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DRUG REVIEW n Management of growth hormone deficiency in adults Successful management of adults with growth hormone deficiency requires an effective shared care partnership between primary and secondary care. In this article, Dr Bujanova and Professor Cummings discuss the signs and symptoms of growth hormone deficiency in adults, the range of growth hormone replacement products available and the GP’s role in management. SPL Jana Bujanova and Michael H Cummings A dult growth hormone deficiency (AGHD) is a recognised clinical syndrome associated with debilitating symptoms affecting quality of life, psychosocial functioning and a number of metabolic abnormalities, and which can improve with growth hormone (GH) replacement therapy.1 Recombinant human GH was first licensed in the UK in 1999 and its use in adults and children with GH deficiency was formalised and standardised by NICE in 2003 and 2010 respectively.2,3 The estimated prevalence of AGHD in the UK is approximately 1 in 10 000 (a total of approximately 6380 patients). If childhood-onset GH deficiency is added to this number (prevalence 1 in 10 000 to 1 in 3500) it is highly probable that every GP practice will come across a patient who has been evaluated for or is currently treated for GH deficiency. Therefore, it is useful for all clinicians involved in GH prescribing to understand the rationale behind treatment initiation, practical aspects of GH therapy, and the expected benefits and side-effects associated with treatment. Causes of growth hormone deficiency Growth hormone is produced by somatotroph cells in the anterior pituitary gland. Any pathological process affecting the pituitary gland or hypothalamus can be a cause of AGHD. In adults the most common cause (76 per cent) of GH deficiency is a pituitary tumour or a consequence of its treatment such as surgery and/or radiotherapy 4 (see Figure 1). Rarer causes include inflammatory diseases affecting the pituitary gland such as sarcoidosis, haemorrhage into the pituitary gland or previous traumatic head injury. Patients with an organic pituitary problem are likely to have multiple pituitary hormone deficiencies and require other hormone replacement therapies such as hydrocortisone, levothyroxine, testosterone or oestrogen preparations. Childhood-onset GH deficiency may be idiopathic and prescriber.co.uk Prescriber December 2015 z 29 n DRUG REVIEW l Growth hormone deficiency Symptoms Fatigue, reduced vitality and energy Depressed mood and emotional lability Greater sense of social isolation Difficulties with sexual relationships Signs Reduced lean body mass Increased abdominal adiposity Reduced muscle strength and exercise capacity Thin and dry skin due to reduced sweating Reduced bone mineral density Cool peripheries and poor venous access Table 1. The clinical features of growth hormone deficiency in adults Figure 1. MRI of patient with pituitary macroadenoma and hypopituitarism isolated, and it continues to adulthood in approximately onethird of affected children. Symptom and signs of GH deficiency The most recognised sign of GH deficiency in childhood is a short stature whereas in adults the main manifestations are less specific (see Table 1). Patients who develop GH deficiency in adulthood are psychologically less healthy and score less on quality-of-life assessment questionnaires.5 Those with GH deficiency have a significantly increased risk of cardiovascular disease and mortality.4,6 Data suggest that GH deficiency in adulthood is associated with dyslipidaemia,7,8 insulin resistance,9 increased inflammatory markers,10 endothelial dysfunction,11 and higher coronary artery calcium score – a marker of early atherosclerosis.12 There is substantial evidence that GH treatment in adults with GH deficiency increases muscle mass, decreases body fat and improves cardiac function. Studies investigating the effect of GH treatment on body composition demonstrated a decrease in central adiposity,13 an increase in lean body mass14 and an increase in exercise capacity.15 GH increases total plasma volume and stimulates erythropoiesis, which may contribute to increased exercise performance.16 Cardiac effects of GH include an increase in left ventricular mass, wall thickness and stroke volume due to the anabolic action of GH on cardiac muscle and an increase in plasma volume.17 There is evidence that GH therapy reduces carotid intima-media thickness18 and has beneficial effect on C-reactive protein – a marker of inflammation. 19 Reduction in low density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB) has been demonstrated in some20 but not all19 studies examining the impact of GH upon plasma lipid profiles. Trials examining the effect of GH replacement have demonstrated an improvement in psychosocial wellbeing and 30 z Prescriber December 2015 quality of life21 and a reduction in consumption of healthcare resources.22 A summary of evidence by Monson suggests that GH does not only provide short-term improvements in the above parameters but its effect is maintained with long-term administration.23 Mortality among recipients of GH replacement therapy is similar to that of the general population, which suggests that treatment may reduce mortality in the population with GH deficiency at risk of cardiovascular disease.24 In our clinical experience, the main benefits reported by patients are changes in cognitive function and interaction and an increase in energy levels. In some, this has had a profound impact on their ability to keep their employment and to remain economically active. Susceptible patient groups GH deficiency in adulthood should be suspected and tested for in symptomatic patients with known hypothalamic or pituitary disease and documented deficiency of other pituitary hormones. Testing should be considered in patients with history of GH deficiency in childhood and in those with a history of traumatic brain injury where damage to the pituitary gland or pituitary stalk could have occurred. An insulin tolerance test (ITT) is the gold standard diagnostic tool for AGHD and utilises insulin-induced hypoglycaemia as a powerful stimulant of GH release. Severe GH deficiency in adults is defined as a peak concentration of <9mU per litre (<3ng per ml) in response to insulin-induced hypoglycaemia. NICE advocates recombinant human GH (somatropin) use in carefully preselected patients who are most likely to benefit.2 Patients must fulfil all three of the following criteria: • Severe growth hormone deficiency defined as GH of < 9mU per litre (<3ng per ml) during an insulin tolerance test or a crossvalidated GH threshold in an equivalent test • Perceived impairment of quality of life demonstrated by a reported score of at least 11 in the disease-specific Quality of Life assessment of growth hormone deficiency in adults (QoLAGHDA) questionnaire2 • Already receiving treatment for any other pituitary hormone deficiencies as required. prescriber.co.uk Growth hormone deficiency l DRUG REVIEW n GH prescribing Typically, treatment of GH deficiency with recombinant human GH should be part of a shared-care protocol between primary and secondary care. Following assessment by and recommendation to commence GH replacement therapy by a consultant endocrinologist with interest in AGHD, a shared-care agreement to confirm local primary care ability to continue prescribing GH must be obtained. Following confirmation of this arrangement, patients are invited to attend a demonstration session run by an endocrine specialist nurse, who is trained in management of AGHD and is able to demonstrate the variety of GH products available. Once patient choice is confirmed, typically a GH starter pack including a three-month supply of GH is provided by the pharmaceutical company. Seven preparations of recombinant human GH are currently available in the UK.25 They come with a variety of delivery devices and vary in price (see Table 2). The average annual cost of therapy depends on the daily maintenance dose, which is determined by age, weight, size of the patient and the concomitant use of oral oestrogen preparations, and is quoted to be approximately £3350 per patient.2 There are no known differences in the efficacy of the various preparations and the choice depends upon the individual area’s prescribing committee and negotiated discounts with pharmaceutical companies as well as patient’s choice of delivery device and local experience. Locally, we demonstrate all available GH products and devices to patients. These vary in price but also in the complexity of assembly and administration. We firmly believe that the patient’s involvement in choosing the right delivery device for their circumstances is extremely important for subsequent compliance with treatment. Patient education, initiation of GH therapy, titration of the dose and monitoring of the patient’s response and GH side-effects is commonly provided by the endocrine specialist nurse. In areas where this arrangement is not available, all GH pharmaceutical companies offer homecare support. This involves initiation of GH therapy in the patient’s home environment by the company’s home support nurse, but does not include IGF-1 monitoring or dose titration. In order to minimise side-effects, GH is initiated at a low dose and gradually titrated. NICE recommends that the initial starting dosage is 0.2–0.3mg (0.6–0.9 units) daily. For the first two to three months, the dosage is adjusted after monthly assessments of insulin-like growth factor 1 (IGF-1) until the maintenance dosage is achieved. The usual maintenance dosage is around 0.4mg (1.2 units) daily and the goal of maintenance therapy is to maintain serum IGF-1 levels within the middle of the age-adjusted normal range. After nine months of treatment, the QoL-AGHDA questionnaire is re-examined and improvement of at least seven points on this scale is required for GH continuation (see Figure 2). Side-effects The most commonly reported side-effect of GH therapy is fluid retention resulting in mild peripheral oedema. Other side-effects include arthralgia, carpal tunnel syndrome, paraesthesia and prescriber.co.uk Diagnosis of GH deficiency and presence of NICE criteria for GH therapy Shared-care agreement with primary care Demonstration of available devices to patients Teaching the chosen device and injection technique Starting GH dosage 0.2–0.3mg (0.6–0.9 units) daily sc Month 1–3 (titration period) Monthly IGF-1 levels and dose titration. Likely to achieve maintenance dose by end of month 3 Month 3–9 Therapeutic trial with maintenance dose Month 9 Assessment of response + Qol-AGHDA scoring QoL-AGHDA score improvement ≥7 and patient wishing to continue with therapy QoL-AGHDA score improvement <7 Discontinuation of GH therapy Ongoing GH therapy Figure 2. Growth hormone (GH) therapy initiation and titration. QoL-AGHDA = Quality of Life assessment of growth hormone deficiency in adults worsening glucose tolerance. The most serious side-effect is benign intracranial hypertension presenting with symptoms of papilloedema, headaches and sickness but this is very rare. Adverse events can be prevented by maintaining IGF-1 within the middle of the age-adjusted reference range. Active malignancy is considered to be a contraindication to GH replacement therapy due to the possibility that the GH can Prescriber December 2015 z 31 n DRUG REVIEW l Growth hormone deficiency stimulate tumour growth, but the exposure to GH therapy does not seem to be associated with pituitary tumour growth or recurrence.26 The GP’s role in management The GP’s involvement in management of patients with GH deficiency is crucial for a successful shared care partnership, as described above. Although GH therapy is costly, patients are carefully preselected and the adult doses of GH are significantly lower than those required in childhood and adolescence. Awareness of potential GH side-effects by GPs and their early identification can ensure that IGF-1 levels are reviewed early and dose is down-titrated to minimise adverse effects. GPs will often be in the front line when diagnosing conditions in which GH is contraindicated such as malignancy. They are crucial in the identification of vulnerable patient groups at risk of hypopituitarism who would not routinely be known to endocrinologists, such as childhood cancer survivors with previous cranial or total body irradiation or those with a history of traumatic brain injury. References 1. Carroll PV, et al. Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. Growth Hormone Research Society Scientific Committee. J Clin Endocrinol Metab 1998;83:382–395. 2. NICE. Human growth hormone (somatropin) in adults with growth hormone deficiency. NICE TA64. August 2003. 3. NICE. Human growth hormone (somatropin) for the treatment of growth hormone failure in children. NICE TA188. May 2010. Brand name Available preparations Device Omnitrope 5mg (15 unit) cartridge 10mg (30 unit) cartridge Omnitrope Pen 5 Omnitrope Pen 10 Genotropin 5.3mg (16 unit) cartridge 12mg (36 unit) cartridge 5.3mg (16 unit) prefilled pen 12mg (36 unit) prefilled pen 0.2mg (0.6 unit) syringe (with diluent) 0.4mg (1.2 unit) syringe (with diluent) 0.6mg (1.8 unit) syringe (with diluent) 0.8mg (2.4 unit) syringe (with diluent) 1.0mg (3 unit) syringe (with diluent) 1.2mg (3.6 unit) syringe (with diluent) 1.4mg (4.2 unit) syringe (with diluent) 1.6mg (4.8 unit) syringe (with diluent) 1.8mg (5.4 unit) syringe (with diluent) 2.0mg (6 unit) syringe (with diluent) Genotropin Pen 5 Genotropin Pen 12 GoQuick prefilled pen GoQuick prefilled pen MiniQuick single dose syringe MiniQuick single dose syringe MiniQuick single dose syringe MiniQuick single dose syringe MiniQuick single dose syringe MiniQuick single dose syringe MiniQuick single dose syringe MiniQuick single dose syringe MiniQuick single dose syringe MiniQuick single dose syringe Humatrope 6mg (18 unit) cartridge (with diluent) 12mg (36 unit) cartridge (with diluent) 24mg (72 unit) cartridge (with diluent) HumatroPen 6 mg HumatroPen 12 mg HumatroPen 24 mg Zomacton 4mg (12 unit) vial (with diluent) 10mg (30 unit) vial (with diluent) For use with ZomaJet 2 Vision device For use with ZomaJet Vision X device NutropinAq 10mg (30 unit) cartridge NutropinAq Pen Norditropin SimpleXx cartridge 5mg (15 unit) SimpleXx cartridge 10mg (30 unit) SimpleXx cartridge 15mg (45 unit) NordiFlex prefilled pen 15mg (45 unit) NordiPen NordiPen NordiPen NordiFlex prefilled pen Saizen 6mg (18 unit) cartridge 12mg (36 unit) cartridge 20mg (60 units) cartridge 8mg (24 unit) vial (in click.easy device with diluent) For use with cool.click or easypod autoinjector device For use with cool.click or easypod autoinjector device For use with cool.click or easypod autoinjector device For use with one.click, cool.click or easypod autoinjector devices Table 2. Recombinant human growth hormone (somatropin) products available in the UK (in order of cost)25 32 z Prescriber December 2015 prescriber.co.uk Growth hormone deficiency 4. Bates AS, et al. The effect of hypopituitarism on life expectancy. J Clin Endocrinol Metab 1996;81:1169–72. 5. Hazem A, et al. Body composition and quality of life in adults treated with GH therapy: a systematic review and meta-analysis. Eur J Endocrinol 2012;166:13–20. 6. Rosèn T, Bengtsson BA. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990;336:285–8. 7. De Boer H, et al. Serum lipid levels in growth hormone-deficient men. Metab Clin Exp 1994;43:199–203. 8. Cuneo RC, et al. Growth hormone treatment improves serum lipids and lipoproteins in adults with growth hormone deficiency. Metabol Clin Exp 1993;42:1519–23. 9. Johansson JO, et al. Growth hormone-deficient adults are insulin resistant. Metab Clin Exp 1995;44:1126–29. 10. Sesmilo G, et al. Inflammatory cardiovascular risk markers in women with hypopituitarism. J Clin Endocrinol Metab 2001;86:5774–81. 11. Elhadd TA, et al. Biochemical and biophysical markers of endothelial dysfunction in adults with hypopituitarism and severe GH deficiency. J Clin Endocrinol Metab 2001;86:4223–32. 12. Cannavò S, et al. High prevalence of coronary calcifications and increased risk for coronary heart disease in adults with growth hormone deficiency. J Endocrinol Invest 2011;34:32–7. 13. Bengtsson BA, et al. Treatment of adults with growth hormone (GH) deficiency with recombinant human GH. J Clin Endocrinol Metab 1993;76:309–17. 14. Baum HB, et al. Effects of physiologic growth hormone therapy on bone density and body composition in patients with adult-onset of growth hormone deficiency. A randomised, placebo controlled trial. Ann Intern Med 1996;125:883–90. 15. Widdowson WM, Gibney J. The effect of growth hormone replacement on exercise capacity in patients with GH deficiency: a meta-analysis. J Clin Endocrinol Metab 2008;93:4413–7. 17. Maison P, Chanson P. Cardiac effects of growth hormone in adults with growth hormone deficiency: a meta-analysis. Circulation 2003;108:2648–52. 18. Colao A, et al. Growth hormone treatment on atherosclerosis: results of a 5-year open prospective, controlled study in male patients with severe growth hormone deficiency. J Clin Endocrinol Metab 2008 prescriber.co.uk l DRUG REVIEW n ;93:3416–24. 19. Beauregard C, et al. Growth hormone decreases visceral fat and improves cardiovascular risk markers in women with hypopituitarism: a randomised, placebo controlled study. J Clin Endocrinol Metab 2008;93:2063–71. 20. Christ ER, et al. Effects of growth hormone (GH) replacement therapy on very low density lipoprotein apolipoprotein B100 kinetics in patients with adult GH deficiency: a stable isotope study. J Clin Endocrinol Metab 1999;84:307–16. 21. McGauley GA. Quality of life assessment before and after growth hormone treatment in adults with growth hormone deficiency. Acta Pediatr Scand 1989;356(Suppl):70–4. 22. Hernberg-Stahl E, et al. Healthcare consumption decreases in parallel with improvements in quality of life during GH replacement in hypopituitary adults with GH deficiency. J Clin Endocrinol Metab 2001;86:5277–81. 23. Monson JP. Long-term experience with GH replacement therapy: efficacy and safety. Eur J Endocrinol 2003;148:S9–14. 24. Bengtsson BA, et al. Growth hormone replacement therapy is not associated with any increase in mortality. KIMS Study Group. J Clin Endocrinol Metab 1999;84:4291–2. 25. BNF Online. October 2015 [last accessed online 2 November 2015]. 26. Frajese G, et al. Hypothalamo-pituitary surveillance imaging in hypopituitary patients receiving long-term GH replacement therapy. J Clin Endocrinol Metab 2001;86:5172–5. Declaration of interests None to declare. Dr Bujanova is a specialist registrar and a clinical research fellow in endocrinology and diabetes at Queen Alexandra Hospital, Portsmouth and Professor Cummings is a consultant in endocrinology and diabetes at Queen Alexandra Hospital, Portsmouth and honorary professor with the University of Portsmouth Prescriber December 2015 z 33