Growth Hormone: Review of the Evidence

Drug Use Research & Management Program DHS Division of Medical Assistance Programs, 500 Summer Street NE, E35; Salem, OR 97301-1079 Phone 503-947-5220 Fax 503-947-1119 Growth Hormone: Review of the Evidence The Oregon Health Services Commission Growth Hormone Guideline states that treatment for growth hormone will only be covered by the Oregon Health Plan for pituitary dwarfism and Turner s syndrome in children. No adult indications are covered. Growth hormone (GH) is approved by the FDA for use in adults for growth hormone deficiency, AIDS wasting and short bowel syndrome. The use of GH in children has been approved for the following indications: Growth Hormone Deficiency (GHD), Turner syndrome, chronic renal insufficiency, small for gestational age or intrauterine growth retardation, Prader-Willi syndrome, Noonan syndrome, short stature homeobox-containing gene (SHOX) and idiopathic short stature (ISS). Replacement of recombinant human Growth Hormone in GH deficient adults has been shown to improve surrogate endpoints associated with low GH levels, such as abnormal body composition, dyslipidemia, insulin resistance, hypertension, bone health and quality of life. Some studies suggest that when GH replacement therapy is given to patients that are hypopituitary mortality rates are normalized to those without disease. Well designed outcome studies are limited making the benefits of GH replacement in adults unclear. Controversy surrounding the optimal tests for diagnosis and management of GH deficiency complicates appropriate treatment recommendations. Estimates from Pfizer s postmarketing surveillance study database (KIMS) show the incremental costeffectiveness ratio for GH therapy is $27,000 per quality-adjusted life year. 1 Treatment Guidelines The American Association of Clinical Endocrinologists (AACE) Guidelines recommend GH replacement for those indications covered by the FDA, regardless of etiology, including: pituitary tumors, pituitary surgical damage, hypothalamic disease, irradiation, trauma, and reconfirmed childhood GHD. Those adults qualifying for treatment should have a recognized cause, clear-cut clinical features of the adult syndrome, and nonrefutable laboratory evidence of GHD. 2 The Guidelines for the Treatment of Growth Hormone Excess and Growth Hormone Deficiency in Adults from The V Consensus Group Meeting suggest that patients treated with GH replacement experienced reduced mortality rates compared to non-treated patients. Additionally, population based studies suggest patients treated with GH have significantly lower fracture rates compared to non-treated patients. No prospective studies have evaluated the effect of GH

replacement on fracture rates. The Guideline recommends serum IGF-I levels to guide GH replacement therapy. 3 Consensus Guidelines from GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society and Endocrine Society of Australia recommend GH replacement for all adult patients with documented severe GHD. GH therapy should be continued beyond linear growth and until full somatic development is achieved, including accrual of maximum bone and muscle mass. Adult onset GHD treatment goals should include improved body mass composition, preserved skeletal mass, normalized cardiovascular risk factors, maintenance of normal IGF-I status and optimal physical and psychological functioning. This guideline recommends against treating age related GH decline. 4 The Endocrine Society Clinical Practice Guideline recommends that adult patients with structural hypothalamic/pituitary disease, surgery or irradiation in these areas, or other pituitary hormone deficiencies should be considered candidates for acquired GHD and treated appropriately. The insulin tolerance test (ITT) or growth hormone releasing hormone (GHRH)-arginine test is recommended for diagnosing GHD. Studies have shown that those with the most severe biochemical and clinical GHD are the ones most likely to benefit from GH treatment. There is moderate evidence to suggest improvements in body composition, exercise-capacity, skeletal integrity and quality of life measures when patients are treated with GH. Ultimately, study data on endpoints such as fracture rates, cardiovascular events and mortality are lacking with GH therapy. 5 Hypopituitary Patients with hypopituitarism have been shown to have increased mortality rates, often as a result of cardiovascular, cerebrovascular and respiratory diseases. 6,7,8,9 Studies have shown improvement in surrogate markers of cardiovascular disease, such as diastolic blood pressure, fat mass, total and LDL cholesterol, when patients are treated with GH. 10,11,12 GH treatment has been shown in some studies to improve bone mineral density (BMD). A 10 year study in 87 adult patients showed GH treatment produced sustained increases in lumbar and femur neck BMD. 13 It is important to note that studies have also shown increased bone turnover in patients treated with GH. 14,15 Quality of life (QoL) studies in patients with corrected GH deficits have demonstrated conflicting results. Several studies have shown improvement in QoL measures however a recent study showed no improvements. 16,17 A mortality study by Svensson et al, retrospectively evaluated 1411 patients with hypopituitarism, mean age 56.9 years. Patients were identified based on inpatient care received between 1987-1992 with a primary or secondary

diagnosis of hypopituitary disease as documented by the National Board of Health and Welfare in Sweden. GH replacement therapy was used in research settings only prior to 1994, so it is assumed patients were not receiving GH therapy before this time. Overall mortality, myocardial infarctions, cerebrovascular events and malignancies were all statistically significantly increased in patients without GH replacement compared with a normal population. For comparison, 289 hypopituitary patients being treated with GH were followed prospectively and compared to a normal background population. Mortality and malignant disease was found to be similar to the normal population in these patients treated with GH. Myocardial infarction rates were lower in the GH treated group compared to the normal background population (p<.005). 18 There are no prospective RCT evaluating the effects of GH replacement on outcomes affecting morbidity and mortality. Recommendation: Do not cover. Aids Wasting Unintentional weight loss and reduced lean body mass in patients with HIV/AIDS has been termed HIV or AIDS-associated wasting. Studies report the incidence of AIDS-wasting in 1.2% to up to 2.4% of individuals affected with AIDs. A 2007 review of clinical trials, guidelines and meta-analyses analyzed the use of GH in patients with HIV-associated wasting. Studies done in the highly active antiretroviral therapy (HAART)-era demonstrated mean changes in whole-body weight from 1.5 kg to 2.96 kg, both were statistically significant, after 12 weeks of GH therapy. Quality of life and physical endurance measurements were also significantly improved. 19 Recommendation: Do not cover. Safety Adverse events associated with GH replacement are dose related and include fluid retention, paresthesia, joint stiffness, peripheral edema, arthralgia and myalgia. There appears to be a small risk or worsening of insulin resistance or type 2 diabetes, warranting long-term follow up. Concerns with GH replacement and an increased risk of malignancies have been raised. This has not been demonstrated conclusively in adults with GHD. 1 Patients with an active malignancy should not be treated with GH. 5 Growth Hormone Treatment in Pediatrics Treatment Guidelines According to the Lawson Wilkins Pediatric Endocrinology Society guidelines children with unexplained short stature and one of the following clinical findings should be considered candidates for GH therapy: short stature and height >2.25

SD below the mean for age and gender on a standard growth chart, a growth velocity <25 th percentile for bone age, bone age >2 SD below the mean for age or low serum IGF-1 and/or insulin-like growth factor binding protein 3 (IGFBP- 3). 20 Consensus Guidelines for the Diagnosis and Treatment of Growth Hormone (GH) Deficiency in Childhood and Adolescence recommends that all children with proven GH deficiency be treated with recombinant GH. Treatment recommendations for specific syndromes related to GH deficiencies are not delineated. 21 Turner Syndrome Turner Syndrome (TS) results in extremely short stature for affected females. A 2009 Cochrane Review assessed the effects of GH in children and adolescents with TS. Four RCTs were included including 365 patients treated over a one year period. Doses ranged from 0.3-0.375mg/kg/week. Only one study reported final height data which showed a mean difference between GH and placebo of 7cm, 95% CI 6-8. Short-term growth velocity was also increased in treated patients at one and two years. In summary, approximately two inches of height is gained with GH treatment, still short of the average eight inch difference found between patients with and without TS. 22 The Canadian Agency for Drugs and Technologies in Health (CADTH) recently reviewed six randomized controlled trials and nine observational studies to compare GH with placebo or no treatment in patients with TS. Results showed that GH accelerates growth and improves final height with no serious adverse events. Data on quality of life was variable and thus no conclusion could be drawn. 23 Recommendation: Cover with a PA. Pituitary Dwarfism Pituitary dwarfism is caused by pituitary dysfunction which can cause lack of all anterior pituitary hormones or just isolated decreases in GH. AACE guidelines recommend treating children with GHD. Some studies have shown that treating children with GH increases height within 2 SD of the normal population. 24 Other data suggests that if GH is started early then catch-up growth is adequate to obtain normal height. 25 Recommendation: Cover with a PA. Idiopathic Short Stature Idiopathic short stature (ISS) occurs in children with heights below the third percentile or are about two standard deviations (SD) below the mean height for a given sex, age and population group. Children with ISS do not have a disease

but are short in comparison to peers. A 2009 Cochrane Review found that children treated with recombinant growth hormone can increase short-term growth, approximately 0.7 SD over one year, and increase (near) final adult height. Overall children treated with GH are still considered relatively short compared to children of normal stature. 26 A consensus statement from the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediaric Endocrinology Workshop on children with ISS states that GH replacement should be considered for children with ISS, especially in the shortest of children. They report average response rates of GH treated children (average duration of treatment of 4-7 years) from 3.5-7.5 cm. 2 Recommendation: Cover with PA. Noonan s Syndrome Limited outcome data suggests that GH therapy in patients with Noonan s Syndrome has some benefit. A recent review demonstrated that GH treatment in patients with Noonan s Syndrome resulted in a height gain to adult age of 0.6 to 2.0 SDs, approximately 4-13 cm. The greatest benefits were seen when treatment was started at a younger age. Patients with the PTPN11 mutation were found to respond less favorably to GH treatment. 28 A postmarketing observational study found that children treated with GH had significantly improved height SDs at near adult height. Mean incremental height gain, above projected Noonan standards, were 10.9 cm for males and 9.2 cm for females. 29 Some studies have shown short term gains in height standard deviation scores for calendar age but no benefit in final height measurements. 30 Quality, randomized, placebo-controlled trials are lacking. Recommendation: Cover with PA. Prader-Willi Syndrome Patients with Prader-Willi syndrome (PWS) are characteristically short statured as a result of hypothalamic-pituitary dysfunction. GH has been used to accelerate linear growth, improve energy expenditure, body composition, physical strength, agility, pulmonary function, and predicted final adult height. Studies have demonstrated increased longitudinal growth when patients are treated with GH. 31,32 A retrospective study by Angulo, et al, studied GH treatment given to 21 children that had reached adult height and were followed for 7.9±1.7 years. These patients were compared to 39 initial height matched patients followed for 6.8 ±1.3 years not receiving GH replacement. The study demonstrated mean initial height and adult height standard deviation scores (SDS) of -1.9±1.7 and -0.3±1.2 respectively (p <0.0001), compared to 39 control patient scores of -1.9±1.3 and -3.1±1respectively (p<0.0001). 33 AACE guidelines recommend that Prader-Willi patients not be required to undergo testing in order

to be candidates for GH treatment. 2 Sudden death in children treated with GH with Prader-Willi syndrome has been observed. Due to other factors predisposing these children to increased mortality it is unknown if GH was the contributing factor. 34 Large, well designed studies documenting final-height data in Prader-Willi syndrome are lacking. Recommendation: Cover with PA. Chronic Renal Failure Final height in chronic renal failure patients is often below the third percentile in up to one-third of effected individuals. Treatment with GH has demonstrated final height gains of 3-9 cm in boys and 4-8 cm in girls. 25 A randomized, placebo, controlled trial in 125 children demonstrated standardized height increases from - 2.94 to -1.55 in children with chronic renal failure (pre-transplant) treated with GH over a two year period. Children in the placebo group experienced a decrease in standardized height from -2.82 to -2.91. These results were statistically significant for both years (p<0.00005). 35 Treating patients post transplantation is not recommended. 20 Recommendation: Cover with PA. X-linked Hypophosphotemia Patients with X-linked hypophosphotemia treated with oral phosphate and calcitriol do not always reach normalized heights. Treatment with GH, in addition to standard therapy, has been suggested to increase growth velocity, phosphate retention and bone mineral density. A 2009 Cochrane Review of relevant studies found only one trial meeting inclusion criteria. This study evaluated 5 participants treated with recombinant GH. Study results demonstrated an improved height standard deviation score, and transient increases in serum phosphate and tubular maximum for phosphate reabsorption. 36 Recommendation: Cover with PA. Small for Gestational Age (SGA)/ Intrauterine Growth Retardation (IGR) Fetal growth is hindered in SGA and IGR due to a pathophysiologic process in utero that stunts fetal growth. Children who do not catch-up in growth length by the age of two are unlikely to regain height in the future. 2 A Consensus Statement by the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society state that GH treatment can help increase linear growth in children with severe growth retardation (height SD score < - 2.5, age 2-4). 37 Studies have demonstrated increased growth rate and stature when given GH. One randomized trial lasting over 2 years showed an increase in near adult height of 0.6 SDS. 20

Recommendation: Cover with PA. Cystic Fibrosis Children with cystic Fibrosis (CF) often have heights and weights that fall below the 10 th percentile for age and gender. Studies have shown that when children with CF are treated with GH they experience increased height velocity, and weight. Improvements in forced vital capacity and decreased hospitalizations and need for intravenous antibiotics have also been noted. 38 A multicenter, randomized, double-blind, placebo-controlled trial in 63 patients with CF found no short term improvements in lung function or height after 24 weeks. 39 Recommendation: Cover with PA -await results from AHRQ review. GH Replacement In Adolescents The Endocrine Society Clinical Practice Guideline recommends that adults with child-onset GHD be re-evaluated, as up to 50 percent will revert to normal GH status. Those individuals with known mutations, embryonic lesions, or irreversible structural lesions/damage commonly don t revert to normal GH levels and do not require additional testing. 5 Patients that continue to be GH deficient should have therapy continued. This consensus is reiterated by the AACE Guidelines. 2 A Consensus Statement on The management of the GH-treated Adolescent in the Transition to Adult Care by The European Society for Paediatric Endocrinology states that strong evidence supports the treatment of patients with GH whom cessation of growth may be finished but somatic maturation is incomplete. They recommend that adolescents should receive a pituitary function re-evaluation when growth and pubertal developments are considered complete (usually before the age of 20). Recommendations are that GH treatment should be stopped and insulin-like growth factor-i (IGF-I) levels and/or GH stimulation tests should be reassessed. Priority should be given to those with severe GH deficiency in childhood with or without additional hormone deficits. It is recommended that all adolescents with severe GH deficiency be treated to allow for normal muscle maturation and achievement of peak bone mass. Recommendations also state for non-ghd pediatric indications (e.g., Turners syndrome, small for gestational age) there is no benefit of GH treatment in adults. GH testing is not recommended for patients with a transcription factor mutation (e.g., POU1F1 (Pit-1), PROP-1, HESX-1, LHX-3, LHX-4), patients with more than 3 pituitary hormone deficits and those with isolated GHD associated with an identified mutation (e.g., GH-1, GHRH-R). ITT cutoff in transition period should be a GH peak 6 µg/l or re-evaluation at the completion of somatic growth (approx. 25 yo). 47 There is no data to support that treating adolescents during the transition period will decrease fracture risk or increase BMD. 40

Recommendation: Cover with a PA for appropriate patients. Safety Safety concerns have been raised with the long-term use of GH in children. Specifically, the increased risk of leukemia and other neoplasms have been suggested. The National Cooperative Growth Study has monitored the safety and efficacy of GH in children from 1985-2006. No increased risk of leukemia was found, however, an increased chance of secondary malignancies was seen in patients previously treated with irradiation. 41 GH treated patients with Prader- Willi syndrome have been observed to have an increased risk of sudden death, but a direct link has not been established. An increased incidence of type 2 diabetes has been observed in patients treated with GH, however, some of the GHD conditions are predisposed to diabetes development. 34 References 1. Dixon S, et al. Preliminary Cost-Effectiveness Model of Treatment with Genotropin in Adults with Growth Hormone Deficiency in the United Kingdom. Paper presented at the 84 th Annual Endocrine Society Meeting; 2002 Jun 19-22; San Francisco CA. 2. American Association of Clinical Endocrinologists. Medical Guidelines for the Clinical Practice for Growth Hormone Use in Adults and Children -2003 Update. Endocr Pract. 2003; 9(1):65-76. 3. Giustina A, et al. Guidelines for the Treatment of Growth Hormone Excess and Growth Hormone Deficiency in Adults. J Endocrinol Invest. 2008 31:820-838. 4. Ho, K. Consensus Guidelines for the Diagnosis and Treatment of Adults with GH Deficiency II: A Statement of the GH Research Society in Association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society and Endocrine Society of Australia. Eur J Endocrinol. 2007; 157:695-700. 5. Molitch M, et al. Evaluation and Treatment of Adult Growth Hormone Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endrocrinol Metab. 2006; 91(5):1621-1634. 6. De Boer H, et al. Clinical Aspects of Growth Hormone Deficiency in Adults. Endocr Rev 1995; 16:63-86. 7. Carroll P, et al. Growth Hormone Deficiency in Adulthood and the Effects of Growth Hormone Replacement: A Review. J Clin Endocrinol Metab. 1998; 83:382-395. 8. Tomlinson J, et al. Association Between Premature Mortality and Hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet. 2001; 357(9254):425-31. 9. Stockholm K, et al. Morbidity and GH Deficiency: A Nationwide Study. Eur J Endocrinol. 2006;158(4):447-57. 10. Abs R, et al. Determinants of Cardiovascular Risk in 2589 Hypopituitary GH-Deficient Adults a KIMS Database Analysis. Eur J Endocrinol. 2006;155(1):79-90. 11. Maison P, et al. Impact of Growth Hormone (GH) Treatment on Cardiovascular Risk Factors in GH-Deficient Adults: A Metaanalysis of Blinded, Randomized, Placebo- Controlled Trials. J Clin Endocrinol Metab. 2004; 89(5):2192-9. 12. Lamberts S. Hypopituitary Control and Complications Study (HypoCCS): A Decade of an Outcome Assessment Observational Study. J Endocrinol Invest. 2008; 31(9 Suppl):2-5. 13. Götherstgröm G, et al. Ten-Year GH Replacement Increases Bone Mineral Density in Hypopituitary Patients with Adult Onset GH Deficiency. Eur J Endocrinol. 2007; 156(1):55-64.

14. Degerblad M, et al. Reduced Bone Mineral Density in Adults with Growth Hormone (GH) Deficiency: Increased Bone Turnover During 12 Months of GH Substitution Therapy. Eur J Endocrinol. 1995; 133(2):180-88. 15. Beshyah S, et al. The Effect of Prolonged Growth Hormone Replacement on Bone Metabolism and Bone Mineral Density in Hypopituitary Adults. Clin Endocrinol (Oxf). 1995; 42(3):249-54. 16. Cohen P, et al. Growth Hormone Treatment: Evidence, Practice and Emerging Issues. Man Care. 2009; 18(6 Suppl):1-19. 17. Giusti M, et al. Impact of Recombinant Human Growth Hormone Treatment on Psychological Profiles in Hypopituitary Patients with Adult-onset Growth Hormone Deficiency. Eur J Clin Invest. 1998; 28(1):13-29. 18. Svensson J, et al. Malignant Disease and Cardiovascular Morbidity in Hypopituitary Adults with or without Growth Hormone Replacement Therapy. J Clin Endocrinol Metab. 2004; 89(7):3306-3312. 19. Gelato M, et al. Role of Recombinant Human Growth Hormone in HIV-Associated Wasting and Cachexia: Pathophysiology and Rationale for Treatment. Clin Ther. 2007; 29:2269-2288. 20. Wilson T, et al. Update of Guidelines for the Use of Growth Hormone in Children: The Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee. J Pediatr. 2003; 143:415-21. 21. GH Research Society. Consensus Guidelines for the Diagnosis and Treatment of Growth Hormone (GH) Deficiency in Childhood and Adolescence: Summary Statement of the GH Research Society. J Clin Endocrin Metab. 2000; 85(11):3990-3993. 22. Bryant L, et al. Recombinant Growth Hormone for Children and Adolescents with Turner Syndrome (Review). The Cochrane Library. 2009; Issue 1. www.thechochranelibrary.com. 23. Li H, et al. Recombinant Human Growth Hormone for Turner Syndrome: Systematic Review and Economic Evaluation. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2007. 24. Rachmiel M, et al. Final Height in Children with Idiopathic Growth Hormone Deficiency Treated with a Fixed Dose of Recombinant Growth Hormone. Horm Res. 2007; 68(5):236-43. 25. Hindmarsh P, et al. Use of Growth Hormone in Children. Nature Clinical Practice Endocrinology and Metabolism. 2005; 2(5):260-268. 26. Baxter L, et al. Recombinant Growth Hormone for Idiopathic Short Stature in Children and Adolescents. Cochrane Database Syst Rev 2007, Issue 1:CD00387. 27. Cohen P, et al. Consensus Statement on the Diagnosis and Treatment of Children with Idiopathic Short Stature: A Summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab. 2008; 93:4210-4217. 28. Dahlgren J. GH Therapy in Noonan Syndrome: Review of Final Height Data. Horm Res. 2009; 72 (suppl 2):46-48. 29. Romano A, et al. Growth Response, Near-Adult Height, and Patterns of Growth and Puberty in Patients with Noonan Syndrome Treated with Growth Hormone. J Clin Endocrinol Metab 2009; 94:2338-2344. 30. Noordam C, et al. Growth Hormone Treatment in Children with Noonan s Syndrome: Four Year Results of a Partly Controlled Trial. Acta Paediatr. 2001; 90(8):889-94. 31. Lindgren A. Somotropin Therapy for Children with Prader-Willi Syndrome. Treat Endocrinol. 2006; 5(4):223-228. 32. Carrel A, et al. Growth Hormone Improves Body Composition, Fat Utilization, Physical Strength and Agility, and Growth in Prader-Willi Syndrome: A Controlled Study. J Pediatr. 1999; 134(2):215-221. 33. Angulo M, et al. Final Adult Height in Children with Prader-Willi Syndrome With and Without Human Growth Hormone Treatment. Am J Medical Genetics Part A. 2007; 143A: 1456-1461.

34. Hardin D, et al. Twenty Years of Recombinant Human Growth Hormone in Children: Relevance to Pediatric Care Providers. Clin Pediatr. 2007; 46(4):279-286. 35. Fine R, et al. Growth After Recombinant Growth Hormone Treatment in Children with Chronic Renal Failure: Report of a Multicenter Randomized Double-Blind Placebo- Controlled Study. Genentech Cooperative Study Group. J Pediatr. 1994;124(3): 374-82. 36. Yang HM, et al. Recombinant Growth Hormone Therapy for X-linked Hypophosphatemia in Children. Cochrane Database of Syst Rev 2005, Issue 1:CD004447. 37. Clayton P, et al. Management of the Child Born Small for Gestational Age through to Adulthood: A Consensus Statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab. 2007; 92:804-810. 38. Hardin D. GH Improves Growth and Clinical Status in Children with Cystic Fibrosis A Review of Published Studies. Eur J Endocrinol. 2004; 151 (Suppl 1):S81-85. 39. Schnabel D, et al. A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Metabolic and Respiratory Effects of Growth Hormone in Children with Cystic Fibrosis. Pediatrics. 2007; 119:e1230-1238. 40. Clayton P, et al. Consensus Statement on the Management of the GH-treated Adolescent in the Transition to Adult Care. European J Endocrin. 2005; 152:165-170. 41. Hogler S, Shaw N. Childhood Growth Hormone Deficiency, Bone Density, Structures and Fractures: Scrutinizing the Evidence. Clin Endocrinol (Oxf). 2009; abstract only. 42. Bell J, et al. Long-Term Safety of Recombinant Human Growth Hormone in Children. J Clin Endocrinol Metab. 2010; 95:167-177.