This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Backeljauw, P. F. Articles by Underwood, L. E. Search for Related Content PubMed PubMed Citation Articles by Backeljauw, P. F. Articles by Underwood, L. E. Pubmed/NCBI databases OMIM Substance via MeSH

Therapy for 6.5–7.5 Years with Recombinant Insulin-Like Growth Factor I in Children with Growth Hormone Insensitivity Syndrome: A Clinical Research Center Study¹

Department of Pediatrics (L.E.U.), Division of Endocrinology, University of North Carolina, Chapel Hill, North Carolina 27599; and Children’s Hospital Medical Center (P.F.B.), Cincinnati, Ohio 45229

Address all correspondence and requests for reprints to: Philippe F. Backeljauw, Division of Pediatric Endocrinology, Department of Pediatrics, Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Eight children with GH insensitivity syndrome were treated with recombinant human insulin-like growth factor I (IGF-I) (80–120 µg/kg sc twice daily) for 6.5–7.5 yr. We previously reported that height velocity (HV) improved with treatment (from mean pretreatment HV of 4.0 cm/yr), to 9.3 cm/yr for the first year and 6.2 cm/yr for the second year. HV remained slightly below this during the subsequent years (mean HV: 5.4, 5.5, 5.2, and 4.8 cm/yr during years 3–6). Mean height SD score before therapy was -5.6; and it improved to -4.5, -4.4, and -4.2 after 2, 4, and 6 yr of therapy, respectively. Treatment was accompanied by gain in body weight and fat. Bone age advanced normally in the prepubertal patients, but it advanced more rapidly during the latter years of treatment in those patients undergoing pubertal changes. The growth of spleen and kidneys (determined by ultrasound) was rapid in the first 2–3 yr of therapy. More age- appropriate growth ensued, but six patients had a renal length for height more than 2 SD above the mean at 6–7 yr of treatment. No major adverse changes in biochemical profile were observed. IGF-I-related hypoglycemia occurred early in treatment with the younger patients, but this problem abated as treatment was continued. IGF-I therapy is effective in promoting statural growth in GH insensitivity syndrome patients, but the growth response is neither as intense nor as well-sustained as the growth response to GH among children with GH deficiency.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
GH INSENSITIVITY SYNDROME (GHIS) encompasses a variety of genetic and acquired conditions in which the action of GH is absent or attenuated (1, 2). Primary GHIS, also known as Laron syndrome, is a hereditary defect involving impaired GH receptor function (3). Affected patients present with growth failure, physical characteristics of severe GH deficiency (4), and low serum concentrations of insulin-like growth factor I (IGF-I) despite high serum GH concentrations (5). One form of secondary or acquired GHIS occurs when children with GH deficiency caused by a deletion in the GH gene develop antibodies to GH during treatment, resulting in an attenuated growth response. Because IGF-I is believed to be a major mediator of the growth-promoting actions of GH (6), replacement therapy of GHIS patients with IGF-I should bypass the blockade of GH action and improve statural growth.

We, with other investigators (7, 8, 9, 10), have reported on the considerable improvement in growth of children with GHIS produced by IGF-I during the first year of treatment. In addition, reports have been made on the effect of continued therapy, usually for 2–3 yr (11, 12, 13, 14, 15, 16, 17). We now present results of prolonged (6.5–7.5 yr) treatment of eight children with GHIS with recombinant human IGF-I.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Eight prepubertal children with GHIS (age 2–11 yr at the beginning of therapy) were treated with IGF-I for 6.5–7.5 yr (Table 1). The experimental protocol was approved by the University of North Carolina Committee for the Protection of the Rights of Human Subjects. Informed consent was obtained from the parents and, when applicable, from the patients. To be included in the study, the patients had to be more than 2 yr old, have open epiphyses, have a height more than 2 SD below the mean for age, have a height velocity (HV) below the 50th percentile for at least 1 yr before treatment, and have documented GHIS. For patients with primary GHIS (Laron syndrome; n = 5), basal serum GH exceeded 5 ng/mL and increased further after provocative testing; serum IGF-I was more than 2 SD below the mean for age and did not increase after injection of GH (0.1 mg/kg daily for 4 days). The three patients with acquired GHIS had deletion of the GH gene and had been treated with GH previously. Each patient developed antibodies to GH, with serum GH-binding capacities exceeding 10 µg/mL. Patient 4 had a poor response to GH from the beginning of therapy. Patients 5 and 6 showed initial acceleration of growth, but this was attenuated by antibodies to GH after 1 and 2 yr of therapy, respectively.

The patients were followed monthly during the first year of therapy, bimonthly during the second year, every 3 months for years 3 and 4, and every 6 months thereafter. The initial encounters were accomplished alternatively by the collaborating pediatric endocrinologists and the principal investigators. The height measurements reported here were obtained by the investigators at The University of North Carolina using a wall-mounted stadiometer. Body mass index (BMI) was calculated (weight/height in m²). Weight relative to height was also expressed as weight-for-height index (WHI), or the patient’s weight calculated as a percentage of the median weight in the normal population for an individual of the same height (18). Before IGF-I therapy was begun, during the initial hospitalization, subsequently at 6 and 12 months, and yearly thereafter, morning fasting blood was obtained for complete blood count, glucose, urea nitrogen, creatinine, electrolytes, calcium, phosphorus, total protein, T₄, TSH, alkaline phosphatase, and liver enzymes. During the first 4–5 yr of therapy, blood was also obtained for IGF-I, IGF-binding protein (IGFBP)-2, IGFBP-3, serum lipid panel, glycosylated hemoglobin, and 1, 25-dihydroxyvitamin D. Spot urine samples were obtained for determination of calcium/creatinine ratio. Before therapy, after 6 and 12 months, and yearly thereafter, body fat and lumbar spine bone mineral density (BMD) were estimated by dual-energy x-ray absorptiometry (DXA, QDR-1000; Hologic, Inc., Waltham, MA). Radiographs were made of the left hand and wrist for assessment of skeletal age, based on a consensus of the authors’ separate interpretation according to the standards of Greulich and Pyle (19). Before therapy, after 6 and 12 months, and every year of IGF-I treatment thereafter, measurements of kidney and spleen length were obtained by ultrasonography. Echocardiography was performed on a yearly basis, after 2 yr of therapy, using a Sonos 1500 cardiac ultrasound machine (Hewlett-Packard Co., Andover, MA).

Complete blood count, glucose, electrolytes, urea nitrogen, creatinine, calcium, phosphorus, liver enzymes, T₄, TSH, lipids, and glycosylated hemoglobin were measured using standard automated techniques and determined in a central facility. Serum concentrations of IGF-I were measured by RIA after IGFBPs were removed by C₁₈ Sep-Pak extraction (Waters Associates, Milford, MA) as previously described (20, 21). 1,25-Dihydroxyvitamin D and serum GH were measured by RIA from kits (Quest Diagnostics, Inc., San Juan Capistrano, CA).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Effects of IGF-I treatment on growth and body composition

Before IGF-I therapy, height SD scores ranged between -3.4 to -7.0 (mean, -5.6) (13), mean HV (observed for 1 yr) was 4.0 cm/yr, and the mean HV SD score was -2.4 (range, -0.3 to -4.3) (Fig. 1, Table 1). As reported previously, the mean HV was 9.3 cm/yr (mean HV SD score, +3.8; Fig. 1A) during the first year of IGF-I therapy and 6.2 cm/yr (mean HV SD score, +0.5) during the second year. Mean HV SD scores during the third to sixth years of therapy were -0.8, -0.8, and -0.4, but improved during the sixth to seventh year to +1.6. There was, however, significant variation among patients (range, -1.8 to +6.6). The average change in height SD score ( SD score) after 6–7 yr of therapy was +1.4 (range, -1.2 to +4.0; Fig. 1B and Table 1). Height for chronological age at the beginning of IGF-I therapy and growth responses during therapy are compared with standards for normal children in Fig. 2.

View larger version (73K): [in this window] [in a new window]   Figure 1. A, Pretreatment (Pre-Rx) HV (black bars) and on-treatment (On Rx) HV (white bars; one bar for each year) for eight patients with GHIS treated with IGF-I. B, SD score for height in each patient before (black) and after (white) 2 yr, 4 yr, and 6–7 yr of IGF-I therapy. Patients 5–7 have proceeded through puberty, have bone ages more than 13.5 yr (two girls; patients 5 and 6) or more than 15 yr (boy; patient 7), and have had therapy discontinued. The height SD score, therefore, is near their adult height score.

View larger version (130K): [in this window] [in a new window]   Figure 2. Individual growth during IGF-I therapy for eight patients with GHIS, compared with the National Center for Health Statistics standards (36 ). Boys are depicted on the left, girls on the right. Each numbered height or weight curve corresponds to the individual subjects as listed in Table 1.

Mean head circumference was -2.6 SD score at baseline. This increased to -1.6 SD (range, -0.2 to -2.6), -1.4 SD (range, +0.4 to -2.6), and -0.9 SD (range, -2.9 to +1.3), after 2, 4, and 6–7 yr, respectively (Table 1).

Skeletal age increased in proportion to chronological age before puberty (Fig. 3). In the four patients who had the onset of puberty during the last 3 yr of treatment, however, the skeleton matured more rapidly (at a mean rate of 1.4 yr per year of therapy).

View larger version (20K): [in this window] [in a new window]   Figure 3. Change in bone age (BA) vs. change in chronological age (CA) for eight patients with GHIS during 6.5–7.5 yr of treatment with IGF-I. The heavy line at approximately 45 degrees depicts equal progression in BA and CA. *, Patients who have stopped treatment.

View larger version (21K): [in this window] [in a new window]   Figure 4. Changes in areal BMD of the lumbar spine in eight patients with GHIS treated with IGF-I for 6.5–7.5 yr. BMD was measured by DXA. Age-related standards (mean ± 2 SD) are derived from data for normal children, as reported by Glastre et al. (37 ).

At baseline, spleen length was below the 10th percentile for age in seven of eight patients. Each patient experienced rapid spleen growth in the first 1–2 yr of therapy (Fig. 5), but this normalized during the last 3–4 yr.

View larger version (21K): [in this window] [in a new window]   Figure 5. Change in size of the spleen in eight patients with GHIS during 6.5–7.5 yr of treatment with IGF-I. Spleen length was measured by ultrasound. The 10th, 50th, and 90th percentile age standards for spleen length are based on sonographic measurements in normal children reported by Kotlus Rosenberg et al. (38 ).

Effects on kidneys and heart

Before IGF-I therapy, kidney length was below the 50th percentile for height in seven of eight patients. Renal size increased rapidly during the first 4 yr of therapy. Five patients achieved a renal length for height at or above the 95th percentile. Renal growth during the last 2 yr of treatment slowed for each patient, but at 6–7 yr of therapy, renal length was above the 95th percentile in six patients (Fig. 6). Less pronounced effects are seen when renal length is plotted against age (data not shown). No structural abnormalities of the kidneys were noted by ultrasound. Creatinine clearance was normal after 4–5 yr of treatment (87–120 mL/min·1.73 m²) and did not change significantly thereafter.

View larger version (18K): [in this window] [in a new window]   Figure 6. Changes in renal length vs. height in eight patients with GHIS treated with IGF-I for 6.5–7.5 yr. Renal length was measured by ultrasound. The mean ± 2 SD values for normal children are based on data reported by Han and Babcock (39 ).

Effects on facial growth

IGF-I therapy caused overgrowth of the soft tissues of the face, leading to a prominent glabella and thickening of the eyebrows, nasal tip, philtrum, and lips. These changes were most prominent in those patients experiencing puberty. In the one patient observed for 14 months after IGF-I therapy was discontinued, considerable reversion of the soft tissue overgrowth was noted (Fig. 7). Observations on the facial bone growth have been made for the five oldest patients during 4 yr of therapy (22), and long-term results of cephalometric analysis will be reported subsequently.

View larger version (83K): [in this window] [in a new window]   Figure 7. Effect of 7.5 yr of treatment with IGF-I on facial maturation and soft tissue growth in one patient with GHIS. From left to right, Photograph taken at the start of therapy, at the end of therapy, and 14 months after completing therapy with IGF-I. Note regression of thickened/coarsened features after treatment was stopped.

Before treatment, several patients had fasting glucose values in the hypoglycemic range (1.7–2.8 mmol/L). In the six older patients, fasting glycemia and glucose values after meals did not change with treatment. For the two youngest patients, the preexisting tendency toward hypoglycemia required temporary reduction of the doses of IGF-I. Baseline serum total cholesterol values were also normal, except for mild elevations in patients 7 and 8. There were no major changes with therapy; however, five patients had borderline-high or high cholesterol concentrations (range, 5.0–5.9 mmol/L). As observed during the first 2 yr of therapy (13), no consistent effects of IGF-I therapy during years 3–6 (or 7) were observed on white cell blood count, red cell indexes, platelets, reticulocytes, total serum protein, albumin, calcium, phosphorus, lactate dehydrogenase, uric acid, alanine and aspartate and aminotransferase (mild elevations of the liver enzymes were noted in the GH-deletion patients), serum electrolytes, T₄, or TSH. Alkaline phosphatase concentrations were relatively low for chronological age, especially in the youngest patients. 1, 25-Dihydroxyvitamin D concentrations were in the normal range before and during treatment.

Adverse events during IGF-I therapy

Lipohypertrophy at the injection sites occurred in five patients. This resolved when the injections were dispersed properly. The problem of lipohypertrophy was greatest in the three patients who exhibited the poorest overall growth response. The hypoglycemia, more frequent and more pronounced in the younger children early in treatment, led to a brief hypoglycemic seizure in one patient.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We observe that treatment with IGF-I improves growth of children with GHIS over a 6.5–7.5-yr period and that IGF-I is reasonably well tolerated. This confirms our earlier report on shorter-duration results (13) and observations by others (8, 9, 10, 12, 16).

Compared with GH treatment of GH-deficient children, catch-up growth is less impressive among GHIS children treated with IGF-I. This supports the dual-effector hypothesis of GH action (23), which proposes that GH promotes growth by expanding populations of precursor cells directly, then by stimulating the production of IGF-I, which in turn facilitates growth of the precursor cell progeny. Contributing factors to lower growth rates in GHIS patients likely involve the aberrations of IGFBPs associated with this condition and the failure of IGF-I therapy to normalize the IGFBP milieu. For example, we, as well as others, observed no increase of the already low IGFBP-3 concentrations with treatment (10, 12, 13, 24). Also, GHIS patients may have inadequate tissue concentrations of IGF-I, despite the high serum concentrations produced by treatment. In studies with transgenic mice with a liver-exclusive IGF-I gene deletion, a 75% reduction of serum IGF-I was achieved (25). Despite this, postnatal growth was normal, leading to the conclusion that, although liver IGF-I production is a major source of circulating IGF-I, it is not essential for growth (26). Therefore, IGF-I produced locally may be more important for the growth promoting properties of GH. The improvement in growth in these GHIS patients may be related to the achievement of high serum concentrations of IGF-I after each SC injection, coupled with the persistence of low serum concentrations of IGFBP-3 during therapy. The latter likely contributes further to an abundance of free IGF-I in serum, which then compensates partly for decreased tissue IGF-I. GHIS patients also have low concentrations of acid-labile subunit (ALS) (24), resulting in failure to form the larger molecular weight serum IGFBP-3/IGF-I/ALS complex. This deficit is not corrected by IGF-I therapy because ALS is GH-dependent but not IGF-I dependent (27). One could argue that injection of IGF-I, combined with recombinant IGFBP-3, might lead to more stable availability of IGF-I at the tissue level, resulting in a better growth-promoting effect.

Our findings confirm a gain in fat mass, reported elsewhere (15). This may be the result of exposure of fat tissue to transient, postinjection excess of IGF-I, with stimulation of fat cell growth via the insulin receptor (28). IGF-I, given therapeutically, seems not to produce balanced tissue growth: spleen enlargement has been observed after administration of IGF-I to rats (29), and our patients initially had rapid growth of their spleen and nasopharyngeal lymphoid tissues. More moderate growth, appropriate for chronological age, during the remaining years of treatment, may indicate that this initial rapid growth is mainly a catch-up phenomenon. A similar growth pattern is observed for the kidneys. Observation during more prolonged treatment will be needed to determine whether this represents specific organ overgrowth.

We observed ongoing maturation of the appearance of each patient’s face during IGF-I treatment. The thickening of the eyebrows, alae nasae, and lips could be interpreted as consistent with acromegaloid growth. Although we consider these changes significant in several of our patients, it is conceivable that these represent exaggerated pubertal maturational changes, now occurring during a shortened time period. Four of our patients entered puberty at a normal age, whereas pubertal development is usually delayed in untreated GHIS (30). This strengthens the notion that IGF-I, and GH indirectly, is involved in normal puberty development. The effect of IGF-I in augmenting gonadal maturation and function in patients with GHIS has been reported (31, 32), and it is known that the duration of puberty in GH-deficient patients is significantly shortened by GH treatment (33). Entry of our patients into puberty during IGF-I therapy was followed by a disproportionate acceleration of their skeletal maturation, which until then had progressed normally. This observation supports the hypothesis that IGF-I enhances gonadotropin-dependent gonadal function (34, 35), and works synergistically with the gonadotropins to assure normal progression through puberty, once the hypothalamic-pituitary-axis has been activated.

With IGF-I therapy, we observed a normal increase in BMD, as expected with aging and growth. Treatment did not result in a sustained catch-up in BMD, but the changes noted were likely more positive than those that would have occurred without treatment.

In conclusion, treatment of children with GHIS with recombinant human IGF-I promotes statural growth. The magnitude of benefit, in this regard, is considerably less than that observed with GH therapy of GH-deficient children. Excessive increase of fat mass and overgrowth of specific organs (such as lymphatic tissues, facial bones, and potentially kidneys) may represent undesirable adverse effects.

	Footnotes

 
¹ Supported by NIH Training Grant DK-07129 and a gift from Genentech, Inc. (South San Francisco, CA). The Clinical Research Center of the University of North Carolina is supported by Grant RR-00046 from the General Clinical Research Centers Program, Division of Research Resources, NIH.

² The Growth Hormone Insensitivity Syndrome (GHIS) Collaborative Group consists of Drs. M. Miras (Cordoba, Argentina), M. C. Arriazu (Mar del Plata, Argentina), J. Heinrich (Buenos Aires, Argentina), L. Ghizzoni (Parma, Italy), S. Blethen (Genentech, Inc.), D. Donaldson (Salt Lake City, UT), W. Cleveland (Miami, FL), and V. Duncan (Chapel Hill, NC).

Received October 9, 2000.

Revised December 27, 2000.

Accepted January 4, 2001.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Rosenfeld RG, Rosenbloom AL, Guevara-Aguirre J. 1994 Growth hormone (GH) insensitivity due to primary GH receptor deficiency. Endocr Rev. 15:369–390.[Abstract/Free Full Text]
2. Rosenbloom AL, Rosenfeld RG, Guevara-Aguirre J. 1997 Growth hormone insensitivity. Pediatr Clin North Am. 44:423–442.[CrossRef][Medline]
3. Laron Z. 1999 Laron syndrome: primary growth hormone resistance. In: Jameson JL, ed. Contemporary endocrinology, hormone resistance syndromes. Totowa, NJ: Humana Press; 17–37.
4. Rosenbloom AL, Guevara-Aguirre J, Rosenfeld RG, Francke U. 1999 Growth hormone receptor deficiency in Ecuador. J Clin Endocrinol Metab. 84:4436–4443.[Free Full Text]
5. Savage MO, Blum WF, Rank MB, et al. 1993 Clinical features and endocrine status in patients with growth hormone insensitivity (Laron syndrome). J Clin Endocrinol Metab. 77:1465–1469.[Abstract]
6. Van Wyk JJ. 1984 The somatomedins: biological actions and physiological control mechanisms. In: Li CH, ed. Hormonal proteins and peptides, vol 12. Orlando, FL: Academic Press; 81–125.
7. Walker JL, Van Wyk JJ, Underwood LE. 1992 Stimulation of statural growth by recombinant insulin-like growth factor I in a child with growth hormone insensitivity syndrome. J Pediatr. 121:641–646.[CrossRef][Medline]
8. Laron Z, Anin S, Klipper-Aurbach Y, Klinger B. 1992 Effects of insulin-like growth factor on linear growth, head circumference and body fat in patients with Laron-type dwarfism. 339:1258–1261.
9. Savage MO, Wilton P, Ranke MB, et al. 1993 Therapeutic response to recombinant IGF-I on thirty-two patients with growth hormone insensitivity [Abstract 17]. Pediatr Res. 33(Suppl):S5.
10. Guevara-Aguirre J, Vasconez O, Martinez V, et al. 1995 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. 80:1393–1398.[Abstract]
11. Klinger B, Laron Z. 1995 Three year IGF-I treatment of children with Laron syndrome. J Pediatr Endocrinol Metab. 8:149–158.[Medline]
12. Ranke MB, Savage MO, Chatelain PG, et al. 1995 Insulin-like growth factor I improves height in growth hormone insensitivity: two years’ results. Horm Res. 44:253–264.[Medline]
13. Backeljauw PF, Underwood LE, the GHIS Collaborative Group. 1996 Prolonged treatment with recombinant insulin-like growth factor-I in children with growth hormone insensitivity syndrome—a Clinical Research Center Study. J Clin Endocrinol Metab. 81:3312–3317.[Abstract]
14. Underwood LE, Backeljauw P, Duncan V, the GHIS Collaborative Group. 1999 Effects of insulin-like growth factor I treatment on statural growth, body composition and phenotype of children with growth hormone insensitivity syndrome. Acta Paediatr Suppl. 428:182–184.
15. Ranke MB, Savage MO, Preece MA, Rosenfeld RG, Wilton P for the Working Group on Growth Hormone Insensitivity Syndromes. 1999 Long-term treatment of growth hormone insensitivity syndrome with IGF-I—results of the European Multicentre Study. Horm Res. 51:128–134.[CrossRef][Medline]
16. Guevara-Aguirre J, Rosenbloom AL, Vasconez O, et al. 1997 Two-year treatment of growth hormone receptor deficiency (GHRD) 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. 82:629–633.[Abstract/Free Full Text]
17. Krzisnik C, Battelino T. 1997 Five-year treatment with IGF-I of a patient with Laron syndrome in Slovenia (a follow-up report). J Pediatr Endocrinol Metab. 10:443–447.[Medline]
18. Cole TJ. 1986 Weight/height compared to weight/height 53 for assessing adiposity in childhood: influence of age during puberty. Ann Hum Biol. 13:433–451.[CrossRef][Medline]
19. Greulich WW, Pyle SI. 1959 Radiographic atlas of skeletal development of the hand and wrist, ed 2. Stanford: Stanford University Press.
20. Copeland KC, Underwood LE, Van Wyk JJ. 1980 Induction of immunoreactive somatomedin C in human serum by growth hormone: dose-response relationships and effect on chromatographic profiles. J Clin Endocrinol Metab. 50:690–697.[Abstract/Free Full Text]
21. Davenport ML, Svoboda ME, Koerber KL, Van Wyk JJ, Clemmons DR, Underwood LE. 1988 Serum concentrations of insulin-like growth factor II are not changed by short term fasting and refeeding. J Clin Endocrinol Metab. 59:228–230.[Abstract/Free Full Text]
22. Backeljauw PF, Kissoondial A, Underwood LE, Simmons KE. 1997 Effects of 4-years treatment with recombinant human insulin-like growth factor-I (rhIGF-I) on craniofacial growth in children with growth hormone insensitivity syndrome (GHIS). Horm Res. 48(Suppl 2):40.
23. Green H, Morikawa M, Nixon T. 1985 A dual effector theory of growth hormone action. Differentiation. 29:195–198.[CrossRef][Medline]
24. Burren CP, Wanek D, Mohan S, Cohen P, Guevara-Aguirre J, Rosenfeld RG. 1999 Serum levels of insulin-like growth factor binding proteins in Ecuadorian children with growth hormone insensitivity. Acta Paediatr Suppl. 428:185–191.
25. Sjögren K, Liu J, Blad K, et al. 1999 Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. Proc Natl Acad Sci USA. 96:7088–7092.[Abstract/Free Full Text]
26. Yakar S, Liu J, Stannard B, et al. 1999 Normal growth and development in the absence of hepatic insulin-like growth factor-I. Proc Natl Acad Sci USA. 96:7324–7329.[Abstract/Free Full Text]
27. Baxter RC. 1988 Characterization of the acid-labile subunit of the growth hormone-dependent insulin-like growth factor binding protein complex. J Clin Endocrinol Metab. 67:265–272.[Abstract/Free Full Text]
28. Zapf J, Schoenle E, Waldvogel M, Sand I, Froesch ER. 1981 Effect of trypsin treatment of rat adipocytes on biological effects and binding of insulin and insulin-like growth factors: further evidence for the action of insulin-like growth factors through the insulin receptor. Eur J Biochem. 113:605–609.[Medline]
29. Guler HP, Zapf J, Scheiwiller E, Froesch ER. 1988 Recombinant human insulin-like growth factor-I stimulates growth and has distinct effects on organ size in hypophysectomized rats. Proc Natl Acad Sci USA. 85:4889–4893.[Abstract/Free Full Text]
30. Rosenbloom AL, Savage MO, Blum WF, Guevara-Aguirre J, Rosenfeld RG. 1992 Clinical and biochemical characteristics of growth hormone receptor deficiency (Laron syndrome). Acta Paediatr Suppl. 383:121–124.[Medline]
31. Klinger B, Anin S, Silbergeld A, Eshet R, Laron Z. 1998 Development of hyperandrogenism during treatment with insulin-like growth factor-I (IGF-I) in female patients with Laron syndrome. Clin Endocrinol (Oxf). 48:81–87.[CrossRef][Medline]
32. Laron Z, Klinger B. 1998 Effect of insulin-like growth factor-I treatment on serum androgens and testicular and penile size in males with Laron syndrome (primary growth hormone resistance). Eur J Endocrinol. 138:176–180.[Abstract]
33. Darendeliler F, Hindmarsh PC, Preece MA, Cox L, Brook CGD. 1990 Growth hormone increases rate of pubertal maturation. Acta Endocrinol (Copenh). 122:414–416.[Abstract/Free Full Text]
34. Mauras N, Rogol AD, Haymond MW, Veldhuis JD. 1996 Sex steroids, growth hormone, insulin-like growth factor-I: neuroendocrine and metabolic regulation in puberty. Horm Res. 45:74–80.[Medline]
35. Adashi EY, Resnick CE, Hernandez ER, et al. 1988 Insulin-like growth factor-I as an amplifier of follicle-stimulating hormone action: studies on mechanism(s) and site(s) of action in cultured rat granulosa cells. Endocrinology. 122:1583–1591.[Abstract/Free Full Text]
36. Hamill PVV, Drizd TA, Johnson CL, et al. 1979 Physical growth: National Center for Health Statistics percentiles. Am J Clin Nutr. 32:607–629.[Abstract/Free Full Text]
37. Glastre C, Braillon P, David L, Cochat P, Meurrier PJ, Delmus PD. 1990 Measurement of bone mineral content of the lumbar spine by dual-energy x-ray absorptiometry in normal children: correlations with growth parameters. J Clin Endocrinol Metab. 70:1330–1333.[Abstract/Free Full Text]
38. Kotlus Rosenberg H, Markowitz RI, Kolberg A, Park C, Hubbard A, Bellah RD. 1991 Normal splenic size in infants and children; sonographic measurements. Am J Roentgenol. 157:119–121.[Abstract/Free Full Text]
39. Han BK, Babcock DS. 1985 Sonographic measurements and appearance of normal kidneys in children. Am J Roentgenol. 145:611–616.[Abstract/Free Full Text]

This article has been cited by other articles:

				Y. Wu, H. Sun, S. Yakar, and D. LeRoith Elevated Levels of Insulin-Like Growth Factor (IGF)-I in Serum Rescue the Severe Growth Retardation of IGF-I Null Mice Endocrinology, September 1, 2009; 150(9): 4395 - 4403. [Abstract] [Full Text] [PDF]

				C. Ohlsson, S. Mohan, K. Sjogren, A. Tivesten, J. Isgaard, O. Isaksson, J.-O. Jansson, and J. Svensson The Role of Liver-Derived Insulin-Like Growth Factor-I Endocr. Rev., August 1, 2009; 30(5): 494 - 535. [Abstract] [Full Text] [PDF]

				P. F. Collett-Solberg, M. Misra, and on behalf of the Drug and Therapeutics Committee o The Role of Recombinant Human Insulin-Like Growth Factor-I in Treating Children with Short Stature J. Clin. Endocrinol. Metab., January 1, 2008; 93(1): 10 - 18. [Abstract] [Full Text] [PDF]

				R. G Rosenfeld IGF-I therapy in growth disorders Eur. J. Endocrinol., August 1, 2007; 157(suppl_1): S57 - S60. [Abstract] [Full Text] [PDF]

				S. D. Chernausek, P. F. Backeljauw, J. Frane, J. Kuntze, L. E. Underwood, and for the GH Insensitivity Syndrome Collaborative Gr 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., March 1, 2007; 92(3): 902 - 910. [Abstract] [Full Text] [PDF]

				C. Camacho-Hubner, S. Rose, M. A. Preece, M. Sleevi, H. L. Storr, F. Miraki-Moud, F. Minuto, J. Frystyk, A. Rogol, G. Allan, et al. Pharmacokinetic Studies of Recombinant Human Insulin-Like Growth Factor I (rhIGF-I)/rhIGF-Binding Protein-3 Complex Administered to Patients with Growth Hormone Insensitivity Syndrome J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1246 - 1253. [Abstract] [Full Text] [PDF]

				P. G Voorhoeve, E. F C van Rossum, S. J te Velde, J. W Koper, H. C G Kemper, S. W J Lamberts, and H. A D.-v. de Waal Association between an IGF-I gene polymorphism and body fatness: differences between generations. Eur. J. Endocrinol., March 1, 2006; 154(3): 379 - 388. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, A. D. Rogol, J. C. Lovejoy, M. Sheffield-Moore, N. Mauras, and C. Y. Bowers Endocrine Control of Body Composition in Infancy, Childhood, and Puberty Endocr. Rev., February 1, 2005; 26(1): 114 - 146. [Abstract] [Full Text] [PDF]

				Z. Laron Laron Syndrome (Primary Growth Hormone Resistance or Insensitivity): The Personal Experience 1958-2003 J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1031 - 1044. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Backeljauw, P. F. Articles by Underwood, L. E. Search for Related Content PubMed PubMed Citation Articles by Backeljauw, P. F. Articles by Underwood, L. E. Pubmed/NCBI databases OMIM Substance via MeSH