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 Woods, K. A. Articles by Savage, M. O. Search for Related Content PubMed PubMed Citation Articles by Woods, K. A. Articles by Savage, M. O.

Effects of Insulin-Like Growth Factor I (IGF-I) Therapy on Body Composition and Insulin Resistance in IGF-I Gene Deletion

Paediatric Endocrinology Section (K.A.W., C.C.-H., M.O.S.), Department of Endocrinology, St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom; Department of Physiology and Biophysics (R.N.B.), University of Southern California Medical School, Los Angeles, California; Queen Elizabeth Hospital (D.B.), King’s Lynn, Norfolk, United Kingdom; and Molecular Endocrinology Laboratory (A.J.L.C.), Department of Endocrinology, St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom

Address correspondence and requests for reprints to: Professor M. O. Savage, Paediatric Endocrinology Section, Department of Endocrinology, St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We have recently reported a patient with a homozygous partial deletion of the insulin-like growth factor-I (IGF-I) gene, resulting in IGF-I deficiency, insulin resistance, and short stature. Recombinant human IGF-I (rhIGF-I) therapy has been shown to improve insulin sensitivity (Si) and growth in other causes of IGF-I deficiency. We now report results of 1 yr of rhIGF-I therapy on body composition, bone mineral density (BMD), insulin sensitivity, and linear growth in this patient. rhIGF-I therapy was initiated at age 16.07 yr (bone age, 14.2 yr), at a starting dose of 40 µg/kg daily, increasing after 3 months to 80 µg/kg daily. Body composition, BMD, markers of bone mineralization, and auxological parameters (height, weight) were measured at 0, 6, and 12 months after start of therapy. Si, acute insulin response to glucose, and glucose effectiveness were determined at baseline, 3 months, and 12 months into therapy. On IGF-I therapy, body mass index increased from 17 kg/m² to 18.6 kg/m². Body composition studies (dual-energy x-ray absorbtiometry) revealed an initial decrease in total body fat, from 19.9% at baseline to 15.1% at 6 months; but by 12 months of therapy, this had reversed, with an increase to 21.8%. Si, calculated using Bergman’s minimal model, was substantially reduced at baseline at 1.45 x 10^-4 min^-1 (µU/mL) [normal value, 5.1 x 10^-4 min^-1 (lean adult male)]. rhIGF-I therapy resulted in a dose-related improvement of Si into the normal range (NR) (rhIGF-I dose: 40 µg/kg·day, Si = 2.06 x 10^-4 min^-1; rhIGF-I dose: 80 µg/kg·day, Si = 4.39 x 10^-4 min^-1). Baseline reduction in Si was accompanied by elevated acute insulin response to glucose, which also fell in a dose-dependent manner. Baseline BMD was severely reduced when compared with age-matched controls (-4.88 SD); however, calculation of bone mineral apparent density indicated that the true reduction in BMD was minimal. rhIGF-I therapy increased BMD by 17% and bone mineral apparent density by 7%, indicating that IGF-I has a greater effect on bone growth than bone mineralization. Bone turnover markers also increased on rhIGF-I; mean serum osteocalcin: 8.3 ng/mL pretreatment, 21.7 ng/mL after 6 months of rhIGF-I (NR for adult male, 3.4–9.1 ng/mL); mean bone specific alkaline phosphatase: 36.5 U/L pretreatment, 82.2 U/L after 6 months of therapy (NR for adult male, 15–41). Height velocity increased from 3.8 cm/yr pretreatment to 7.3 cm/yr on 80 µg/kg·day of rhIGF-I.

In this patient with severe insulin resistance, therapy with rhIGF-I resulted in beneficial effects on Si, body composition, bone size, and linear growth. These results have implications for IGF-I therapy in a variety insulin resistant states.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
WE HAVE recently identified a patient with severe insulin-like growth factor-I (IGF-I) deficiency secondary to a homozygous partial deletion of the IGF-I gene, who presented with severe pre- and postnatal growth failure, mental retardation, microcephaly, and sensorineural deafness (1). The physiologic circumstances of this patient, in whom there is elevated GH secretion combined with an intact GH signaling pathway, yet an inability to produce IGF-I either locally or systemically, allow a unique insight into the individual actions of GH and IGF-I and the relationship between GH secretion and Si.

IGF-I deficiency caused by GH resistance is also seen in GH receptor deficiency (GHRD) (2, 3). However, because this condition is secondary to inactivating mutations of the GH receptor gene, affected individuals lack the biologic effects of both GH and IGF-I. In recent years, recombinant human IGF-I (rhIGF-I) therapy has become available for treatment of individuals with GHRD, and a number of studies have now reported improvement in growth (4, 5, 6, 7). However, the growth response to rhIGF-I in GHRD is more modest than that usually seen in individuals with severe GH deficiency (GHD) treated with human GH (8), which may suggest that a direct GH effect is necessary for optimal growth. Other possible explanations for the suboptimal growth response in GHRD include the low levels of the GH-dependent peptides IGF binding protein-3 (IGFBP-3) and acid labile subunit (ALS), which normally stabilize IGF-I in the circulation (9, 10).

In this patient with IGF-I gene deletion, direct GH actions are intact, and both IGFBP-3 and ALS are present in normal amounts. GH secretion is elevated, resulting in reduced Si (1). Systemic rhIGF-I therapy, in this child, has been shown to restore the functioning of the GH-IGF-I axis close to normal (11), although it can not restore paracrine/autocrine effects of IGF-I. In addition to their role in growth, both GH and IGF-I have effects on glucose and lipid metabolism and bone mineralization (7, 12). This report describes the effects of 12 months of rhIGF-I therapy on this patient’s body composition, bone mineralization, Si, and linear growth.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patient details

We have previously reported the full details of the case history (1). At the age of 15.75 yr, auxological parameters were as follows: height, 119.1 cm (-6.88 SD); weight, 23.0 kg (-6.49 SD); body mass index, 16.2 kg/m² (-1.9 SD); upper-to-lower segment ratio, 1.07 (mean, 0.98 at 15 yr); triceps skinfold thickness, 6.0 cm (-0.93 SD); and subscapular skinfold thickness, 7.6 cm (-0.0 SD). The patient was mildly dysmorphic, with micrognathia, bilateral ptosis, and a low hairline. There was bilateral clinodactyly and a left-sided single palmar crease. Neurological examination demonstrated severe bilateral sensorineural deafness and mild myopia.

Endocrine investigations revealed elevated GH secretion, both on overnight GH profile (peaks up to 350 mU/L with lack of full suppression during troughs) and to provocative stimuli (clonidine: peak, 188 mU/L; insulin: peak, 122 mU/L). IGF-I levels were undetectable. IGFBP-3 was normal for age (3.3 mg/L), IGF-II mildly elevated (1430 ng/mL; normal serum pool, 1002 ng/mL), and ALS was normal on immunoblot. Molecular studies revealed a homozygous IGF-I gene deletion involving exons 4 and 5, predicting a severely truncated and abnormal IGF-I peptide. His parents, who were consanguineous, were heterozygous for the deletion.

rhIGF-I therapy was commenced at the age of 16.07 yr (bone age, 14.2 yr). Height was 120.4 cm (-7.44 SD) and Tanner stage of puberty P2, G2, testicular volume (Tvol) 8/10 mL. The starting dose of rhIGF-I was 40 µg/kg by daily sc injection. After 3 months of therapy, an overnight GH profile indicated that GH secretion remained elevated, and the dose was increased to 80 µg/kg·day. A repeat overnight GH profile indicated adequate GH suppression on this dose (11), which was continued for the remaining 9 months of treatment.

Auxology

Height measurements were obtained using a wall-mounted stadiometer. Bone age was assessed using the Tanner-Whitehouse-2 RUS method (13).

Assays

Levels of androgens, sex hormone binding globulin (SHBG), and insulin were measured by standard RIA procedures. Glucose levels were determined by a glucose analyzer. Bone turnover markers (serum osteocalcin and bone specific alkaline phosphatase) were assayed using immunoassays obtained from Metra Biosystems UK (Great Haseley, Oxford, UK).

Bergman-modified minimal model frequent sampling iv glucose tolerance test (FSIGT)

The 180-min FSIGT was used to provide an accurate assessment of ß-cell function and Si in the patient. These parameters are calculated after a bolus of IV glucose at 0 min and tolbutamide at 20 min, and computer mathematical analysis of insulin and glucose kinetics using the MINMOD program (the minimal modeling technique). This test has been validated for use in children (14).

The test was performed at three time points: test 1, pretreatment; test 2, after 1 month therapy with IGF-I (dose 40 µg/kg·day); and test 3, after 6 months therapy with IGF-I (dose 80 µg/kg·day). Samples for the analysis of insulin and glucose were taken at the following times (minutes): -15, -10, -5, -1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 19, 22, 23, 24, 25, 27, 30, 40, 50, 60, 70, 90, 100, 120, 140, 160, and 180. Glucose (300 µg/kg) was injected at t = 0 and tolbutamide (100 mg/kg) at t = 20. The following parameters were calculated using MINMOD’: 1) insulin sensitivity (Si); 2) glucose effectiveness (Sg); and 3) acute insulin response to glucose (AIRg). The study protocol was approved by the Local Ethics Committee, and informed written consent was obtained from the patient’s parents.

Determination of bone mineral density (BMD) and body composition

BMD and body composition were determined at three time points (pretreatment, 6 months on treatment, and 12 months on treatment) by dual-energy x-ray absorbtiometry using the Lunar Corp. DPX densitometer (Supplied by Aura Scientific, West Lothian, UK). Baseline lumbar (L2–L4) BMD was converted to an age-matched SD score using Lunar Corp. pediatric software (control data collected by Lunar Corp.). To correct for bone size, the volumetric BMD [bone mineral apparent density (BMAD)] of the lumbar spine was calculated at each time point, using the formula BMAD = BMC/(Ap)^1.5, where BMC = bone mineral content, and AP = projected area (15)

Adverse effects

Regular ophthalmic and ear, nose, and throat examinations were performed to monitor for the development of papilloedema and tonsillar hypertrophy at 0, 3, 6, and 12 months of therapy.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Changes in body composition on rhIGF-I therapy (Table 1)

Over the first 6 months of rhIGF-I therapy (3 months at 40 µg/kg·day and 3 months at 80 µg/kg·day), there was a marked reduction in total body fat, from 19.9% to 15.1%, which increased during the subsequent 6 months of rhIGF-I therapy (80 µg/kg·day throughout), to result in a net elevation from baseline at 21.8% (Table 1).

Changes in bone mineralization on rhIGF-I therapy (Table 2)

Lumbar BMD at baseline was severely reduced, compared with age-matched controls (L2–L4 region, 0.58 g/cm ²; SD score, -4.88). BMAD at baseline was 0.14 g/cm³. Appropriate age- and sex-matched control values for BMAD have not been published; however, this value compares with a BMAD of 0.165 g/cm³ ± - 0.114 SD in 75 female subjects (mean age, 24.4 yr), calculated using the same formula (15). Over the 1 yr of therapy, BMD increased by 17% and bone mineral content by 26%. BMAD increased by 7%. Markers of bone formation and turnover (serum osteocalcin and bone specific alkaline phosphatase) increased substantially by 6 months. By 12 months, levels remained above baseline but were lower than the 6-month values.

Changes in Si and secretion on rhIGF-I therapy (Table 3, Fig. 1)

Before initiation of rhIGF-I therapy, there was fasting hyperinsulinemia [insulin, 28.9 mU/L (normal range, NR, for stage 2 puberty, 8–18)], although plasma glucose (mean, 4.9 mmol/L) and glycated hemoglobin [3.2% (NR, 3–5%)] were normal. Administration of both iv glucose and tolbutamide resulted in an exaggerated insulin response. Using the MINMOD program, Si was markedly reduced, and AIRg was greatly elevated. Sg was normal. There was a dose-dependent improvement in Si and AIRg to rhIGF-I therapy, the higher (80 µg/kg·day) dose resulting in a fall of Si into the NR for age and puberty status. SHBG was initially undetectable and increased almost into the normal adult range.

View larger version (18K): [in this window] [in a new window]   Figure 1. Insulin responses during Bergman FSIGT. Glucose (300 µg/kg) was injected at t = 0 min and tolbutamide S (100 mg/m2) at t = 20 min. Therapy with rhIGF-I resulted in a dose-dependent reduction in basal and stimulated insulin responses. (), Pre-rhIGF-I; (), rhIGF-I (40 µg/kg·day); (), rhIGF-I (80 µg/kg·day).

Changes in linear growth and maturation during rhIGF-I therapy (Table 4)

Pretreatment height velocity was 3.8 cm/yr. On rhIGF-I (40 µg/kg for 3 months), height velocity increased modestly to 4.2 cm/yr. After the increase in rhIGF-I dose to 80 µg/kg, there was a more pronounced increase in height velocity, to 7.3 cm/yr. Puberty progressed from G2, PH2, Tvol 8/10 to G4, PH4, Tvol 12/12 over the 12 months of therapy.

The patient reported no significant adverse effects of rhIGF-I therapy. In particular, no hypoglycemic episodes occurred after rhIGF-I injection, as observed in rhIGF-I therapy of patients with GHRD (8). Regular opthalmologic and ear, nose, and throat examinations revealed no evidence of papilloedema or adenotonsillar hypertrophy.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This paper describes the effects of 1 yr of rhIGF-I therapy on body composition, bone mineralization, Si, and growth in this patient with severe IGF-I deficiency secondary to a homozygous partial deletion of the IGF-I gene.

A marked reduction in Si, using the modified FSIGT devised by Bergman and co-workers, confirmed that this patient was significantly insulin resistant before the onset of rhIGF-I therapy. Marked hypersecretion of insulin, in response to glucose and tolbutamide, was observed, suggesting exaggerated ß-cell reactivity, a feature often associated with insulin-resistant states (16). Sustained exposure to elevated GH levels is well described to reduce Si, as seen in conditions such as acromegaly (17, 18, 19). An increase in the direct effects of GH, secondary to the elevation in GH secretion at baseline, thus provides the likely explanation for the insulin resistance of this patient. This hypothesis is supported by the dose-dependent improvement in Si observed during rhIGF-I therapy. Elevated GH secretion is thought to be one explanation for the insulin resistance observed in adolescent insulin-dependent diabetes mellitus, and rhIGF-I therapy has been shown to improve glycemic control in this condition (20).

SHBG levels, reduced to below the limits of assay detection at baseline, increased into the NR for age and pubertal stage during rhIGF-I therapy. This may reflect either the fall in insulin or GH levels during therapy, both of which have an inverse relationship with SHBG (21, 22, 23).

IGF-I has been described to have both short-term antilipolytic and long-term lipolytic effects (12). Patients with severe GHD and GHRD tend to have increased adiposity, most likely secondary to the lack of the direct antilipolytic effect of GH (24). The body fat content of our patient, at 19.9%, is considerably less than that of prepubertal GHRD children in a recent study, in whom the mean total body fat was 28.3% (7). In the first 6 months of IGF-I therapy, his total body fat fell, but by 12 months there had been a net increase. This gain in body fat, suggesting an overall lipogenic effect of treatment, may be secondary to the fall in GH levels induced by rhIGF-I, which for the first 3 months of therapy were inadequately suppressed on the lower dose of rhIGF-I.

The measurement of BMD, using dual-energy x-ray absorbtiometry scanning in short children and adults, is confounded by the effects of reduced bone size and may lead to underestimation of true bone density (25). The effect of reduced bone size on the calculation of BMD can be overcome, however, by the calculation of BMAD (15). Both children and adults with GHD have been reported to have reduced BMAD, suggesting that GH, either acting directly on bone tissue and/or mediated by IGF-I, plays an important role in bone mineralization (26, 27, 28). Children with GHRD have also been reported to have low BMD, which improves with rhIGF-I therapy (7); however, BMD was not adjusted for height in this study. In contrast, a recent study of adults with GHRD demonstrated no reduction in BMAD, compared with controls, thereby questioning the role of the GH-IGF-I axis in bone mineralization (29). Our patient had a low BMD, compared with age-matched controls at baseline. However, his baseline BMAD was only mildly reduced, compared with a reference population of young adult women. During rhIGF-I therapy, BMD and BMC increased markedly and BMAD less so, suggesting that much of the apparent increase in BMD was, in fact, attributable to an increase in bone size. As puberty progressed from Tanner stage 2 to stage 4 during the period of therapy, the modest increase in BMAD may well be secondary to the effects of puberty, which has been shown to be associated with an increase in BMAD (30), rather than an effect of rhIGF-I therapy. Thus, rhIGF-I had a much greater effect on bone growth than on bone mineralization.

A growth response to rhIGF-I was clearly seen, with a near doubling of growth velocity on the higher (80 µg/kg·day) dose of rhIGF-I. Considering that the patient was in puberty at the time of rhIGF-I administration, this growth response is perhaps less than might be expected for a similar individual with severe GHD receiving hGH therapy for the first time. Direct GH actions are intact in our patient, and rhIGF-I clearance is normal. However, systemic rhIGF-I therapy cannot correct the lack of local IGF-I production, and this may be the explanation for the suboptimal growth response.

In summary, this paper reports the results of rhIGF-I therapy for 1 yr in this unique patient with IGF-I gene deletion. The main benefits of therapy were an improvement in body composition and normalization of Si. rhIGF-I has the potential to improve metabolic status in a variety of insulin-resistant states.

	Acknowledgments

 
We thank Pharmacia & Upjohn, Inc., United Kingdom, for the supply of rhIGF-I.

Received June 29, 1999.

Revised October 18, 1999.

Accepted December 15, 1999.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Woods KA, Camacho-Hübner C, Savage MO, Clark AJL. 1996 Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med. 335:1363–1367.[Free Full Text]
2. Savage MO, Blum WF, Ranke MB, et al. 1993 Clinical features and endocrine status in patients with growth hormone insensitivity (Laron syndrome). J Clin Endocrinol Metab. 77:1465–1471.[Abstract]
3. Rosenfeld RG, Rosenbloom AL, Guevara-Aguirre J. 1994 Growth hormone (GH) insensitivity due to primary GH receptor deficiency [Review]. Endocr Rev. 15:369–390.[Abstract/Free Full Text]
4. Laron Z, Klinger B. 1994 Laron syndrome: clinical features, molecular pathology and treatment. Horm Res. 42:198–202.[Medline]
5. 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]
6. Ranke MB, Savage MO, Chatelain PG, Preece MA, Rosenfeld RG, Blum WF. 1995 Insulin-like growth factor (IGF)-I improves height in growth hormone insensitivity. Two years results. Horm Res. 44:253–264.[Medline]
7. Backeljauw PF, Underwood LE. 1996 Prolonged treatment with recombinant insulin-like growth factor-I in children with growth hormone insensitivity syndrome–a clinical research center study. GHIS Collaborative Group. J Clin Endocrinol Metab. 81:3312–3317.[Abstract]
8. Ranke MB. 1996 Treatment of growth hormone insensitivity syndrome (GHIS) with insulin-like growth factor (IGF-I). In: Savage MO, Ross RJM, eds. Growth hormone resistance. London: Ballière Tindall; 401–410.
9. Baxter RC. 1990 Circulating levels and molecular distribution of the acid-labile subunit of the high molecular weight insulin-like growth factor-binding protein complex. J Clin Endocrinol Metab. 70:1347–1353.[Abstract/Free Full Text]
10. Grahnén A, Kastrup K, Heinrich U, et al. 1993 Pharmacokinetics of recombinant human insulin-like growth factor I given subcutaneously to healthy volunteers and to patients with growth hormone receptor deficiency. Acta Paediatr. [Suppl 82 ]391 :9–13.
11. Camacho-Hübner C, Woods KA, Miraki-Moud F, et al. 1999 Effects of recombinant human insulin-like growth factor I (IGF-I) therapy on the growth hormone-IGF system of a patient with a partial IGF-I gene deletion. J Clin Endocrinol Metab. 84:1611–161650.[Abstract/Free Full Text]
12. Berneis K, Keller U. 1966 Metabolic actions of growth hormone: direct and indirect. In: Ross RJM, Savage MO, eds. Growth hormone resistant states. London: Ballière-Tindall; 337–352.
13. Cameron N. 1978 The methods of auxological anthropometry. In: Faulkner F, Tanner JM, eds. Human growth. New York: Plenum Press; 35–37.
14. Cutfield WS, Bergman RN, Menon RK, Sperling MA. 1990 The modified minimal model: application to measurement of insulin sensitivity in children. J Clin Endocrinol Metab. 70:1644–1650.[Abstract/Free Full Text]
15. Carter DR, Bouxsein ML, Marcus R. 1992 New approaches for interpreting projected bone densitometry data. J Bone Miner Res. 7:137 -145.[Medline]
16. Kahn SE, Prigeon RL, McCulloch DK, et al. 1993 Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes. 42:1663–1672.[Abstract]
17. Bratusch-Marrain PR, Smith D, DeFronzo RA. 1982 The effect of growth hormone on glucose metabolism and insulin secretion in man. J Clin Endocrinol Metab. 55:973–982.[Abstract/Free Full Text]
18. Hansen I, Tsalikian E, Beaufrere B, Gerich J, Haymond M, Rizza R. 1986 Insulin resistance in acromegaly: defects in both hepatic and extrahepatic insulin action. Am J Physiol. 250:E269–E273.
19. Moller N, Butler PC, Antsiferov MA, Alberti KG. 1989 Effects of growth hormone on insulin sensitivity and forearm metabolism in normal man. Diabetologia. 32:105–110.[CrossRef][Medline]
20. Acerini CL, Patton CM, Savage MO, Kernell A, Westphal O, Dunger DB. 1997 Randomised placebo-controlled trial of human recombinant insulin-like growth factor I plus intensive insulin therapy in adolescents with insulin-dependent diabetes mellitus. Lancet. 350:1199–1204.[CrossRef][Medline]
21. Weaver JU, Holly JM, Kopelman PG, et al. 1990 Decreased sex hormone binding globulin (SHBG) and insulin-like growth factor binding protein (IGFBP-1) in extreme obesity. Clin Endocrinol (Oxf). 33:415–422.[Medline]
22. Plymate SR, Matej LA, Jones RE, Friedl KE. 1988 Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin. J Clin Endocrinol Metab. 67:460–464.[Abstract/Free Full Text]
23. Gafny M, Silbergeld A, Klinger B, Wasserman M, Laron Z. 1994 Comparative effects of GH, IGF-I and insulin on serum sex hormone binding globulin. Clin Endocrinol (Oxf). 41:169–175.[Medline]
24. Laron Z. 1984 Laron-type dwarfism (hereditary somatomedin deficiency): a review. In: Frick H, von Harnack G, Kochesiek K, Martini GA, Prader A, eds. Advances in Internal Medicine. Berlin: Springer-Verlag; 117–150.
25. Saggese G, Baroncelli GI, Bertelloni S, Barsanti S. 1996 The effect of long-term growth hormone (GH) treatment on bone mineral density in children with GH deficiency. Role of GH in the attainment of peak bone mass. J Clin Endocrinol Metab. 81:3077–3083.[Abstract/Free Full Text]
26. Inzucchi SE, Robbins RJ. 1994 Clinical review 61: effects of growth hormone on human bone biology. J Clin Endocrinol Metab. 79:691–694.[Abstract]
27. Baroncelli GI, Bertonelli S, Ceccarelli C, Saggese S. 1998 Measurement of volumetric bone mineral density accurately determines degree of lumbar undermineralisation in children with growth hormone deficiency. J Clin Endocrinol Metab. 83:3150–3154.[Abstract/Free Full Text]
28. De Boer H, Blok GJ, van Lingen A, Teule GJ, Lips P, van der Veen EA. 1994 Consequences of childhood onset growth hormone deficiency for adult bone mass. J Bone Miner Res. 9:1319–1326.[Medline]
29. Bachrach LK, Marcus R, Ott SM, et al. 1998 Bone mineral, histomorphometry, and body composition in adults with growth hormone receptor deficiency. J Bone Miner Res. 13:415–421.[CrossRef][Medline]
30. Boot AM, de Ridder MAJ, Huibert APP, Krenning EP, de Muink Keitzer-Schrama SMPF. 1997 Bone mineral density in children and adolescents: relation to puberty, calcium intake, and physical activity. J Clin Endocrinol Metab. 82:57–62.[Abstract/Free Full Text]
31. Hofman PL, Cutfield WS, Robinson EM, et al. 1997 Insulin resistance in short children with intrauterine growth retardation. J Clin Endocrinol Metab. 82:402–406.[Abstract/Free Full Text]

This article has been cited by other articles:

				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]

				Q. Fu, X. Yu, C. W. Callaway, R. H. Lane, and R. A. McKnight Epigenetics: intrauterine growth retardation (IUGR) modifies the histone code along the rat hepatic IGF-1 gene FASEB J, August 1, 2009; 23(8): 2438 - 2449. [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]

				S. A. Kaplan and P. Cohen REVIEW: The Somatomedin Hypothesis 2007: 50 Years Later J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4529 - 4535. [Abstract] [Full Text] [PDF]

				M J E Walenkamp and J M Wit Genetic disorders in the GH IGF-I axis in mouse and man Eur. J. Endocrinol., August 1, 2007; 157(suppl_1): S15 - S26. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, and C. Y. Bowers Somatotropic and Gonadotropic Axes Linkages in Infancy, Childhood, and the Puberty-Adult Transition Endocr. Rev., April 1, 2006; 27(2): 101 - 140. [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]

				P. E Mullis Genetic control of growth Eur. J. Endocrinol., January 1, 2005; 152(1): 11 - 31. [Abstract] [Full Text] [PDF]

				R. Bouillon, E. Koledova, O. Bezlepkina, J. Nijs, E. Shavrikhova, E. Nagaeva, O. Chikulaeva, V. Peterkova, I. Dedov, A. Bakulin, et al. Bone Status and Fracture Prevalence in Russian Adults with Childhood-Onset Growth Hormone Deficiency J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4993 - 4998. [Abstract] [Full Text] [PDF]

				W. M. Drake, D. L. Kendler, C. J. Rosen, and E. S. Orwoll An Investigation of the Predictors of Bone Mineral Density and Response to Therapy with Alendronate in Osteoporotic Men J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5759 - 5765. [Abstract] [Full Text] [PDF]

				M. Haluzik, S. Yakar, O. Gavrilova, J. Setser, Y. Boisclair, and D. LeRoith Insulin Resistance in the Liver-Specific IGF-1 Gene-Deleted Mouse Is Abrogated by Deletion of the Acid-Labile Subunit of the IGF-Binding Protein-3 Complex: Relative Roles of Growth Hormone and IGF-1 in Insulin Resistance Diabetes, October 1, 2003; 52(10): 2483 - 2489. [Abstract] [Full Text] [PDF]

				H. G. Maheshwari, R. Bouillon, J. Nijs, V. S. Oganov, A. V. Bakulin, and G. Baumann The Impact of Congenital, Severe, Untreated Growth Hormone (GH) Deficiency on Bone Size and Density in Young Adults: Insights from Genetic GH-Releasing Hormone Receptor Deficiency J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2614 - 2618. [Abstract] [Full Text] [PDF]

				J. Nakae, Y. Kido, and D. Accili Distinct and Overlapping Functions of Insulin and IGF-I Receptors Endocr. Rev., December 1, 2001; 22(6): 818 - 835. [Abstract] [Full Text] [PDF]

				K. Sjogren, K. Wallenius, J.-L. Liu, M. Bohlooly-Y, G. Pacini, L. Svensson, J. Tornell, O. G.P. Isaksson, B. Ahren, J.-O. Jansson, et al. Liver-Derived IGF-I is of Importance for Normal Carbohydrate and Lipid Metabolism Diabetes, July 1, 2001; 50(7): 1539 - 1545. [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 Woods, K. A. Articles by Savage, M. O. Search for Related Content PubMed PubMed Citation Articles by Woods, K. A. Articles by Savage, M. O.