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
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.
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.
The current recommendation by the Growth Hormone Research Society 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) and low serum IGF-I. The latter assumes other factors that influence IGF-I are corrected, eg. thyroid, sex-steroid, and insulin/nutritional status.
Table 1. Features of growth hormone deficiency in adults
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).
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.
The aim of treatment is physiological hormone replacement. 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.
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. 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
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
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
The loss of GH's anabolic action affects heart muscle. Mild cardiac dysfunction is well documented and likely to contribute to functional impairment. GH has potent antinatriuretic actions, resulting in reduced plasma and total body water volumes in adults with GHD, which may explain cold intolerance, reduced sweating and difficulties with venesection in these patients
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. 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
Adults with GHD have a mean 10% or one standard deviation score reduction in bone mineral density, and an increased fracture rate
Psychological assessment of adults with GHD has revealed major problems with depression, social isolation and poor motivation. 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.
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.
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.
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.
An Article from:
Paper Published Format: Current Therapeutics, December 2001/January 2002
The full text of this article is available
on the CurrentTherapeutics website
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