1
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
1The Newman Centre for Sport and Exercise Research, Newman University College, Birmingham, UK 2Royal Gwent Hospital, Newport, Gwent, Wales, UK, 3University of Glamorgan, Pontypridd, Wales, UK 4Centre for Child Research, Swansea University, Swansea, UK 5Division 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.
TABLE OF CONTENTS
ABSTRACT 1
1. PHYSIOLOGICAL ASPECTS 2
2. Growth Hormone Deficiency (GHD) 3
3. Side-effects of GH replacement 4
4. GH Excess (Acromegaly) 4
5. Effects of GH replacement on Quality of Life 4
6. Effects of GH on Anthropometry & Performance 4
7. Effects of GH on Blood Pressure 7
8. Effects of GH on Heart Rate 7
9. Effects of GH on Haemoglobin and Packed Cell Volume 8
10. Arterial Pulse Wave Velocity in Pathological GH States 8
11. GH on Inflammatory Markers of Cardiovascular Disease (CVD) 9
12. Prevention of oxidative stress by igf-i 9
13. Effects of GH & IGF on activities of daily living (ADL) 10
14. Use of GH IGF-I as replacement therapy in adults 11
15. Conclusion 12
REFERENCES 12
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.
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
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 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).