Growth hormone therapy
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《美国医学杂志》
1 Division of Pediatric Endocrinology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
2 Department of Pediatrics, Armed Forces Hospital, Kuwait
Abstract
Growth hormone (GH) therapy has revolutionized treatment of children with growth hormone deficiency (GHD). Improved height outcome with final height in the target height range has been achieved in these children. Identification of Creutzfeldt-Jakob disease, a deadly prion mediated disorder, in recipients of pituitary GH accelerated the transition from pituitary derived GH to recombinant GH. Once daily subcutaneous administration of the freeze-dried preparation at evening is the recommended mode of GH therapy. Studies have led to use of higher dose of GH for improving height outcome (0.33 mg/kg/week or 0.14 IU/kg/day) albeit at a significantly high cost. Growth velocity increases from 3-4 cm/year before therapy to 10-12 cm/year during the first two years of therapy and is maintained at 7-8 cm/year after a period of two years. Close follow-up with regular clinical and laboratory monitoring is essential for achieving a desirable height outcome. A theoretical unlimited supply has led to wide spread use of GH in a variety of disorders other than GHD. Initially started in children with Turner syndrome, GH has now been used in chronic renal failure, idiopathic short stature and intrauterine growth restriction besides a wide array of newly emerging indications.
Keywords: Growth hormone; Growth hormone deficiency; Idiopathic short stature; Turner syndrome
Growth hormone (GH) therapy forms the cornerstone of management of children with growth hormone deficiency (GHD). Pituitary derived GH was used for over 25 years with remarkable success. Limited supply however restricted its widespread use. Identification of Creutzfeldt-Jakob disease More Details, a deadly prion-mediated disorder, in recipients of pituitary GH accelerated the transition from pituitary derived GH to recombinant GH. A theoretical unlimited supply has led to widespread use of GH in a variety of disorders other than GHD.
Route of Administration
Intramuscular route was initially recommended for GH due to the possible immunogenic effect of subcutaneous injection. Efficacy, pharmacokinetic effects and immunogenic potential of subcutaneous injection of GH are similar to intramuscular administration.[1],[2] Subcutaneous injection is currently the route of choice for GH administration. Trials on intranasal administration of GH are under way.
Time of Administration
Pituitary derived GH was administered two to three times in a week. Studies have shown that daily GH is superior to intermittent administration with regard to growth, IGF response and serum GH levels.[3] Twice daily GH has not been shown to be superior to once daily.[4] Evening administration of GH leads to higher GH levels, greater IGF response and better metabolic profile compared to morning or afternoon administration.[5] Once daily administration at evening is the recommended mode of GH therapy.
Preparations and Mode of Administration
Freeze-dried preparations are the commonest forms of GH available. Liquid preparations of GH have the advantage of ease of administration. A long acting analog of GH has shown promising results in initial studies.[6] GH has traditionally been injected with a syringe. Automated pen devices have the advantage of ease of administration, accuracy of dose and less inconvenience to the patient.
Dose Expression
The dose of GH has traditionally been expressed as unit/kg/day. Recently there is a trend of using mg/kg/day or mg/m2/week for calculation of dose of GH. As per WHO standards 1 mg of recombinant GH has a bioactivity equivalent to 3 IU. Expressing dose by surface area compared to body weight has the advantage of lower variation from infancy to adolescence and is more representative of body requirement.[7] Estimation of GH dose according to body weight is in particular nonphysiological in obese children as GH levels correlate negatively with body fat content. Despite these limitations GH dose is expressed according to body weight in most countries.
Dosage
The endogenous production rate of GH is variable and ranges from 20 g/kg/day during pre-pubertal period to 35 g/kg/day during puberty.[8] Dose of 0.16 mg/kg/week (0.07 IU/kg/day, 22 g/kg/day) therefore represents physiological replacement dose for GH. Initial dose recommendations for patients with GHD have been based on these estimates. Studies on GH therapy in GHD have shown that this dose is unlikely to produce sustained catch-up growth and have led to use of higher dose for improving height outcome (0.33 mg/kg/week, 0.14 IU/kg/day, 45 g/kg/day). In conditions other than GHD higher doses of GH are required to achieve pharmacological effects.
Gh therapy in different disorders
The scope of GH therapy has been expanded dramatically in the last two decades with use in a variety of genetic syndromes, skeletal dysplasias and chronic diseases. GHD however remains the most important indication of GH therapy.
Growth Hormone Deficiency
GH therapy has been shown to significantly improve height outcome in GHD. Close follow-up with regular clinical and laboratory monitoring is essential for achieving desirable height outcome.
Diagnosis
The diagnosis of GHD should be based on a combination of auxological and laboratory parameters. Compromised height (standard deviation score, SDS < -2) with low growth velocity (SDS < -1) in the presence of inappropriate response to two stimulation tests is required for establishing the diagnosis of GHD.[9] Recent recommendations suggest that peak GH levels below 10 ng/ml are diagnostic of GHD compared to previously used levels of 5-7 ng/ml.
Initiating Therapy
GH therapy should be initiated only after other anterior pituitary hormone deficiencies have been excluded or treated. Parents should be explained about the cost of therapy and the need of long-term follow-up. Giving GH for less than two years is futile and should be strongly discouraged. Initial GH dose is determined according to age, skeletal maturation and pubertal status of the patient. Thus while lower dose may be acceptable in a four-year-old child, higher doses are definitely indicated in a nine-year-old girl approaching puberty. Prediction models, a recent advance in the management of children with GHD, may be used for determining appropriate GH dose for the patient.[10],[11] Initial dose of 0.17-0.33 mg/kg/week (0.07-0.14 IU/kg/day, or 4.6-9.2 mg/m2/week) has been used for treatment of GHD. Studies have however shown that higher doses of GH may be helpful in improving height outcome albeit at a significantly higher cost.[12], [13]
Treatment of Concomitant Anterior Pituitary Deficiencies
Cortisol should be the first hormone to be replaced in a child with multiple pituitary hormone deficiency. Replacement doses of glucocorticoids in these patients (8-12 mg/m2/day) are low compared to those with primary adrenal insufficiency (12-15 mg/m2/day). Mineralocorticoid replacement is not required. Free thyroxine (FT4) levels should be maintained in the normal range. It is important to emphasize that overtly aggressive thyroid replacement may lead to inappropriate skeletal maturation and compromised height. Replacement of sex hormones should be delayed (12 years in girls and 14 years in boys) to provide adequate time for GH therapy.
Follow-up
Children on GH therapy should be followed-up every three months. Evaluation at each visit should include measurements of height, weight, height SDS, growth velocity SDS and assessment for complications of therapy. Bone age is of limited utility in follow-up of children on GH therapy except for the patient nearing completion of statural growth. IGF-1 and IGFBP-3 levels should be measured annually and maintained at high normal range for the age and gender of the child.[14] GH therapy may unmask hypothyroidism in children with borderline thyroid status. Diabetogenic effect of GH may induce insulin resistance and result in impaired glucose tolerance or overt type 2 diabetes mellitus. Blood sugar and FT4 levels should be estimated after an interval of three, six and twelve months of initiation of GH therapy. Thereafter annual estimation of blood sugar and FT4 levels should be performed. It is important to emphasize that intra-cranial tumors may be missed on initial CNS imaging leading to a misdiagnosis of idiopathic GHD. These children should be closely monitored for development of features indicating CNS involvement. table1
Response to Therapy
GH therapy is associated with significant improvement in growth velocity, which increases from 3-4 cm/year before therapy to 10-12 cm/year during the first two years of treatment.[15] This catch-up response, however is not maintained and growth velocity declines to 7-8 cm/year after a period of two years. This apparent loss of effect of GH does not represent failure of therapy but demonstrates growth at a normal rate following correction of GH deficient state.[16] Inappropriate response to GH therapy should prompt evaluation of compliance, injection technique, hypothyroidism or reconsideration of the diagnosis of GHD table2. Decline in growth velocity following an initial increase suggest the possibility of unmasking of hypothyroidism while no response should prompt reconsideration of the diagnosis of GHD Figure1. Doses of GH should be adjusted according to growth velocity, pubertal status and IGF-1 and IGFBP-3 levels. Prediction models have been used for optimizing GH dose.[10]
Optimization of Therapy During Puberty
Pubertal growth in children with GHD is similar to normal individuals.[17],[18] Compromised height at puberty is therefore invariably associated with compromised final height. Two different approaches have been tried for maximizing benefits of GH therapy in individuals who are short at the onset of puberty. In the first approach higher doses of GH (up to 0.15-0.2 IU/kg/day) have been used during puberty.[19] In a randomized controlled trial high dose GH during puberty (0.7 mg/kg/week, 0.3 IU/kg/day) was associated with significantly higher growth velocity compared to lower dose (0.3 mg/kg/week, 0.13 IU/kg/day).[20] Prolongation of puberty with the use of gonadotropin releasing hormone analogs forms the basis of the other approach.[21] In a randomized controlled trial combination of GnRH analog with GH for a period of three years was associated with better outcome (final height SDS -1.3) compared to GH alone (height SDS -2.7).[22] GnRH analog therapy should be used for a period of at least two years as treatment for shorter duration may lead to initial acceleration of puberty due to the agonist activity of the hormone.
Discontinuation of Therapy
GH therapy should be continued till final height has been achieved. Growth velocity below 2 cm in the preceding year with bone age of 14 years in girls and 16 years in boys is considered as indicator of final height. The issue of continuation of GH therapy during adulthood should be discussed with the family.
Effect on Final Height
Studies involving a large number of patients with GHD have shown significant improvement in final height following GH therapy.[23],[24],[25],[26] Most of these studies however have used historical controls for comparison. Untreated severe GHD is associated with final height SDS in the range of -4 to -6 while long term GH therapy is associated with final height SDS in the range of -1 to -2. This could translate in a height gain of 20-30 cm. The efficacy of GH in children with severe GHD remains unequivocal; its impact on milder forms of disease may not be as dramatic.
Factors Influencing Outcome
An understanding of factors influencing height outcome is helpful in appropriate management of these children. Studies have shown that early diagnosis, higher dose, higher target height SDS, greater height SDS at the time of onset of puberty and longer duration of therapy are associated with better height outcome.[25],[26],[27],[28],[29] Height gain during first year of therapy is an important predictor of overall response. This emphasizes the need of appropriate management and close monitoring during initial part of GH therapy. table3 summarizes factors influencing height outcome in GHD and interventions directed at improving outcome. Children with combined pituitary deficiency have better height outcome compared to those with isolated GHD.[30] This may be due to delay in puberty due to concomitant gonadotropin deficiency.
Cost of Therapy
One of the major limitations of GH therapy is high cost. In a study conducted in United States the cost of GH therapy for a 20 kg child with GHD was estimated to be $ 15,000 per year. In India the approximate cost for a 20 kg child would be Rs 200,000 per year. Cost considerations are the major limiting factors of wide spread use of GH therapy in resource-poor settings.
Adverse Effects
Recombinant GH has been shown to be safe during its widespread use table4. The most common initial adverse effects include headache and vomiting due to pseudotumor cerebri and edema due to fluid and sodium retention.[31] These effects improve over time without any intervention. It is however important to emphasize that headache in a child with a diagnosis of idiopathic GHD may be a pointer of an intra-cranial tumor and should prompt appropriate CNS imaging. Initial reports suggested an increased risk of leukemia in subjects receiving GH; subsequent studies have however failed to substantiate these findings.[32],[33],[34] The use of GH in children with intra-cranial tumors is in particular a major cause of concern due to the theoretical possibility of reappearance of tumors. In a large study involving 1000 children with intra-cranial malignancy GH therapy was not associated with increased risk of tumor recurrence.[35] GH therapy may unmask hypothyroidism and induction of insulin resistance mandating the need of close follow-up for these complications during therapy.[36] Slipped capital femoral epiphyses and obstructive sleep apnea have not been shown to be higher in children receiving GH therapy compared to children with GHD who are not on GH.[37],[38] table5
Therapy Following Completion of Statural Growth
Initially GH therapy was limited to periods of active growth. Recent studies have shown that GHD in adults is associated with significant complications in the form of risk of atherosclerosis, altered body composition and poor quality of life.[39] These complications improve with GH.[40] These observations have led to the recommendations of GH therapy in adults with GHD. Retesting for GHD should be performed after discontinuing the drug for a period of 1 month. A significant number of children with isolated idiopathic GHD (50-70%) would not be GH deficient during re-testing. This may reflect inaccuracies of initial GH test on one hand and transient nature of GHD on the other. Patients with peak GH levels below 3 ng/ml (cutoff levels for adults) should be started on 0.5 mg/day of GH. These recommendations however are difficult to follow in resource-poor setting.
GH THERAPY IN NON-GHD SHORT STATURE
Turner Syndrome
Turner syndrome was the first disorder besides GHD for which GH therapy was approved. Long-term studies have suggested significant improvement in final height following GH ranging from 4-9 cm over predicted height at initiation of therapy.[41],[42],[43] The dose of GH in Turner syndrome is higher compared to GHD (0.35 mg/kg/week or 0.15 IU/kg/day). Use of even higher dose (0.3 IU/kg/day) has been shown to produce height gain in the range of 16 cm.[44] Early GH therapy is recommended for maximizing benefits. GH therapy should be started in girls with Turner syndrome when height falls below 5th centile for the normal growth curve. GH stimulation test is not required. Oxandrolone (50 g/kg/day) should be added after the age of 8 years. Early initiation of GH along with delayed induction of puberty (at least four years after starting GH) combined with oxandrolone is associated with best height outcome in Turner syndrome.[45]
Chronic Renal Failure (CRF)
Chronic renal failure is associated with significant growth compromise that persists despite renal replacement therapy. High dose GH improves height outcome in children with CRF.[46] In a randomized controlled study involving 38 pre-pubertal children with CRF, treatment with GH led to increase in height SDS by 1.4 compared to decline in height SDS by 0.6 in the control group.[47] This response however is not sustained over a long period of time without kidney transplantation.
Idiopathic Short Stature (ISS)
Idiopathic short stature represents a mix of children with mild defects of the GH and IGF axis and low genetic potential. Marginal benefits have been reported with the use of GH. A gain of 5-7 cm compared to historical controls was observed in a study using high dose GH (0.33 mg/kg/week or 0.14 IU/kg/day).[48] In a meta-analysis involving 1089 patients with idiopathic short stature treated with GH height gain of 4-6 cm was noted.[49] The cost of therapy remains exorbitant at $13000 for every cm of height gained. Trial of GH therapy in children with idiopathic short stature should be continued for at least six months. The drug may be discontinued in children who do not show catch up growth. GnRH analog could be combined with GH for maximizing height gain.
Intra-uterine Growth Restriction (IUGR)
IUGR comprises of a heterogeneous mix of individuals with genetic, environmental and placental compromise. Majority of these patients show catch up growth with final height in the low normal range. However 15% of these individuals have compromised height and are at risk of short stature. In a randomized control trial involving 54 children with IUGR, GH therapy was associated with increase in height SDS by 2 SDS.[50] Importantly, children receiving lower dose (0.1 IU/kg/day) had similar height gain compared to those on higher dose (0.2 IU/kg/day).
Prader-Willi syndrome More Details
Children with this syndrome have significant complications like obesity, low muscle mass, hypotonia and compromised height. GH therapy in a dose of 0.1 IU/kg/day has been associated with improved height outcome, fat mass, body composition and respiratory functions.[51]
Other Disorders
The list of disorders for which GH has been used is increasing every day. Favorable results have been reported in dysmorphic syndromes like Seckel and Silver Russel syndromes and bone disorders like skeletal dysplasia and hypophosphatemic rickets. Long-term outcome however remains unclear in most of these conditions. GH therapy has also been tried in catabolic disorders like burns, HIV infection and anorexia nervosa.
References
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4. Van Teunenbroek A, de Munick Keizer-Schrama S, Stijnen T et al. Growth response and levels of growth after two years growth hormone treatment are similar for once or twice daily regimen in girls with Turner syndrome. Clin Endocrinol (Oxford) 1997; 46: 451-459.
5. Zadik Z, Liberman E, Altman Y, Chen M, Limoni Y, Landau H. Effect of timing of growth hormone on plasma growth-hormone-binding activity, insulin like growth factor-1 and growth in children with subnormal secretion of growth hormone. Horm Res 1993; 39: 188-191.
6. Silverman BL, Blethen SL, Reiter EO, Attie KM, Neuwirth RB, Ford KM. A long-acting human growth hormone (Nutropin Depot): efficacy and safety following two years of treatment in children with growth hormone deficiency. J Pediatr Endocrinol Metab 2002; 15 (Suppl 2): 715-722.
7. Wit JM. Growth hormone therapy. Clinical Endocrinol Metab 2002; 16: 483-504.
8. Martha PM, Gorman KM, Blizzard RM, Rogol AD, Veldhuis JD. Endogenous growth hormone secretion and clearance rates in normal boys, as determined by deconvolution analysis: relationship to age, pubertal status and body mass. J Clin Endocrinol Metab 1992; 74: 336-344.
9. Hintz RL. Management of disorders of size. In Brook CGD, Hindmarsh PC, eds. Clinical Pediatric Endocrinology, 4th edn. London: Blackwell Science 2001; 124-139.
10. Ranke MB, Lindberg A, Chatelain P, Wilton P, Cutfield W, Albertson-Wikland K, Price DA. Derivation and validation of a mathematical model for predicting the response to exogenous recombinant human growth hormone (GH) in prepubertal children with GH deficiency. J Clin Endocrinol Metab 1999; 84: 1174-1183.
11. Muller V, Hoepffner W, Kiess W, Keller E. Prediction of height velocity of prepubertal children with growth hormone deficiency in the first year of treatment with recombinant human growth hormone. J Pediatr Endocrinol Metab 2000; 13: 893-897.
12. Radetti G, Buzi F, Paganini C, Pilotta A, Felappi B. Treatment of GH-deficient children with two different GH doses: effect on final height and cost-benefit implications. Eur J Endocrinol 2003; 148: 515-518.
13. Blethen SL, Bapista J, Kuntze J, Foley T, LaFranchi S, Johanson A. Adult height in growth hormone deficient children treated with biosynthetic GH: the Genetech growth study group. J Clin Endocrinol Metab 1997; 82: 418-420.
14. Tanaka T, Cohen P, Clayton PE, Laron Z, Hintz TL, Sizoneneko PC. Diagnosis and management of growth hormone deficiency in childhood and adolescence. Part 2: Growth hormone treatment in growth hormone deficient children. Growth Horm IGF Res 2002; 12: 323-341.
15. Rosenfield GR, Cohen P. Disorders of growth hormone/insulin like growth factor and action. In Sperling MA, ed. Pediatric Endocrinology, 2nd edn. Philadelphia, WB Saunders, 2002; 211-288.
16. Clayton PE, Cowell CT. Safety issues in children and adolescents during growth hormone therapy- a review. Growth Horm IGF Res 2000; 10: 306-317.
17. Buckler JM. A longitudinal study of adolescent growth. London, Springer 1990.
18. Tanaka T, Konatsu K, Takada G, Miyashita M, Ohno T. Prediction of adult height in healthy Japanese children. Acta Pediatr 1996; 417 (suppl): 57-60.
19. Stanhope R, Uruena M, Hindmarsh P, Leiper AD, Brook CG. Management of growth hormone deficiency through puberty. Acta Pediatr Scand 1998; 372 (suppl): 47-52.
20. Albertson-Wikland K, Alm F, Aronsson S et al. Effect of growth hormone (GH) during puberty in GH-deficient children: preliminary results form an ongoing trial with different dose regimens. Acta Pediatr 1998; 428 (suppl): 80-84.
21. Tanaka T, Satoh M, Yasunaga T, Horikawa R, Tanae A, Katsumata N, Tachibana K, Nose O, Hibi I. When and how to combine growth hormone with a luteinizing hormone-releasing hormone analogue. Acta Pediatr 1999; Suppl 88: 85-88.
22. Merciq MV, Eggers M, Avila A, Cutler GB Jr, Cassorola F. Near final height in pubertal growth hormone (GH) deficient parents treated with GH alone or in combination with leutenizing releasing hormone analog: results of a prospective, randomized trial. J Clin Endocrinol Metab 2000; 85: 569-573.
23. Cutfield WS, Lindberg A, Chatelain P et al. Final height following growth hormone treatment idiopathic growth hormone deficiency in KIGS. In Ranke MB, Wilton P, eds. Growth Hormone Therapy in KIGS- 10 Year Experience. Heidelberg 1999. Pp 93-109.
24. August GP, Julius JR, Blethen SL. Adult height in growth hormone deficient children treated with biosynthetic GH. The national cooperative growth study experience. Pediatrics 1998; 49: 80-85.
25. Cacciari E, Cicognani A, Pirazolli P et al. Final height of patients treated for isolated GH deficiency examination on 83 patients. Eur J Endocrinol 197; 137: 53-60.
26. Ranke MB, Price DA, Albertsson-Wikland K, Maes M, Lindbe A. Factors determining pubertal growth and final height in growth hormone treatment of idiopathic growth hormone deficiency. Horm Res 1997; 48: 62-71.
27. Burns EC, Tanner JM, Preece MA, Cameron N. Final height and pubertal development in 55 children with idiopathic growth hormone deficiency. Eur J Pediatr 1981; 137: 155-164.
28. Hibi I, Tanaka T. Final height of patients with idiopathic growth hormone deficiency after long-term growth hormone treatment. Committee for Treatment of Growth Hormone Deficient Children, Growth Science Foundation, Japan. Acta Endocrinol (Copenh) 1989; 120: 409-415.
29. Rikken MB, Massa GG, Wit JM. Final height in a large cohort of Dutch patients with growth hormone deficiency treated with growth hormone. Horm Res 1997; 48: 62-71.
30. Tanaka T, Takano K, Igarashi Y et al. Growth hormone (GH) treatment and puberty in GH treated GH children. Clin Pediatr Endocrinol 1999; 8 (Suppl 12): 37-44.
31. Lampit M, Nave T, Hochberg Z. Water and sodium retention during short-term administration of growth hormone to short normal children. Horm Res 1998; 50: 83-88.
32. Watanabe S, Tsunematsu Y, Fujimoto J, Korniyama A. Leukemia in patients treated with growth hormone. Lancet 1989; 80: 822-825.
33. Allen DB, Rundle AC, Graves DA, Blethen SL. Risk of leukemia in children with growth hormone: review and reanalysis. J Pediatr 1997; 131: S32-S36.
34. Nishi Y, Tanaka T, Takano K et al. Recent status in the occurrence of leukemia in growth hormone treated patients in Japan. J Clin Endocrinol Metab 1999; 84: 1961-1965.
35. Swerdkow AJ, Reddubgius RE, Higgins CD et al. Growth hormone treatment of children with brain tumors and risk of recurrence. J Clin Endocrinol Metab 2000; 85: 4444-4449.
36. Blethen SL, Allen DB, Graves D, August G, Moshang T, Rosenfield R. Safety of recombinant deoxyribonucleic acid derived growth hormone: the national cooperative growth study experience. J Clin Endocrinol Metab 1996; 81: 1704-1710.
37. Rappaport EB, Fife D. Slipped capital femoral epiphysis in growth hormone deficient patients. Am J Dis Child 1985; 139: 396-399.
38. Blethen SL, Rundle AC. Slipped capital femoral ephiphysis in children treated with growth hormone. Horm Res 1996; 46: 113-116.
39. Vahl N, Juul A, Jorgenesen JO et al. Continuation of growth hormone (GH) treatment I GH deficient patients during transition form childhood to adulthood: a two year placebo-controlled study. J Clinical Endocrinol Metab 2000; 85: 1874-1881.
40. Saggese G, Ranke MB, Saenger P et al. Diagnosis and treatment of growth hormone deficiency in children and adolescents: towards a consensus. Ten years after availability of recombinant growth hormone. Horm Res 1998; 50: 320-340.
41. Rosenfield R, Attie K, Frane J et al. Growth hormone therapy of Turner syndrome: beneficial effect on adult final height. J Pediatr 1998; 132: 319-324.
42. Carel J, Mathivon L, Gendrel C et al. Near normalization of final height with adapted doses of growth hormone in Turner syndrome. J Clin Endocrinol Metab 1998; 83: 1462-1466.
43. Nillson K, Albertson-Wikland K, Alm J et al. Improved final height in girls with Turner syndrome treated with growth hormone and oxandrolone. J Clin Endocrinol Metab 1996; 81: 635-640.
44. Sas T, de Munic Keizer-Schrama S, Stijen T et al. Near-normalization of heights in girls with Turner syndrome after long term growth hormone treatment: results of a randomized dose trial. J Clin Endocrinol Metab 1999; 84: 4607-4612.
45. Saenger P. Albertson-Wikland K, Cowy G et al. Recommendations of diagnosis and management of Turner syndrome. J Clin Endocrinol Metab 2001; 86: 3061-3069.
46. Hokken-Kolega A, Mulder P, De Jong R et al. Long term effects of growth hormone treatment on growth and puberty in patients with chronic renal insufficiency. Pediatr Nephrol 2000; 14: 701-706.
47. Haffner D, Schaefer F, Nissel R, Wuhl E, Tonshoff B, Mehls O. Effect of growth hormone treatment on the adult height of children with chronic renal failure. German Study Group for Growth Hormone Treatment in Chronic Renal Failure. N Engl J Med 2000 28; 343: 923-930.
48. Buchlis JG, Irizarry L, Crotzer BC et al. Comparison of final height of growth hormone treated versus untreated children with idiopathic growth failure. J Clin Endocrinol Metab 1998; 83: 1075-1079.
49. Van Pareren Y, Mulder P, Houdijk M, Jansen M, Reeser M, Hokken-Koelega A. Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial. J Clin Endocrinol Metab 2003; 88: 3584-3590.
50. Coutant R, Carel JC, Letrait M, Bouvattier C, Chatelain P, Coste J et al. Short stature associated with intrauterine growth retardation: final height of untreated and growth hormone-treated children. J Clin Endocrinol Metab 1998; 83: 1070-1074.
51. Myers SE, Carrel AL, Whitman BY, Allen DB. Sustained benefit after 2 years of growth hormone treatment on body composition, fat utilization, physical strength, agility and growth in Prader-Willi syndrome. Eur J Pediatr 1999; 158: 245-249.(Bajpai Anurag, Menon P SN)
2 Department of Pediatrics, Armed Forces Hospital, Kuwait
Abstract
Growth hormone (GH) therapy has revolutionized treatment of children with growth hormone deficiency (GHD). Improved height outcome with final height in the target height range has been achieved in these children. Identification of Creutzfeldt-Jakob disease, a deadly prion mediated disorder, in recipients of pituitary GH accelerated the transition from pituitary derived GH to recombinant GH. Once daily subcutaneous administration of the freeze-dried preparation at evening is the recommended mode of GH therapy. Studies have led to use of higher dose of GH for improving height outcome (0.33 mg/kg/week or 0.14 IU/kg/day) albeit at a significantly high cost. Growth velocity increases from 3-4 cm/year before therapy to 10-12 cm/year during the first two years of therapy and is maintained at 7-8 cm/year after a period of two years. Close follow-up with regular clinical and laboratory monitoring is essential for achieving a desirable height outcome. A theoretical unlimited supply has led to wide spread use of GH in a variety of disorders other than GHD. Initially started in children with Turner syndrome, GH has now been used in chronic renal failure, idiopathic short stature and intrauterine growth restriction besides a wide array of newly emerging indications.
Keywords: Growth hormone; Growth hormone deficiency; Idiopathic short stature; Turner syndrome
Growth hormone (GH) therapy forms the cornerstone of management of children with growth hormone deficiency (GHD). Pituitary derived GH was used for over 25 years with remarkable success. Limited supply however restricted its widespread use. Identification of Creutzfeldt-Jakob disease More Details, a deadly prion-mediated disorder, in recipients of pituitary GH accelerated the transition from pituitary derived GH to recombinant GH. A theoretical unlimited supply has led to widespread use of GH in a variety of disorders other than GHD.
Route of Administration
Intramuscular route was initially recommended for GH due to the possible immunogenic effect of subcutaneous injection. Efficacy, pharmacokinetic effects and immunogenic potential of subcutaneous injection of GH are similar to intramuscular administration.[1],[2] Subcutaneous injection is currently the route of choice for GH administration. Trials on intranasal administration of GH are under way.
Time of Administration
Pituitary derived GH was administered two to three times in a week. Studies have shown that daily GH is superior to intermittent administration with regard to growth, IGF response and serum GH levels.[3] Twice daily GH has not been shown to be superior to once daily.[4] Evening administration of GH leads to higher GH levels, greater IGF response and better metabolic profile compared to morning or afternoon administration.[5] Once daily administration at evening is the recommended mode of GH therapy.
Preparations and Mode of Administration
Freeze-dried preparations are the commonest forms of GH available. Liquid preparations of GH have the advantage of ease of administration. A long acting analog of GH has shown promising results in initial studies.[6] GH has traditionally been injected with a syringe. Automated pen devices have the advantage of ease of administration, accuracy of dose and less inconvenience to the patient.
Dose Expression
The dose of GH has traditionally been expressed as unit/kg/day. Recently there is a trend of using mg/kg/day or mg/m2/week for calculation of dose of GH. As per WHO standards 1 mg of recombinant GH has a bioactivity equivalent to 3 IU. Expressing dose by surface area compared to body weight has the advantage of lower variation from infancy to adolescence and is more representative of body requirement.[7] Estimation of GH dose according to body weight is in particular nonphysiological in obese children as GH levels correlate negatively with body fat content. Despite these limitations GH dose is expressed according to body weight in most countries.
Dosage
The endogenous production rate of GH is variable and ranges from 20 g/kg/day during pre-pubertal period to 35 g/kg/day during puberty.[8] Dose of 0.16 mg/kg/week (0.07 IU/kg/day, 22 g/kg/day) therefore represents physiological replacement dose for GH. Initial dose recommendations for patients with GHD have been based on these estimates. Studies on GH therapy in GHD have shown that this dose is unlikely to produce sustained catch-up growth and have led to use of higher dose for improving height outcome (0.33 mg/kg/week, 0.14 IU/kg/day, 45 g/kg/day). In conditions other than GHD higher doses of GH are required to achieve pharmacological effects.
Gh therapy in different disorders
The scope of GH therapy has been expanded dramatically in the last two decades with use in a variety of genetic syndromes, skeletal dysplasias and chronic diseases. GHD however remains the most important indication of GH therapy.
Growth Hormone Deficiency
GH therapy has been shown to significantly improve height outcome in GHD. Close follow-up with regular clinical and laboratory monitoring is essential for achieving desirable height outcome.
Diagnosis
The diagnosis of GHD should be based on a combination of auxological and laboratory parameters. Compromised height (standard deviation score, SDS < -2) with low growth velocity (SDS < -1) in the presence of inappropriate response to two stimulation tests is required for establishing the diagnosis of GHD.[9] Recent recommendations suggest that peak GH levels below 10 ng/ml are diagnostic of GHD compared to previously used levels of 5-7 ng/ml.
Initiating Therapy
GH therapy should be initiated only after other anterior pituitary hormone deficiencies have been excluded or treated. Parents should be explained about the cost of therapy and the need of long-term follow-up. Giving GH for less than two years is futile and should be strongly discouraged. Initial GH dose is determined according to age, skeletal maturation and pubertal status of the patient. Thus while lower dose may be acceptable in a four-year-old child, higher doses are definitely indicated in a nine-year-old girl approaching puberty. Prediction models, a recent advance in the management of children with GHD, may be used for determining appropriate GH dose for the patient.[10],[11] Initial dose of 0.17-0.33 mg/kg/week (0.07-0.14 IU/kg/day, or 4.6-9.2 mg/m2/week) has been used for treatment of GHD. Studies have however shown that higher doses of GH may be helpful in improving height outcome albeit at a significantly higher cost.[12], [13]
Treatment of Concomitant Anterior Pituitary Deficiencies
Cortisol should be the first hormone to be replaced in a child with multiple pituitary hormone deficiency. Replacement doses of glucocorticoids in these patients (8-12 mg/m2/day) are low compared to those with primary adrenal insufficiency (12-15 mg/m2/day). Mineralocorticoid replacement is not required. Free thyroxine (FT4) levels should be maintained in the normal range. It is important to emphasize that overtly aggressive thyroid replacement may lead to inappropriate skeletal maturation and compromised height. Replacement of sex hormones should be delayed (12 years in girls and 14 years in boys) to provide adequate time for GH therapy.
Follow-up
Children on GH therapy should be followed-up every three months. Evaluation at each visit should include measurements of height, weight, height SDS, growth velocity SDS and assessment for complications of therapy. Bone age is of limited utility in follow-up of children on GH therapy except for the patient nearing completion of statural growth. IGF-1 and IGFBP-3 levels should be measured annually and maintained at high normal range for the age and gender of the child.[14] GH therapy may unmask hypothyroidism in children with borderline thyroid status. Diabetogenic effect of GH may induce insulin resistance and result in impaired glucose tolerance or overt type 2 diabetes mellitus. Blood sugar and FT4 levels should be estimated after an interval of three, six and twelve months of initiation of GH therapy. Thereafter annual estimation of blood sugar and FT4 levels should be performed. It is important to emphasize that intra-cranial tumors may be missed on initial CNS imaging leading to a misdiagnosis of idiopathic GHD. These children should be closely monitored for development of features indicating CNS involvement. table1
Response to Therapy
GH therapy is associated with significant improvement in growth velocity, which increases from 3-4 cm/year before therapy to 10-12 cm/year during the first two years of treatment.[15] This catch-up response, however is not maintained and growth velocity declines to 7-8 cm/year after a period of two years. This apparent loss of effect of GH does not represent failure of therapy but demonstrates growth at a normal rate following correction of GH deficient state.[16] Inappropriate response to GH therapy should prompt evaluation of compliance, injection technique, hypothyroidism or reconsideration of the diagnosis of GHD table2. Decline in growth velocity following an initial increase suggest the possibility of unmasking of hypothyroidism while no response should prompt reconsideration of the diagnosis of GHD Figure1. Doses of GH should be adjusted according to growth velocity, pubertal status and IGF-1 and IGFBP-3 levels. Prediction models have been used for optimizing GH dose.[10]
Optimization of Therapy During Puberty
Pubertal growth in children with GHD is similar to normal individuals.[17],[18] Compromised height at puberty is therefore invariably associated with compromised final height. Two different approaches have been tried for maximizing benefits of GH therapy in individuals who are short at the onset of puberty. In the first approach higher doses of GH (up to 0.15-0.2 IU/kg/day) have been used during puberty.[19] In a randomized controlled trial high dose GH during puberty (0.7 mg/kg/week, 0.3 IU/kg/day) was associated with significantly higher growth velocity compared to lower dose (0.3 mg/kg/week, 0.13 IU/kg/day).[20] Prolongation of puberty with the use of gonadotropin releasing hormone analogs forms the basis of the other approach.[21] In a randomized controlled trial combination of GnRH analog with GH for a period of three years was associated with better outcome (final height SDS -1.3) compared to GH alone (height SDS -2.7).[22] GnRH analog therapy should be used for a period of at least two years as treatment for shorter duration may lead to initial acceleration of puberty due to the agonist activity of the hormone.
Discontinuation of Therapy
GH therapy should be continued till final height has been achieved. Growth velocity below 2 cm in the preceding year with bone age of 14 years in girls and 16 years in boys is considered as indicator of final height. The issue of continuation of GH therapy during adulthood should be discussed with the family.
Effect on Final Height
Studies involving a large number of patients with GHD have shown significant improvement in final height following GH therapy.[23],[24],[25],[26] Most of these studies however have used historical controls for comparison. Untreated severe GHD is associated with final height SDS in the range of -4 to -6 while long term GH therapy is associated with final height SDS in the range of -1 to -2. This could translate in a height gain of 20-30 cm. The efficacy of GH in children with severe GHD remains unequivocal; its impact on milder forms of disease may not be as dramatic.
Factors Influencing Outcome
An understanding of factors influencing height outcome is helpful in appropriate management of these children. Studies have shown that early diagnosis, higher dose, higher target height SDS, greater height SDS at the time of onset of puberty and longer duration of therapy are associated with better height outcome.[25],[26],[27],[28],[29] Height gain during first year of therapy is an important predictor of overall response. This emphasizes the need of appropriate management and close monitoring during initial part of GH therapy. table3 summarizes factors influencing height outcome in GHD and interventions directed at improving outcome. Children with combined pituitary deficiency have better height outcome compared to those with isolated GHD.[30] This may be due to delay in puberty due to concomitant gonadotropin deficiency.
Cost of Therapy
One of the major limitations of GH therapy is high cost. In a study conducted in United States the cost of GH therapy for a 20 kg child with GHD was estimated to be $ 15,000 per year. In India the approximate cost for a 20 kg child would be Rs 200,000 per year. Cost considerations are the major limiting factors of wide spread use of GH therapy in resource-poor settings.
Adverse Effects
Recombinant GH has been shown to be safe during its widespread use table4. The most common initial adverse effects include headache and vomiting due to pseudotumor cerebri and edema due to fluid and sodium retention.[31] These effects improve over time without any intervention. It is however important to emphasize that headache in a child with a diagnosis of idiopathic GHD may be a pointer of an intra-cranial tumor and should prompt appropriate CNS imaging. Initial reports suggested an increased risk of leukemia in subjects receiving GH; subsequent studies have however failed to substantiate these findings.[32],[33],[34] The use of GH in children with intra-cranial tumors is in particular a major cause of concern due to the theoretical possibility of reappearance of tumors. In a large study involving 1000 children with intra-cranial malignancy GH therapy was not associated with increased risk of tumor recurrence.[35] GH therapy may unmask hypothyroidism and induction of insulin resistance mandating the need of close follow-up for these complications during therapy.[36] Slipped capital femoral epiphyses and obstructive sleep apnea have not been shown to be higher in children receiving GH therapy compared to children with GHD who are not on GH.[37],[38] table5
Therapy Following Completion of Statural Growth
Initially GH therapy was limited to periods of active growth. Recent studies have shown that GHD in adults is associated with significant complications in the form of risk of atherosclerosis, altered body composition and poor quality of life.[39] These complications improve with GH.[40] These observations have led to the recommendations of GH therapy in adults with GHD. Retesting for GHD should be performed after discontinuing the drug for a period of 1 month. A significant number of children with isolated idiopathic GHD (50-70%) would not be GH deficient during re-testing. This may reflect inaccuracies of initial GH test on one hand and transient nature of GHD on the other. Patients with peak GH levels below 3 ng/ml (cutoff levels for adults) should be started on 0.5 mg/day of GH. These recommendations however are difficult to follow in resource-poor setting.
GH THERAPY IN NON-GHD SHORT STATURE
Turner Syndrome
Turner syndrome was the first disorder besides GHD for which GH therapy was approved. Long-term studies have suggested significant improvement in final height following GH ranging from 4-9 cm over predicted height at initiation of therapy.[41],[42],[43] The dose of GH in Turner syndrome is higher compared to GHD (0.35 mg/kg/week or 0.15 IU/kg/day). Use of even higher dose (0.3 IU/kg/day) has been shown to produce height gain in the range of 16 cm.[44] Early GH therapy is recommended for maximizing benefits. GH therapy should be started in girls with Turner syndrome when height falls below 5th centile for the normal growth curve. GH stimulation test is not required. Oxandrolone (50 g/kg/day) should be added after the age of 8 years. Early initiation of GH along with delayed induction of puberty (at least four years after starting GH) combined with oxandrolone is associated with best height outcome in Turner syndrome.[45]
Chronic Renal Failure (CRF)
Chronic renal failure is associated with significant growth compromise that persists despite renal replacement therapy. High dose GH improves height outcome in children with CRF.[46] In a randomized controlled study involving 38 pre-pubertal children with CRF, treatment with GH led to increase in height SDS by 1.4 compared to decline in height SDS by 0.6 in the control group.[47] This response however is not sustained over a long period of time without kidney transplantation.
Idiopathic Short Stature (ISS)
Idiopathic short stature represents a mix of children with mild defects of the GH and IGF axis and low genetic potential. Marginal benefits have been reported with the use of GH. A gain of 5-7 cm compared to historical controls was observed in a study using high dose GH (0.33 mg/kg/week or 0.14 IU/kg/day).[48] In a meta-analysis involving 1089 patients with idiopathic short stature treated with GH height gain of 4-6 cm was noted.[49] The cost of therapy remains exorbitant at $13000 for every cm of height gained. Trial of GH therapy in children with idiopathic short stature should be continued for at least six months. The drug may be discontinued in children who do not show catch up growth. GnRH analog could be combined with GH for maximizing height gain.
Intra-uterine Growth Restriction (IUGR)
IUGR comprises of a heterogeneous mix of individuals with genetic, environmental and placental compromise. Majority of these patients show catch up growth with final height in the low normal range. However 15% of these individuals have compromised height and are at risk of short stature. In a randomized control trial involving 54 children with IUGR, GH therapy was associated with increase in height SDS by 2 SDS.[50] Importantly, children receiving lower dose (0.1 IU/kg/day) had similar height gain compared to those on higher dose (0.2 IU/kg/day).
Prader-Willi syndrome More Details
Children with this syndrome have significant complications like obesity, low muscle mass, hypotonia and compromised height. GH therapy in a dose of 0.1 IU/kg/day has been associated with improved height outcome, fat mass, body composition and respiratory functions.[51]
Other Disorders
The list of disorders for which GH has been used is increasing every day. Favorable results have been reported in dysmorphic syndromes like Seckel and Silver Russel syndromes and bone disorders like skeletal dysplasia and hypophosphatemic rickets. Long-term outcome however remains unclear in most of these conditions. GH therapy has also been tried in catabolic disorders like burns, HIV infection and anorexia nervosa.
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