Articles
What Does the Newest Hormone Replacement Therapy Do?
Adult Growth Hormone Deficiency
WHAT DOES THE NEWEST HORMONE REPLACEMENT THERAPY DO?
Adult growth hormone deficiency (GHD) has recently been identified as a distinct syndrome. Replacement therapy with recombinant human growth hormone (rhGH) has been approved in Australia. Management of these patients requires multi-disciplinary teams
- What is GHD in Adults?
Conventionally growth hormone (GH) is viewed as being responsible for linear growth during childhood. Deficiency results in short stature in children and adolescents. However, in adults GHD results in a discrete syndrome,[1,2] with the key features listed in Table 1.
The syndrome results from inadequate actions of both GH and insulin-like growth factor-I (IGF-I). GH is secreted by the pituitary gland into the circulation where it has direct metabolic effects. Additionally, GH stimulates IGF-I production from the liver and other tissues, where IGF-I has mitogenic and metabolic actions (Figure 1). The features of GHD are outlined in Table 2.
- Which Adults are Likely to Have GHD?
Given that the individual clinical features of GHD in adults are not sufficiently specific for a clinical diagnosis to be made, biochemical testing of at-risk patients is required. All patients with known pituitary or hypothalamic disease (eg. pituitary adenomas, craniopharyngiomas, hypophysitis, gliomas, etc), and those treated with surgery or radiotherapy to the region must be considered at high risk. GHD is one of the first hormone deficiencies to develop following pituitary compression by an expanding mass lesion, or following radiotherapy. Isolated GHD, in the absence of other pituitary disorders is rare in adults. Of specific concern are children treated with rhGH for short stature. Current recommendations are that all such patients be retested for GH status prior to starting rhGH replacement as adults, since a number appear to have regained secretory capacity.[11]
- How is the Diagnosis Established?
The current recommendation by the Growth Hormone Research Society[12] is that a diagnosis of GHD in adults is based on a low GH response to insulin-induced hypo-glycaemia. Other stimulation tests are being developed, but are not currently approved. For the patient with epilepsy or ischaemic heart disease, who should not be exposed to hypoglycaemia, the literature supports a diagnosis based on panhy-popituitarism (making the likelihood of GHD very high)[13] and low serum IGF-I. The latter assumes other factors that influence IGF-I are corrected, eg. thyroid, sex-steroid, and insulin/nutritional status.
- Salient Points
- All patients with known pituitary or hypothalamic disease, or surgery or radiation treatment to the area could have growth hormone deficiency
- Growth hormone deficiency in adults is an approved indication for recombinant human growth hormone treatment in Australia
- Diagnosis currently requires measurement of growth hormone response to insulin hypoglycaemia
- Many patients have dramatic improvements in body composition, functional capacity and psychological well-being following recombinant human growth hormone replacement
Table 1. Features of growth hormone deficiency in adults
Diagnostic features
Known pituitary pathology (tumour, surgery, and/or radiotherapy)
Subnormal GH response to ITT (peak GH <3 ng/L), +/- low serum IGF-I
Abnormal body composition
Increased fat mass (generalised and truncal)
Increased visceral fat (by DXA, etc)
Reduced lean body mass or body cell mass
Reduced skeletal muscle mass
Reduced connective tissue mass (possible; thin, dry skin)
Reduced total body water and plasma volume (cool peripheries; poor venous access)
Reduced bone mass
Reduced body hair
Abnormal cardiovascular biology
Reduced left ventricular wall mass (childhood-onset only)
Reduced resting and maximal cardiac output (probable)
Reduced chronotropic tone (possible)
Increased systemic vascular resistance and reduced nitric oxide production
Reduced renal blood flow and glomerular filtration rate
Increased prevalence of atheromatous plaques and increased arterial intimal thickness
Abnormal coagulation or fibrinolysis (possible)
Increased mortality rates due to cardiac and cerebral vascular disease (probable)
Abnormal intermediary metabolism
Fasting hypoglycaemia (prolonged fasting); insulin resistance (in obese subjects)
Dyslipidaemia (increased serum total and LDL-cholesterol, possible reduced HDL-cholesterol, increased triglycerides)
Reduced whole-body protein synthesis rate
Reduced brain glucose metabolism
Abnormal endocrine function
Reduced peripheral de-iodination of thyroxine (reduced serum free tri-iodothyronine) Reduced fertility rates
Abnormal physical performance
Reduced maximal and submaximal exercise performance and oxygen uptake Reduced sweat rate and increased risk of exercise-induced hyperthermia Reduced skeletal-muscle-force generation
Abnormal psychological and CNS performance
Impaired quality of life (depressed mood, anxiety poor motivation and energy, social isolation and blunted social interaction, impaired self-control)
Impaired social function (probable reduced rates of marriage and employment)
Abnormal sleep patterns
Abnormal cerebrospinal fluid neurotransmitter concentrations
CNS = central nervous system; DXA = dual energy x-ray absorptiometry; GH = growth hormone; IGF-1 = insulin-iike growth factor 1; ITT = insulin tolerance test.
Figure 1. Key elements of the growth hormone (GH) insulin-like growth factor-1 (IGF-1).
- How is GHD Treated in Adults?
Recombinant human GH (Humatrope, Eli Lilly; Genotropin, Pharmacia, Norditropin, Novo Nordisk, Saizen, Serono) is identical to native pituitary GH, but free of risk from prion disease (Creutzfeldt-Jakob disease). Treatment requires daily nocturnal subcutaneous injection. Pen injectors similar to those used by patients with diabetes offer convenience.
The Therapeutic Goods Administration has recently approved adult GHD as an indication for the use of rhGH. At the time of writing, application for reimbursement under the Pharmaceutical Benefit Scheme is pending.
- How Much rhGH is Required?
The aim of treatment is physiological hormone replacement.[14] Factors influencing endogenous GH production need to be considered before deciding on the dose of rhGH. Given the lifetime peak in GH secretion and IGF-I concentration in late puberty and the slow decline throughout adult life, conventional rhGH replacement doses currently aim to correct serum IGF-I to age-related normal values. Males appear to be more sensitive to a given rhGH dose than females and oral oestrogens induce an additional element of GH-resistance. With these factors in mind, daily doses of between 1-4 IU are employed, translating to approximately 0.02-0.03 lU/kg/day. Nocturnal administration mimics the physiological nocturnal GH surge.
Monitoring should aim to normalise serum IGF-I. Age-related reference ranges need to be carefully considered in interpreting IGF-I results. During initial dose titration, monthly assessment may be required, but 6-monthly checks should suffice once stability is achieved.
- What are the Effects of rhGH Replacement?
Nearly all the symptoms and abnormalities of GHD are improved or normalised with rhGH treatment.[15,16] For example, major changes in body composition occur over 3-6 months, with considerable reductions in visceral and total fat mass, and increases in lean body mass and muscle mass and fluid volumes. Total bodyweight changes little. Patients often describe quite dramatic improvements in physical capacity and psychological well-being. Total-cholesterol is reduced by about 8-10%, with a fall in LDL-cholesterol and either no change or a small rise in HDL-cholesterol.
Data are not currently available to determine whether rhGH replacement reduces vascular and total mortality rates. Short-term and 10-year treatment data suggest that abnormal intimal vascular thickening is improved with rhGH replacement.[17] While rhGH replacement increases bone mineral density progressively over several years, in the order of 10%, no data are available to assess whether fracture rates are reduced. Prospective studies are underway to assess these important questions.
Table 2. Effects of growth hormone deficiency in adults
Body composition
Adults with growth hormone deficiency (GHD) have reduced lean body mass and muscle mass, due to deficient anabolic actions of GH and IGF-I. In addition, fat mass is excessive, reflecting the loss of GH's lipolytic effect. The adiposity is generalised, with a substantial central and visceral component. Fat mass is increased approximately 20% and lean body mass decreased 8-10%. Skin thinning may also reflect the catabolic state
Functional
Muscle strength is reduced in proportion to the loss of muscle mass, and maximal and submaximal exercise capacity is reduced by approximately 20%.[3,4] Patients often complain of prominent fatiguability
Haemodynamic/fluid
The loss of GH's anabolic action affects heart muscle. Mild cardiac dysfunction is well documented and likely to contribute to functional impairment.[5] GH has potent antinatriuretic actions, resulting in reduced plasma and total body water volumes in adults with GHD,[6] which may explain cold intolerance, reduced sweating and difficulties with venesection in these patients
Metabolic/vascular risks
GHD may result in fasting hypoglycaemia, a problem more common in children than adults. Hyperchlolesterolaemia, especially due to LDL-cholesterol excess, is well described with group mean total cholesterol-concentrations over 6 mmol/L.[7] Doubling of vascular mortality rates in adults with hypopituitarism treated with conventional pituitary hormone replacement is currently believed to be due to GHD, caused by hypercholesterolaemia and visceral adiposity[8]
Bone
Adults with GHD have a mean 10% or one standard deviation score reduction in bone mineral density, and an increased fracture rate[9]
CNS
Psychological assessment of adults with GHD has revealed major problems with depression, social isolation and poor motivation.[10] Sleep quality is reduced, but duration of sleep is increased. Cerebrospinal fluid neurotransmitter concentrations mimic those in patients with major depression
GHD = growth hormone deficiency; IGF-1 = insulin-like growth factor 1; LDL = low-density lipoprotein.
- Side Effects
Acute effects include sodium retention and arthralgias. The former may include ankle swelling, tight hands and, occasionally, carpal tunnel symptoms. Initiation of therapy at low doses and approaching target doses over a month or two minimises or abolishes these effects. Older subjects appear to be at greater risk of side effects than young individuals. The incidence of diabetes mellitus or impaired glucose tolerance and hypertension is very low, but clinical and biochemical monitoring are recommended.
Long-term concerns about pituitary tumour recurrence or increases in other malignancies following rhGH replacement are being investigated with prospective and post-marketing surveillance in Europe and the USA. Data concerning thousands of patient-years in adults with GHD have revealed no concerns to date. Extensive surveys of paediatric patients treated with human GH over the last 40 years confirms the safety of the treatment.[18]
- Wider Implications
Relative deficiencies of GH and or IGF-I occur during normal ageing, catabolic illnesses, diabetes mellitus and obesity. Very exciting research is underway to explore additional applications for GH and related therapies. Unfortunately, elite sports people are believed to be abusing human GH to enhance sporting performance, but research to develop a test is well advanced.[19]
Founder of AGHDaware:
JENNIFER D WALLACE
Metabolic Research Unit Department of Medicine, University of Queensland, and Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane, QLD ( 1990 - 2005 ) Neuroendocrine Research Group, Griffith University Learning Centre, Logan Hospital, Brisbane, Qld. Australia.
This Article "Adult Growth Hormone Deficiency- What Does The Newest Hormone Replacement Therapy Do?" Authors' Details
Assoc Professor Ross Cuneo, is a Clinical Endocrinologist in the Metabolic Research Unit, University of Queensland and the Department of Diabetes and Endocrinology at the Princess Alexandra Hospital.
Jennifer Wallace, was Senior Scientist and Clinical Research Director of the Metabolic Research Unit at the University of Queensland. ( at the time of printing )
They both have a special interest in pituitary pathology and are actively researching growth hormone and insulin-like growth factor pathophysiology in patients with growth hormone deficiency, liver disease, ageing and exercise.
- References
- Cuneo RC, Salomon F, McGauley GA, Sonksen PH. The growth hormone deficiency syndrome in adults. Clin Endocrinol 1992; 37: 387-97
- Carroll PV, Christ ER, Bengtsson B-A et al. Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. J Clin Endocrinol Metab 1998; 83: 382-95
- Cuneo RC, Salomon F, Wiles CM et al. Growth hormone treatment in growth hormone-deficient adults. 1. Effects on muscle mass and strength. J Appl Physiol 1991; 70: 688-94
- Cuneo RC, Salomon F, Wiles CM et al. Growth hormone treatment in growth hormone-deficient adults. 11. Effects on exercise performance. J Appl Physiol 1991; 70: 695-700
- Cuneo RC, Salomon F, Wilmshurst P et al. Cardiovascular effects of growth hormone treatment in growth-hormone-deficient adults: stimulation of the renin-aldosterone system. Clin Sci 1991; 81: 587-92
- Rosen T, Bosaeus I, Toll! J et al. Increased body fat mass and decreased extracellular fluid volume in adults with growth hormone deficiency. Clin Endocrinol 1993; 38: 63-71
- Cuneo RC, Salomon F, Watts GF et al. Growth hormone treatment improves serum lipids and lipoproteins in adults with growth hormone deficiency. Metabolism 1993; 42: 1519-23
- Rosen T, Bengtsson B. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990; 336: 285-8
- Rosen T, Wilhelmsen L, Landin Wilhelmsen K et al. Increased fracture frequency in adult patients with hypopituitarism and GH deficiency. EurJ Endocrinol 1997; 137: 240-5
- McGauley GA, Cuneo RC, Salomon F et al. Psychological well-being before and after growth hormone treatment in adults with growth hormone deficiency. Horm Res 1990; 33(Suppl 4): 52-4
- De Boer H, van der Veen EA. Editorial: why retest young adults with childhood-onset growth hormone deficiency? Clin Endocrinol Metab 1997; 82: 2032-6
- Growth Hormone Research Society. Invited report of a workshop: consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the growth hormone research society workshop on adult growth hormone deficiency. J Clin Endocrinol Metab 1998; 83: 379-81
- Toogood AA, Beardwell CG, Shalet SM. The severity of growth hormone deficiency in adults with pituitary disease is related to the degree of hypopituitarism. Clin Endocrinol 1994; 41: 511-6
- Jorgensen JOL. Human growth hormone replacement therapy: pharmacological and clinical aspects. Endo Rev 1991; 12: 189-207
- Cuneo RC, Judd S, Wallace JD et al. The Australian multicenter trial of growth hormone (GH) treatment in GH-deficient adults. J Clin Endocrinol Metab 1998; 83: 107-16
- Attanasio AF, Lamberts SW, Matranga AM et al. Adult growth hormone (GH>deficient patients demonstrate heterogeneity between childhood onset and adult onset before and during human GH treatment. Adult Growth Hormone Deficiency Study Group. J Clin Endocrinol Metab 1997; 82: 82-8
- Gibney J, Wallace JD, Wierzibicki A et al. The effects of 10 years of recombinant human growth hormone J Clin Endocrinol Metabl 1999; 84: 2596-2602
- Clayton PE, Cowell CT. Safety issues in children and adolescents during growth hormone therapy - a review. Growth Horm IGF Res 2000; 10: 306-17
- Wallace JD, Cuneo RC. Growth hormone abuse in athletes: a review. The Endocrinologist 2000; 10: 175-840
An Article from:
PRACTICAL THERAPEUTICS
Paper Published Format: Current Therapeutics, December 2001/January 2002
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