Growth Hormone Resistance Medication
- Author: Arlan L Rosenbloom, MD; Chief Editor: Stephen Kemp, MD, PhD more...
Human IGF-I was synthesized by recombinant DNA techniques in 1986 and preparations of rhIGF-I for subcutaneous injection became available in 1990. The initial manufacturers in Japan (Fujisawa) and Sweden (Kabi) provided rhIGF-I for approximately 70 children with GHRD internationally and a handful of GH gene deletion patients with acquired GH insensitivity due to GH inactivating antibodies developing after treatment with rhGH.
Eventually, the 3 manufacturers stopped production of rhIGF-I because of the limited market. Subsequently, a company licensed by Genentech (Tercica Inc, Brisbane, California) obtained orphan drug approval of their rhIGF-I (mecasermin, [Increlex]) from the US Food and Drug Administration (FDA) in late 2005. Soon thereafter, an equimolar preparation of rhIGF-I and rhIGFBP3 (mecasermin rinfabate [Iplex], Insmed Inc, Glen Allen, Virginia) was approved by the FDA. In addition to the purported pharmacokinetic advantage permitting once daily injection for the latter preparation, a lower risk for hypoglycemia was proposed. As a result of legal action, Iplex is no longer available for growth therapy; this is not a problem because the preparation was less effective than rhIGF-I alone.
Pharmacokinetic profiles done at doses of 40, 80, and 120 mcg/kg suggested a plateau effect for circulating IGF-I concentrations between 80 and 120 mcg/kg per dose. It was considered that the carrying capacity of the IGFBPs was saturated at this level. In a randomized, double-blind, placebo-controlled trial, 17 prepubertal Ecuadorian patients were given IGF-I at 120 mcg/kg SC bid for 6 months, following which all subjects received IGF-I. The 9 placebo-treated patients had a modest but not significant increase in height velocity from 2.8 ± 0.3 to 4.4 ± 0.7 cm/y, accounted for by 3 individuals with 6-month velocities of 6.6-8 cm/y.
This response was attributed to improved nutritional status as noted with nutrition-induced catch up growth by Crosnier et al in their GHRD patient with anorexia. For those receiving IGF-I, the height velocity increased from 2.9±0.6 to 8.8±0.6 cm/y and all 16 patients had accelerated velocities during the second 6-month period when all were receiving IGF-I.
In the comparison of growth response of the 22 Ecuadorian GHRD patients treated with rhIGF-I and 11 GHD patients treated with rhGH in the same setting and with comparable growth impairment, growth velocity increase in those with GHRD over the first year of treatment with IGF-I was 63% of that with GH treatment of GHD; in the second year the increment was less than 50% of that with GH-treated GHD. The difference in growth response between GHRD treated with IGF-I and that treated with GHD was consistent with the hypothesis that 20% or more of GH-influenced growth is due to the direct effects of GH on growing bone.
The collective experience of treating the rare conditions in which responsiveness to GH is severely impaired includes approximately 150 individuals, mostly with GHRD, and fewer than 10% with GH inactivating antibodies. The growth velocity increment in the first year was 4.3 cm in the European and mecasermin (Genentech/Tercica) study populations, and 5.6 cm in the Ecuadorian population, all groups receiving comparable doses of rhIGF-I administered twice daily. In the Israeli population given a single injection of a comparable total daily dose, the increment was only 3.6 cm.
Height SDS improvement in the first year of treatment paralleled these increments at 0.7, 0.8, and 0.6 for the twice daily rhIGF-I in the European, Ecuadorian, and International-mecasermin groups, respectively, and 0.2 for the Israeli population. The stimulatory effect on growth wanes rapidly after the first year, with only modest continued improvement. Among 76 patients treated for a mean 4.4 years, overall height SDS improvement was 1.4.
In a three-year study comparing 80 µg/kg rhIGF-I twice daily in 7 subjects to 120 µg/kg twice daily in 14 subjects, no differences in height velocity were seen, but osseous maturation increased choices rapidly in the higher dose and correlated with the increase in percentage body fat and with adrenal size increase. Thus, the commonly used dosage of 120 µg/kg twice daily was considered excessive, disproportionately accelerating osseous maturation probably from the combined effects greater accumulation of body fat and inappropriate adrenal growth, compromising adult height potential.
That growth failure due to GH insensitivity cannot be corrected with endocrine IGF-I replacement is not explained by concomitant IGFBP3 deficiency. Substantial tissue delivery is reflected in profound effects on adipose tissue, facies, and lymphoid tissue in treated patients (see below).
Episodes of hypoglycemia, which may be severe, are common in infants and children with GHRD. In contrast to the hypoglycemia of GHD, which is corrected by GH replacement therapy, IGF-I treatment enhances the risk in children with GHRD. Hypoglycemia has been the most common early adverse event, reported in 49% of subjects in the largest series, including 5% with seizures. 
In a 6-month placebo-controlled study, hypoglycemia was reported in 67% of those receiving placebo and 86% of those treated with rhIGF-I, an insignificant difference.  Fingerstick blood glucose measurements in 23 subjects residing on a research unit documented frequent hypoglycemia before breakfast and lunch, which did not increase in frequency with rhIGF-I administration. Five of the subjects participated in a crossover placebo-controlled study for 6 months with a 3-month washout period with fasting glucose determinations done thrice daily by caregivers for the entire 15-month study. The percentage of glucose values < 50 mg/dL was 2.6% on placebo and 5.5% on rhIGF-I—not a significant difference.  In practice, hypoglycemia appears reasonably controllable with adequate food intake.
Pain at the injection site is common. Injection site lipohypertrophy is frequent, affecting at least one third of subjects; this is the result of failure to rotate injections, and injection into the lumps can attenuate growth response.
The inotropic effect of IGF-I results in asymptomatic tachycardia in all treated patients, which clears after several months of continued use.
Benign intracranial hypertension or papilledema has been noted in approximately 5% of IGF-treated subjects. While headache is frequent, the placebo-controlled study found no difference between those receiving placebo injections and those receiving IGF-I.
Parotid swelling and facial nerve palsy have been described.
Lymphoid tissue hypertrophy occurs in upwards of one fourth of patients, with hypoacusis, snoring, and tonsillar/adenoidal hypertrophy that required surgical intervention in more than 10% of patients. Thymic hypertrophy was noted in 35% of subjects having regular chest radiographs. Some of these side effects may be more frequent than reported because they take time to develop; for example, snoring incidence in the first year for the 25 subjects treated longest in the mecasermin study was only 4%, but increased to 65% for the entire period. 
Anti-IGF-I antibodies have developed in approximately half of the patients treated with IGF-I during the first year of treatment, but these have had no effect on response. [40, 46]
Transient elevation of liver enzymes has also been noted.
Anaphylaxis has been reported. 
Coarsening of facial features reminiscent of acromegaly has been noted in many patients, particularly those of pubertal age.
In contrast to the increase in lean body mass and decreasing percentage of body fat that occurs with GH treatment of GHD, both lean and fat mass increase with rhIGF-I therapy, particularly at the higher dosages given. [43, 48] Mean body mass index (BMI) increased from +0.6 SDS to +1.8 SDS during 4-7 years of treatment with rhIGF-I in the European multicenter trial, and severe obesity has occasionally occurred.  BMI measurement may not accurately reflect the degree of obesity, which can be a doubling or tripling of body fat as demonstrated by dual energy x-ray absorptiometry. 
Whether there might be long-term mitogenic effects of extended therapy with rhIGF-I in growing children is not known. The role of IGF-I in carcinogenesis as an anti-apoptotic agent favoring the survival of precancerous cells, increased cancer risk in hypersomatotropic states, and the evidence for aberrant tissue effects in patients treated with rhIGF-I dictate a need for long-term follow-up of these patients. [50, 51]
Peptide growth factors
rhIGF-I is a member of the somatomedin polypeptide hormones. IGF-I mediates the anabolic and growth-promoting effects of GH. Endogenous IGF-I is required for normal intrauterine growth and brain development. This intrauterine IGF-I is not GH dependent. GH dependent IGF-I is also required for normal extra uterine growth, but not brain development. GH stimulation of IGF-I production in liver (endocrine secretion) and peripheral tissues (autocrine/paracrine secretion) accounts for approximately 50% of normal growth. Mecasermin (Increlex) is the only rhIGF-I product available in the United States.
Recombinant human insulinlike growth factor-I (rhIGF-I). Used to treat children with growth hormone insensitivity or resistance due to receptor deficiency (GHRD, Laron syndrome), in whom a GH receptor mutation results in inability to synthesize IGF-I in the liver or peripheral tissues or due to postreceptor genetic defects interfering with IGF-I synthesis and also for children with GH gene deletion who develop blocking antibodies against recombinant GH. Increlex has not been studied in children younger than 2 y.
Rosenbloom AL. The physiology of human growth: a review. Reviews in Endocrinology. July 2008. 36-48:
Rosenbloom AL. Recombinant insulin growth factor I in growth therapy. Preedy VR (ed). Handbook of Growth and Growth Monitoring in Health and Disease Springer. New York: Verlag; 2012 p. 2743-2762.
Woods KA, Camacho-Hübner C, Savage MO, Clark AJ. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med. 1996 Oct 31. 335(18):1363-7. [Medline].
Walenkamp MJ, Karperien M, Pereira AM, et al. Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation. J Clin Endocrinol Metab. 2005 May. 90(5):2855-64. [Medline].
Bonapace G, Concolino D, Formicola S, Strisciuglio P. A novel mutation in a patient with insulin-like growth factor 1(IGF1) deficiency. J Med Genet. 2003. 40:913–7.
Netchine I, Azzi S, Houang M, Seurin D, Perin L, Ricort JM. Partial primary deficiency of insulin-like growth factor (IGF)-I activity associated with IGF1 mutation demonstrates its critical role in growth and brain development. J Clin Endocrinol Metab. 2009 Oct. 94(10):3913-21. [Medline].
Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, et al. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med. 2003 Dec 4. 349(23):2211-22. [Medline].
Rosenbloom AL, Guevara-Aguirre J, Rosenfeld RG, Francke U. Growth hormone receptor deficiency in Ecuador. J Clin Endocrinol Metab. 1999 Dec. 84(12):4436-43. [Medline].
Laron Z, Kopchick JJ. History of Israeli cohort of Laron syndrome patients (1958-2009). Laron syndrome-from Man to Mouse. Berlin-Heidelberg: Springer-Verlag; 2011. 3-7.
Kranzler JH, Rosenbloom AL, Martinez V, Guevara-Aguirre J. Normal intelligence with severe insulin-like growth factor I deficiency due to growth hormone receptor deficiency: a controlled study in a genetically homogeneous population. J Clin Endocrinol Metab. 1998 Jun. 83(6):1953-8. [Medline].
Nadeau K, Hwa V, Rosenfeld RG. STAT5b deficiency: an unsuspected cause of growth failure, immunodeficiency, and severe pulmonary disease. J Pediatr. 2011 May. 158(5):701-8. [Medline].
Gonçalves FT, Fridman C, Pinto EM, Guevara-Aguirre J, Shevah O, Rosembloom AL, et al. The E180Splice mutation in the GHR gene causing Laron Syndrome: Witness of a Sephardic Jewish exodus from the Iberian Peninsula to the New World?. Am J Med Genet. 2014. Part A 9999:1-5. [Medline].
Domene HM, Bengolea SV, Martinez AS, Ropelato MG, Pennisi P, Scaglia P, et al. Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene. N Engl J Med. 2004 Feb 5. 350(6):570-7. [Medline].
Hwa V, Haeusler G, Pratt KL, Little BM, Frisch H, Koller D, et al. Total absence of functional acid labile subunit, resulting in severe insulin-like growth factor deficiency and moderate growth failure. J Clin Endocrinol Metab. 2006 May. 91(5):1826-31. [Medline].
Domene HM, Scaglia PA, Lteif A, Mahmud FH, Kirmani S, Frystyk J, et al. Phenotypic effects of null and haploinsufficiency of acid-labile subunit in a family with two novel IGFALS gene mutations. J Clin Endocrinol Metab. 2007 Nov. 92(11):4444-50. [Medline].
Heath KE, Argente J, Barrios V, Pozo J, Díaz-González F, Martos-Moreno GA, et al. Primary acid-labile subunit deficiency due to recessive IGFALS mutations results in postnatal growth deficit associated with low circulating insulin growth factor (IGF)-I, IGF binding protein-3 levels, and hyperinsulinemia. J Clin Endocrinol Metab. 2008 May. 93(5):1616-24. [Medline].
van Duyvenvoorde HA, Kempers MJ, Twickler TB, van Doorn J, Gerver WJ, Noordam C, et al. Homozygous and heterozygous expression of a novel mutation of the acid-labile subunit. Eur J Endocrinol. 2008 Aug. 159(2):113-20. [Medline].
Fofanova-Gambetti OV, Hwa V, Kirsch S, Pihoker C, Chiu HK, Högler W, et al. Three novel IGFALS gene mutations resulting in total ALS and severe circulating IGF-I/IGFBP-3 deficiency in children of different ethnic origins. Horm Res. 2009. 71(2):100-10. [Medline].
Fofanova-Gambetti OV, Hwa V, Wit JM, Domene HM, Argente J, Bang P. Impact of heterozygosity for acid-labile subunit (IGFALS) gene mutations on stature: results from the international acid-labile subunit consortium. J Clin Endocrinol Metab. 2010 Sep. 95(9):4184-91. [Medline].
Kawashima Y, Kanzaki S, Yang F, Kinoshita T, Hanaki K, Nagaishi J, et al. Mutation at cleavage site of insulin-like growth factor receptor in a short-stature child born with intrauterine growth retardation. J Clin Endocrinol Metab. 2005 Aug. 90(8):4679-87. [Medline].
Walenkamp MJ, van der Kamp HJ, Pereira AM, Kant SG, van Duyvenvoorde HA, Kruithof MF, et al. A variable degree of intrauterine and postnatal growth retardation in a family with a missense mutation in the insulin-like growth factor I receptor. J Clin Endocrinol Metab. 2006 Aug. 91(8):3062-70. [Medline].
Inagaki K, Tiulpakov A, Rubtsov P, Sverdlova P, Peterkova V, Yakar S, et al. A familial insulin-like growth factor-I receptor mutant leads to short stature: clinical and biochemical characterization. J Clin Endocrinol Metab. 2007 Apr. 92(4):1542-8. [Medline].
Walenkamp MJ, de Muinck Keizer-Schrama SM, de Mos M, Kalf ME, van Duyvenvoorde HA, Boot AM, et al. Successful long-term growth hormone therapy in a girl with haploinsufficiency of the insulin-like growth factor-I receptor due to a terminal 15q26.2->qter deletion detected by multiplex ligation probe amplification. J Clin Endocrinol Metab. 2008 Jun. 93(6):2421-5. [Medline].
Fang P, Schwartz ID, Johnson BD, Derr MA, Roberts CT Jr, Hwa V, et al. Familial short stature caused by haploinsufficiency of the insulin-like growth factor i receptor due to nonsense-mediated messenger ribonucleic acid decay. J Clin Endocrinol Metab. 2009 May. 94(5):1740-7. [Medline].
Kruis T, Klammt J, Galli-Tsinopoulou A, Wallborn T, Schlicke M, Müller E. Heterozygous mutation within a kinase-conserved motif of the insulin-like growth factor I receptor causes intrauterine and postnatal growth retardation. J Clin Endocrinol Metab. 2010 Mar. 95(3):1137-42. [Medline].
Wallborn T, Wuller S, Klammt J, Kruis T, Kratzsch J, Schmidt G. A heterozygous mutation of the insulin-like growth factor-I receptor causes retention of the nascent protein in the endoplasmic reticulum and results in intrauterine and postnatal growth retardation. J Clin Endocrinol Metab. 2010 May. 95(5):2316-24. [Medline].
Choi JH, Kang M, Kim GH, Hong M, Jin HY, Lee BH, et al. Clinical and functional characteristics of a novel heterozygous mutation of the IGF1R gene and IGF1R haploinsufficiency due to terminal 15q26.2->qter deletion in patients with intrauterine growth retardation and postnatal catch-up growth failure. J Clin Endocrinol Metab. 2011 Jan. 96(1):E130-4. [Medline].
Fang P, Cho YH, Derr MA, Rosenfeld RG, Hwa V, Cowell CT. Severe short stature caused by novel compound heterozygous mutations of the insulin-like growth factor 1 receptor (IGF1R). J Clin Endocrinol Metab. 2012 Feb. 97(2):E243-7. [Medline].
Mohn A, Marcovecchio ML, de Giorgis T, Pfaeffle R, Chiarelli F, Kiess W. An insulin-like growth factor-I receptor defect associated with short stature and impaired carbohydrate homeostasis in an Italian pedigree. Horm Res Paediatr. 2011. 76(2):136-43. [Medline].
Kawashima Y, Higaki K, Fukushima T, Hakuno F, Nagaishi J, Hanaki K. Novel missense mutation in the IGF-I receptor L2 domain results in intrauterine and postnatal growth retardation. Clin Endocrinol (Oxf). 2012 Aug. 77(2):246-54. [Medline].
Laron Z, Pertzelan A, Mannheimer S. Genetic pituitary dwarfism with high serum concentation of growth hormone--a new inborn error of metabolism?. Isr J Med Sci. 1966 Mar-Apr. 2(2):152-5. [Medline].
Guevara-Aguirre J, Rosenbloom AL, Fielder PJ, Diamond FB Jr, Rosenfeld RG. Growth hormone receptor deficiency in Ecuador: clinical and biochemical phenotype in two populations. J Clin Endocrinol Metab. 1993 Feb. 76(2):417-23. [Medline].
Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW, et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. 2011 Feb 16. 3(70):70ra13. [Medline]. [Full Text].
Gannage-Yared MH, Klammt J, Chouery E, Corbani S, Mégarbané H, Abou Ghoch J. Homozygous mutation of the IGF1 receptor gene in a patient with severe pre- and postnatal growth failure and congenital malformations. Eur J Endocrinol. 2013 Jan. 168(1):K1-7. [Medline].
Rosenbloom AL, Guevara-Aguirre J. Lessons from the genetics of laron syndrome. Trends Endocrinol Metab. 1998 Sep. 9(7):276-83. [Medline].
Ayling RM, Ross R, Towner P, Von Laue S, Finidori J, Moutoussamy S, et al. A dominant-negative mutation of the growth hormone receptor causes familial short stature. Nat Genet. 1997 May. 16(1):13-4. [Medline].
Iida K, Takahashi Y, Kaji H, Nose O, Okimura Y, Abe H, et al. Growth hormone (GH) insensitivity syndrome with high serum GH-binding protein levels caused by a heterozygous splice site mutation of the GH receptor gene producing a lack of intracellular domain. J Clin Endocrinol Metab. 1998 Feb. 83(2):531-7. [Medline].
Metherell LA, Akker SA, Munroe PB, Rose SJ, Caulfield M, Savage MO, et al. Pseudoexon activation as a novel mechanism for disease resulting in atypical growth-hormone insensitivity. Am J Hum Genet. 2001 Sep. 69(3):641-6. [Medline]. [Full Text].
Crosnier H, Gourmelen M, Prévot C, Rappaport R. Effects of nutrient intake on growth, insulin-like growth factors, and their binding proteins in a Laron-type dwarf. J Clin Endocrinol Metab. 1993 Jan. 76(1):248-50. [Medline].
Guevara-Aguirre J, Vasconez O, Martinez V, Martinez AL, Rosenbloom AL, Diamond FB Jr, et al. A randomized, double blind, placebo-controlled trial on safety and efficacy of recombinant human insulin-like growth factor-I in children with growth hormone receptor deficiency. J Clin Endocrinol Metab. 1995 Apr. 80(4):1393-8. [Medline].
Rosenbloom AL. Mecasermin (recombinant human insulin-like growth factor I). Adv Ther. 2009 Jan. 26(1):40-54. [Medline].
Ekstrom K, Carlsson-Skwirut C, Ritzen EM, Bang P. Insulin-like growth factor-I and insulin-like growth factor binding protein-3 cotreatment versus insulin-like growth factor-I alone in two brothers with growth hormone insensitivity syndrome: effects on insulin sensitivity, body composition and linear growth. Horm Res Paediatr. 2011. 76(5):355-66. [Medline].
Guevara-Aguirre J, Rosenbloom AL, Vasconez O, Martinez V, Gargosky SE, Allen L, et al. Two-year treatment of growth hormone (GH) receptor deficiency with recombinant insulin-like growth factor I in 22 children: comparison of two dosage levels and to GH-treated GH deficiency. J Clin Endocrinol Metab. 1997 Feb. 82(2):629-33. [Medline].
Daughaday WH, Rotwein P. Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev. 1989 Feb. 10(1):68-91. [Medline].
Ranke MB, Savage MO, Chatelain PG, Preece MA, Rosenfeld RG, Wilton P. Long-term treatment of growth hormone insensitivity syndrome with IGF-I. Results of the European Multicentre Study. The Working Group on Growth Hormone Insensitivity Syndromes. Horm Res. 1999. 51(3):128-34. [Medline].
Chernausek SD, Backeljauw PF, Frane J, Kuntze J, Underwood LE. Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity. J Clin Endocrinol Metab. 2007 Mar. 92(3):902-10. [Medline].
Klinger B, Laron Z. Three year IGF-I treatment of children with Laron syndrome. J Pediatr Endocrinol Metab. 1995 Jul-Sep. 8(3):149-58. [Medline].
Guevara-Aguirre J, Rosenbloom AL, Guevara-Aguirre M, Saavedra J, Procel P. Recommended IGF-I dosage causes greater fat accumulation and osseous maturation than lower dosage and may compromise long-term growth effects. J Clin Endocrinol Metab. 2013 Feb. 98(2):839-45. [Medline].
Rosenbloom AL, Rivkees SA. Off-label use of recombinant igf-I to promote growth: is it appropriate?. J Clin Endocrinol Metab. 2010 Feb. 95(2):505-8. [Medline].
Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev. 2007 Feb. 28(1):20-47. [Medline].
Perry JK, Emerald BS, Mertani HC, Lobie PE. The oncogenic potential of growth hormone. Growth Horm IGF Res. 2006 Oct-Dec. 16(5-6):277-89. [Medline].
Guevara Aguirre J, Rosenbloom AL, Balasubramaniam P, Teran E, Guevara Aguirre M, Guevara C, et al. Absent GH counterregulation due to GH receptor deficiency with obesity and enhanced insulin sensitivity. Guevara Aguirre J, Rosenbloom AL, Balasubramaniam P, Teran E, Guevara Aguirre M, Guevara C, Procel P, Alfaras I, De Cabo R, Di Biase S, Narvaez L, Saavedra, J, Longo VD. 2015. 100:2589-2596.
Rosenbloom AL. Genetic disorders of the hypothalamic-pituitary-GH/IGF-I axis. Preedy VR, ed. Handbook of Growth and Growth Monitoring in Health and Disease. New York: Springer-Verlag; 2012. 2723-41.
|Condition||Growth failure||GH||GH binding protein||IGF-I||IGFBP3|
|GHRD - Recessive forms||Severe||Elevated||Absent-low*||Very low||Very low|
|GHRD - Dominant negative forms||Mild-moderate||Elevated||Increased||Very low||Low-normal|
|STAT5b mutation||Severe||Elevated||Normal||Very low||Very low|
|ALS mutation||None-moderate||Normal||Normal||Very low||Very low|
|IGF-I gene mutation||Severe||Elevated||Normal||Absent-high**||Low-normal|
|IGF-I receptor mutation||Mild-moderate||Normal-elevated||Normal||Normal-elevated||Normal-elevated|
|GH inhibiting antibodies||Severe||Absent||Normal||Very low||Low|
|*Increased in mutations of or near the transmembrane domain of the GH receptor**Absent with partial IGF1 gene deletion; very high with abnormal IGF-I|