Growth hormone deficiency in adults
By T. Kearney, MBBS, MRCP and D.G. Johnston, FRCP, PhD
Adult onset growth hormone deficiency is estimated to affect 10 people per million annually worldwide. This article examines the management of growth hormone deficiency in adults. Its causes, clinical features and treatment are discussed. A previous article, published on June 17 (p917), examined growth hormone deficiency in childrenGrowth hormone (GH) is released from the anterior pituitary in a pulsatile fashion. Release is stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostatin, both of which are released from the hypothalamus. GH appears to have trophic, antinatriuretic, lipolytic and anti-insulin actions, some of which are mediated by insulin-like growth factor-1 (IGF-1), which is predominantly hepatically derived in response to circulating GH.
Growth hormone deficiency
Growth hormone deficiency (GHD) is defined as failure to mount satisfactory growth hormone responses to provocation tests, when compared with controls. It should be noted that GH levels are physiologically lower in males and in advancing age, and are higher in obesity. Clinically relevant GH deficiency in adults is usually associated with a stimulated GH level of less than 6mU/L. The incidence of adult onset growth hormone deficiency (AOGHD) is unknown, but is estimated to affect approximately 10 people per million annually in the United Kingdom. Most cases arise as a result of pituitary tumours, or their treatment (see Panel 1), and hence AOGHD is usually associated with other endocrine deficiencies. Studies suggest that adults with growth hormone deficiency have greater morbidity and mortality than their counterparts, which may be ameliorated by growth hormone replacement.
Panel 1: Causes of congenital GHD
|Idiopathic (GHD diagnosed at some stage in childhood)||Isolated GHD|
Causes of GHD
GHD may be congenital (Panel 1) or acquired (Panel 2). About 50 per cent of children with idiopathic GHD will continue to be deficient on re-testing as adults; however, AOGHD usually occurs as a result of damage to the pituitary gland. The common causes include non-functioning adenomas, craniopharyngiomas, prolactinomas, radiotherapy or surgery.
Panel 2: Causes of acquired AOGHD
|Pituitary tumours||Non-functioning tumours which do not secrete active hormones (adenomas, carcinomas, sarcomas)|
Functioning tumours which secrete active hormones (eg, prolactin, ACTH, FSH, LH, and/or TSH)
|Parapituitary tumours||Germinomas, choriocarcinomas, ependymoma, chondrosarcomas, optic nerve glioma, reticulosis|
|Metastasis||Carcinoma of the breast and lung|
|Infections||Tuberculosis, abscess, syphilis|
|Infiltrations||Sarcoid, histiocytosis X, cholesteatoma, haemochromatosis|
|Abbreviations: ACTH (adenocorticotrophic hormone); FSH (follicle stimulating hormone); LH (luteinising hormone); TSH (thyroid stimulating hormone)|
Clinical Features of AOGHD
The effects of GHD are widespread. The symptoms and signs associated with AOGHD are outlined in Panel 3. Subjects may also display symptoms and signs related to a pituitary mass and associated endocrine deficiencies or excesses
Panel 3: Clinical features of AOGHD
Symptoms Depression, anxiety, poor memory, reduced vitality, social isolation, malaise, weakness, poor exercise tolerance, easy fatiguability, weight gain
Signs Central obesity, elevated waist:hip ratio, fine wrinkling around eyes, premature ageing
Metabolic effects of AOGHD
Effects on body composition
Total body weight In most studies, total body weight is unaffected by AOGHD. However, one Swedish study suggested a mean increase in body weight of 7.5kg in males and 3.6kg in females with AOGHD, compared with weight predicted from height measurements. However, most studies show no change in body weight with GH replacement, suggesting that GHD may not be aetiologically important.
The presence of multiple pituitary deficiencies appears to favour increased weight.
Lean body mass (LBM) Most studies have demonstrated a mean reduction in LBM of 7 to 8 per cent (approximately 4 to 5kg) in AOGHD subjects compared with healthy controls. In most studies, GH replacement therapy (GHR) has shown an increase in LBM by a mean of 2.5 to 5kg. This effect is seen both in adults and children with GHD. Similar changes are seen in skeletal muscle mass and cross-sectional area of thigh muscle.
Fat mass Fat mass is increased by 4 to 8 per cent in subjects with AOGHD. The excess fat is distributed centrally and viscerally, as shown by MRI and CT imaging, and there is an increase in waist-hip ratio. This particular pattern of fat deposition is associated with increased risk of cardiovascular diseases. GHR reduces fat mass by approximately 4 to 6kg in both adult and child onset GHD subjects, with greatest effect on abdominal and visceral fat.
Fluid volume Total body water, especially extracellular water, is reduced in these subjects. Reduced plasma volume and total blood volume may contribute to the reduced extracellular water. An increase in plasma volume and total blood volume (of about 400ml) is observed with GH therapy and may be secondary to the antinatriuretic action of this hormone. This may be a direct effect on renal tubules or may occur due to changes in the renin-angiotensin system.
Fracture rates One retrospective study demonstrated a significantly higher fracture rate in older GHD subjects compared with controls (24.1 per cent vs 11.8 per cent, respectively). There are no data available on the effect of GH replacement on fracture rates.
Bone mineral density (BMD) Studies have demonstrated reduced BMD at various anatomical sites (forearm, spine, femoral neck), as well as total body BMD. Bone biopsies are consistent with delayed bone mineralisation. Three months of GH therapy has not been shown to affect bone mass; however, in some studies, six or 12 months of therapy increased BMD by 4 to 10 per cent, with effects maintained at two years. The effects are most dramatic in those with lower baseline BMD. These results have not been uniformly demonstrated; some studies have shown reduced BMD after 12 months of treatment, with BMD increasing thereafter while treatment continues. GH appears to stimulate bone remodelling. Bone biopsies after between six and 12 months of treatment have shown reduced resorption and increased formation of cortical bone. Studies examining the effects of growth hormone on vitamin D, parathyroid hormone (PTH), serum calcium and phosphate have produced inconsistent results.
In summary (Table 1), AOGHD is associated with reduced bone mineral density and an increase in fracture rate. GH has an anabolic effect, which appears to be biphasic; initially, bone resorption is stimulated followed by bone formation, resulting in a net gain of bone mass. The effect on fracture rate remains unknown.
Table 1: Summary of effects of GHR on bone metabolism
|Parameter measured||AOGHD vs control||Effect of GH replacement|
|Fracture rate||24.1% vs 11.8%||No data available|
|BMD||Reduced||Increased by 4 to 10%|
|Osteocalcin levels (marker of bone formation)||Variable||Increased at 6 and 12 months|
|Urinary pyridinolones (marker of bone resorption)||Higher with multiple hormone deficiencies only||Increase at 6 months|
|Bone biopsies||Delayed mineralisation||Reduced resorption, increased formation|
|Calcium, parathyroid hormone, vitamin D||Variable||Variable|
Muscle strength Muscle strength appears to be reduced in parallel to the reduction in lean body mass seen in AOGHD subjects. Reduced exercise, as a result of easy fatiguability, may be a contributing factor. GHR resulted in increased limb girdle strength after six months and increased quadriceps strength after 12 months, with normalisation seen after three years of treatment.
Exercise performance Exercise performance in those with AOGHD, as gauged by maximum oxygen uptake, is approximately 72 to 82 per cent of the predicted value. GH therapy resulted in normalisation of exercise tolerance by six months, probably as a result of increased muscle mass, although IGF-1 is known to stimulate red blood cell formation, which may be a contributing factor.
Life expectancy Data suggest that people with hypopituitarism on routine replacement (of ACTH, thyroxine and sex steroids when deficiencies occur) have reduced life expectancy, with an increase in cardiovascular mortality; the standardised mortality ratio (SMR) is 1.74. This is mainly attributable to increased cerebrovascular disease (SMR=3.39), especially in women (SMR=4.91). More recent studies support these data, although the increased mortality appears to be less than originally perceived. However, these results are not uniformly found. The effect of GHR on mortality remains unknown.
Atherosclerosis In the majority of studies, atherosclerotic risk factors, such as body mass index (BMI), waist:hip ratio (WHR) and an abnormal lipid profile, are increased in subjects with AOGHD. Hypertension and prothrombotic factors (ie, plasminogen activator inhibitor-1 and fibrinogen) may also be increased. Ultrasound of the carotid arteries has shown increased plaque formation in hypopituitary subjects and markers of atherosclerosis (ie, carotid intima-medial thickness and aortic compliance) also suggest increased disease. Studies suggest an improvement in BMI, WHR and lipid profile (see below) following GHR. The effects on the other parameters mentioned are conflicting or unknown.
Cardiac structure and function Echocardiographic studies variably suggest reduced left ventricular mass, reduced left ventricular wall thickness and impaired diastolic function in AOGHD. In other patient groups, these findings are thought to indicate early myocardial disease and/or ischaemia. The significance remains unknown in GHD subjects.
In one study, six months of GHR was found to increase left ventricular mass by 18 per cent, stroke volume by 28 per cent and cardiac output by 43 per cent. This effect was sustained at three years, although these parameters fell to baseline after cessation of therapy. Again, results have been variable.
Lipid metabolism Most studies in AOGHD subjects demonstrate an increase in total cholesterol, LDL-cholesterol and triglyceride levels, in association with a low HDL level. This pro-atherogenic lipid profile may be ameliorated by GH replacement (Table 2), although the results have been variable. However, some studies have demonstrated increased lipoprotein-a levels with GH therapy, which may be pro-atherogenic.
Carbohydrate metabolism Untreated hypopituitarism is associated with increased insulin sensitivity and reduced glycogen stores. GH replacement is associated with an initial increase in fasting glucose and insulin levels (Table 2). However, insulin resistance appears to be reduced following more prolonged therapy, possibly as a result of changes in body composition, in particular, the reduction in central obesity.
Protein metabolism Protein synthesis and flux are reduced in AOGHD. Replacement with GH causes a non-sustained increase in protein synthesis (Table 2).
Table 2: Effect of AOGHD and GHR on metabolism
|Parameter measured||Effect of AO GHD||Effect of GHR therapy|
|Protein metabolism||Decreased flux and synthesis||Increased synthesis initially, not sustained|
|Carbohydrate metabolism||Decreased insulin resistance|
Decreased glycogen stores
|Increased insulin resistance in first six weeks with return to baseline by three months|
|Lipid metabolism||Increased total and LDL-cholesterol|
|Decrease or no change in total and LDL-cholesterol|
No change or decrease in total triglyceride
No change or increase in HDL-cholesterol
Increase or no change in lipoprotein-a
|Where there have been conflicting findings, the outcome found in the majority of studies is printed in bold type|
Quality of life (QOL)
QOL is difficult to measure and various questionnaires have been employed, making comparisons between studies difficult. Some studies have shown reduced QOL in AOGHD, which may be proportional to the duration of GHD. Contributory features include reduced energy levels, emotional lability, poor sexual relationships and increased social isolation. Poor memory and concentration skills have also been demonstrated. Most studies have shown an improvement in reported QOL, particularly in mood, concentration, memory and energy levels, after six months of GHR.
GH is available as a subcutaneous injection, administered via a pen device. A commonly employed replacement regimen in adults is to initiate therapy at a dose of 0.125 IU/kg/week, which is divided into seven nightly injections. The dose is then increased as required. Plasma IGF-1 levels are used to assess response to therapy, the aim being to maintain this towards the upper end of the age and sex matched normal range. Females appear to have a more marked response to GH than males.
Most common side effects of growth hormone therapy (Table 3) are attributable to the antinatriuretic action of the hormone, and respond quickly to dose reduction. They occur mostly in elderly males, in those who have dramatic increases in IGF-1 levels in response to GH therapy, and in those in whom therapy was initiated at a high dose.
Rare complications include reports of benign intracranial hypertension (BIH), hypertension, atrial fibrillation, development of encephalocele, tinnitus and gynaecomastia. Earlier reports suggested that GH therapy may increase development of both haematological and solid malignancies. No definite data exist for this at present, but it is stressed that desirable levels of GH are physiological, not excessive.
Table 3: Common adverse reaction rates
|Adverse reaction||Occurrence (per cent)|
Absolute contraindications include evidence of any active tumour, BIH, pregnancy, and post-renal transplantation. Relative contraindications include a previous large aggressive pituitary lesion or cardiac, renal or hepatic failure (mainly because of possible risk of fluid overload).
The majority of studies suggest that GHD is associated with increased morbidity and mortality, and that GHR may ameliorate some of these problems. However, non-physiological replacement of thyroxine, cortisol and sex steroids may also influence these findings.
The long-term effects of GH therapy, particularly on fracture rates, cardiovascular disease, overall mortality and the development of tumours, have yet to be determined.
Dr Kearney is clinical research fellow and Professor Johnston is professor of clinical endocrinology and metabolism, department of metabolic medicine, St Mary’s hospital, London
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Citation: The Pharmaceutical Journal URI: 20001940
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