GH-IGF Axis & ADL 1 Journal of Exercise Physiologyonline (JEPonline) Volume 12 Number 6 December 2009 Managing Editor Review Tommy Boone, PhD, MPHGrowth Editor-in-Chief Hormone Therapy in Health and Disease. Could GH and IGF-I Combination Jon K. Linderman, PhD Therapy Combat the Somatopause? Review Board Todd Astorino, PhD Julien Baker, PhD MICHAEL GRAHAM1,3, PETER EVANS2, BRUCE DAVIES3, NON Tommy Boone, PhD THOMAS4, JULIEN BAKER3,5 Eric Goulet, PhD Robert Gotshall, PhD 1 The Newman Centre for Sport and Exercise Research, Newman University Alexander Hutchison, PhD College, Birmingham, UK 2Royal Gwent Hospital, Newport, Gwent, Wales, UK, M. Knight-Maloney, PhD 3 University of Glamorgan, Pontypridd, Wales, UK 4Centre for Child Research, Len Kravitz, PhD James Laskin, PhD Swansea University, Swansea, UK 5Division of Sport, Faculty of Engineering Derek Marks, PhD and Science, University of the West of Scotland, Paisley Campus, Paisley, UK. Cristine Mermier, PhD Chantal Vella, PhD ABSTRACT Ben Zhou, PhD Graham MR, Evans P, Davies B, Thomas NE, and Baker JS. Growth Official Research Journal of Hormone Therapy in Health and Disease. Could GH and IGF-I the American Society of Combination Therapy Combat the Somatopause? JEPonline 2009;12 Exercise Physiologists (6):1-24. Recombinant human growth hormone (rhGH) has allowed (ASEP) investigations of the role of GH and identified the effects of rhGH replacement in GH-deficiency (GHD). Both obese and elderly subjects ISSN 1097-975 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.
GH-IGF Axis & ADL 2TABLE OF CONTENTS Review.........................................................................................................................................1TABLE OF CONTENTS...........................................................................................................................2Disclaimer................................................................................................................................................23Physiological AspectsGenetic elements normally determine the ability of the somatotroph cells in the anterior pituitary tosynthesize and secrete the polypeptide, human growth hormone (GH). The development ofsomatotrophs is determined by a gene called the Prophet of Pit-1 (PROP1), which controls thedevelopment of cells of the Pit-1 (POU1F1) transcription factor lineage. Pit-1 binds to the growthhormone promoter within the cell nucleus, developing somatotrophs and growth hormonetranscription. When it is translated, 70-80% of the GH is secreted as a 191-amino-acid, 4-helix bundleprotein and 20-30% as a less abundant 176-amino-acid form (1, 2). Hypothalamic-releasing andhypothalamic-inhibiting hormones acting via the hypophysial portal system and acting directly onspecific somatotroph surface receptors, control the secretion of GH, which is then secreted into thecirculation in a pulsatile manner (3).Growth hormone releasing hormone (GHRH) induces the synthesis and secretion of GH andsomatostatin suppresses the secretion of GH. Growth hormone is also controlled by ghrelin, a growthhormone secretagogue–receptor ligand (4) that is synthesized mainly in the gastrointestinal tract. Inhealthy persons, the GH level is usually < 0.2 μg.L-1 throughout most of the day. There areapproximately 10-12 intermittent bursts of GH in a 24 hour period, mostly at night, when the level canrise to 30 μg.L-1 (3).Aging is associated with decreased secretion and GH declines at 14% per decade (5). GH action ismediated by a GH receptor, which is expressed mainly in the liver and is composed of dimers thatchange conformation when occupied by a GH ligand (6). Cleavage of the GH receptor provides acirculating 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 thereceptor 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 thenucleus, initiating transcription of GH target proteins (7). Intracellular GH signalling is suppressed bysuppressors 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 toinhibit apoptosis (9).IGF-binding proteins (IGFBP) and their proteases regulate the access of ligands to the IGF-I receptoraffecting its action. Levels of IGF-I are at their peak during late adolescence and decline throughoutadulthood, duplicating the activity of GH (10). IGF-I levels usually reflect the secretory activity ofgrowth 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 calciummetabolism (12) and therefore body composition. Direct effects result from the interaction of GH withits specific receptors on target cells. In the adipocyte, GH stimulates the cell to break downtriglyceride and suppresses its ability to uptake and accumulate circulating lipids. Indirect effects aremediated primarily by IGF-I. Many of the growth promoting effects of GH, are due to the action ofIGF-I on its target cells. In most tissues, IGF-I has local autocrine and paracrine actions, but the liveractively secretes IGF-I and its binding proteins, into the circulation.
GH-IGF Axis & ADL 3Growth Hormone Deficiency (GHD)Recombinant human growth hormone (rhGH) development has resulted in investigations of the roleof 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 butbefore the age of 25 years should be treated with rhGH. Treatment should continue until adult peakbone 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 totalbody water (19) and reduced bone mass (20, 21, 22). There is also reduced strength, exercisecapacity, (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 ofcardiovascular disease (CVD).Side-Effects of GH ReplacementThe 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, canoccur 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 beenreported, but are rare (14, 17). There have also been reports of cerebral side effects, such asencephalocele (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 aconsequence 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 atrans-sphenoidal resection of the pituitary, or hypothalamo-pituitary radiotherapy. Today use of thesomatostatin analogue; octreotide and the GH receptor anatagonist; pegvisomant are the treatmentsof choice, either after inadequate surgery, radiation or both (13).Effects of GH Replacement on Quality of LifeDecreased psychological well-being has been reported in hypopituitary patients despite pituitaryreplacement with all hormones but growth hormone (38). A-OGHD reduces psychological well-beingand quality of life (QoL) (39). The quality of life (QoL) and mental state was shown to improve, afterGH administration for six months, in adults with GHD after completing the Nottingham Health Profileand the Psychological Well-being Schedule (40).There has been an increasing interest in hormone replacement therapy to improve health and QoL ofolder men with age-related decline in hormone levels (41). Despite adequate adrenal, thyroid or sexhormone replacement therapy, A-OGHD patients complain of attention and memory disabilities.RhGH treatment, demonstrated a beneficial effect on attention performance, in A-OGHD whentreated for at least 3 months (42).Six months of GH substitution in C-OGHD patients resulted in improved memory functioning, both forlong-term and working memory. Brain functional magnetic resonance imaging showed activationsduring the working memory task in prefrontal, parietal, motor, and occipital cortices, as well as in theright thalamus and anterior cingulate cortex. Decreased activation in the ventrolateral prefrontalcortex was observed after rhGH treatment, indicating decreased effort and more efficient recruitmentof the neural system involved (43).Effects of GH on Anthropometry & Performance
GH-IGF Axis & ADL 4RhGH administration has therapeutic value as a replacement therapy for GHD adults increasing leanbody 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 monthsreplacement therapy (23, 25, 46), after 12 months therapy (47) and after 36 months therapy, butreversed following cessation (46). RhGH treatment increased LBM and results were sustained after 5years in A-OGHD (48).After five years of rhGH replacement therapy, there is little observable difference between C-OGHDand A-OGHD groups in any variable body composition or isometric or concentric knee extensorstrength, knee flexor strength, or left-hand grip strength (49). Five years of rhGH replacement therapyin 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 theprotein 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 inCushing’s syndrome (52). This was consistent with rhGH stimulating the availability of amino acidtransporters. However, when large therapeutic doses of rhGH are used in the treatment of cachexia,in human immunodeficiency (HIV) wasting syndrome, diabetic symptoms occur relatively morequickly than development of lean body mass (53, 54). RhGH infusion over 24 hours causes a netglutamine release from skeletal muscle into the circulation and increased glutamine synthetasemessenger-ribonucleic acid (mRNA) levels (55). This possibly compensates for reduced glutamineprecursor 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 inchildren with cystic fibrosis (56). This presumably resulted from the combined effects of GH on themuscular, 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 proteinbreakdown increased by 50% confirmed by skeletal muscle biopsies from the vastus lateralisperformed at 6-monthly intervals during 18 months of rhGH treatment. Myostatin mRNA expressionwas significantly inhibited to 31% of control by GH. The inhibitory effect of GH on myostatin wassustained after 12 and 18 months of GH treatment. These effects were associated with significantlyincreased lean body mass at 6 months, 12 months, and 18 months and translated into significantlyincreased 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 mechanismswhereby rhGH administration affects an individual. Initial research experimented on athletes usingbiosynthetic methionyl hGH (met-hGH), consisting of 192 amino-acids, as opposed to recombinanthGH (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 andsignificantly 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, significantlyincreases forearm net balance of amino acids (63). The effects were claimed to have occurredthrough the stimulation of protein synthesis rather than decreased protein breakdown. Increased LBMhas not yet been translated into increased strength or power. The administration of rhGH appears tocause no further increase in muscle mass or strength, than that provided by resistance training in any
GH-IGF Axis & ADL 5healthy young athletes (60, 64, 65, 66, 67) or indeed in healthy middle aged elderly men (68). Therehas been no substantial evidence that it can increase strength in healthy men and women greaterthan sixty years of age (69).RhGH administration did not enhance the muscle anabolism associatedwith 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 liftersbefore and at the end of 14 days of subcutaneous rhGH administration (65). RhGH treatment of 8healthy, non-obese males (23.4 years) for a period of six weeks, had no effect on maximal strengthduring concentric contraction of the biceps and quadriceps muscles (66). RhGH administration for16-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 6months in 26 healthy elderly men (75 years) with well-preserved functional ability, but low baselineIGF-I levels, significantly increased LBM (by 4.3%). However, there were no significant differencesseen in knee or hand grip strength or in systemic endurance (70). There was no improvement inphysical 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 10healthy older men (68 years) (72). A single rhGH dose in 7 highly trained men (26 years) whoperformed 90 min of bicycling for 4 hours prevented two subjects from completing the exerciseprotocol. It significantly increased plasma lactate and glycerol as well as serum non-esterified fattyacids (NEFA) which may have compromised exercise performance. RhGH had no signifcant effect onthe 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 termsof increased glucose tolerance, in elderly subjects, would appear to be negated by rhGH use. RhGHsignificantly increased the myosin heavy chain (MHC) 2X isoforms, which may be regarded as achange into a younger MHC composition, possibly induced by the rejuvenation of systemic IGF-1levels (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 substantialincreases in quadriceps isokinetic strength, power, and CSA; but these RT induced improvementswere not further augmented by additional rhGH administration. In the RT and GH group, there was asignificant 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 26weeks, 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 andglycerol rate of appearance (Ra) at rest and during and after exercise increased during rhGHtreatment. Glucose Ra and glucose rate of disappearance (Rd) were greater after exercise duringrhGH treatment compared with placebo. Resting energy expenditure and fat oxidation were greaterunder resting conditions during rhGH treatment (76). Any effect on exercise performance wasundetermined.Nine men (23.7 years) completed six, 30-min randomly assigned bicycle ergometer exercise trials ata power output midway between the lactate threshold and peak oxygen consumption. Subjectsreceived an rhGH infusion, followed by a 30-min exercise trial (77). There were no significantcondition 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 lowerVO2max without a drop-off in power output, which was considered energy efficient. There was noincrease in strength in 20 physically active and healthy individuals of both genders (10 men and 10
GH-IGF Axis & ADL 6women), mean age 25.9 years, who received rhGH for 1 month. IGF-I significantly increased by134%, body mass significantly increased by 2.7%, LBM significantly increased by 5.3%, total bodywater significantly increased by 6.5%, extracellular water (ECW) significantly increased by 9.6% andbody fat significantly decreased by 6.6% (78).The interaction of GH and 11ßhydroxysteroid dehydrogenase (11ßHSD1 and 11ßHSD2) has beensuggested in the pathogenesis of central obesity. After 6 weeks rhGH, 11ßHSD1 significantlydecreased. After 9 months rhGH, 11ßHSD2 significantly increased. Between 6 weeks to 9 monthsglucose disposal rate increased and visceral fat mass decreased. Changes in 11ßHSD1 activitycorrelated with body composition and insulin sensitivity in 30 men (48-66 years) with abdominalobesity. 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 rhGHadministration for 4 weeks, in 6 trained male athletes. This had the effect of increasing resting energyexpenditure and fat oxidation and increased glucose production and uptake after exercise (80). Therelevance of these effects for athletic performance is as yet unknown, but one cannot exclude thatenhancement is possible.It is possible that the dosages and subject numbers used by researchers have been too low toachieve the results that are still anecdotally claimed to be the result of self-administration. It wasmany years before researchers accepted that androgenic anabolic steroids (AAS) could increasemuscle mass and strength in adult males (81). However, effects of rhGH have also been studied atgreater than physiological dosages, and although these may well have been below the dosagesabused in sport, they have still resulted in serum concentrations of IGF-1 that are at least twicenormal (65, 68). There have been significant physiological effects: increased lipolysis, alteredcarbohydrate metabolism, activation of the renin-angiotensin system, and water retention. WhenrhGH was given to severely GHD subjects, both protein synthesis and protein degradation increasedwith a net anabolic effect (12). Another explanation for the lack of evidence of increased strength inapparently healthy individuals is that rhGH has been reported to have anabolic effects on bone andcollagen metabolism (82, 83) and the collagenous components of skeletal muscle and connectivetissue elements of skin may also present as new lean body mass. A small increase in visceral proteinand collagen could equate to an increased positive nitrogen balance. This effect on connective tissuewould not necessarily make the muscle generate greater strength or power, which would beadvantageous to athletes. Current evidence would appear to contradict an ergogenic effect of rhGHon the strength healthy human muscle.Effects of GH on Blood PressureThe research on the effects of rhGH on blood pressure (BP) has involved its replacement in GHD. Ina 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 rhGHreplacement (84). Short term, placebo-controlled rhGH trials of 4-12 months’ duration in GHD havedemonstrated 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 notplasma volume nor blood pressure in GHD adults was shown in rhGH replacement in physiologicaldosages and supraphysiological dosages for 7 days (35). The renin-angiotensin-aldosterone systemhas been demonstrated to be one of the systems responsible for the antinatriuretic effects of GHincreasing plasma volume and extracellular fluid (87). Studies have also demonstrated a reduceddiastolic BP in men and women as an effect of reduced peripheral vascular resistance (88, 89).
GH-IGF Axis & ADL 7Further 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 wouldsuggest that among other reasons, the BP response also has a dosage related action over differenttime intervals (90). An improvement in systolic cardiac function during exercise has also beendemonstrated during rhGH administration in GHD, suggesting a direct inotropic and chronotropicaction by GH on the heart muscle (91).GHD leads to a reduced mass of both ventricles and to impaired cardiac performance with low heartrate (hypokinetic syndrome). These alterations are particularly evident during physical exercise andprovide an important contribution to the reduced exercise capacity of GHD patients. Theconsequences 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 beenmade by research enthusiasts to extrapolate the anabolic effects of GH in GHD, to individuals in astate of senescence (75) and also to the exercising athlete, in combination with AAS (93). Fewsignificant 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 RateNo alteration was recorded in the heart rate, using physiological dosages, three times per week inGHD for six months (15). An increase was recorded in heart rate at rest in GHD following dailyreplacement therapy with physiological dosages of rhGH (35, 90). Cardiovascular morbidity andmortality are increased in the GH excess condition of acromegaly. Both GH and IGF-I excess inducesa specific cardiomyopathy. Concentric biventricular hypertrophy and diastolic dysfunction can occur insuch individuals ending in heart failure if untreated (94). Resting, but not maximal heart rate wassignificantly higher, in early-onset growth hormone excess, prior to treatment with the GH antagonistoctreotide. Following treatment, a significant reduction in the resting and maximal heart rate, with noamelioration of the elevated peak BP was demonstrated (95). Maximal heart rate differences have notbeen recorded in healthy athletes, who have administered rhGH (77). An acute single dose of rhGHat 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 excessgrowth hormone disease states (96). This suggests that reduced levels of platelet NO linked to GHexcess may contribute to vascular alterations affecting heart rate and endothelial dysfunction.Effects of GH on Haemoglobin and Packed Cell VolumeErythropoietin (Epo), the primary regulator of erythropoiesis and GH/IGF systems share similarreceptors and pathways. Epo receptor activation seems to exert its effect by inhibiting apoptosisrather than by affecting the commitment of erythroid lineage, although the mechanism by which thisoccurs is unclear (97). Foetal and early postnatal erythropoiesis are dependent on factors in additionto Epo and the likely candidates are GH and IGF-I (98). GHD patients do not necessarily haveanaemia, but have haematopoietic precursor cells in the lower normal range, and rhGH replacementtherapy over a period of 24 months has a marked effect on erythroid and myeloid progenitorprecursor cells, but negligible effects on peripheral blood cells in GHD (99).Haemoglobin (Hb) levelswere shown to be decreased in children with GHD compared with age-corrected norms (100). Hbconcentration in children with short stature was positively correlated with relative body height and withserum IGF-1 levels, but not with the concentrations of Epo (101). Treatment with rhGH acceleratedgrowth significantly and elevated Hb and serum IGF-1. When GHD is associated with multiplepituitary hormone deficiencies there are pathological influences on erythropoiesis which are notcorrected until rhGH treatment is started, indicating a permissive role of GH in haematopoiesis (102).
GH-IGF Axis & ADL 8Erythropoiesis is impaired in adult GHD and rhGH therapy has been shown to stimulateerythropoiesis and the significantly increased plasma volume and total blood volume may contributeto increased exercise performance (103).Arterial Pulse Wave Velocity in Pathological GH StatesThe potential mechanisms accounting for any abnormality on Arterial Pulse Wave Velocity (APWV) inGHD or GH excess may result from a direct IGF-I-mediated effect via attenuated or increasedproduction 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 toendothelial dysfunction.Growth hormone deficiencyIncreased oxidative stress exists in GHD adults, which may be a factor in atherogenesis and reducedby 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 ofvascular disease, have impaired endothelial function (assessed by flow-mediated dilatation of thebrachial artery) and increased augmentation index (AIx) compared with controls. Replacement withrhGH resulted in improvement of both endothelial function and AI x, without changing BP (108).Administration of rhGH for 3 months corrected endothelial dysfunction in patents with chronic heartfailure (109). Endothelial dysfunction in GHD is reversed in renal failure by rhGH therapy (110). Renalfailure induces growth hormone resistance at the receptor and post-receptor level, which can beovercome by rhGH therapy.Growth hormone excessAcromegaly is associated with changes in the central arterial pressure waveform, suggesting largeartery stiffening. This may have important implications for cardiac morphology and performance aswell as increasing the susceptibility to atheromatous plaque formation . Large artery stiffness wasreduced in surgically “cured” acromegaly (GH < 2.5mU.L-1) and partially reversed afterpharmacological 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 andGHD. Human peripheral blood, T cells, B cells, natural killer (NK) cells and monocytes express IGF-Ireceptors. Animal studies suggest a role for GH and IGF-I in the modulation of both cell-mediated andhumoral 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 tumourtarget cells, in healthy adults (113). NK activity was significantly increased within the first week andthis 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 andcentral fat decreased significantly in growth hormone recipients compared with placebo recipients inGHD after 18 months rhGH (116). Several studies have established homocysteine (HCY)concentration as an independent risk factor for atherosclerosis (117, 118). HCY impairs vascularendothelial function through significant reduction of NO production. This appears to potentiateoxidative stress and atherogenic development (119). Acute hyperhomocysteinemia has beenidentified 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 forvascular disease, if there are no other risk factors present (121). Pegvisomant (a GH receptorantagonist) induced significant acute changes in triglycerides, one of the major risk markers for CVD,
GH-IGF Axis & ADL 9 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 (brainGH/IGF-axis pathology and retina) against cell injury-induced oxidativeAPWV↑; HCY↑; NO↓; CRP↑; Fibrinogen↑; Lipids↑; stress, in cerebral ischaemia-reperfusion. It up-plasminogen activator inhibitor↑; Glucose↑ 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).
GH-IGF Axis & ADL 10 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 cyclicFigure 1. The GH–IGF axis and regulation of GH and AMP response element binding protein (CREB)IGF-I synthesis and secretion. and the pro-apoptotic effector proteins glycogen synthaseGH is secreted from the pituitary gland under the control of kinase-3beta (GSK-3beta) andthe hypothalamic hormones, somatostatin and GHRH, as forkhead (FKHR). IGF-I regulates survival at thewell as the mainly gastric ghrelin. GHRH and ghrelin bind to nuclear level through accumulation of phospho-their respective receptors in the pituitary and stimulate GH Akt in DRG neuronal nuclei, increased CREB-secretion. Somatostatin inhibits GH secretion. GH circulates,bound to GHBP, and acts through specific cell-surface mediated transcription, and nuclear exclusion of FKHR. High glucose levels increase expressionreceptors. Most of the anabolic actions of GH are mediatedby IGF-I, which is produced in many different tissues, with of the pro-apoptotic Bcl protein Bim (amost circulating IGF-I being derived from the liver. IGF-I actsthrough the IGF-I receptor by autocrine, paracrine and transcriptional target of FKHR). High glucoseclassical endocrine mechanisms. IGF-I is present in the also induces loss of the initiator caspase-9 and increases caspase-3 cleavage, effects blockedcirculation and extracellular space, almost entirely bound to by IGF-I, suggesting that IGF-I preventsIGFBPs that coordinate and regulate the biological functionsof the IGFs. Over 99% of circulating IGF-I is bound in aapoptosis in DRG neurons by regulatingternary complex comprising IGF-I, IGFBP-3 and an ALS. PI3K/AktThe major source of circulating IGFBPs and ALS is the liver. pathway effectors, including GSK-3beta, CREB, and FKHR, and by blockingIGF-I inhibits GHRH and GH secretion in a classical negativefeedback mechanism. Abbreviations: ALS, acid labile caspase activation (137).subunit; APWV, arterial pulse wave velocity; CRP, C-reactive protein; GH, growth hormone; GHBP, GH-binding The unique role of IGF-IR in maintaining theprotein; GHRH, GH-releasing hormone; HCY,Homocysteine; IGF, insulin-like growth factor; IGFBP, IGF- balance of death and survival in foetal brownbinding protein; NO, nitric oxide. adipocytes, in IGF-IR deficiency has been demonstrated (138). A vascular protective rolefor IGF-I has been suggested because of its ability to stimulate NO production from endothelial andvascular smooth muscle cells. IGF-I probably plays a role in aging, atherosclerosis andcerebrovascular disease, cognitive decline, and dementia. In cross sectional studies, low IGF-I levelshave 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 predictfuture development of ischaemic heart disease. The fall in IGF-I levels with aging correlates withcognitive 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 hasanti-apoptotic and neuro-protective effects and promotes projection neuron growth, dendriticarborisation 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 (feedingourselves, bathing, dressing, grooming), work, homemaking, and leisure can be used as a verypractical measure of ability or disability in many disorders. In the independent elderly, functionalability appears to be determined favourably by muscle strength and adversely by fat mass. Lowserum 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
GH-IGF Axis & ADL 11associated 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 andIGF-I receptors are located in several brain areas such as the hippocampus, a brain area which isknown to play an essential role in cognitive processes, especially memory and learning (142). Theexact mechanism by which the GH/IGF-I axis influences cognitive functions is still a mystery and littleis known about cognition in adults with both CO-GHD and AO-GHD.Alzheimers disease (AD) is an ADL destructive disease process. When an acetylcholinesteraseinhibitor, a specific treatment for AD, is acutely administered to individuals with AD, the area underthe curve of the GH response to GHRH doubles, showing that acetylcholinesterases are powerfuldrugs in the enhancement of GH release. Such data would suggest that improvement of the clinicalmanifestations of AD requires activation of GH/IGF-I axis, stimulating rejuvenation, resulting in anoverall physiological benefit (143). Although the age-related decline in the activity of the GH/IGF-Iaxis 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 andtherefore 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 onstrength 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 ofpharmacological doses of GH, which were able to counteract the negative effects of surgery, allowingearlier return to independent life (147). The evidence that treatment with rhGH or rhIGF-I significantlyimproves cognitive parameters, memory or mood in normal elderly subjects has tended to beequivocal (148). These results are in contrast to those in young adult GHD patients, in whom apositive 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 insulinresistance, have been recorded during rhGH therapy, in a dose-dependent manner (150). This is arelevant point, considering that glycaemic control is already impaired in aged subjects (150). Thelong-term safety of increasing GH and IGF-I levels in aged people has become a concern because ofreports of an association between serum IGF-I levels and cancer risk, especially of prostate, colonand breast. However, long-term data from children and adults with GHD treated with GH have shownno 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, hasbeen shown to restore spontaneous GH secretion and IGF-I levels in the elderly. Significant positiveeffects 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 AdultsLimited studies have directly compared the effects of GH with IGF-I in the metabolic pathways inhumans. Many of the features of GHD can be improved with rhGH therapy (153, 45). As early aswithin 2 months of rhGH treatment there is increased lean body mass and decreasesd adiposity. After8 months therapy there is also increased bone mineral density. Exercise capacity and skeletal musclestrength have also been shown to improve in GHD treated with rhGH. Qol measures, includingenergy level, mood, sensitivity to pain and emotional lability can improve on rhGH replacementtherapy. The effects of GH on plasma lipids show a lowering of LDL cholesterol concentrations andoverall improvement of the lipid profile. A group of young, GHD adults were studied before and after
GH-IGF Axis & ADL 12four weeks of daily SC GH followed by twice daily IGF-I for four weeks, each subject served ashis/her own control. GH and IGF-I shared common effects on protein, muscle and calciummetabolism but different effects on lipid and carbohydrate metabolism in GHD (154). These findingsconcurred with much shorter treatment of similar subjects for seven days (155). The effect of GH andIGF-I treatment in GHD subjects was compared with that of IGF-I treatment in GH receptordeficiency. GH had the most potent effects on whole body protein synthesis (154). However, IGF-I iseffective 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 oflipolysis and significantly decreased the percent fat mass and increased lean body mass after eightweeks in 10 adults with GH receptor deficiency (156). These results were similar to rhGHreplacement in GHD (154). IGF-I administration may be beneficial as a long-term replacement of theGH receptor deficient individual.CONCLUSIONThere 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 replacementhormone therapy is still in its infancy. It was only 3 decades ago that rhGH became available andsignificant progress into the somatopause and related pathologies has occurred. The future maypropose the concomitant use of rhGH and rhIGF as has been used in certain refractory cases ofdiabetes and GH resistance (157). The reviews of rhGH replacement in obesity have not beenrevolutionary (158). Identification of any beneficial effects of rhGH and rhIGF in deficient states is thenext step forward. After all, it wasn’t until 1999 that hypothyroidism was identified as being moreappropriately treated with T3 and T4, than T4 alone (159).Address for correspondence: : Graham MR, PhD, The Newman Centre for Sport and ExerciseResearch, Newman University College, Birmingham, UK. Phone (+4401214831181 extn 2516);Email: firstname.lastname@example.org.REFERENCES1. 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.
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