors. Animal studies suggest a role for GH and IGF-I in the modulation of both cell-mediated and humoral immunity. Administration of either can reverse the immunodeficiency of Snell dwarf mice (112). Met-hGH induced a significant overall increase in the percent specific lysis of K562 tumour target cells, in healthy adults (113). NK activity was significantly increased within the first week and this level was maintained throughout the remaining 6 week period of administration. In vitro studies, using human lymphocytes indicate that GH is important for the development of the immune system (114). Pre-operative administration of rhGH did not alter the release of C-reactive protein (CRP), serum amyloid A (SAA) or the inflammatory cytokine interleukin-6 (IL-6) (115). CRP, IL-6 levels and central fat decreased significantly in growth hormone recipients compared with placebo recipients in GHD after 18 months rhGH (116). Several studies have established homocysteine (HCY) concentration as an independent risk factor for atherosclerosis (117, 118). HCY impairs vascular endothelial function through significant reduction of NO production. This appears to potentiate oxidative stress and atherogenic development (119). Acute hyperhomocysteinemia has been identified in bodybuilders regularly self-administering supraphysiological doses of various AAS (120). HCY levels are not significantly elevated in GHD adults and are unlikely to be a major risk factor for vascular disease, if there are no other risk factors present (121). Pegvisomant (a GH receptor antagonist) induced significant acute changes in triglycerides, one of the major risk markers for CVD, 8
  • 9. GH-IGF Axis & ADL in apparently healthy abdominally obese men (122). This suggested that the secondary metabolic changes, e.g. inflammatory factors, which develop as a result of long-standing GHD are of primary importance in the pathogenesis of atherosclerosis in patients with GHD. Patients with active acromegaly have significantly lower CRP and significantly higher insulin levels than healthy controls (123). Administration of pegvisomant significantly increased CRP levels. GH secretory status may be an important determinant of serum CRP levels, but the mechanism and significance of this finding is as yet unknown. Inflammatory markers are predictive of atherosclerosis and cardiovascular events (124, 125, 126). The metabolic syndrome (MS) is correlated with elevated CRP and a predictor of coronary heart disease and diabetes mellitus (DM) (127). IL-6 concentrations were significantly increased (208% and 248%) in GHD, compared to BMI-matched and non-obese controls, respectively (128). CRP significantly increased (237%) in patients compared to non-obese controls, but not significantly different compared to BMI-matched controls. Age, low density lipoprotein (LDL)-cholesterol, and IL-6 were positively correlated, and IGF-I was negatively correlated to arterial intima-media thickness (IMT) in the patient group, but only age and IL-6 were independently related to IMT. An association between raised HCY levels in long term AAS users and sudden death has been identified (129). The effects of endogenous GH on apoptosis in a T cell lymphoma over-expressing GH showed increased NO formation. This suggested a possible mechanism for the anti-apoptotic effects of endogenous GH through the production of NO. It supported the idea that endogenous GH may play an important role in the survival of lymphocytes exposed to stressful stimuli (130). Varying low physiological doses of rhGH in males and females had no improvement on CRP, leptin nor adiponectin (adipokines, whose levels are associated with obesity and the metabolic syndrome) over a period of six months (131). However, the doses used were within a low physiological range and could explain the lack of significant effects on these inflammatory markers, despite improvements in lean body mass and anthropometry. Prevention of Oxidative Stress by IGF-I Oxidative stress represents a mechanism leading to the destruction of neuronal and vascular cells. Oxidative stress occurs as a result of the production of free radicals or reactive oxygen species (ROS). ROS consist of entities including the superoxide anion, hydrogen peroxide, superoxide anion, NO, and peroxynitrite. The production of ROS, such as peroxynitrite and NO, can lead to cell injury through cell membrane lipid destruction and cleavage of DNA (132). Production of excess ROS can result in the peroxidation of docosahexaenoic acid (DHA), a precursor of neuroprotective docosanoids (133). DHA is a fatty acid released from membrane phospholipids and is derived from dietary essential fatty acids. It is involved in memory formation, excitable membrane function, photoreceptor cell biogenesis and function and neuronal signalling. DHA may have a role in modulating IGF-I binding in retinal cells (134). Neuroprotectin D1 (NPD1) is a DHA-derived mediator that protects the central nervous system (brain and retina) against cell injury-induced oxidative stress, in cerebral ischaemia-reperfusion. It up- regulates the anti-apoptotic Bcl-2 proteins, Bcl-2 and Bclxl and decreases pro-apoptotic Bax and Bad expression (135). IGF-I also blocks Bcl-2 interacting mediator of cell death (Bim) induction and intrinsic death signalling in cerebellar granule neurons (136). 9 GH/IGF-axis pathology APWV↑; HCY↑; NO↓; CRP↑; Fibrinogen↑; Lipids↑; plasminogen activator inhibitor↑; Glucose↑
  • 10. GH-IGF Axis & ADL Dorsal root ganglia (DRG) neurons express IGF-I receptors (IGF-IR), and IGF-I activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. High glucose exposure induces apoptosis, which is inhibited by IGF-I through the PI3K/Akt pathway. IGF-I stimulation of the PI3K/Akt pathway phosphorylates three known Akt effectors: the survival transcription factor cyclic AMP response element binding protein (CREB) and the pro-apoptotic effector proteins glycogen synthase kinase-3beta (GSK-3beta) and forkhead (FKHR). IGF-I regulates survival at the nuclear level through accumulation of phospho- Akt in DRG neuronal nuclei, increased CREB- mediated transcription, and nuclear exclusion of FKHR. High glucose levels increase expression of the pro-apoptotic Bcl protein Bim (a transcriptional target of FKHR). High glucose also induces loss of the initiator caspase-9 and increases caspase-3 cleavage, effects blocked by IGF-I, suggesting that IGF-I prevents apoptosis in DRG neurons by regulating PI3K/Akt pathway effectors, including GSK- 3beta, CREB, and FKHR, and by blocking caspase activation (137). The unique role of IGF-IR in maintaining the balance of death and survival in foetal brown adipocytes, in IGF-IR deficiency has been demonstrated (138). A vascular protective role for IGF-I has been suggested because of its ability to stimulate NO production from endothelial and vascular smooth muscle cells. IGF-I probably plays a role in aging, atherosclerosis and cerebrovascular disease, cognitive decline, and dementia. In cross sectional studies, low IGF-I levels have been associated with an unfavourable profile of CVD risk factors, such as atherosclerosis, abnormal lipoprotein levels and hypertension, while in prospective studies, lower IGF-I levels predict future development of ischaemic heart disease. The fall in IGF-I levels with aging correlates with cognitive decline and it has been suggested that IGF-I plays a role in the development of dementia. IGF-I is highly expressed within the brain and is essential for normal brain development. IGF-I has anti-apoptotic and neuro-protective effects and promotes projection neuron growth, dendritic arborisation and synaptogenesis (139). Effects of GH and IGF on Activities of Daily Living (ADL) Activities of daily living (ADL), the things we normally do in daily living, including self-care (feeding ourselves, bathing, dressing, grooming), work, homemaking, and leisure can be used as a very practical measure of ability or disability in many disorders. In the independent elderly, functional ability appears to be determined favourably by muscle strength and adversely by fat mass. Low serum IGFBP-2 concentrations are a powerful indicator for overall good physical functional status, probably inversely reflecting the integrated sum of nutrition and the biological effects of GH and IGF-I (140). In the elderly, living in the community, lower levels of total serum free IGF-I and IGFBP-3 are 10 Figure 1. The GH–IGF axis and regulation of GH and IGF-I synthesis and secretion. GH is secreted from the pituitary gland under the control of the hypothalamic hormones, somatostatin and GHRH, as well as the mainly gastric ghrelin. GHRH and ghrelin bind to their respective receptors in the pituitary and stimulate GH secretion. Somatostatin inhibits GH secretion. GH circulates, bound to GHBP, and acts through specific cell-surface receptors. Most of the anabolic actions of GH are mediated by IGF-I, which is produced in many different tissues, with most circulating IGF-I being derived from the liver. IGF-I acts through the IGF-I receptor by autocrine, paracrine and classical endocrine mechanisms. IGF-I is present in the circulation and extracellular space, almost entirely bound to IGFBPs that coordinate and regulate the biological functions of the IGFs. Over 99% of circulating IGF-I is bound in a ternary complex comprising IGF-I, IGFBP-3 and an ALS. The major source of circulating IGFBPs and ALS is the liver. IGF-I inhibits GHRH and GH secretion in a classical negative feedback mechanism. Abbreviations: ALS, acid labile subunit; APWV, arterial pulse wave velocity; CRP, C-reactive protein; GH, growth hormone; GHBP, GH-binding protein; GHRH, GH-releasing hormone; HCY, Homocysteine; IGF, insulin-like growth factor; IGFBP, IGF-binding protein; NO, nitric oxide.
  • 11. GH-IGF Axis & ADL associated with impairment of cognitive performance, suggesting that the GH/IGF-I axis (Figure 1) may play an important role in the age-related decline of cognitive performance (141). Both GH and IGF-I receptors are located in several brain areas such as the hippocampus, a brain area which is known to play an essential role in cognitive processes, especially memory and learning (142). The exact mechanism by which the GH/IGF-I axis influences cognitive functions is still a mystery and little is known about cognition in adults with both CO-GHD and AO-GHD. Alzheimer's disease (AD) is an ADL destructive disease process. When an acetylcholinesterase inhibitor, a specific treatment for AD, is acutely administered to individuals with AD, the area under the curve of the GH response to GHRH doubles, showing that acetylcholinesterases are powerful drugs in the enhancement of GH release. Such data would suggest that improvement of the clinical manifestations of AD requires activation of GH/IGF-I axis, stimulating rejuvenation, resulting in an overall physiological benefit (143). Although the age-related decline in the activity of the GH/IGF-I axis is considered to contribute to age-related changes similar to those observed in GHD adults, GH/IGF-I deficiency or resistance is also known to result in prolonged life expectancy in animals (144, 145). This raises the question whether or not GHD constitutes a beneficial adaptation to ageing and therefore requires no therapy? Studies designed to evaluate the independent effects of GH treatment and lifestyle interventions (e.g. exercise program and resistance training) could not demonstrate any additional effects of GH on strength training in terms of increased muscle strength, resistance or physical performance (146). The increase of GH/IGF-I activity has positively influenced ageing “frailty” by administration of pharmacological doses of GH, which were able to counteract the negative effects of surgery, allowing earlier return to independent life (147). The evidence that treatment with rhGH or rhIGF-I significantly improves cognitive parameters, memory or mood in normal elderly subjects has tended to be equivocal (148). These results are in contrast to those in young adult GHD patients, in whom a positive effect of GH replacement therapy on cognitive function and well-being have been reported (149). Moreover, increased glucose and insulin concentrations, resulting from differing degrees of insulin resistance, have been recorded during rhGH therapy, in a dose-dependent manner (150). This is a relevant point, considering that glycaemic control is already impaired in aged subjects (150). The long-term safety of increasing GH and IGF-I levels in aged people has become a concern because of reports of an association between serum IGF-I levels and cancer risk, especially of prostate, colon and breast. However, long-term data from children and adults with GHD treated with GH have shown no increased overall occurrence of neoplasia or increased rate of growth of primary pituitary tumours (151). Treatment with GHRH, administered in short-time studies and in small cohorts of patients, has been shown to restore spontaneous GH secretion and IGF-I levels in the elderly. Significant positive effects on body composition have been recorded, but no increase in physical performance scores, nor enhancement of the effect of exercise were demonstrated during GHRH therapy (152). Use of GH & IGF-I as Replacement Therapy in Adults Limited studies have directly compared the effects of GH with IGF-I in the metabolic pathways in humans. Many of the features of GHD can be improved with rhGH therapy (153, 45). As early as within 2 months of rhGH treatment there is increased lean body mass and decreasesd adiposity. After 8 months therapy there is also increased bone mineral density. Exercise capacity and skeletal muscle strength have also been shown to improve in GHD treated with rhGH. Qol measures, including energy level, mood, sensitivity to pain and emotional lability can improve on rhGH replacement therapy. The effects of GH on plasma lipids show a lowering of LDL cholesterol concentrations and overall improvement of the lipid profile. A group of young, GHD adults were studied before and after 11
  • 12. GH-IGF Axis & ADL four weeks of daily SC GH followed by twice daily IGF-I for four weeks, each subject served as his/her own control. GH and IGF-I shared common effects on protein, muscle and calcium metabolism but different effects on lipid and carbohydrate metabolism in GHD (154). These findings concurred with much shorter treatment of similar subjects for seven days (155). The effect of GH and IGF-I treatment in GHD subjects was compared with that of IGF-I treatment in GH receptor deficiency. GH had the most potent effects on whole body protein synthesis (154). However, IGF-I is effective in GHD and GH receptor-deficient individuals in enhancing whole body protein synthesis, supportive of the potent protein-anabolic role of both of these hormones. IGF-I decreased the oxidation of protein, stimulated rates of protein synthesis increased the rates of lipolysis and significantly decreased the percent fat mass and increased lean body mass after eight weeks in 10 adults with GH receptor deficiency (156). These results were similar to rhGH replacement in GHD (154). IGF-I administration may be beneficial as a long-term replacement of the GH receptor deficient individual. CONCLUSION There is a causal link between the age-related decline in GH and IGF-I levels and physical, cardiovascular and cognitive deficits in older persons. Research into the benefits of replacement hormone therapy is still in its infancy. It was only 3 decades ago that rhGH became available and significant progress into the somatopause and related pathologies has occurred. The future may propose the concomitant use of rhGH and rhIGF as has been used in certain refractory cases of diabetes and GH resistance (157). The reviews of rhGH replacement in obesity have not been revolutionary (158). Identification of any beneficial effects of rhGH and rhIGF in deficient states is the next step forward. After all, it wasn’t until 1999 that hypothyroidism was identified as being more appropriately treated with T3 and T4, than T4 alone (159). Address for correspondence: : Graham MR, PhD, The Newman Centre for Sport and Exercise Research, Newman University College, Birmingham, UK. Phone (+4401214831181 extn 2516); Email: drgraham.ac.uk@live.co.uk. REFERENCES 1. Resendez-Perez D, Ortiz-Lopez R, et al. HGH isoforms: cDNA expression, adipogenic activity and production in cell culture. Biochim Biophys Acta 1993; 20: 49-54. 2. Wu Z, Bidlingmaier M, Dall R, et al. Detection of doping with human growth hormone. Lancet 1999; 353: 895. 3. Melmed S, Medical progress: Acromegaly. N Engl J Med 2006; 14: 2558-2573. 4. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 9: 656-660. 5. Iranmanesh A, Lizarralde G, Velduis JD. Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone secretory bursts and the half- life of endogenous GH in healthy men. J Clin Endocrinol Metab 1991; 73: 1081-1088. 6. Brown RJ, Adams JJ, Pelekanos RA, et al. Model for growth hormone receptor activation based on subunit rotation within a receptor dimmer. Nat Struct Mol Biol 2005; 12: 814-821. 12
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