Insulin-like Growth factor-I Peak Research Articles

Optimal Monitoring of Weekly IGF-I Levels During Growth Hormone Therapy With Once-Weekly Somapacitan.

ContextSomapacitan is a long-acting growth hormone (GH) in development for once-weekly treatment of GH deficiency (GHD). Optimal monitoring of insulin-like growth factor-I (IGF-I) levels must account for weekly IGF-I fluctuations following somapacitan administration.ObjectiveTo develop and assess the reliability of linear models for predicting mean and peak IGF-I levels from samples taken on different days after dosing.DesignA pharmacokinetic/pharmacodynamic model was used to simulate IGF-I data in adults and children following weekly somapacitan treatment of GHD.Setting and Patients39 200 IGF-I profiles were simulated with reference to data from 26 adults and 23 children with GHD.Intervention(s)The simulated dose range was 0.02 to 0.12 mg/kg for adults and 0.02 to 0.16 mg/kg for children. Simulated data with >4 average standard deviation score were excluded.Main Outcome Measure(s)Linear models for predicting mean and peak IGF-I levels based on IGF-I samples from different days after somapacitan dose.ResultsRobust linear relationships were found between IGF-I sampled on any day after somapacitan dose and the weekly mean (R2 > 0.94) and peak (R2 > 0.84). Prediction uncertainties were generally low when predicting mean from samples taken on any day (residual standard deviation [RSD] ≤ 0.36) and peak from samples taken on day 1 to 4 (RSD ≤ 0.34). IGF-I monitoring on day 4 and day 2 after dose provided the most accurate estimate of IGF-I mean (RSD < 0.2) and peak (RSD < 0.1), respectively.ConclusionsLinear models provided a simple and reliable tool to aid optimal monitoring of IGF-I by predicting mean and peak IGF-I levels based on an IGF-I sample following dosing of somapacitan. A short visual summary of our work is available (1).

Are the Effects of Oral and Vaginal Contraceptives on Bone Formation in Young Women Mediated via the Growth Hormone-IGF-I Axis?

Purpose: Combined hormonal contraceptive therapy has been associated with negative bone mineral density outcomes that may be route-dependent [i.e., combined oral contraception (COC) vs. contraceptive vaginal ring (CVR)] and involve the hepatic growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. The objective of the pilot study was to assess the impact of route of contraceptive administration on IGF-I and procollagen type I N-terminal propeptide (PINP) responses to an IGF-I Generation Test. We hypothesized that the peak rise in IGF-I and PINP concentration and area under the curve (AUC) would be attenuated following COC, but not CVR, use.Methods: Healthy, premenopausal women not taking hormonal contraception were recruited. Women were enrolled in the control group (n = 8) or randomly assigned to COC (n = 8) or CVR (n = 8) for two contraceptive cycles. IGF-I Generation Tests were used as a probe to stimulate IGF-I release and were completed during the pre-intervention and intervention phases. Serum IGF-I and PINP were measured during both IGF-I Generation Tests. The study was registered at ClinicalTrials.gov (NCT02367833).Results: Compared to the pre-intervention phase, peak IGF-I concentration in response to the IGF-I Generation Test in the intervention phase was suppressed in the COC group (p < 0.001), but not the CVR or Control groups (p > 0.090). Additionally, compared to the pre-intervention phase, PINP AUC during the intervention phase was suppressed in both COC and CVR groups (p < 0.001), while no difference was observed in the control group (p = 0.980).Conclusion: These data suggest that changes in recombinant human GH-stimulated hepatic IGF-I synthesis in response to combined hormonal contraception (CHC) use are dependent on route of CHC administration, while the influence on PINP is route-independent. Future research is needed to expand these results with larger randomized control trials in all age ranges of women who utilize hormonal contraception.Clinical Trial Registration: www.ClinicalTrials.gov registration NCT02367833.

Progesterone and Insulin‐Like Growth Factor I Levels in Blood of Boer Goats During Puerperium Out‐of‐Season in a Mild Climate Region

The aims of this study were to compare insulin-like growth factor-I (IGF-I) and progesterone concentrations as indicators of cycle activity in the blood of Boer goats during puerperium out-of-season in mild climate conditions and to investigate the influence of parity and litter size on the concentration of IGF-I and progesterone in serum during the study period. Twenty Boer (8 primiparous and 12 pluriparous) goats were examined in this study. Blood samples were taken every 4 days starting on the 3rd day and up to the 40th day of puerperium. IGF-I and progesterone (P4) blood levels were determined using radio immune assay (RIA). Results indicated cyclic ovarian activity outside the breeding season in 18 of 20 Boer goats. IGF-I levels in blood sera followed oestrus and cyclic ovarian activity. IGF-I concentrations correlated significantly with P4 concentrations. The IGF-I peak preceded the P4 peak by approximately 8 days in cycling goats. IGF-I and P4 blood levels were not influenced by parity or litter size. Changes in blood serum P4 and IGF-I concentrations levels during puerperal period can assist in the evaluation of reproductive status of goats.

Insulin-like growth factor-I (IGF-I) serum concentrations in healthy children and adolescents: Relationship to level of contamination by DDT-derivative pesticides

Context Serum levels of Insulin-like growth factor I (IGF-I) play a critical role in children growth and in the pathogenesis of several diseases. In addition, recent studies suggest that DDT-derivative organochlorine pesticides (OC–DDTs) could influence IGF levels in human beings. Objective and design Because it has been suggested that IGF-I peak levels at puberty could determine IGF-I levels in adulthood, we developed a cross-sectional study of the potential association between serum levels of OC–DDTs and IGF system in 160 serum samples from young people (81 boys and 79 girls) living in the Canary Islands (Spain). Results Multivariate tests were used adjusting for confounding variables (age, height, and weight) and stratifying by gender and age: IGF-I serum levels were significantly lower in pre-pubertal male children (6–15 years) who showed detectable values of p, p′-DDE, and p, p′-DDD than in pre-pubertal male children with undetectable levels of these OC–DDTs-metabolites ( p = 0.023 and p = 0.049, respectively). In addition, in this multivariate model, a non-linear dose–response curve was observed between Total DDT body burden (sum of the three DDT-derivatives measured: p, p′-DDT, p, p′-DDE, and p, p′-DDD) and IGF-I in pre-pubertal male children (6–15 years; p = 0.043). Conclusion These findings suggest that OC–DDTs could modulate the IGF-system in a way that is highly influenced by gender and age. Improvements in our understanding of exogenous determinants of the IGF-system may provide new insights into the role played by environmental contaminants in IGF-related diseases.

The insulin-like growth factor-I (IGF-I) generation test as an indicator of growth hormone status

The aim of the study was to evaluate the IGF-I generation test (IGF-I gen) as a possible indirect test of Growth Hormone (GH) secretory status. Sixty-five GH deficient (GHD 1 and 2) and 86 control children were studied. Children in the GHD-1 subgroup (n=33) had low GH values (<10 microg/L) after clonidine and levo-dopa while those in the GHD-2 subgroup (n=32) had normal GH values after pharmacologic provocation but low 24-hour GH secretory rates compared to 187 Normal Statured (NS) children. Of the 86 controls, who underwent IGF-I gen,50 were NS and 36 Short-Statured (SS). Serum IGF-I was measured prior to and daily during hGH administration (hGH 0.033 mg/kg/dayx4 days). The prepubertal and pubertal GHD-1 and GHD-2 children had low baseline IGF-I values but their peak IGF-I values during the IGF-I gen reached those of the controls. The percent increase of IGF-I during the test was greater in the GHD groups than in the controls; in the prepubertal groups: 516+/-58% in the GHD-1, 433+/-50% in the GHD-2, 106+/-12% in the NS, and 102+/-18% in the SS (p=0.001); in the pubertal groups: 191+/-28% in the GHD-1, 141+/-20% in the GHD-2, 48+/-8% in the NS, and 61+/-17% in the SS (p=0.003). The IGF-I response during the IGF-I gen seems to reflect the GH status in children.

Physical Effects of Short-Term Recombinant Human Growth Hormone Administration in Abstinent Steroid Dependency

Background/Aims: Recombinant human growth hormone (rhGH) as opposed to cadaver pituitary GH is misused for physical improvement. Six days’ rhGH administration, in abstinent anabolic-androgenic steroid dependents, was compared with controls. Method: Male subjects (n = 48) were randomly divided into two groups: (1): control group (C), n = 24, mean ± SD, age 32 ± 11 years, height 1.8 ± 0.06 m; (2): rhGH-using group (0.058 IU·kg^–1·day^–1) (GH), n = 24, mean ± SD, age 32 ± 9 years, height 1.8 ± 0.07 m. Physiological measurements included anthropometry, strength, power and peak oxygen uptake (VO₂ peak). Biochemical measurements included haemoglobin, packed cell volume, glucose, sodium, potassium, urea, creatinine, total protein, albumin, thyroid function, testosterone, prolactin, cortisol, GH and insulin-like growth factor-I (IGF-I). Results: Strength, peak power output and IGF-I significantly increased and total protein, albumin and free tetra-iodothyronine significantly decreased compared to controls (p < 0.05) and within the GH group (p < 0.017). Fat-free mass index and VO₂ peak significantly increased, while body fat and thyroid-stimulating hormone significantly decreased within the GH group (p < 0.017). Conclusions: Short-term rhGH increased strength and power. Of therapeutic value is the possibility that muscle bulk and strength could be increased in patients with muscle-wasting conditions.

Linear Growth, Growth-Hormone Secretion and IGF-I Generation in Children with Neglected Hypothyroidism Before and After Thyroxine Replacement

We studied growth hormone (GH) stimulation and insulin-like growth factor -I (IGF-I) generation tests in 15 children with neglected congenital hypothyroidism (CH) (age = 6.4 +/- 4.2 years) and measured their growth parameters for >1 years after starting thyroxine (T4) replacement. One year after treatment, height SDS (HtSDS) increased from -4.3 +/- 2.5 to -2.7 +/- 2.3. Peak GH response to clonidine increased from 3.2 +/- 1.2 ng ml(-1) to 7.62 +/- 1.38 ng ml(-1) after treatments. Basal and peak IGF-I response to GH increased from (34.66 +/- 17.3 ng ml(-1) and 58.4 +/- 36.99 ng ml(-1), respectively) before treatment to (130.6 +/- 97.8 ng ml(-1) and 193.75 +/- 122.5 ng ml(-1), respectively). HtSDS increments were correlated significantly with basal free T4 concentrations (r = 0.622, P < 0.01). In summary, after long period of hypothyroidism, T4 replacement produced significant, although incomplete, catch-up growth through a partial recovery of GH- IGF-I axis.

Serum IGF-I and IGFBP-3 Levels of Turkish Children during Childhood and Adolescence: Establishment of Reference Ranges with Emphasis on Puberty

Aims/Methods: We established age- and sex-related reference ranges for serum insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) levels in 807 healthy Turkish children (428 boys, 379 girls), and constructed a model for calculation of standard deviation scores of IGF-I and IGFBP-3 according to age, sex and pubertal stage. Results: Serum IGF-I and IGFBP-3 concentrations tended to be higher in girls compared to boys of the same ages, but the differences were statistically significant only in pubertal ages (9–14 years) for IGF-I and only in prepubertal ages for IGFBP-3 (6–8 years) (p < 0.05). Peak IGF-I concentrations were observed earlier in girls than boys (14 vs. 15 years, Tanner stage IV vs. V) starting to decline thereafter. IGFBP-3 levels peaked at age 13 and at Tanner stage IV in both sexes with a subsequent fall. Serum levels of IGF-I and IGFBP-3 increased steadily with age in the prepubertal stage followed by a rapid increase in IGF-I in the early pubertal stages. A relatively steeper increase in IGF-I but not in IGFBP-3 levels was observed at age 10–11 years in girls and at 12–13 years in boys which preceded the reported age of pubertal growth spurt. At late pubertal stages, both IGF-I and IGFBP-3 either did not change or decreased by increasing age. Interrelationships between growth factors and anthropometric measurements have been described, and the physiologic consequences of these have been discussed in detail. Conclusions: Differences in the pattern of IGF-I and IGFBP-3 in the present paper and those reported in other studies emphasize the importance of locally established reference ranges. Establishment of this reference data and a standard deviation score prediction model based on age, sex and puberty will enhance the diagnostic power and utility of IGF-I and IGFBP-3 in evaluating growth disorders in our population.

Pharmacodynamic Considerations with Recombinant Human Insulin-Like Growth Factor-I in Children

To report effects of weight-based recombinant human insulin-like growth factor-I (rhIGF-I) on IGF axis parameters in children with hyperinsulinism.Open label trial with subcutaneous rhIGF-I (40 microg/kg/dose). Patients studied were children (1 month to 11 years) with diffuse hyperinsulinism (n = 7). Serial serum IGF and insulin-like growth factor binding protein (IGFBP) concentrations were measured by RIA and analyzed by linear Pearson regression.Following the initial rhIGF-I dose, total insulin-like growth factor-I (IGF-I) rose by 56% at 30 min (p < 0.01) and 85% at 120 min (p < 0.02). Serum IGF-II, IGFBP-2, and IGFBP-3 levels did not change. Peak serum IGF-I levels within 12 h of the initial rhIGF-I dose were 167-700 mg/ml. The variable peak IGF-I response is attributable in part to IGFBP-3 differences across this pediatric age range. Models of rhIGF-I dosing based upon body surface area (BSA) or initial IGFBP-3 resulted in predictable peak serum IGF-I levels (r = 0.78; p < 0.03). Recalculating rhIGF-I dosing based upon the BSA . IGFBP-3 product correlated closely with peak IGF-I level (r = 0.85; p < 0.007).Weight-based IGF-I dosing in this cohort resulted in variable IGF-I levels. Considering BSA and serum IGFBP-3 concentration in children is appropriate for subcutaneous IGF-I administration. A combination of these values may yield predictable individualization of rhIGF-I dosing.

Characterization of subcutaneous Contramid® implantation: host response and delivery of a potent analog of the growth hormone-releasing factor

Cross-linked high amylose starch (Contramid®) was investigated as a solid implant for evaluation of host response in mice and as a possible delivery system for a human growth hormone-releasing factor analog (Hex-hGRF) release profile in pigs. Seventy mice were administered subcutaneously one 3 mm diameter Contramid® pellet and host reaction was evaluated over 6 months. Thirty pigs were divided into four groups. All animals of the three implanted groups were administered subcutaneously 15 mg Hex-hGRF, (1) one pure Hex-hGRF implant; (2) four 30/70 w/w Hex-hGRF/Contramid® implants; or (3) eight 15/85 w/w Hex-hGRF/Contramid® implants. The fourth group ( n=6) was injected subcutaneously twice daily with 10 μg/kg of Hex-hGRF over 5 consecutive days. Serum insulin-like growth factor-I (IGF-I) was monitored over 1 month. In mice, no adverse reaction occurred after implantation. Macroscopic and microscopic inflammatory reactions were always localized. Polymorphonuclear cells (PMNs) and macrophages predominated within and around the pellets, respectively. Thin fibrovascular septas eventually subdivided Contramid® pellets which were progressively phagocytosed by macrophages. In pigs, serum IGF-I concentrations were increased over a 10 day period in all implanted groups. The initial IGF-I peak observed in the daily injected group was avoided in both Contramid® implant groups but not in the pure Hex-hGRF implant group. These encouraging results warrant the development of Contramid® implants as a sustained delivery system for peptidic drugs.

Plasma insulin-like growth factor-I concentrations increase during the estrous phase in goats

The objective of this study was to characterize plasma insulin-like growth factor-I (IGF-I) profiles during the estrous cycle in goats. Frequent blood samples were drawn during the day of estrus and during the luteal phase on Day 10 after estrus, and plasma growth hormone (GH) and IGF-I profiles were examined. Then, daily blood samples were drawn throughout the estrous cycle or during induction of estrus by prostaglandin F 2α (PGF 2α) to further clarify the IGF-I profiles. GH was secreted in an episodic manner in the estrous and luteal phases in goats. There were no significant differences in the mean concentrations, pulse amplitude and pulse frequency of GH between the estrous and luteal phases. IGF-I concentrations during estrous phase were higher than those in the luteal phase (P < 0.05). Plasma IGF-I increased approximately two days before behavioral estrus, and the IGF-I peak was observed in accordance with the appearance of estrus. The elevated IGF-I levels then declined to basal values 4 to 5 days after estrus. When estrus was induced by PGF 2α, plasma IGF-I concentrations increased after treatment, and the concentration 2 days after treatment (day of appearance of behavioral estrus) was significantly higher than concentrations before treatment (P < 0.05). The elevated IGF-I levels then declined during the 3 days after treatment. These results indicate that plasma IGF-I concentrations increase during estrus in goats.

Systemic and splanchnic metabolic response to exogenous human growth hormone

Background: Evidence exists indicating that growth hormone (GH) resistance in some disease states such as hypercatabolic conditions may limit the metabolic benefit associated with recombinant human growth hormone (rhGH) administration. It was the purpose of this study to compare the systemic and splanchnic effects of rhGH in patients with sepsis exhibiting systemic inflammatory response syndrome (SIRS) with the response observed in normal volunteers. Because insulin-like growth factor I (IGF-I) is believed to be the dominant factor responsible for the anabolic effects of rhGH, particular attention was given to this secondary effector. Methods: The systemic and splanchnic effects of rhGH (0.15 mg/kg/day) were studied in normal volunteers (n = 5), critically ill patients with sepsis exhibiting SIRS (n = 6), and patients with sepsis exhibiting SIRS while receiving total parenteral nutrition (n = 6). Basal and end study IGF-I, urinary urea excretion, hepatic blood flow, hepatic venous oxygen content, and splanchnic oxygen exchange were measured after a 48-hour course of rhGH. Results: Fasting basal IGF-I concentrations were reduced by 75% to 83% in patients with sepsis/SIRS relative to normal control subjects. After 48 hours of rhGH, peak IGF-I concentrations were 74% and 76% lower in patients in the Sepsis/SIRS and Sepsis/SIRS + Nutrition groups, respectively, compared with normal control subjects. Despite the attenuated IGF-I rise in patients, urea excretion declined by a similar magnitude in all three groups. Hepatic blood flow remained unaffected, but rhGH administration increased splanchnic oxygen consumption in all groups (control, +57%*; Sepsis/SIRS, +13%; Sepsis/SIRS + Nutr, +42%*; *p < 0.05 relative to corresponding basal) resulting in a decline of basal to end therapy hepatic venous oxygen saturation (control, 67 ± 4% to 62 ± 11%; Sepsis/SIRS, 51% ± 14% to 43% ± 14%*; Sepsis/SIRS + Nutr, 62% ± 11% to 55% ± 16%; *p < 0.05 relative to corresponding control value), suggesting that rhGH may induce centrilobular hepatic hypoxia, which may contribute to the diminished IGF-I response. Conclusions: Although critically ill patients exhibit an IGF-I increase in response to exogenous rhGH, the rise is markedly attenuated compared with healthy volunteers, indicating the presence of GH resistance. Unexpectedly, the changes in the anabolic hormone IGF-I did not appear to be related to the reduction in urea excretion. This may provide some additional evidence for IGF-I resistance. Finally, rhGH is associated with an augmented splanchnic oxygen consumption but no corresponding increase in regional blood flow. As a result, regional tissue hypoxia may arise and contribute to the impaired or suboptimal IGF-I response pattern. (Surgery 1998;123:528-38.)

National Cooperative Growth Study substudy VI: The clinical utility of growth-hormone–binding protein, insulin-like growth factor I, and insulin-like growth factor–binding protein 3 measurements

Objective: To assess the clinical utility of growth-hormone–binding protein (GHBP), along with growth hormone (GH), insulin-like growth factor I (IGF-I), and insulin-like growth factor–binding protein 3 (IGFBP-3), levels in the evaluation of short stature. Study design: Prospective substudy of the National Cooperative Growth Study, a multicenter observational study. Results: A total of 6447 assessable subjects undergoing workup for short stature were enrolled at 197 sites. At baseline the cause of short stature was undefined in 77% of subjects. Mean GHBP levels were lowest in subjects with renal disease and highest in those with Turner syndrome. No cases of complete GH insensitivity syndrome (Laron syndrome) were identified. Subjects with low GHBP levels were among those tested for GH receptor mutations. IGF-I standard deviation scores (SDS) and IGFBP-3 SDS were positively correlated; both increased during GH therapy. There was a weak positive correlation between log peak GH levels and both IGF-I SDS and IGFBP-3 SDS and a weak negative correlation between log peak GH levels and GHBP SDS. Mean changes in GHBP SDS in subjects treated with GH and untreated subjects were not significant. Change in height SDS in subjects treated with GH was negatively correlated with age and IGF-I level but not correlated with baseline GHBP SDS. Conclusion: GHBP levels are GH independent and not predictive of responses to GH therapy, although low GHBP levels may indicate GH receptor abnormalities and partial GH insensitivity. (J Pediatr 1997;131:S56-60)

Localization of insulin-like growth factor-I (IGF-I) and -II messenger ribonucleic acid and type 1 IGF receptors in the ovine uterus during the estrous cycle and early pregnancy.

Insulin-like growth factor-I (IGF-I), IGF-II, and the type 1 IGF receptor (IGF-IR) gene transcripts were localized in sections of ovine uterus collected from 53 ewes at different stages during the estrous cycle and the first 3 weeks of pregnancy using in situ hybridization with synthetic oligonucleotides. Binding studies on cryostat sections using [125I]IGF-I or [125I]des(1-3)IGF-I were carried out to assess whether binding sites for IGF-I colocalized with sites of IGF-IR gene transcription. Peak IGF-I mRNA concentrations occurred at estrus in both the periepithelial endometrial stromal cells and the longitudinal and circular muscle cells of the myometrium. Concentrations of transcript returned to basal levels by 48 h after estrus. The variations in IGF-I mRNA concentration during the estrous cycle showed significant correlations with the estradiol receptor concentration in the same cell types, measured in the same animals by immunocytochemistry (P < 0.01). IGF-II mRNA was localized exclusively to the caruncular stroma (high transcription) and endometrial stroma (low transcription), with levels showing no positive correlation to the concentration of estradiol receptors, progesterone receptors, or plasma progesterone, but decreasing gradually between estrus and days 14-15 (P < 0.05). IGF-IR mRNA was localized mainly to the deep and superficial glandular epithelium, with lower levels of transcription in the caruncular stroma and myometrium. Transcription in the deep glands remained high throughout the cycle, but in the superficial glands and myometrium, a small peak occurred in the early luteal phase (days 1-2), 24-48 h after peak IGF-I gene transcription. [125I]IGF-I- and des(1-3)IGF-I-binding sites colocalized with sites of IGF-IR gene transcription. Additional binding sites were revealed with the iodinated ligands in the myometrium, superficial glands, deep stroma, and blood vessel walls, which were probably attributable to the presence of binding proteins (IGFBPs). The different affinities of des(1-3)IGF-I for IGFBP-3, -2, and -1 lead us to suggest that IGFBP-2 and/or -1 are present in the deep stroma and glands, whereas IGFBP-3 may be responsible for the additional binding sites in the myometrium and blood vessel walls. Comparisons between pregnant and nonpregnant ewes on days 2-15 after estrus did not reveal any clear pregnancy-associated differences in either the sites or levels of IGF-I, IGF-II, or IGF-IR gene transcription.

Serum insulin-like growth factor-I in 1030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size, and body mass index.

Serum levels of insulin-like growth factor-I (IGF-I) increase with age and pubertal development. The large variation in circulating IGF-I levels in adolescence makes it difficult to use the IGF-I value of a single child in the assessment of his growth status. In addition, the interference of IGF-binding proteins in many IGF-I assays contributes to this problem. We measured IGF-I in acid-ethanol-extracted serum from 1030 healthy children, adolescents, and adults, employing a RIA that reduces interference of IGF-binding proteins by using monoiodinated Tyr31-[125I]des-(1-3)IGF-I as radioligand. Mean serum IGF-I concentrations increased slowly in prepubertal children from 80-200 micrograms/L with a further steep increase during puberty to approximately 500 micrograms/L. After puberty, a subsequent continuous fall in circulating IGF-I levels was apparent throughout adulthood to a mean of 100 micrograms/L at the age of 80 yr (P < 0.0001). Girls had maximal IGF-I levels at 14.5 yr of age, whereas boys had peak IGF-I levels 1 yr later. This is almost 2 yr later than average peak height velocity. The large variation in serum IGF-I levels during puberty was diminished when data were separated according to sex and Tanner stage of puberty. Interestingly, we found a significant variation with age within the Tanner stages; there was an increase in serum IGF-I concentrations with age in the early pubertal stages and a decrease in the late stages (P < 0.05). Serum IGF-I increased concomitantly with increasing testicular volume. Multiple regression analysis revealed that serum IGF-I levels predicted height velocity in the following year (r = 0.33; P < 0.0001). Body mass index did not correlate significantly with serum IGF-I in prepubertal children in a multiple regression analysis. In conclusion, there was a significant variation in serum IGF-I levels with age within a given Tanner stage of puberty in addition to the well known increase with increasing age or pubertal stage. Accordingly, the effects of sex, age, and puberty on serum IGF-I cannot be separated into simple additive components when studying 1030 children in a cross-sectional design. Thus, the age-, sex-, and puberty-corrected IGF-I values may, in fact, improve the use of serum IGF-I as a diagnostic tool to distinguish between a child with retarded puberty and a GH-deficient individual.

Effect of dietary protein intake and intravenous glucose infusion on plasma concentrations of insulin-like growth factor-I in lambs.

Two separate experiments were carried out to examine the effect of dietary protein intake on basal and GH-stimulated plasma insulin-like growth factor-I (IGF-I) concentrations during either saline or glucose infusion into the jugular vein. In experiment 1, six castrated male lambs (27.1 +/- 1.2 kg live weight (LW)) were fed a diet restricted in both metabolizable energy (ME; 0.18 MJ/kg LW per day) and nitrogen (2.0 g/kg LW per day) intakes, while in experiment 2 a further six lambs were fed a similar restricted ME intake but an increased nitrogen intake (3.0 g/kg LW per day). In both experiments glucose (experiment 1, 0.009 mmol/kg LW per min; experiment 2, 0.015 mmol/kg LW per min) or saline (0.25 ml/min) was infused for 6 days and plasma samples were obtained from the jugular vein at hourly intervals on day 4 (basal) or on days 5 and 6 after an i.v. GH challenge. In experiment 1 there was no increase in plasma IGF-I concentrations in response to the GH challenge during saline infusion, but during glucose infusion the plasma concentration of IGF-I increased to a peak after 24 h and declined over the next 20 h. Basal concentrations of IGF-I, insulin and glucose were significantly higher during glucose infusion. In experiment 2 the area under the IGF-I peak in response to the GH challenge was the same for the infusions of saline and glucose but the peak value for IGF-I was significantly higher during glucose infusion due to higher concentrations in the basal period.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma clearance of chicken and human insulin-like growth factor-I and their association with circulating binding proteins in chickens

We have investigated the clearance of 125I-labelled chicken and recombinant human insulin-like growth factor-I (IGF-I) from the circulation of chickens as well as the role that IGF-binding proteins play in this process. Analysis of plasma samples by high-performance liquid chromatography (HPLC) neutral gel permeation on a TSK G3000SW column indicated that the i.v. injected radioactivity was rapidly partitioned between at least three pools. Most of the radioactivity occurred in a complex with binding protein(s), while smaller amounts of radioactivity chromatographed in the free IGF-I peak or appeared as low molecular weight degradation products. The labelled chicken and human IGF-I were rapidly cleared during the first 90 min. The calculated half-life for total labelled IGF-I during this period was 54 min for the chicken tracer and 33 min for the human tracer. The clearance was monitored for 10 h during which the human tracer continued to be cleared more rapidly than the chicken tracer. The proportion of radioactivity appearing as low molecular weight degradation products increased with time. Acid gel permeation and reverse-phase HPLC of the binding protein-associated radioactivity demonstrated that the labelled IGF-I bound was intact IGF-I. Sephadex G-200 gel permeation chromatography of chicken plasma samples at pH 7 x 4 showed that the binding protein complex labelled in vivo with chicken IGF-I tracer had a molecular mass of 55 kDa. Furthermore, the tracer associated with the binding protein coeluted with the major peak of endogenous IGF-I, suggesting that the tracer was bound to the physiologically relevant binding protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin-like growth factor-I concentration in Holstein female cattle: variations with age, stage of lactation and growth hormone-releasing factor administration

Plasma insulin-like growth factor-I (IGF-I) concentrations were monitored in Holstein females through different periods of their growth, lactation and after acute or chronic growth hormone-releasing factor (GRF) administration. Plasma samples were radioimmunoassayed using a human IGF-I antibody after a 24 hr incubation in a HC1(.1N)-glycine(.2M) buffer (pH 2). In a first study, IGF-I concentrations were measured in Holstein females of different ages and(or) stages of lactation (n = 6 per group). The IGF-I concentrations in newborn calves (102.0 ± 11.3 ng/ml) markedly decreased (P<.01) in 1 mo old animals (50.2 ± 7.1 ng/ml), then increased (P<.01) to 137.0 ± 5.1 and 137.4 ± 11.0 ng/ml in 6 and 10 mo old heifers, respectively. In dairy cows, IGF-I concentrations were low 24 hr post-partum (44.7 ± 7.6 ng/ml) and then increased (P<.05) to remain stable throughout lactation (91.3 ± 4.9, 92.8 ± 12.9, 96.1 ± 7.6, 90.7 ± 8.8 ng/ml at 2, 3, 6 and 9 mo of lactation, respectively). There was a further increase (P<.05) to 113.7 ± 3.1 ng/ml during the dry period. In a second trial, blood samples were collected from lactating dairy cows every 2 hr for 24 hr following a sc injection of saline (n = 4) or human (h) GRF (1–29)NH 2 (10 μg/kg BW, n = 4). The IGF-I peak concentration was reached on average 10 hr after the GRF injection and was higher (P<.01) in treated cows than in control cows (135.4 vs 86.9 ± 16.2 ng/ml). In the last trial, daily sc injections of 10 μg of hGRF(1–29)NH 2 per kg BW to dairy cows (252 days of lactation) for 57 days, which increased milk production by 14% (2 kg/day), also increased (P<.01) IGF-I concentration: 127.1 ± 5.3 and 118.0 ± 1.6 vs 90.7 ± 4.7 and 96.0 ± 5.0 ng/ml on days 29 and 57 of treatment for treated (n = 9) and control (n = 8) cows, respectively. Thus, the IGF-I concentration in dairy cattle varies with age and stage of lactation, and is increased by GRF administration in lactating dairy cows.

Binding protein, radioreceptor and biological activities of recombinant methionyl insulin-like growth factor-I variants

Reversed-phase chromatography (RFC) was used to resolve two variants of recombinant amino terminal methionyl residue (TV-Met) insulin-like growth factor-I (IGF-I) with the same amino acid constitution but different disulphide linkages. Following radioiodination, equilibration with plasma and size exclusion chromatography at neutral pH the major form on RPC (approximate abundance 60%) demonstrated > 80% binding to 150 kDa and 40–50 kDa IGF binding proteins. This peptide has the RPC elution characteristics and disulphide assignment (Cys 6-Cys 48, Cys 18-Cys 61, Cys 47-Cys 52) of authentic IGF-I (termed TV-Met IGF-I peak 2 peptide). By contrast, a second peptide (approximate abundance 25%) with mismatched disulphides (Cys 6-Cys 47, Cys 18-Cys 61, Cys 48-Cys 52; N-Met IGF-I peak 1 peptide) demonstrated < 15% binding under similar conditions. Potency of the peptides was investigated in competitive IGF-I plasma binding protein and L6 myoblast radioreceptor assays. The peak 2 peptide proved equipotent to purified ovine plasma IGF-I in each system but by contrast the peak 1 peptide was 40-fold and 200-fold less potent in the binding protein and radioreceptor assays respectively. Biological potency was examined in a non-competitive assay based on incorporation of [ 3H]leucine into confluent cultures of L6 myoblasts. In this system the N-Met IGF-I peak 1 peptide proved 15-fold less potent than the peak 2 peptide with correct disulphide linkages. Refolding variants may prove useful in establishing structure/function relationships for IGF-I.