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Biomedical subjects

C Camacho-Hübner

Publications and source records attributed to C Camacho-Hübner.

At least 37 records · Page 2Linked to original sources
PubMed2000

Effects of insulin-like growth factor I (IGF-I) therapy on body composition and insulin resistance in IGF-I gene deletion.

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 microg/kg daily, increasing after 3 months to 80 microg/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 (microU/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 microg/kg x day, Si = 2.06 x 10-4 min-l; rhIGF-I dose: 80 microg/kg x 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 microg/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.

Absorptiometry, Photon↗
PubMed1999

IGF-I levels rise and GH responses to GHRH decrease during long-term prednisone treatment in man.

Glucocorticoid excess is associated with a blunted GH response to GHRH. IGF-I levels in hypercortisolism are controversial and have been reported as low, normal or high. The aim of this study was to evaluate longitudinally time-dependent changes in the GH response to GHRH, IGF-I, IGFBP-3 and albumin values in patients during corticotherapy. Six patients received GHRH before and after one week and one month of prednisone administration (20-60 mg/d, orally). IGF-I, IGFBP-3 and albumin were determined in each test, at time 0. Ten normal controls were also evaluated in one occasion. There were no differences in basal GH values, GH response to GHRH, IGF-I and IGFBP-3 levels between controls and patients before starting corticotherapy. Albumin (g/l; mean+/-SE) values were lower in patients before treatment (31+/-4) than in controls (43+/-1). After one week of prednisone administration there was a significant decrease in peak GH (microg/l) levels (before: 18.8+/-7.4; 1 week: 5.0+/-1.3), which was maintained after one month (8.1+/-3.5). IGF-I (microg/l) levels increased significantly, from 145+/-23 to 205+/-52 after one week of therapy, reaching levels of 262+/-32 after one month. IGFBP-3 (mg/l) values did not increase significantly (before: 2.1+/-0.2; 1 week: 2.5+/-0.3; 1 month: 2.8+/-0.2). Albumin levels showed a significant rise both after one week (36+/-4) and one month (42+/-3) of corticotherapy. In summary, we observed a marked decrease in the GH response to GHRH after one week and one month of prednisone administration associated with an increase in circulating IGF-I and albumin values. The physiological implications of these findings are still uncertain. It is possible that glucocorticoids increase hepatic IGF-I and albumin synthesis, although other mechanisms may have a role.

Adult↗
PubMed1999

Insulin-like growth factor-I deficiency caused by a partial deletion of the IGF-I gene: effects of rhIGF-I therapy.

Insulin-like growth factor-I (IGF-I) is one of the most important regulator of growth. IGF-I deficiency is associated with prenatal and post-natal growth failure and may arise primarily as a result of GH receptor/post-receptor abnormalities or defects in the synthesis and transport of IGF-I. We have previously reported a 17.2-year-old boy with severe growth retardation and undetectable serum levels of IGF-I caused by a partial deletion of the IGF-I gene. This short review will concentrate on results of a recent study which examined the effects of rhIGF-I therapy on the GH-IGF system of this patient. Similar to healthy individuals, this patient had normal IGFBP-3 but elevated ALS levels. IGF-I treatment has improved linear growth and insulin sensitivity in this patient by restoring IGF-I levels and by normalizing circulating GH, IGFBPs and insulin levels.

Adolescent↗
PubMed1999

Correlation between cortisol and insulin-like growth factor-binding proteins (IGFBPs) under physiological conditions in children.

OBJECTIVE: A positive correlation between 24-h spontaneous growth hormone (GH) and cortisol secretion was previously reported in children. This observation prompted us to examine the relationship between physiological diurnal cortisol variation and the levels of insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) under physiological conditions. DESIGN AND PATIENTS: Starting at 0800 h, blood was sampled every 20 minutes over 24 h for measurement of GH and cortisol concentration in nine non-GH- deficient boys as part of a protocol for the investigation of short stature. MEASUREMENTS: IGFBP-1 and insulin were measured in samples drawn every 4 h over the 24-h period while IGF-I, IGF-II, IGFBP-2 and IGFBP-3 were determined in samples collected at the end of the study. RESULTS: No correlation was observed between IGF-I or IGF-II and mean cortisol levels. IGFBP-1 concentrations showed a marked circadian variation that was superimposed on the circadian rhythm for cortisol while a significant positive correlation was found for single point measurements between IGFBP-1 concentrations and cortisol levels measured in the same sample (r = 0.53) or at the preceding 20 minutes (r = 0.43), 40 minutes (r = 0.47) and 2 h (r = 0.38), suggesting an interplay between cortisol and IGFBP-1. A negative correlation (r = - 0.54) was found between IGFBP-1 and insulin levels determined in the same sample. A negative correlation (r = - 0.93) was also found between IGFBP-2 levels and mean cortisol concentrations during the preceding 12 h. No correlation was observed between plasma IGFBP-3 measured by IRMA and mean cortisol levels. CONCLUSION: Our data indicate a clear correlation between cortisol and IGFBP-1 and IGFBP-2 levels. Thus, the interplay of spontaneous GH and cortisol secretion in children may involve changes in IGFBP-1 and IGFBP-2 levels.

Adolescent↗
PubMed1999

Serum insulin-like growth factor (IGF)-I concentrations are reduced by short-term dietary restriction and restored by refeeding in domestic cats (Felis catus).

Nutritional modulation of insulin-like growth factors (IGF) and their binding proteins (IGFBP) is well established. The effect of nutritional restriction on the serum IGF/IGFBP system of adult cats was investigated to evaluate serum IGF-I as a biochemical marker of nutritional status. Assays for measuring feline serum IGF and IGFBP were validated and normal ranges established in a study population of 46 healthy nonobese adult cats. Serum concentrations of IGF-I and IGF-II correlated significantly with body weight (r = 0.75, P < 0. 0001 and r = 0.34, P < 0.03, respectively). Serum IGFBP profiles were similar to other species, including humans, dogs and guinea pigs. IGFBP-3 was the predominant binding protein reflecting IGF-I concentrations and body size. Serum IGFBP-2 concentrations were high relative to the normal human serum pool (NHS) control. Food withdrawal for 18 h followed by refeeding did not alter circulating IGF or IGFBP concentrations, including IGFBP-1, in nine cats. Short-term dietary restriction of nine adult cats to supply initially 56% (56%M) and then 42.5% (42.5%M) of calculated maintenance energy requirements for 14 d resulted in a significant weight loss (P < 0.01). However, serum IGF-I concentrations fell significantly (-51%, P < 0.01) only with 42.5%M restriction. Serum IGF-II, IGFBP, insulin and albumin concentrations were not altered during the study. We conclude that nutrition does modulate the adult feline IGF/IGFBP system, but to a lesser extent than in other species. Further evaluation is required before serum IGF-I can be used for the assessment of nutritional status in adult cats.

Animals↗
PubMed1999

Growth in Crohn's disease.

Abnormal linear growth is frequent in children and adolescents with Crohn's disease. The typical pattern is of growth retardation associated with delayed skeletal maturation. Puberty is also frequently delayed. Over 50% of patients may have a subnormal height velocity, and approximately 25% will have short stature. The endocrine status is characterized by normal growth hormone secretion and a slightly subnormal serum level of insulin-like growth factor I, which is related to nutritional status. Principal therapeutic options are intestinal resection for localized disease, and enteral nutrition--using a polymeric diet--for more widespread disease, particularly involving the small intestine. Growth responses to both modalities are often excellent and produce considerable psychological benefit. Optimum therapy is achieved by close collaboration between gastroenterologists and endocrinologists, and by the use of auxological methods to document pre- and post-therapeutic management.

Adolescent↗
PubMed1999

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.

We have previously reported a 17.2-yr-old boy with severe growth retardation and undetectable serum levels of insulin-like growth factor I (IGF-I) due to a partial deletion of the IGF-I gene. The aim of this study was to investigate the effects of recombinant human IGF-I (rhIGF-I) therapy on the GH-IGF system of this patient to gain further insights into its growth-promoting and metabolic actions. To assess the changes in GH, IGFs, IGF-binding proteins (IGFBPs), acid-labile subunit (ALS), and insulin levels, blood samples were obtained before therapy and during the first year of treatment. Hormones were analyzed by specific RIAs. Overnight GH profiles were performed before and at 1, 6, and 12 months of therapy. Fasting ALS, IGF-II, IGFBP-3, IGFBP-2, IGFBP-1, and insulin levels before rhIGF-I treatment were 46.3 mg/L, 1044 microg/L, 5.8 mg/L, 73 ng/mL, 4.7 ng/mL, and 27.3 mU/L, respectively. IGF-II, ALS, and insulin levels were elevated, whereas IGFBP-1 and IGFBP-2 levels were decreased compared to reference values. Twenty-four hours after a single s.c. injection of rhIGF-I (40 microg/kg), the concentrations were 46 mg/L, 888 microg/L, 6.9 mg/L, 112 ng/mL, 5.0 ng/mL, and 21.0 mU/L, respectively. After a single s.c. injection of rhIGF-I of 40 or 80 microg/kg x day and modelling the data using a two-compartment model, the half-lives of elimination were 15.7 and 14.3 h, with a maximum increase in IGF-I levels to 341 and 794 microg/L around 7 h, respectively. An increase in IGFBP-3 levels was observed with both doses of rhIGF-I, with a peak values of 9 mg/L. GH profiles showed a decrease in peak amplitude from 342 to 84 mU/L at 1 month, to 67 mU/L at 6 months, and to 40 mU/L at 1 yr of therapy, with no significant changes in peak number. A significant increase in IGFBP-1 levels was observed during treatment with 80 microg/kg x day IGF-I, reflecting the inhibitory effect of rhIGF-I on insulin secretion. The clinical response to rhIGF-I therapy was an increased height velocity from 3.8 cm/yr before treatment to 6.6 cm/yr. Increased lean body mass correlated with changes in the doses of rhIGF-I and, in turn, with the biochemical changes in the GH-IGF axis. Similar to healthy individuals, this patient had normal IGFBP-3 and ALS levels, which are the major regulators of the pharmacokinetics of rhIGF-I. In summary, rhIGF-I treatment has improved linear growth and insulin sensitivity in this patient by restoring IGF-I levels and by normalizing circulating GH, IGFBP, and insulin levels.

Adolescent↗
PubMed1998

Insulin-like growth factor axis of gluten-sensitive dogs during a gluten challenge.

Eight gluten-sensitive Irish setters underwent a gluten challenge to investigate changes in the insulin-like growth factor (IGF) axis. In the first study, they were challenged with an acute intraduodenal administration of tryptic-peptic gluten digest and then maintained on dietary gluten for three months. In the second study, the challenge came solely from dietary gluten fed for three months. After the acute intraduodenal administration of gluten, serum IGF-I levels decreased significantly by 21.8 per cent, (P = 0.01) on day 3 after challenge and then returned to normal. There was also a decrease (52.5 per cent, P < 0.03) in the levels of serum IGF-binding protein-3 (IGFBP-3) until day 14 after challenge but they had returned to normal by day 28. In two dogs IGFBP-3 levels decreased through specific serum protease activity. There were no changes in serum IGF-I or IGFBP levels during the second study after the dietary gluten challenge alone, or in four non-gluten-sensitive beagles studied as controls during the acute intraduodenal/dietary gluten challenge.

Animals↗
PubMed1998

Changes in serum IGF-I and IGFBP-3 concentrations during the IGF-I generation test performed prospectively in children with short stature.

OBJECTIVE: Genotype and phenotype heterogeneity in patients with GH insensitivity syndrome suggests that partial defects exist in the GH receptor. Children with partial GH resistance would be expected to have short stature, elevated GH levels and relatively low levels of IGF-I and IGFBP-3. Provocation tests of the GH-IGF-I axis may help to identify such children. The IGF-I generation test in particular may demonstrate impaired secretion of IGF-I and IGFBP-3. This prospective study assesses the usefulness of the IGF-I generation test in the identification of short children with possible GH insensitivity. DESIGN: Prepubertal children referred for assessment of short stature underwent a standard GH provocation test followed by an IGF-I generation test. SUBJECTS: Thirty-seven prepubertal children (14 girls, 23 boys) with short stature (height < 2nd centile UK standards 1990) aged 4.5-12.6 years were investigated prospectively. METHODS: Assessment included history, physical examination, auxological observations (height, weight, bone age). GH provocation tests (glucagon 15 micrograms/kg i.m. or insulin 0.15 U/kg/i.v.) was followed by an IGF-I generation test (hGH 0.1 iu/kg/s.c. daily for 4 days). MEASUREMENTS: GH was assayed during the provocation test. IGF-I and IGFBP-3 were measured at 0900 h on day 0 and 4 of the IGF-I generation test. GH and IGF-I were measured by radioimmunoassay, IGFBP-3 by IRMA and basal GHBP by HPLC. STATISTICAL ANALYSIS: Height SDS was calculated according to the UK Height Standards 1990. The absolute and percentage changes of IGF-I and IGFBP-3 during the IGF-I generation test were calculated. RESULTS: The 37 children were divided into three groups according to the peak GH level (mean +/- SEM) during the provocation test: Group 1 (peak GH < 20 mU/l) n = 11, five girls, six boys age 7.1 +/- 0.7 years, height SDS -2.5 +/- 0.1, peak GH 14.5 +/- 1.6 mU/l, IGF-I 92.0 +/- 10.4 micrograms/l, IGFBP-3 2.6 +/- 0.4 mg/l. Group 2 (peak GH 20-40 mU/l) n = 12, six girls, six boys age 8.6 +/- 0.7 years, height SDS -2.6 +/- 0.1, peak GH 28.4 +/- 1.6 mU/l, IGF-I 121-5 +/- 13.4 micrograms/l, IGFBP-3 2.9 +/- 0.2 mg/l. Group 3 (peak GH > 40 mU/l) n = 14, three girls, 11 boys, aged 8.5 +/- 0.6 years, height SDS -2.3 +/- 0.1, peak GH 60.7 +/- 4.1 mU/l, IGF-I 112.4 +/- 10.9 micrograms/l, IGFBP-3 3.1 +/- 0.3 mg/l. There were no significant differences in the absolute increases of IGF-I or IGFBP-3 (mean +/- SEM) during the IGF-I generation test, IGF-I; Group 1, 48.8 +/- 9.5 micrograms/l, Group 2, 42.7 +/- 4.8 micrograms/l. Group 3, 45.5 +/- 5.1 micrograms/l, IGFBP-3; Group 1, 1.1 +/- 1.2 mg/l. Group 2, 1.2 +/- 0.2 mg/l, Group 3, 0.85 +/- 0.1 mg/l. There were no significant differences in the percentage increases (mean +/- SEM) of IGF-I; Group 1, 55 +/- 9%, Group 2, 35 +/- 5%, Group 3, 42 +/- 8%, or IGFBP-3; Group 1, 64 +/- 17%, Group 2, 44 +/- 8%, Group 3.32 +/- 6%. GHBP values were normal in all three groups. In Group 3 (peak GH > 40 mU/l) four individual patients had either low basal IGF-I levels (n = 2) (< 5th centile of normal range for age) or low basal IGFBP-3 levels (n = 1) (< 5th centile of normal range for age) or low IGF-I responses in the IGF-I generation test (2 x CV of IGF-I assay) (n = 1). No single subject had all the characteristics of GH insensitivity syndrome. CONCLUSION: The responses during an IGF-I generation test did not identify a clear group of children with GH insensitivity. Individual patients had low basal IGF-I or IGFBP-3 values and a poor response in the generation test, features which, in the presence of high GH levels on provocation, are consistent with partial GH insensitivity.

Carrier Proteins↗
PubMed1998

Responsiveness of IGF-I and IGFBP-3 to therapeutic intervention in children and adolescents with Crohn's disease.

OBJECTIVE: Abnormal linear growth is common in childhood and adolescent Crohn's disease. We have studied the concentrations of the inflammatory marker CRP and of serum IGF-I and IGFBP-3 in patients with active Crohn's disease and have assessed the changes in these parameters during therapeutic intervention with enteral nutrition or intestinal resection. DESIGN: Children and adolescents attending the inflammatory bowel disease clinic at our hospital underwent treatment either with enteral nutrition (Study A) or intestinal resection (Study B). These are two separate studies and the results cannot be compared. Serum concentrations of CRP, IGF-I and IGFBP-3 were determined at 0, 2, 8 and 16 weeks after start of enteral nutrition and in addition to height velocity, at 0 and 6 months after intestinal resection. SUBJECTS: Study A: 14 patients, 9 male, 5 female, median age 12.5 years (range 7.0-17.2), puberty stage 1 (n = 13), stage 3 (n = 1). All had active Crohn's disease. Study B: 9 patients, 7 male, 2 female, median age 13.5 years (range 7.8-16.5), puberty stage 1 (n = 5), stages 2-4 (n = 4). All had Crohn's disease resistant to medical therapy. METHODS: Crohn's disease was confirmed radiologically, endoscopically and histologically. Disease activity was scored using the Lloyd Still index (LSI). Study A: nutritional support was with a polymeric, casein-based formula feed AL 110. Study B: surgical procedures were small bowel resection (n = 2), right hemicolectomy (n = 5), subtotal colectomy (n = 2). MEASUREMENTS: Study A: weight SDS, CRP, IGF-1 and IGFBP-3 were measured at 0, 2, 8, 16 weeks after start of enteral feeding. Study B: height velocity, CRP, IGF-I and IGFBP-3 were measured 0, 6 months after intestinal resection. STATISTICAL ANALYSIS: Medians and ranges were used. Significance of changes was calculated using the Wilcoxon rank test for the analysis of paired data. RESULTS: Study A: median LSI before treatment was 39 and increased after 8 weeks of enteral nutrition to 60 (P < 0.05). Weight SDS increased at 8 and 16 weeks (P < 0.05) compared to pretreatment. CRP was elevated at 0 weeks, falling during treatment. Median (range) values (normal < 5 mg/l) at 0 at 2, 8, 16 weeks were 53 mg/l (15-150), 8 mg/l (5-25), 7 mg/l (5-83) and 14 mg/l (5-39), all P < 0.001 compared with pretreatment. Median IGF-I-values increased during treatment. Median (range) values at 0, 2, 8, 16 weeks (all P < 0.005) compared to pretreatment, median (range) values at 0, 2, 8, 16 weeks were 78 micrograms/l (50-204), 131 micrograms/l (73-251), 119 micrograms/l (77-291) and 133 micrograms/l (67-497), all P < 0.005 compared to pre-treatment. IGFBP-3 levels increased during treatment. Median (range) values at 0, 2, 8, 16 weeks were 2.4 mg/l (1.4-3.1), 2.9 mg/l (1.8-4.6), 3.0 mg/l, 3.2 mg/l (1.8-4.5), all P < 0.01 compared to pretreatment. Study B: height velocity increased during 6 months after surgery. Median (range) values; 3.3 cm/year (0-8.3) before surgery, 8.4 cm/year (2-12.6) 6 months post-surgery, P < 0.01. Median (range) CRP values fell from 45 mg/l (5-150) to 8 mg/l (5-31) and IGF-I-values increased from 163 micrograms/l (64-286) to 226 micrograms/l (71-391). These changes were not statistically significant. IGFBP-3 values did not change. CONCLUSION: The IGF system, as shown by serum IGF-I and IGFBP-3, is responsive to therapeutic intervention in active Crohn's disease. It is likely that a combination of decreased inflammatory activity and improved nutrition contributes to these changes.

Adolescent↗
PubMed1998

Changes in protein turnover, IGF-I and IGF binding proteins in children with cancer.

Changes in insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding proteins (IGFBPs) were correlated with protein synthesis and breakdown using [1-13C]leucine before chemotherapy and during subsequent febrile neutropenia (FN) in eight children with cancer, aged 6.3-17.5 y. IGF-I levels were similar to age-matched controls before chemotherapy (mean +/- SEM: 250+/-28 and 228+/-22 microg l(-1), respectively). During FN, IGF-I fell to 156+/-22 microg l(-1) (p = 0.02), and rose to 276+/-27 microg l(-1) with recovery at 6 months (p = 0.004). Similarly, IGFBP-3 decreased from 4.0+/-0.2 mg l(-1) before chemotherapy to 3.0+/-0.3 mg l(-1) during FN (p = 0.01), and returned to 4.1+/-0.2 mg l(-1) at 6 months (p = 0.01). IGF-I correlated with IGFBP-3 (r = +0.7, p < 0.001). Scanning densitometry showed a decrease in IGFBP-3 from 94 to 54% during FN, when the presence of IGFBP-3 protease activity was observed. Compared with normal human serum, IGFBP-2 was elevated throughout the study. IGFBP-1 increased from 14.6+/-3.5 to 30.6+/-2.8 microg l(-1) (p = 0.004), whereas serum insulin decreased from 26.5+/-6.8 to 7.8+/-0.8 mU l(-1) (p = 0.03) before and during FN, respectively. Whilst IGF-I and IGFBP-3 fell, daytime growth hormone increased from 3.3+/-0.6 to 6.7+/-0.8 mU l(-1) (p=0.01), and cortisol from 197+/-48 to 594+/-98 nmol l(-1) (p = 0.005). Albumin decreased from 47+/-2 to 38+/-2 g l(-1) (p = 0.004) and improved to 47+/-2 g l(-1) with recovery (p = 0.003). Protein synthesis increased from 4.5+/-0.4 to 5.0+/-0.6 g kg(-1)d(-1) before chemotherapy and during FN, while protein breakdown rose from 5.4+/-0.4 to 6.3+/-0.4 kg(-1)d(-1). Increasing protein breakdown was related to falling IGF-I and IGFBP-3 levels. Modification of IGFBP-3 by circulating proteolytic activity may alter IGF bioavailability, allowing protein synthesis to increase during periods of severe catabolic stress.

Adolescent↗
PubMed1998

Optimizing growth hormone replacement therapy by dose titration in hypopituitary adults.

Although growth hormone (GH) replacement therapy is increasingly utilized in the management of adult hypopituitary patients, optimum dosing schedules are poorly defined. The use of weight-based or surface area-based dosing may result in overtreatment, and individual variation in susceptibility on the basis of gender and other factors is now being recognized. To optimize GH replacement and to explore further gender differences in susceptibility, we used a dose titration regimen, starting at the initiation of GH replacement therapy, in 50 consecutive adult-onset hypopituitary patients, and compared the results with those in 21 patients previously treated using a weight-based regimen. Titrated patients commenced GH 0.8 IU/day subcutaneously (0.4 IU/day if hypertensive or glucose tolerance impaired). Serum insulin-like growth factor I (IGF-I) was measured at 0, 2, 4, 6, 8, 10, and 12 weeks in all patients. Serum IGF binding protein 3 and acid labile subunit were measured at the same time points in 17 patients (8 male, 9 female). Patients were reviewed every 4 weeks and the dose of GH increased, if necessary, to achieve a serum IGF-I level between the median and the upper end of the age-related reference range. There was no significant difference between mean serum IGF-I at 2 and 4 weeks, or between 6 and 8 weeks, indicating that the full effects of a change in dose are evident within 2 weeks of that change. Maintenance doses were significantly higher in females than males [1.2 (0.8-2.0) vs. 0.8 (0.4-1.6) IU/day; median (range); P < 0.0001], and the median time to achieve maintenance dose was significantly shorter in males [4 (2-12) vs. 9 (2-26) weeks; P < 0.0001]. Median maintenance dose was lower overall than in a group of 21 patients initially commenced on GH using a weight-based dosing schedule, with subsequent adjustment of dose during clinical follow-up [1.5 (0.4-3.2) IU/day; P = 0.02]. Reduction in waist measurement and waist to hip ratio at 6 and 12 months was similar in females (P < 0.001) and males (P < 0.01). Well-being improved significantly after 3 months of GH therapy (14.2 +/- 5.9 vs. 7.4 +/- 4.5 SD; P < 0.0001), and there were no gender differences. Adult Growth Hormone Deficiency Assessment (AGHDA) scores at 6 months were similar to maintenance scores in patients commenced on weight-based regimens. Measurements of ALS and IGFBP-3 added no useful extra information to IGF-I in managing the dose titration. The practical scheme outlined for dose titration of GH replacement resulted in rapid achievement of lower maintenance doses than those achieved using conventional weight-based regimens without loss of efficacy. It was particularly important in female patients who demonstrated decreased overall sensitivity to GH and required higher doses to achieve the same effects as males. This constitutes the first report of a uniform titration regimen based on a defined target range of serum IGF-I in a large patient cohort.

Adolescent↗
PubMed1998

Dose-related effects of growth hormone on IGF-I and IGF-binding protein-3 levels in non-islet cell tumour hypoglycaemia.

Mesenchymal tumours are a well recognised cause of spontaneous hypoglycaemia. The mechanism is thought to relate to hypersecretion by tumour cells of high molecular mass insulin-like growth factor-II (pro-IGF-II), with consequent suppression of growth hormone (GH) secretion. The use of recombinant human (rh)GH has been reported to alleviate hypoglycaemia in non-islet cell tumour hypoglycaemia, and the mechanism is thought to relate to GH-mediated increments in serum levels of IGF-binding protein-3 (IGFBP-3), thereby reducing the bioavailability of IGF-II. We report the effect of increasing doses of rhGH on the clinical condition and serum IGF-I and IGFBP-3 levels in two patients with solitary pleural fibrous tumours causing severe hypoglycaemia. Hypoglycaemia was successfully alleviated in each patient although, despite using large doses of rhGH, the observed increments in IGFBP-3 were only modest. We postulate that the beneficial effects of rhGH in this situation are likely to be multifactorial and not simply related to increments in serum IGFBP-3 levels.

Aged↗
PubMed1998

Nutritional modulation of canine insulin-like growth factors and their binding proteins.

The response of canine insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) to moderate nutritional restriction followed by refeeding has not previously been studied in detail. The purpose of these studies was to examine the effects of nutritional restriction on the IGF system of adult dogs. Normal serum IGF values were established after validation of heterologous RIAs for measuring canine IGFs-I and -II. Canine serum IGFBP profiles were examined by Western ligand blotting (WLB), using radiolabelled recombinant human (rh) IGF-I as the ligand, and were found to be similar to those of other species. IGF-I and IGFBP-3 concentrations correlated with body weight, thus reflecting breed size as previously shown, whereas IGF-II concentrations did not. IGFBP-2 serum concentrations and band intensity on WLB were increased compared with normal human serum IGFBP-2. Overnight fasting had no effect on IGF or IGFBP concentrations, including IGFBP-1, nor did refeeding. Prolonged restriction to 56% and then 42.5% of maintenance energy requirements for 2 weeks decreased IGF-I concentrations by 20.4% and 32.7% respectively. Feeding of the same diet ad libitum for 2 weeks normalised IGF-I concentrations. There were no changes in IGF-II or insulin levels. Serum IGFBP-2 concentrations increased with 56% restriction of maintenance energy (P = 0.03). We conclude that serum IGF-I is potentially a useful marker of short-term change in nutritional status in the adult dog.

Animals↗
PubMed1997

Acromegaly or chronic renal failure: a diagnostic dilemma.

Uraemic patients may have markedly elevated serum GH concentrations yet, for hitherto unknown reasons, they do not develop acromegaly. We discuss the diagnostic dilemma presented by a 33-year-old Caucasian male with chronic renal failure (creatinine clearance 10 ml/min) secondary to polycystic kidney disease, elevated GH concentrations (fasting concentration of 22.6 rising to 77.9 mU/l 30 minutes after a 75-g oral glucose load) as well as acromegalic features. Review of the patient's relatives and the findings of a normal serum IGF-I concentration and a normal pituitary fossa on magnetic resonance imaging, suggest that the patient's acromegalic appearance is a familial trait and his abnormal GH dynamics a result of his renal failure rather than acromegaly. The patient's normal GH bioactivity and reduced GH binding protein concentration supports the current belief that chronic renal failure leads to an increase in peripheral tissue resistance to GH due to decreased GH receptor numbers. These changes, together with reduced IGF-I bioactivity, may explain why patients with chronic renal failure do not develop acromegaly in the presence of abnormally elevated levels of GH.

Acromegaly↗
PubMed1997

Insulin-like growth factor I gene deletion causing intrauterine growth retardation and severe short stature.

The first human case of a homozygous molecular defect in the gene encoding insulin-like growth factor I (IGF-I) is described. The patient was a 15-year-old boy from a consanguineous pedigree who presented with severe intrauterine growth failure, sensorineural deafness and mild mental retardation. Endocrine evaluation of the growth hormone (GH)--IGF-I axis revealed elevated GH secretion, undetectable serum IGF-I and normal serum IGF-binding protein-3, acid-labile subunit, and GH-binding activity. Analysis of the IGF-I gene revealed a homozygous partial IGF-I gene deletion involving exons 4 and 5, which encodes a severely truncated mature IGF-I peptide. This patient demonstrates that complete disruption of the IGF-I gene in man is compatible with life, and indicates a major role for IGF-I in human fetal growth. In addition, his neurological abnormalities suggest that IGF-I may be involved in central nervous system development.

Adolescent↗
PubMed1997

Girls with virilisation in childhood: a diagnostic protocol for investigation.

AIM: To analyse critically a protocol for the investigation of girls presenting with virilisation in childhood. METHODS: Twenty five girls aged 1.6-8.7 years with features of virilisation were evaluated. Twenty four had presented with pubic hair, eight with auxilliary hair, seven with facial acne, four with clitoromegaly, and 10 with tall stature. They underwent clinical assessment (height, weight, height velocity, staging of puberty, physical examination for acne, body odour, and clitoromegaly) and laboratory assessment comprising basal concentrations of cortisol, 17 OH-progesterone (17 OHP), androstenedione, dehydroepiandrosteronesulphate (DHEAS), testosterone, and oestradiol. The above steroids were also measured during the short synacthen test (0.25 mg intramuscularly) in 16 subjects and low dose dexamethasone suppression tests (0.5 mg at six hourly intervals over 48 hours). Pelvic ultrasound, computed tomography and magnetic resonance imaging of adrenals were carried out when the biochemical findings suggested that there might be an autonomous source of androgen secretion. RESULTS: Clinical and laboratory assessments differentiated the patients into three diagnostic categories: adrenarche (18 cases), congenital adrenal hyperplasia (five cases), and adrenocortical tumour (two cases). The last had elevated concentrations of DHEAS, 1.5 and 19.1 mumol/l (normal value < 0.5 mumol/l), androstenedione, 24.6 and 21.8 nmol/l (normal < 1 nmol/l), and testosterone, 4.5 and 2.4 nmol/l (normal < 0.8 nmol/l), with none suppressing on dexamethasone suppression. Congenital adrenal hyperplasia subjects had elevated basal serum concentrations of 17 OHP (n = 4): 250, 140, 14, and 14.1 nmol/l (normal < 10 nmol/l) and elevated peak values of 17 OHP after synacthen (n = 3): 76, 179.5, and 175 nmol/l. Adrenarche patients had elevated basal concentrations of DHEAS (median: 2.3 mumol/l; n = 17) and androstenedione (median 2.6 nmol/l; n = 17). Nine patients also had elevated basal serum testosterone concentrations (median 0.9 nmol/l). Peak values of 17 OHP after synacthen were significantly different from baseline (n = 12) and were < 50% of the lowest value in congenital adrenal hyperplasia. Serum DHEAS, androstenedione, and testosterone suppressed following dexamethasone suppression (n = 16), thereby distinguishing adrenarche patients from adrenal tumour patients. Clinical details did not distinguish patients, except for clitoromegaly which was present only in the tumour and congenital adrenal hyperplasia patients. CONCLUSIONS: This protocol proved useful and practical in cases of virilisation presenting particular diagnostic difficulty.

Adrenal Cortex Neoplasms↗