Title: Growth Hormone Treatment for Adult Growth Hormone Deficiency

Transcription

1 Title: Growth Hormone Treatment for Adult Growth Hormone Deficiency Date: 05 October, 2007 Context and policy issues: Growth hormone (GH) is produced by the pituitary gland and plays a role in increasing growth in children and also plays a role in regulation of protein, lipid and carbohydrate metabolism. 1 Secretion of GH is at its maximum level during adolescence. GH deficiency in adulthood may be a result of adult or childhood onset GH deficiency. 1 Reduced quality of life (QoL), reduced lean body mass and increased fat mass, reduced bone mineral density (BMD), dry skin, reduced muscle strength and exercise capacity, lipid abnormalities, insulin resistance and impaired cardiac function are associated with adult growth hormone deficiency. 1-4 The insulin tolerance test is the gold standard for the diagnosis of GH deficiency. 2,4 Other tests include stimulation with arginine, clonidine, L-dopa, glucagon, and growth hormone releasing hormone (GHRH) followed by measurement of GH levels. A GH level less than 3 μg/l in the insulin tolerance test and less than 5 μg/ L in the other tests indicate GH deficiency. Growth hormone is administered by daily subcutaneous injection. Headache, joint pain, muscle pain, fluid retention, mild hypertension, and nausea and vomiting are some of the side effects associated with growth hormone treatment. 1 GH treatment can improve body composition by increasing lean tissue and decreasing adipose tissue, and can also improve bone density, cardiovascular function and QoL in adults with GH deficiency. 2,5 Although guidelines are clear for treatment of children with GH deficiency, the benefits and harm of continued treatment into adulthood are unclear. In addition, information about when to discontinue GH treatment as well as whether GH is required in these patients is limited. Evidence regarding GH treatment in adults with childhood onset GH deficiency is necessary to enable proper treatment of this patient population. Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information on available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 Research questions: 1. What are the guidelines for adult growth hormone treatment in patients with growth hormone deficiency originally diagnosed in childhood? 2. Are there physiological markers or age cut-offs for discontinuing GH treatment in children? 3. Is there clinical evidence for re-starting treatment in patients with childhood growth hormone deficiency once they reach adulthood? Methods: A literature search was conducted on key health technology assessment resources, including Medline, Embase on OVID platform, The Cochrane Library (Issue 2, 2007), University of York Centre for Reviews and Dissemination (CRD) databases, ECRI s HTAIS, EuroScan, international HTA agencies, and a focused Internet search. Results include English language publications from 1997 to date. Summary of findings: One health technology assessment, five guidelines and 10 randomized controlled trials were found on the topic of growth hormone treatment in adults with growth hormone deficiency. 1. What are the guidelines for adult growth hormone treatment in patients with growth hormone deficiency originally diagnosed in childhood? Canadian guidelines for the management of adult GH deficiency were developed from a consensus workshop and were published in The committee completed a systematic review of the literature on GH deficiency and GH treatment and provided recommendations for diagnosis of GH deficiency and guidelines for GH treatment. A consensus approach was used to develop the guidelines. Patients with a history of childhood onset GH deficiency, with a history of hypothalamic-pituitary disease or surgery, history of cranial irradiation or a history of moderate or severe traumatic brain injury should be tested for GH deficiency. The recommended tests to diagnose GH deficiency are the insulin tolerance test, and stimulation with clonidine, L-arginine, L-dopa, glucagon and growth hormone releasing hormone. If GH deficiency is diagnosed, treatment should be under an endocrinologist s supervision. Pediatric doses (25 to 43 μg/kg/day) of GH result in more side effects in adults and the dose for adults should not exceed 12.5 μg/kg/day (approximately 1 mg/day). If symptoms do not improve, the dose of GH should be increased by 0.1 mg/day every 2 to 3 months, and it may take 6 to 12 months to see an improvement in symptoms. Patients with adult GH deficiency may receive GH treatment continuously throughout their lifetime, but they may require less GH over time. If there is no improvement in symptoms, the decision to continue treatment should take into account the risks and benefits of GH. The National Institute for Clinical Excellence (NICE) published guidelines on the use of GH in adults with GH deficiency in The method was not reported for development of these guidelines. They state that growth hormone is recommended in adults with severe GH deficiency and a perceived impairment of quality of life. Nine months after beginning GH treatment, quality of life should be re-assessed and if there is no improvement, treatment should be discontinued. Once linear growth has been achieved, treatment should be stopped for 2 to 3 Adult GH Deficiency 2

3 months and then growth hormone deficiency should be re-confirmed in adults with childhood onset growth hormone deficiency. Growth hormone should be continued until peak adult bone mass is reached, which is typically around age 25 to 30 years. The Endocrine Society developed clinical practice guidelines for the use of GH in GH deficient adults in These guidelines were developed after a review of the literature and grading of the evidence. A moderate level of evidence was found to suggest that GH therapy significantly improved body composition, exercise capacity, skeletal integrity and QoL. The guidelines recommend that the reevaluation of GH deficiency in adults be conducted after GH treatment has been discontinued for 1 month. Adults on GH treatment should be monitored every 6 months. The American Association of Clinical Endocrinologists (AACE) published guidelines in 2003 for GH use in adults and children. 2 GH deficiency should be re-confirmed in adults with childhood onset GH deficiency by an insulin tolerance test. The dose of GH should start at 0.1 mg/day to 0.3 mg/day and increase slowly. There is no set interval for the transition time from childhood to adult treatment for GH deficiency. 2. Are there physiological markers or age cut-offs for discontinuing GH treatment in children? There was limited evidence discussing the physiological markers or age cut-offs for GH discontinuation. The NICE guidelines for the use of growth hormone in children state that growth hormone treatment should be discontinued when final height has been reached or when the growth in the last year is less than 2 cm. 6 The NICE guidelines for the use of GH in adults with GH deficiency also states that GH be stopped when growth velocity is less than 2 cm/year and GH deficiency should then be re-confirmed. 1 The AACE guidelines state that GH in children be discontinued when final height is achieved or at epiphyseal closure Is there clinical evidence for re-starting treatment in patients with childhood growth hormone deficiency once they reach adulthood? Only one health technology assessment published in 2002 examined the effect of growth hormone on quality of life in adults with GH deficiency. 3 This study, however, did not report results separately for childhood onset and adult onset GH deficiency and therefore the adult onset population could not be assessed further. Ten randomized controlled trials (RCTs) were found that examined various outcomes for GH treatment in adults with childhood onset GH deficiency Detailed information regarding the results of these RCTs can be found in Appendix 1. Data on quality of life and body composition are highlighted. The first six RCTs 7,9-11,14,15 described assessed re-starting GH treatment by administering GH or placebo to patients who were not currently on GH treatment. The remaining four RCTs 12,13,16,17 were designed to administer GH or placebo to the patients for a specific period of time (6 months to 1 year) followed by a period in which all patients were administered GH treatment. In these studies, the placebo group then becomes the group who are re-starting GH treatment. A multi-national RCT published in 2005 compared QoL in childhood onset GH deficient patients in the transition from childhood to adulthood. 11 Patients were included who were no longer taking GH treatment, had a growth velocity of less than 1 cm/yr, and had reconfirmed GH deficiency. Patients were randomized to receive a high dose of GH (25 μg/kg/day; pediatric Adult GH Deficiency 3

4 dose), a low dose of GH (12.5 μg/kg/day; adult dose) or no treatment for 2 years. There were 25 patients who received the pediatric dose, 28 who received the adult dose and 13 who did not receive treatment (control). QoL was assessed by a validated questionnaire (QLS-H) at baseline, 1 year and 2 years after treatment. The two GH groups were combined as there were no differences between the two doses. There was a non-significant difference in the QoL score in the GH groups compared to the control group. There was no difference after 2 years between both GH groups and the control group, and there were no differences between the GH doses. The only significant differences found were a change in body shape and sexual arousal in the GH treated group. A placebo group was not use in this study, which may be considered a limitation. The authors suggest that although QoL measures were similar in the GH and control groups, GH should not be discontinued once final height is achieved, but should be continued to attain adult body shape. Fifty men with childhood onset GH deficiency were studied in a 2005 RCT from the Netherlands. 15 The men had not been taking GH for at least one year before the start of the study. Only 38 men were randomized to receive one of three different doses of GH for 2 years. All patients then received the same dose of GH and were followed for a total of 5 years. This study found an increase in BMD and bone mineral content (BMC) with GH treatment over baseline. A limitation to this study is the absence of a control group, as all patients received GH treatment. An older RCT (1999) examined the same group of patients for 39 to 69 months. 14 This study found that bone mass was improved with GH treatment. A larger RCT was published in 2003 and examined the effect of GH in adults with childhood onset GH deficiency on bone mineralization. 10 This multi-national study randomized patients to receive GH at an adult dose of 12.5 μg/kg/day (n=58), a pediatric dose of 25 μg/kg/day(n=59) or no treatment with GH (n=32). Patients had not received GH for at least 6 weeks prior to the start of the study, all had GH deficiency reconfirmed, and had a height velocity of less than 1 cm/year. There was a greater increase in bone mineral content and bone mineral density in the both GH groups compared to the control group. The authors conclude that discontinuation of GH may affect bone mass. The same group of patients were reported in another RCT published in 2004 on the effects of GH treatment on body composition. 9 This study found that there was in increase in height in all groups, with a significant increase in the GH groups compared to control (p = 0.003). Lean body mass increased and fat mass decreased in the group that received GH. This study found that maturational events dependent upon GH treatment take place in the transition from childhood to adulthood, and thus GH treatment may be required to continue into adulthood. A possible limitation to these studies is the lack of a placebo control. A 2003 multicentre RCT examined GH treatment in adults with childhood onset GH deficiency. 7 Patients were included who had reached adult height, had not had GH for at least 1 year, were no more than 35 years of age, and had a bone age of at least 14 years for females and 15 years for males. The patients were randomized to receive GH or placebo for 24 months. GH was administered to 16 patients at a dose of 12.5 μg/kg/day and 14 patients at 25 μg/kg/day; 15 patients received placebo. There were no differences in QoL scores in the groups that received GH compared to placebo. There was a decrease in total body fat mass in the groups that received growth hormone and an increase in the placebo group. Furthermore, there was a significant increase in lean mass in the GH groups. An RCT from Denmark in 2000 studied GH treatment in 19 childhood onset GH deficient patients transitioning from childhood to adulthood. 13 Patients received GH for at least 3 years before the study began. Treatment was stopped for 1 week and GH deficiency was Adult GH Deficiency 4

5 reconfirmed. Two patients withdrew from the study after randomization. Patients received GH (n = 9) or placebo (n = 10) for 1 year, followed by 1 year in which all patients received GH. Body composition and QoL was examined. Overall, there were no changes in any of the measurements in the group that received GH for the entire 24 months. There were changes in the placebo group that were evident at 12 months after receiving the placebo and that were reversed after this group received GH in the second year of the study. body fat was increased in the group that received placebo. Stopping GH treatment in these patients resulted in numerous unfavorable changes, such as alterations in hormone levels, and therefore the authors suggest continuing GH treatment in transition patients. A possible limitation to this study may be that patients were only off GH for 1 week before GH deficiency was reconfirmed, and guidelines suggest that GH deficiency be re-confirmed after not taking GH for 1 month to 3 months. 1,5 The same group of patients was studied in another 2000 RCT which examined the effect of GH on insulin sensitivity. 16 GH deficiency was confirmed in all patients and patients were then randomized to receive placebo (n = 9) or GH (n = 9) for 12 months, followed by 12 months in which all patients received GH. Insulin sensitivity increased and circulating levels of insulin decreased in the group that received placebo. body fat increased in the placebo group in the first 12 months, and this effect was reversed when these patients received GH for the second 12 months of the study. The authors conclude that GH has a beneficial effect on body composition. Exercise capacity was examined in a 1998 RCT. 8 Patients had childhood onset GH deficiency, had not received GH in the past 2 years and had their GH deficiency reconfirmed. Twenty adult patients were randomized to receive GH (n = 10) or placebo (n = 10) for 6 months, followed by a period of 36 months in which all patients received GH. Exercise capacity was increased by GH treatment over baseline, although muscle strength was not changed. Forty-six men with childhood onset GH deficiency were studied in a 1997 RCT from the Netherlands. 12 These men received treatment with GH for at least 2 years, but had not received treatment for at least 1 year at the start of the study. GH deficiency was reconfirmed and patients were randomized to receive one of 3 doses of GH (n = 33) or placebo (n = 13) for 6 months. Forty patients completed the study; 29 received GH and 11 received placebo. Following the first 6 months, the placebo patients received GH for the next 6 months. Only adult hair scores and hormone levels were reported in this study. Body hair scores were increased in the GH treated group compared to the placebo treated group after 6 months of treatment and were further increased after 12 months of treatment. In general, studies found a beneficial effect of GH treatment for adults with childhood onset GH deficiency. There were some differences between the studies. The patient population in the studies was variable, with some studies focusing on patients transitioning from childhood to adulthood and some focusing on an older population. Different criteria were used in the studies for assessment of final height; the growth velocity ranged from 1 cm/year to 2.5 cm/year for assessing achievement of final height. A limitation to the majority of RCTs described is the small sample size. In all but one study, the sample size was less than 50 patients which may affect the generalizability of the results. Limited information was provided in all RCTs regarding the methods of randomization, and invalid methods of randomization may introduce bias into the results. Excluded studies included those that did not specify whether GH was discontinued from childhood or whether patients were currently taking GH and therefore the effect of re-starting treatment could not be assessed. Adult GH Deficiency 5

6 Conclusions and implications for decision or policy making: There were four guidelines found for GH treatment in adults with GH deficiency, which included one Canadian guideline. The Canadian guideline focused on the tests to be used to diagnose adult GH deficieny and the dose of GH to be used in adults. Other guidelines suggest that GH be continued until adult peak bone mass is achieved and that QoL should be re-assessed after 9 months of treatment to determine whether symptoms are improving. There was limited information about the age limits or physiological markers for the discontinuation of GH treatment in children. No age was specified in the literature. All guidelines stated that GH should be discontinued in children when final height has been achieved or when the growth rate was less than 2 cm in the past year. One guideline also suggested that GH be discontinued at epiphyseal closure. Evidence for re-starting GH treatment was gathered from RCTs that examined the effect of GH treatment on adults with GH deficiency. In general, these RCTs were not of high quality due to the small sample sizes and the lack of information regarding methods of randomization. The RCTs either administered GH to adults who were not currently taking GH treatment, or administered GH or placebo for 6 months to one year followed by a period in which all patients received GH treatment. This allowed for interpretation of the effects of re-starting GH treatment. Five studies examined the effect of GH treatment on body composition, three studied the effect on bone mineral density and bone mineral content and three studied the effect on quality of life. Overall, body composition, bone mineral density and bone mineral content appear to be improved by GH treatment in adults with GH deficiency. Only three studies measured quality of life, which did not seem to be affected by re-starting GH treatment. Prepared by: Lesley Dunfield, PhD, Research Officer Emmanuel Nkansah, MLS, MA, Information Specialist Health Technology Inquiry Service htis@cadth.ca Tel: Adult GH Deficiency 6

7 References: 1. National Institute for Clinical Excellence. Growth hormone deficiency (adults) - human growth hormone: guidance [Technology Appraisal no. 64]. Reviewed July London: National Institute for Clinical Excellence; 2003 Aug. N0265. Available: (accessed 2007 Sep 18). 2. American Association of Clinical Endocrinologists medical guidelines for clinical practice for growth hormone use in adults and children update. [summary]. Rockville (MD): National Guideline Clearinghouse; Available: (accessed 2007 Sep 19). 3. Bryant J, Loveman E, Chase D, Mihaylova B, Cave C, Gerard K, et al. Clinical effectiveness and cost-effectiveness of growth hormone in adults in relation to impact on quality of life: a systematic review and economic evaluation. Health Technol Assess 2002;6(19): Ur E, Serri O, Legg K, Murphy LJ, Ezzat S. Canadian guidelines for the management of adult growth hormone deficiency. Clin Invest Med 2006;29(2): Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Shalet SM, Vance ML, et al. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2006;91(5): Available: (accessed 2007 Oct 4). 6. National Institute for Clinical Excellence. Guidance on the use of human growth hormone (somatropin) in children with growth failure [Technology Appraisal Guidance no. 42]. Reviewed June London: National Institute for Clinical Excellence; 2002 May. N0095 1P 10k May 02 (ABA). Available: (accessed 2007 Sep 18). 7. Underwood LE, Attie KM, Baptista J, Genentech Collaborative Study Group. Growth hormone (GH) dose-response in young adults with childhood-onset GH deficiency: a twoyear, multicenter, multiple-dose, placebo-controlled study. J Clin Endocrinol Metab 2003;88(11): Available: (accessed 2007 Oct 4). 8. Gullestad L, Birkeland K, Bjønerheim R., Djøseland O., Trygstad O, Simonsen S. Exercise capacity and hormonal response in adults with childhood onset growth hormone deficiency during long-term somatropin treatment. Growth Horm IGF Res 1998;8(5): Attanasio AF, Shavrikova E, Blum WF, Cromer M, Child CJ, Paskova M, et al. Continued growth hormone (GH) treatment after final height is necessary to complete somatic development in childhood-onset GH-deficient patients. J Clin Endocrinol Metab 2004;89(10): Available: (accessed 2007 Oct 4). 10. Shalet SM, Shavrikova E, Cromer M, Child CJ, Keller E, Zapletalová J, et al. Effect of growth hormone (GH) treatment on bone in postpubertal GH-deficient patients: a 2-year randomized, controlled, dose-ranging study. J Clin Endocrinol Metab 2003;88(9): Available: (accessed 2007 Oct 4). Adult GH Deficiency 7

8 11. Attanasio AF, Shavrikova EP, Blum WF, Shalet SM. Quality of life in childhood onset growth hormone-deficient patients in the transition phase from childhood to adulthood. J Clin Endocrinol Metab 2005;90(8): Available: (accessed 2007 Oct 4). 12. Blok GJ, De Boer H, Gooren LJ, Van Der Veen EA. Growth hormone substitution in adult growth hormone-deficient men augments androgen effects on the skin. Clin Endocrinol (Oxf ) 1997;47(1): Vahl N, Juul A, Jørgensen JO, Ørskov H, Skakkebaek NE, Christiansen JS. Continuation of growth hormone (GH) replacement in GH-deficient patients during transition from childhood to adulthood: a two-year placebo-controlled study. J Clin Endocrinol Metab 2000;85(5): Available: (accessed 2007 Oct 4). 14. ter Maaten JC, De Boer H, Kamp O, Stuurman L, Van Der Veen EA. Long-term effects of growth hormone (GH) replacement in men with childhood-onset GH deficiency. J Clin Endocrinol Metab 1999;84(7): Available: (accessed 2007 Oct 4). 15. Bravenboer N, Holzmann PJ, ter Maaten JC, Stuurman LM, Roos JC, Lips P. Effect of long-term growth hormone treatment on bone mass and bone metabolism in growth hormone-deficient men. Journal of Bone & Mineral Research 2005;20(10): Nørrelund H, Vahl N, Juul A, Møller N, Alberti KG, Skakkebaek NE, et al. Continuation of growth hormone (GH) therapy in GH-deficient patients during transition from childhood to adulthood: impact on insulin sensitivity and substrate metabolism. J Clin Endocrinol Metab 2000;85(5): Available: (accessed 2007 Oct 4). 17. Knoepfelmacher M, Jallad RS, Liberman B. Absence of effects of long-term growth hormone replacement therapy on insulin sensitivity in adults with growth hormone deficiency of childhood-onset (GHDA-CO). Growth Horm IGF Res 2003;13(5): Adult GH Deficiency 8

9 Appendix 1: Data from RCTs examining various outcome measures for GH treatment in GH deficient adults Study Attanasio et al, Number of patients (n=66), control (n=13), pediatric GH dose (n=25), adult GH dose (n=28) Age (years) 17.5 ± ± 1.9 Outcome measure QoL Body shape and sexual arousal Results No significant difference Greater change in the GH group compared to the control group (p = and 0.038) Bravenboer et al, (n=38), 1IU/m 2 /day (n=10), 2 IU/m 2 /day (n=18), 3 IU/m 2 /day (n=10) 28 ± 4 BMD BMC Increased from 9% to 16% in various regions (p value not reported) Increased 17.7% (p value not reported) Attanasio et al, (n=149), control (n=32), 12.5 μg/kg/ day (n=58), 25 μg/kg/ day (n=59) 19.4 ± ± 3.1 Height increase Lean body mass Fat mass Serum total cholesterol LDL/HDL ratio Increase in all groups with a significant increase in the GH groups compared to control (p = 0.003) Increase in GH groups compared to control (p < 0.001) Decreased in GH groups compared to control (p = 0.006) Increase in control group compared to baseline (p = 0.009) Increase in the control group after 2 years compared to baseline (p = 0.039) Significant difference between GH and control at 1 year (p < 0.001) and 2 year (p = 0.05) Shalet et al, (n=149), control (n=32), 12.5 μg/kg/ day (n=58), 25 μg/kg/ day (n=59) 19.4 ± ± 3.1 BMC BMD Increased in control group from baseline (p< 0.001) Increased in both GH groups compared to control (p = 0.003) GH increased compared to control (p = 0.045) Underwood et al, (n=45), placebo (n=15), 23.8 ± 4.2 Spine BMD Decrease in all groups at 6 months; significant in the 25 μg GH group (p = 0.001); Dose dependent increase at 24 Adult GH Deficiency 9

10 Study Number of patients 12.5 μg GH (n=16), 25 μg GH (n=14) Age (years) Outcome measure Results months (p = 0.018) body fat mass Increase in the placebo group, decrease in the GH groups at 12 months (similar decrease at both doses). Increase in the placebo group, decrease in the 12.5 μg GH group and greater decrease in the 25 μg GH group. (p values not reported) Lean mass Increase in the 25 μg group (p < 0.001) and 12.5 μg group (p < 0.05). Cholesterol No change in the placebo group Significant decrease in the 25 μg GH group (p < 0.04). No change in 12.5 μg or placebo groups IGF-1 Increase in the 25 μg group at 6 months (p 0.003), no change at the other time points Increase in the 12.5 μg group, normal at 12 and 24 months (p value not reported) No changed in the placebo group QoL Cardiac status Adverse events No change in any of the groups All measures were normal at baseline and did not change with treatment Edema: 7 patient in the 25 μg group, 4 in the 12.5 μg group, 1 placebo Arthralgia: 2 in the 25 μg group, 2 in the 12.5 μg group, 1 placebo Discontinued due to adverse events: 3 in the 25 μg group, 2 in the placebo group Vahl et al, (n=19), placebo (n- 10), GH (n=9) IGF-1 IGFBP-1 IGFBP-3 body fat Placebo: increase at 12 months (p < 0.001), decrease at 24 months (p = 0.001) Placebo: Increase at 12 months (p = 0.12), decrease at 24 months (p = 0.4) Placebo: Decrease at 12 months (p = 0.002), increase at 24 months (p = 0.02) Placebo: Increase at 12 months (p = 0.01), decrease at 24 months (p = 0.065) Adult GH Deficiency 10

11 Study Number of patients Age (years) Outcome measure Results Thigh fat mass Placebo: Increase at 12 months (p = 0.007), decrease at 24 months (p = 0.3) Lean body mass Placebo: No change at 12 months, increase at 24 months (p = 0.006) Intraabdominal fat mass and subcutaneous abdominal fat mass Muscle mass Lipoproteins and triglycerides Fasting glucose Serum insulin Placebo: Increase at 12 months (0.13 and 0.04), decreased at 24 months (p = 0.13 and 0.4) Placebo: Decrease at 12 months (p = 0.12), increase at 24 months (0.002) Placebo: No change Placebo: Decrease at 12 months (p = 0.05), increase at 24 months (p = 0.03) Placebo: Decreased at 12 months (p = 0.08), increase at 24 months (p = 0.16) HbA1c Placebo: No change at 12 months, increase at 24 months (p = 0.6) FT 3 (Free thyroid hormone) TT 4 (total thyroid hormone) QoL scores Placebo: Decrease at 12 months (p = 0.02), increase at 24 months (p = 0.8) Placebo: increase at 12 months (p = 0.03), decrease at 24 months (p = 0.09) Placebo: no change at 12 months (p = 0.5), decreased at 24 months (p = 0.07) Nørrelund et al, (n=18), placebo (n=9), GH (n=9) 20 ± 1 Insulin sensitivity body fat Fat-free mass Circulating insulin levels Increased in the placebo group at 12 months (p < 0.05) Increased in the placebo group at 12 months (p = 0.1) Decreased in the placebo group at 24 months (p < 0.05) Increase in the placebo group from 12 months to 24 months (p < 0.05) Decreased in the placebo group at 12 months (p < 0.01) Adult GH Deficiency 11

12 Study Number of patients Age (years) Outcome measure Results Increased in the placebo group at 24 months (p < 0.05) Lipid oxidation Decreased in placebo group at 12 months (p < 0.05) Energy expenditure Decrease in placebo group at 12 months (p = 0.1) Respiratory exchange ratio Increase in placebo group at 12 months (p < 0.05) ter Maaten et al, (n=38) 1IU/m 2 /day (n=10), 2 IU/m 2 /day (n=18), 3 IU/m 2 /day (n=10) 28 ± 4 Mean body weight Increased over baseline by 17.2% (p values not reported) Leg muscle area Increased over baseline by 28.7% Skin fold thickness Decreased over baseline by 30.9% Decreased over baseline by 46.0% Intraabdominal fat area BMD Increase over baseline by 9.6 ± 8.0%, 11.1 ± 12.8%, 16.2 ± 9.4% for various regions BMC Increased over baseline by 13.8 ± 7.9% Cardiac function Exercise capacity Increased over baseline for all measures Increased over baseline Gullestad et al, (n=20), placebo (n= 10), GH (n=10) 30 ± 2 Exercise duration (accumulated) work Peak Vo 2 Maximal ventilation, respiratory exchange, systolic blood pressure Muscle strength Increased in the GH group compared to baseline (p < 0.05) Increased in the GH group compared to baseline (p < 0.05); significantly different from placebo (p < 0.05) Increased in the GH group compared to baseline (p < 0.01); significantly different from placebo (p < 0.05) Increased with GH treatment No change Blok et al, (n=40), placebo (n=11), GH (n=29) NR Body hair scores Increased in the GH group compared to placebo (p < ) BMD = bone mineral density IGF-1 = insulin-like growth factor 1 BMC = bone mineral content IGFBP = insulin-like growth factor binding protein GH = growth hormone LDL = low density lipoprotein VO 2 = pulmonary oxygen uptake HDL = high density lipoprotein FT 3 = free thyroid hormone QoL = quality of life TT 4 = total thyroid hormone Adult GH Deficiency 12