Mean IGF-I Concentrations Research Articles

Infections and systemic inflammation are associated with lower plasma concentration of insulin-like growth factor I among Malawian children

ABSTRACTBackgroundInsulin-like growth factor I (IGF-I) is the most important hormonal promoter of linear growth in infants and young children.ObjectivesThe objectives of this study were to compare plasma IGF-I concentration in a low- compared with a high-income country and characterize biological pathways leading to reduced IGF-I concentration in children in a low-income setting.MethodsWe analyzed plasma IGF-I concentration from 716 Malawian and 80 Finnish children at 6–36 mo of age. In the Malawian children, we studied the association between IGF-I concentration and their environmental exposures; nutritional status; systemic and intestinal inflammation; malaria parasitemia and viral, bacterial, and parasitic enteric infections; as well as growth at 18 mo of age. We then conducted a pathway analysis to identify direct and indirect associations between these predictors and IGF-I concentration.ResultsThe mean IGF-I concentrations were similar in Malawi and Finland among 6-mo-old infants. At age 18 mo, the mean ± SD concentration was almost double among the Finns compared with the Malawians [24.2 ± 11.3 compared with 12.5 ± 7.7 ng/mL, age- and sex-adjusted difference in mean (95% CI): 11.8 (9.9, 13.7) ng/mL; P < 0.01]. Among 18-mo-old Malawians, plasma IGF-I concentration was inversely associated with systemic inflammation, malaria parasitemia, and intestinal Shigella, Campylobacter, and enterovirus infection and positively associated with the children's weight-for-length z score (WLZ), female sex, maternal height, mother's education, and dry season. Seasonally, mean plasma IGF-I concentration was highest in June and July and lowest in December and January, coinciding with changes in children's length gain and preceded by ∼2 mo by the changes in their WLZ.ConclusionsThe mean plasma IGF-I concentrations are similar in Malawi and Finland among 6-mo-old infants. Thereafter, mean concentrations rise markedly in Finland but not in Malawi. Systemic inflammation and clinically nonapparent infections are strongly associated with lower plasma IGF-I concentrations in Malawi through direct and indirect pathways.

The effect of growth hormone on bioactive IGF in overweight/obese women

ObjectiveOverweight/obesity is characterized by decreased growth hormone (GH) secretion whereas circulating IGF-I levels are less severely reduced. Yet, the activity of the circulating IGF-system appears to be normal in overweight/obese subjects, as estimated by the ability of serum to activate the IGF-I receptor in vitro (bioactive IGF). We hypothesized that preservation of bioactive IGF in overweight/obese women is regulated by an insulin-mediated suppression of IGF-binding protein-1 (IGFBP-1) and IGFBP-2, and by suppression of IGFBP-3, mediated by low GH. We additionally hypothesized that increases in bioactive IGF would drive changes in body composition with low-dose GH administration. DesignCross-sectional analysis and 3-month interim analysis of a 6-month randomized, placebo-controlled study of GH administration in 50 overweight/obese women without diabetes mellitus. Bioactive IGF (kinase receptor activation assay) and body composition (DXA) were measured. ResultsPrior to treatment, IGFBP-3 (r = −0.33, p = 0.02), but neither IGFBP-1 nor IGFBP-2, associated inversely with bioactive IGF. In multivariate analysis, lower IGFBP-3 correlated with lower peak stimulated GH (r = 0.45, p = 0.05) and higher insulin sensitivity (r = −0.74, p = 0.003). GH administration resulted in an increase in mean serum IGF-I concentrations (144 ± 56 to 269 ± 66 μg/L, p < 0.0001) and bioactive IGF (1.29 ± 0.39 to 2.60 ± 1.12 μg/L, p < 0.0001). The treatment-related increase in bioactive IGF, but not total IGF-I concentration, predicted an increase in lean mass (r = 0.31, p = 0.03) and decrease in total adipose tissue/BMI (r = −0.43, p = 0.003). ConclusionsOur data suggest that in overweight/obesity, insulin sensitivity and GH have opposing effects on IGF bioactivity through effects on IGFBP-3. Furthermore, increases in bioactive IGF, rather than IGF-I concentration, predicted GH administration-related body composition changes.Clinical Trial Registration Number: NCT00131378.

Circulating concentrations of insulin‐like growth factor‐I, insulin‐like growth factor‐binding protein‐3, genetic polymorphisms and mammographic density in premenopausal Mexican women: Results from the ESMaestras cohort

The insulin-like growth factor (IGF) axis plays an essential role in the development of the mammary gland. High circulating levels of IGF-I and of its major binding protein IGFBP3 have been related with increased mammographic density in Caucasian premenopausal women. Some common single nucleotide polymorphisms (SNPs) in genes of the IGF pathway have also been suggested to play a role in mammographic density. We conducted a cross-sectional study nested within the large Mexican ESMaestras cohort to investigate the relation between circulating levels of IGF-I, IGFBP-3, the IGF-I/IGFBP-3 ratio, five common SNPs in the IGF-1, IGFBP-3 and IGF-1R genes and mammographic density in 593 premenopausal Mexican women. Mean age at mammogram was 43.1 (standard deviation, SD = 3.7) years, and average body mass index (BMI) at recruitment was 28.5 kg/m(2). Mean percent mammographic density was 36.5% (SD: 17.1), with mean dense tissue area of 48.3 (SD: 33.3) cm(2) . Mean IGF-I and IGFBP-3 concentrations were 15.33 (SD: 5.52) nmol/l and 114.96 (SD: 21.34) nmol/l, respectively. No significant associations were seen between percent density and biomarker concentrations, but women with higher IGF-I and IGF-I/IGFBP-3 concentrations had lower absolute dense (p(trend) = 0.03 and 0.09, respectively) and nondense tissue areas (p(trend) < 0.001 for both parameters). However, these associations were null after adjustment by BMI. SNPs in specific genes were associated with circulating levels of growth factors, but not with mammographic density features. These results do not support the hypothesis of a strong association between circulating levels of growth hormones and mammographic density in Mexican premenopausal women.

Response to divergent selection for insulin-like growth factor-I concentration and correlated responses in growth traits in Angus cattle

A divergent selection experiment for serum IGF-I concentration was established in 1989 at the Eastern Agricultural Research Station located in Belle Valley, Ohio. One hundred spring-calving (50 high line and 50 low line) and 100 fall-calving (50 high line and 50 low line) cows with unknown IGF-I concentrations were randomly assigned to the 2 divergent selection lines. Results of this study included 2,507 calves from the 1989 through 2005 calf crops. (Co)variance components were estimated for direct and maternal additive genetic effects using an animal model and multiple-trait, derivative-free, REML (MTDFREML) computer programs. Estimated breeding values were also obtained and regressed on years to estimate direct and correlated responses to divergent selection for serum IGF-I concentration. Estimates of direct heritability for growth traits from a single trait model were moderate and ranged from 0.33 ± 0.06 for birth weight to 0.42 ± 0.06 for preweaning BW gain. Heritability estimates for direct effects were 0.44 ± 0.07, 0.43 ± 0.07, 0.35 ± 0.06, and 0.48 ± 0.07 for IGF-I concentration at d 28, 42, and 56 of the 140-d postweaning period, and for mean IGF-I concentration, respectively. Maternal heritability and the proportion of phenotypic variance due to permanent environment effect of dam were ≤0.25 for growth traits and IGF-I concentrations. Cattle in the high line had significantly (P < 0.001) greater direct effects of mean IGF-I concentration than those in low line (high line: 66.92 ± 4.40 ng/mL vs. low line: -40.82 ± 5.18 ng/mL) in 2005. Direct responses per year for mean IGF were 5.18 ng/mL in the high line and -3.76 ng/mL in the low line. The regression of direct effects of preweaning BW gain on year were not significantly different from zero in either the high or low line. However, genetic trends were negative and significant for birth weight and postweaning BW gain in the high line and were positive and significant in the low line. Results demonstrated that divergent selection for serum IGF-I concentration in beef cattle will change the genetic potential for IGF-I concentration and that selection for lesser IGF-I concentration will result in increased birth weights and postweaning BW gains.

Postnatal Decrease in Circulating Insulin-Like Growth Factor-I and Low Brain Volumes in Very Preterm Infants

IGF-I and IGF binding protein-3 (IGFBP-3) are essential for growth and maturation of the developing brain. The aim of this study was to evaluate the association between postnatal serum concentrations of IGF-I and IGFBP-3 and brain volumes at term in very preterm infants. Fifty-one infants with a mean (sd) gestational age (GA) of 26.4 (1.9) wk and birth weight (BW) of 888 (288) g were studied, with weekly blood sampling of IGF-I and IGFBP-3 from birth until 35 gestational weeks (GW) and daily calculation of protein and caloric intake. Magnetic resonance images obtained at 40 GW were segmented into total brain, cerebellar, cerebrospinal fluid, gray matter, and unmyelinated white matter volumes. We evaluated brain growth by measuring brain volumes using magnetic resonance imaging. Mean IGF-I concentrations from birth to 35 GW correlated with total brain volume, unmyelinated white matter volume, gray matter volume, and cerebellar volume [r = 0.55 (P < 0.001); r = 0.55 (P < 0.001); r = 0.44 (P = 0.002); and r = 0.58 (P < 0.001), respectively]. Similar correlations were observed for IGFBP-3 concentrations. Correlations remained after adjustment for GA, mean protein and caloric intakes, gender, severe brain damage, and steroid treatment. Protein and caloric intakes were not related to brain volumes. Infants with BW small for GA had lower mean concentrations of IGF-I (P = 0.006) and smaller brain volumes (P = 0.001-0.013) than infants with BW appropriate for GA. Postnatal IGF-I and IGFBP-3 concentrations are positively associated with brain volumes at 40 GW in very preterm infants. Normalization of the IGF-I axis, directly or indirectly, may support normal brain development in very preterm infants.

Components of the porcine anterior pituitary insulin-like growth factor system throughout the estrous cycle

Components of the circulating and anterior pituitary insulin-like growth factor (IGF) system vary in response to steroids in pigs. However, whether serum and anterior pituitary concentrations of the IGF system vary throughout the estrous cycle has not been determined. To further examine this relationship, estrus was synchronized in 40 gilts of similar age and weight (180 d; 120 kg) by feeding 15 mg altrenogest for 15 d to synchronize estrus. Gilts were checked twice daily for expression of estrus beginning 3 d after the end of altrenogest treatment and continuing for 7 d. The first day each gilt exhibited estrus was designated as day 1 of the estrous cycle. Blood samples were obtained by jugular venipuncture on days 1, 4, 7, 10, 13, 16, 19, and 22 of the estrous cycle. On days 7, 13, 19, and 22 of the estrous cycle 10 pigs were killed and anterior pituitary glands (AP) were collected. Serum concentrations of IGF-I and AP concentrations of IGF-I were determined by radioimmunoassay. Relative amounts of AP IGF binding protein (IGFBP) were determined by western ligand blot analysis. Relative expression of AP IGF-I, IGF-I receptor (IGF-I-R), gonadotropin-releasing hormone receptor (GnRHR), and luteinizing hormone (LH)-β subunit were determined by real-time reverse transcription polymerase chain reaction. Serum concentrations of IGF-I fluctuated throughout the estrous cycle. Mean serum concentrations of IGF-I decreased ( P < 0.02) from day 1 through day 10, increased ( P < 0.02) on days 13 through 16, and then decreased ( P < 0.02) from days 19 through 22. Mean AP concentrations of IGF-I were greater ( P < 0.03) on day 19 than on all other days, whereas no difference was detected ( P > 0.05) in mean AP concentrations of IGF-I on days 7, 13, and 22. Mean relative amounts of AP IGFBP-2 and -5 were each greater ( P < 0.02) in gilts on day 19 than on all other days, whereas no difference was detected ( P > 0.05) in mean relative amounts of AP IGFBP-2 and -5 among pigs on days 7, 13, and 22 of the estrous cycle. Relative expression AP IGF-I was greater ( P < 0.05) on days 13, 19, and 22 than on day 7 of the estrous cycle. Similarly, the relative expression of AP IGF-IR was increased ( P < 0.05) in gilts on days 13, 19, and 22 compared with day 7. The relative expression of GnRHR was greater ( P < 0.05) on days 13 and 22 of the estrous cycle than on day 7. The relative expression of LHβ subunit was greater ( P < 0.05) on day 19 of the estrous cycle than on days 7, 13, and 22. Anterior pituitary release of LH throughout the porcine estrous cycle may be modulated by changes in the intrapituitary IGF system.

Effectofrosiglitazoneonserum IGF-I concentrations in uncontrolled acromegalic patients under conventional medical therapy: Results froma pilot phase 2 study

Current therapies for acromegaly are unsatisfactory for some patients. High-dose thiazolidinediones have been reported to reduce serum GH levels in animal models of acromegaly. The objective of the study was to evaluate the effect of increasing doses of rosiglitazone on serum GH and IGF-I concentrations in acromegalic patients. Phase 2 clinical trial. Five consecutive patients with active and uncontrolled acromegaly under conventional medical therapies were treated with increasing doses of rosiglitazone [4 mg/day every month, starting from 8 up to 20 mg/day] added to previous medical therapies for acromegaly. Mean serum IGF-I concentrations decreased from 547 ± 91 to 265 ± 126 μg/l (p<0,001) during rosiglitazone treatment: 4 patients had normal serum IGF-I concentrations, and a patient had lowered serum IGF-I values, although still abnormal, at the end of the study. On the contrary, serum GH concentrations did not significantly changed during rosiglitazone therapy as well as other pituitary hormones. No relevant side effects of rosiglitazone were observed during the study period. Quantitative real time PCR and Western blotting showed that rosiglitazone lowered GH-dependent hepatic generation of IGF-I in HepG2 cell line. Rosiglitazone reduces serum IGF-I concentrations in patients with uncontrolled acromegaly under conventional medical therapies, likely acting on the GH-dependent hepatic synthesis of IGF-I. Large studies are necessary to confirm the role of rosiglitazone as an adjunctive therapy for uncontrolled acromegalic patients under conventional medical therapies.

Paracrine Regulation of Growth Hormone Secretion by Estrogen in Women

Paracrine regulation is emerging as a discrete control mechanism in the endocrine system. In hypogonadal men, stimulation of GH secretion by testosterone requires prior aromatization to estradiol, a paracrine effect unmasked by central estrogen receptor blockade with tamoxifen. In hypogonadal women, estrogen replacement via a physiological non-oral route fails to enhance GH secretion, indicating an absence of an endocrine effect. The aim was to investigate whether local estrogens produced from aromatization regulate GH secretion. We conducted an open-label, two-phase, crossover study. We compared the effects on GH secretion of tamoxifen with estradiol valerate in postmenopausal women. Ten women were treated with tamoxifen (10 and 20 mg/d) and estradiol valerate (2 mg/d) via oral route for 2 wk each, with a washout period of at least 6 wk. We measured the GH response to arginine and circulating levels of IGF-I and SHBG, markers of hepatic estrogen effect. The GH response to arginine was reduced by 10- and 20-mg tamoxifen in a dose-dependent manner and potentiated significantly (P<0.05) by estradiol valerate. Mean IGF-I concentration was reduced significantly with high-dose tamoxifen (P<0.01) and estradiol valerate treatment (P<0.05), whereas mean SHBG levels rose with both (P<0.01). Blunted GH response to stimulation occurring in the face of reduced IGF-I feedback inhibition with tamoxifen indicates that GH secretion was suppressed by estrogen receptor antagonism. Because circulating estradiol was unaffected, these data indicate a significant role of local estrogen in the central control of GH secretion. We conclude that aromatase mediates the paracrine control of GH secretion in women.

Estimates of inbreeding depression for serum insulin-like growth factor I concentrations, body weights, and body weight gains in Angus beef cattle divergently selected for serum insulin-like growth factor I concentration1,2,3

Data for the current study were obtained from a divergent selection experiment in which the selection criterion was the average serum IGF-I concentration of 3 postweaning blood samples collected from purebred Angus calves. Multiple trait derivative-free REML procedures were used to obtain estimates of inbreeding depression for IGF-I concentration and for BW and BW gains measured from birth to the conclusion of a 140-d postweaning performance test. Included in the analysis were 3,243 animals in the A(-1) matrix, 2,182 of which had valid records for IGF-I concentration. Over the course of the entire selection experiment, inbreeding of the calf averaged 3.3% (SD = 3.1%) and inbreeding of the dam averaged 1.8% (SD = 2.7%). Mean inbreeding levels at the end of the study were 6.82 +/- 0.38% and 4.20 +/- 0.36% for calves and dams, respectively. Annual rates of increase in inbreeding of calves and dams were 0.36 +/- 0.01 (P < 0.0001) and 0.25 +/- 0.01%/yr (P < 0.0001), respectively. Insulin-like growth factor I concentration at d 28 (IGF28), 42 (IGF42), and 56 (IGF56) of the 140-d postweaning test and mean IGF-I concentration decreased by 0.62 +/- 0.88, 1.86 +/- 0.96, 1.92 +/- 0.89, and 1.48 +/- 0.76 ng/mL per 1% increase in inbreeding of calf. Only the regression coefficient for IGF56 differed significantly from zero, although the regression coefficients for IGF42 and mean IGF-I approached significance (P < 0.10). Increases in inbreeding levels of the dams also tended to result in reduced IGF-I concentrations, although the regression coefficients were not significantly different from zero. Inbreeding of calf had highly significant negative effects on all BW and BW gain traits examined, except for birth weight, with regression coefficients ranging from -0.74 +/- 0.20 kg/% increase in calf inbreeding for postweaning BW gain to -1.68 +/- 0.33 kg/% increase in calf inbreeding for off-test BW. Inbreeding of dam had a significant negative effect on birth weight of progeny and tended to have a negative effect on postweaning BW gain (P < 0.10). Preweaning gain of the progeny and BW other than birth weight were not influenced by increases in dam inbreeding. Results indicate that reductions in serum IGF-I concentration due to inbreeding may contribute to the decline in BW and BW gains that is typically associated with increases in inbreeding within populations.

Fresh-Frozen Plasma as a Source of Exogenous Insulin-Like Growth Factor-I in the Extremely Preterm Infant

Preterm birth is followed by a decrease in circulatory levels of IGF-I and IGF binding protein (IGFBP)-3, proteins with important neurogenic and angiogenic properties. Our objective was to evaluate the effects of iv administration of fresh-frozen plasma (FFP) from adult donors on circulatory levels of IGF-I and IGFBP-3 in extremely preterm infants. A prospective cohort study was performed in 20 extremely preterm infants [mean (SD) gestational age 25.3 (1.3) wk] with clinical requirement of FFP during the first postnatal week. Sampling was performed before initiation of transfusion, directly after, and at 6, 12, 24, and 48 h after completed FFP transfusion. Concentrations of IGF-I and IGFBP-3 before and after transfusion of FFP were determined. FFP with a mean (SD) volume of 11 ml/kg (3.1) was administered at a median postnatal age of 2 d (range 1-7). Mean (SD) IGF-I and IGFBP-3 concentrations in administered FFP were 130 (39) and 2840 microg/liter (615), respectively. Immediately after FFP transfusion, mean (SD) concentrations of IGF-I increased by 133% from 11 (6.4) to 25 microg/liter (9.3) (P < 0.001) and IGFBP-3 by 61% from 815 (451) to 1311 microg/liter (508) (P < 0.001). Concentrations of IGF-I and IGFBP-3 remained higher at 6 (P < 0.001, P = 0.009) and 12 h (P = 0.017, P = 0.018), respectively, as compared with concentrations before FFP transfusion. Typical half-life of administrated IGF-I was 3.4 h for a 1-kg infant. Transfusion of FFP to extremely preterm infants during the first postnatal week elevates levels of IGF-I and IGFBP-3.

Testosterone Supplementation in Older Men Restrains Insulin-Like Growth Factor’s Dose-Dependent Feedback Inhibition of Pulsatile Growth Hormone Secretion

Pulsatile GH secretion declines in older men. The causal mechanisms are unknown. Candidates include deficient feedforward (stimulation) by endogenous secretagogues and excessive feedback (inhibition) by GH or IGF-I due to age and/or relative hypoandrogenemia. Testosterone (T) supplementation in healthy older men will restrain negative feedback by systemic concentrations of IGF-I. Twenty-four healthy men (ages, 50 to 75 yr; body mass index, 24 to 30 kg/m(2)) participated in the study. We performed a prospectively randomized, double-blind, placebo-controlled assessment of the impact of pharmacological T supplementation on GH responses to randomly ordered separate-day injections of recombinant human IGF-I doses of 0, 1.0, 1.5, and 2.0 mg/m(2). Deconvolution and approximate entropy analyses of pulsatile, basal, and entropic (pattern-sensitive) modes of GH secretion were conducted. Recombinant human IGF-I injections 1) elevated mean and peak serum IGF-I concentrations dose-dependently (both P < 0.001); 2) suppressed pulsatile GH secretion (P = 0.003), burst mass (P = 0.025), burst number (P = 0.005), interpulse variability (P = 0.032), and basal GH secretion (P = 0.009); and 3) increased secretory pattern regularity (P = 0.020). T administration did not alter experimentally controlled IGF-I concentrations, but it elevated mean GH concentrations (P = 0.015) and stimulated pulsatile GH secretion (frequency P = 0.037, mass per burst P = 0.038). Compared with placebo, T attenuated exogenous IGF-I's inhibition of GH secretory-burst mass (P < 0.038) without restoring pulse number, basal secretion, or pattern regularity. The capability of systemic T to mute IGF-I feedback on pulsatile GH secretion suggests a novel mechanism for augmenting GH production.

Estradiol Supplementation in Postmenopausal Women Attenuates Suppression of Pulsatile Growth Hormone Secretion by Recombinant Human Insulin-like Growth Factor Type I

Why pulsatile GH secretion declines in estrogen-deficient postmenopausal individuals remains unknown. One possibility is that estrogen not only enhances stimulation by secretagogues but also attenuates negative feedback by systemic IGF-I. SITE: The study took place at an academic medical center. Subjects were healthy postmenopausal women (n=25). The study included randomized assignment to estradiol (n=13) or placebo (n=12) administration for 16 d and randomly ordered administration of 0, 1.0, 1.5, and 2.0 mg/m2 recombinant human IGF-I sc on separate days fasting. Deconvolution analysis of pulsatile and basal GH secretion and approximate entropy (pattern-regularity) analysis were done to quantify feedback effects of IGF-I. Recombinant human IGF-I injections increased mean and peak serum IGF-I concentrations dose dependently (P<0.001) and suppressed mean GH concentrations (P<0.001), pulsatile GH secretion (P=0.001), and approximate entropy (P<0.001). Decreased GH secretion was due to reduced secretory-burst mass (P=0.005) and frequency (P<0.001) but not basal GH release (P=0.52). Estradiol supplementation lowered endogenous, but did not alter infused, IGF-I concentrations while elevating mean GH concentrations (P=0.012) and stimulating pulsatile (P=0.008) and basal (P<0.001) GH secretion. Estrogen attenuated IGF-I's inhibition of pulsatile GH secretion (P=0.042) but was unable to restore physiological GH pulse frequency or normalize approximate entropy. Short-term estrogen replacement in postmenopausal women selectively mutes IGF-I-mediated feedback on pulsatile GH secretion. Disinhibition of negative feedback thus confers a novel mechanism by which estrogen may obviate hyposomatotropism.

Genetic parameter estimates for serum insulin-like growth factor I concentrations, and body weight and weight gains in Angus beef cattle divergently selected for serum insulin-like growth factor I concentration1,2,3

Data for the current study were obtained from a divergent selection experiment in which the selection criterion was the average serum IGF-I concentrations of 3 postweaning blood samples collected from purebred Angus calves. Multiple-trait derivative-free REML procedures were used to obtain genetic parameter estimates for IGF-I concentrations and for BW and BW gains measured from birth to the conclusion of a 140-d postweaning performance test. Included in the analysis were 2,674 animals in the A(-1) matrix, 1,761 of which had valid records for IGF-I concentrations. Direct heritability estimates +/- SE for IGF-I concentration at d 28, 42, and 56 of the postweaning period and for mean IGF-I concentrations were 0.44 +/- 0.07, 0.51 +/- 0.08, 0.42 +/- 0.07, and 0.52 +/- 0.08, respectively. Heritability estimates for maternal genetic effects ranged from 0.10 +/- 0.05 to 0.20 +/- 0.06. The proportion of total phenotypic variance due to the maternal permanent environmental effect was essentially zero for all measures of IGF-I concentrations. Genetic correlations of IGF-I concentrations with weaning and post-weaning BW ranged from 0.07 +/- 0.12 to 0.32 +/- 0.11 and generally demonstrated an increasing trend during the postweaning period. Averaged across the various measures of IGF-I, the genetic correlation of IGF-I with preweaning gain was 0.14, whereas the genetic correlation with postweaning gain was 0.29. Genetic correlations between IGF-I and BW gain were positive during all time intervals, except between weaning and the beginning of the postweaning test and from d 84 to 112 of the postweaning period. Environmental and phenotypic correlations of IGF-I with BW and BW gains were generally positive, but small. These results indicate that postweaning serum IGF-I concentration is moderately to highly heritable and has small positive genetic, environmental, and phenotypic correlations with BW other than birth weight and with pre- and postweaning gain. Therefore, if IGF-I proves to be a biological indicator of an economically important trait (e.g., efficiency of feed use for growth) in beef cattle, it should be possible to rapidly change IGF-I concentrations via selection without significantly altering live weight or rate of gain.

Treatment of growth hormone excess in dogs with the progesterone receptor antagonist aglépristone

Acromegaly or hypersomatotropism in dogs is almost always due to progestin-induced hypersecretion of GH originating from the mammary gland. The aim of this study was to investigate whether aglépristone, a progesterone receptor antagonist, can be used to treat this form of canine acromegaly. In five Beagle bitches hypersomatotropism was induced by administration of MPA for over 1 year. Subsequently, aglépristone was administered. Blood samples were collected before MPA administration, immediately before, during, and 3.5 and 5.5 weeks after the last administration of aglépristone for determination of the plasma concentrations of GH and IGF-I. In addition, blood samples for the determination of the 6-h plasma profile of GH were collected before MPA administration, before aglépristone administration, and 1 week after the last aglépristone treatment.MPA administration resulted in a significant increase of the mean plasma IGF-I concentration, whereas analysis of the pulsatile plasma profile demonstrated a trend (P=0.06) for a higher mean basal plasma GH concentration and a higher mean AUC0 for GH. Treatment with aglépristone resulted in a significant decrease of the mean plasma GH and IGF-I concentrations. Analysis of the pulsatile plasma profile showed a trend (P=0.06) for a lower mean basal plasma GH concentration and a lower mean AUC0 for GH 1 week after the last aglépristone treatment compared with these values before aglépristone administration. Three and a half and 5.5 weeks after the last aglépristone administration the mean plasma IGF-I concentration increased again.In conclusion, aglépristone can be used successfully to treat dogs with progestin-induced hypersomatotropism.

Noonan Syndrome: Relationships between Genotype, Growth, and Growth Factors

Half of the patients with Noonan syndrome (NS) carry mutation of the PTPN11 gene, which plays a role in many hormonal signaling pathways. The mechanism of stunted growth in NS is not clear. The objective of the study was to compare growth and hormonal growth factors before and during recombinant human GH therapy in patients with and without PTPN11 mutations (M+ and M-). This was a prospective multicenter study in 35 NS patients with growth retardation. Auxological data and growth before and during 2 yr of GH therapy are shown. GH, IGF-I, IGF binding protein (IGFBP)-3, and acid-labile subunit (ALS) levels were evaluated before and during therapy. Molecular investigation of the PTPN11 coding sequence revealed 12 different heterozygous missense mutations in 20 of 35 (57%). Birth length was reduced [mean -1.2 sd score (SDS); six m+ and two m- were < -2 SDS] but not birth weight. M+ vs. M- patients were shorter at 6 yr (P = 0.04). In the prepubertal group (n = 25), GH therapy resulted in a catch-up height SDS, which was lower after 2 yr in M+ vs. M- patients (P < 0.03). The mean peak GH level (n = 35) was 15.4 +/- 6.5 ng/ml. Mean blood IGF-I concentration in 19 patients (11 m+, eight m-) was low (especially in M+) for age, sex, and puberty (-1.6 +/- 1.0 SDS) and was normalized after 1 yr of GH therapy (P < 0.001), without difference in M+ vs. M- patients. ALS levels (n = 10) were also very low. By contrast, the mean basal IGFBP-3 value (n = 19) was normal. In NS patients with short stature, some neonates have birth length less than -2 SDS. Growth of M+ is reduced and responds less efficiently to GH than M- patients. The association of low IGF-I and ALS with normal IGFBP-3 levels could explain growth impairment of M+ children and could suggest a GH resistance by a late postreceptor signaling defect.

Low-dose GH improves exercise capacity in adults with GH deficiency: effects of a 22-month placebo-controlled, crossover trial

Fifty-five patients with adult-onset GH deficiency (mean age, 49 years) were enrolled in a placebo-controlled, crossover study to investigate the effects of GH therapy on exercise capacity, body composition, and quality of life (QOL). GH and placebo were administered for 9 months each, separated by a 4-month washout period. GH therapy was individually dosed to obtain an IGF-I concentration within the normal range for age and sex. The final mean daily dose of GH was 1.2 IU/day for men and 1.8 IU/day for women. Mean IGF-I concentration at baseline was higher in men than in women (95+/-33 vs 68+/-41 microg/l respectively; P < 0.04) and increased to a similar level on GH therapy. Body fat mass was reduced by 1.9+/-2.9 kg and lean body mass was increased by 1.8+/-2.8 kg (P = 0.0001 for each) with GH treatment. Total and low-density cholesterol levels decreased. Absolute maximal oxygen uptake increased by 6% (P = 0.01), relative to body weight by 9% (P = 0.004), and there was a trend toward increased endurance performance by 7% (P = 0.07). There were no significant effects on QOL. In conclusion, treatment with a low, physiologic dose of GH produced positive effects on body composition and lipids and improved exercise capacity, likely to be of clinical relevance. No changes in QOL were seen, possibly because of a good QOL at baseline.

Effects of estradiol implantation on growth, carcass traits and circulating concentrations of insulin-like growth factors (IGFs) and IGF-binding protein-3 in finishing barrows

Eighty crossbred barrows aged 120 to 141 days and weighing 71.2±0.8 kg were randomly divided into eight pens, after which each of 40 animals in four pens was implanted with 24 mg of estradiol-17β (E 2; Compudose®). The animals were allowed an unrestricted access to water and a finisher diet containing 16% crude protein and 3.4 Mcal DE/kg and slaughtered at 107.4±0.8 kg. Blood samples were obtained by jugular venipuncture at day 0 before the implantation and at days 21 and 42. Serum concentration of E 2 increased between days 0 and 21 after the implantation and declined to a level above that of day 0 ( P<0.01) by day 42. E 2 implantation caused a decrease ( P<0.01) in feed intake and backfat thickness and a tendency ( P=0.08) of decreased average daily gain. However, feed conversion efficiency (FCE; live weight gain/feed intake) did not change due to the implantation ( P=0.20). The E 2 implantation did not affect physicochemical characteristics of longissimus muscle including percentages of protein ( P=0.17) and fat ( P=0.43), 24-h pH ( P=0.39), drip loss ( P=0.99), L* (lightness; P=0.78) and a* (redness; P=0.49) values. Serum concentration of insulin-like growth factor (IGF)-I decreased between days 0 and 21 ( P<0.01) and also between days 21 and 42 ( P<0.05) in unimplanted pigs, but not in implanted pigs ( P>0.05), which resulted in a greater ( P<0.05) mean IGF-I concentration in the implanted vs. unimplanted group. By contrast, serum concentrations of IGF-II and IGF-binding protein-3 did not differ between the two groups ( P>0.05). In summary, results suggest that E 2 suppresses voluntary feed intake and backfat deposition without significantly affecting growth efficiency and muscle characteristics in barrows and that effects of E 2 may be partly mediated by IGF-I.

Idiopathic osteoporosis in premenopausal women.

Although osteoporosis predominantly affects older postmenopausal women, low bone mineral density also occurs in men and younger women. In men, it is often unexplained by recognized secondary causes. These men with idiopathic osteoporosis have reductions in serum IGF-I as well as indices of reduced bone formation. Younger women also experience bone loss of unknown etiology (IOP). Whether premenopausal women with IOP have similar decreases in IGF-I levels and reduced indices of bone formation is unknown. We prospectively evaluated a group of premenopausal women with unexplained low bone mass and compared them to normal premenopausal women with respect to serum concentrations of IGF-I. Thirteen premenopausal women (34.2+/-2.3 years) with low bone density (mean lumbar spine T-score -2.26+/-0.20) were compared with 13 premenopausal women (35.7+/-1.7 years) with normal bone density of similar age, height and ethnic composition. Body mass index (BMI) was lower in subjects than controls (20.5+/-0.7 versus 25.2+/-1.1 kg/m(2), P<0.01). A family history of osteoporosis and a history of fragility fractures were found more frequently in subjects than controls (P< or =0.05). Calciotropic hormones did not differ between the two groups. In contrast to our observations in men with idiopathic osteoporosis, mean serum IGF-I concentrations did not differ between subjects and controls (subjects: 22.5+/-2.2 nmol/l versus controls: 20.8+/-1.6 nmol/l; NS). Moreover, serum IGF-I levels did not correlate significantly with serum estradiol or with BMD at either the lumbar spine or femoral neck. However, lower follicular phase serum estradiol levels among non-oral contraceptive users were found in subjects as compared to controls (subjects: 124.1+/-13 pmol/l versus controls 194.9+/-24 pmol/l, P=0.06). Calculated free, bioavailable estradiol levels were significantly lower overall in subjects than controls (0.6+/-0.1 versus 1.2+/-0.2 pmol/l, P<0.05). Total serum estradiol levels correlated with BMD at the femoral neck (r=+0.50; P<0.05). Free, bioavailable estradiol correlated with BMD and BMAD at the lumbar spine (r=+0.54, P<0.01 and r=+0.54, P<0.05, respectively) and femoral neck (r=+0.60 and r=+0.55 respectively, both P<0.01). Urinary NTX excretion, although within the normal premenopausal range, was 45% higher in subjects than controls (41.6+/-5.9 nmol BCE/l versus 28.3+/-2.4 nmol BCE/l; P<0.05). Bone-specific alkaline phosphatase activity was also higher (17.4+/-1.6 ng/ml versus 14.7+/-0.8 ng/ml), although the difference was not statistically significant. These results suggest differences in the pathogenesis of idiopathic osteoporosis in women as compared to men with IOP.

Skin deiodinase profiles and associated patterns of hair follicle activity in cashmere goats of contrasting genotypes

The roles of skin deiodinase enzymes in the expression of genotypic differences in hair follicle activity and cashmere fibre growth and moult were studied in 9 Siberian (S) and 10 Scottish cashmere (SC) goats. The proportion of animals exhibiting cashmere growth was significantly greater in S than in SC goats in both late July (P &lt; 0.001; early in the season of growth) and between January and April (P &lt; 0.001; late in the season of growth), but there was no significant difference in the time of moult onset. Patterns of hair follicle activity exhibited similar seasonal differences, with secondary follicle activity being higher in S than in SC animals during the January–June period. Overall mean concentrations of IGF-I were lower (P &lt; 0.01) in S than in SC animals and mean T4 concentrations were higher (P &lt; 0.05) in S than in SC animals, but these differences were not related to genotypic differences in follicle activity or cashmere fibre growth. Mean concentrations of insulin, prolactin, and T3 did not differ with genotype. Between January and early April, mean prolactin concentrations were higher in S than in SC animals (P &lt; 0.05). Monodeiodinase type II (MDII) activity in skin samples was highest (P &lt; 0.001) during December and January (short day photoperiod) and was lower in S than in SC animals (P &lt; 0.05) at these times. Mean monodeiodinase type III (MDIII) activity was highest during June and July (long day photoperiod). There was no difference between genotypes in the overall mean levels of deiodinase activity but, during January–March, when prolactin concentrations were higher in S than in SC goats, there was a higher rate of follicle activity and fibre growth in S goats. It is postulated that individual and genotype differences in hair follicle activity and cashmere growth are partially dependent on the pattern of expression of deiodinase enzymes in the skin. However, the actions of each enzyme are likely to depend on, among other factors, the absolute levels of expression of each type, the ratio of MDIII to MDII, the physiological state of the follicle, and the associated hormone profiles.

Insulin-like growth factors in patients with liver cysts.

Insulin-like growth factors (IGFs) play an important role in cell growth and differentiation, and the liver is the main source of IGFs and IGF-binding proteins (IGFBPs) that appear in the circulation. The effect of liver cysts on the circulating IGF system was studied in this work. Serum concentrations of IGF-I and -II were measured by radioimmunoassay, IGFBP patterns were characterised by ligand-affinity and immunoblotting, and a lectin-binding assay was used to investigate the glyco component of IGFBP-3 complexes. IGF-I and -II concentrations in patients with cysts were significantly lower compared to those in healthy individuals (P<0.0001 and P<0.01, respectively), and the decrease was related to age but not sex. The overall mean concentrations of IGF-I and -II were not significantly different whether the cysts were caused by Echinococcus granulosus, cross-reactive pathologies, or some other factor. IGFBP profiles correlated with the amount of IGF present: patients with lower IGF-I concentrations expressed decreased IGFBP-3 and elevated IGFBP-2 levels. Increased IGFBP-3 proteolytic activity in the patients' blood was not detected by immunoblotting. In the lectin-binding assay, IGFBP-3 complexes in the circulation of patients demonstrated reactivity similar to that in healthy persons, suggesting that the overall structure of the saccharide moieties of the IGFBP-3 complexes was not significantly altered due to liver cyst formation.