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N Mauras

Publications and source records attributed to N Mauras.

At least 37 records · Page 2Linked to original sources
PubMed1998

Testosterone deficiency in young men: marked alterations in whole body protein kinetics, strength, and adiposity.

To investigate specific effects of androgens on whole body metabolism, we studied six healthy lean men (mean +/- SEM age, 23.2 +/- 0.5 yr) before and after gonadal steroid suppression with a GnRH analog (Lupron), given twice, 3 weeks apart. Primed infusions of [13C]leucine, indirect calorimetry, isokinetic dynamometry, growth factor measurements, and percutaneous muscle biopsies were performed at baseline (D1) and after 10 weeks of treatment (D2); each subject served as his own control. Testosterone concentrations were markedly suppressed after 10 weeks of treatment (D1, 535 +/- 141 ng/dL; D2, 31 +/- 9). Leucine's rate of appearance (index of proteolysis) was markedly suppressed after 10 weeks of hypogonadism (-13%; P = 0.01) as well as the nonoxidative leucine disposal, an index of whole body protein synthesis (-13%; P = 0.01) without any changes in plasma amino acid concentrations. All subjects studied after 10 weeks showed a decrease in fat-free mass, as measured by skinfold calipers and dual emission x-ray absortiometry scans (D1, 56.5 +/- 2.9 kg; D2, 54.4 +/- 2.5; P = 0.005), and an increase in percent fat mass (D1, 19.2 +/- 2.5%; D2, 22.2 +/- 2.5; P = 0.001). Rates of lipid oxidation decreased (-31%; P = 0.05) after treatment, with parallel changes in resting energy expenditure (-9%; P = 0.05). Mean and peak GH concentrations (measured every 10 min for 6 h) and GH production rates did not decrease after testosterone deficiency, with an actual increase in basal secretion (P < 0.02). Plasma insulin-like growth factor I (IGF-I) concentrations did not change significantly after 10 weeks of treatment (D1, 227 +/- 44 micrograms/L; D2, 291 +/- 60; P = 0.08). Isokinetic dynamometry of leg extensors at 60 degrees and 180 degrees/s was also decreased after 10 weeks of hypogonadism. Total ribonucleic acid (RNA) was isolated from muscle biopsy samples, and ribonuclease protection assays were performed using human complementary DNA clones for IGF-I, IGF-binding protein-4, myosin, and actin. Ten weeks after Lupron treatment, messenger RNA (mRNA) concentrations of IGF-I decreased significantly, whereas there was a trend toward higher IGF-binding protein-4 concentrations, with no change in myosin or actin mRNA concentrations. In conclusion, testosterone deficiency in young men is associated with a marked decrease in measures of whole body protein anabolism, decreased strength, decreased fat oxidation, and increased adiposity. These effects of testosterone deficiency are independent of changes in peripheral GH production and IGF-I concentrations, even though im IGF-I mRNA concentrations decrease. These data suggest a direct effect of androgens on whole body lipid and protein metabolism.

Adipose Tissue↗
PubMed1998

Optimizing estrogen replacement treatment in Turner syndrome.

Estrogen has a biphasic effect on growth, stimulatory at low doses but inhibitory at higher doses. Therefore, designing optimal sex hormone replacement treatment in girls with Turner syndrome (TS) who are being treated with growth hormone (GH) involves considering the dose and form of the estrogen as well as the route and timing of its administration. We report here a preliminary analysis of a study to test the concept that an optimal estrogen replacement regimen should consist of estradiol administered in a low dose by a systemic route. The study population consisted of 9 girls with TS who had been treated with GH for 6 or more months. When the girls were 12 to 15 years old, we added depot estradiol at a monthly intramuscular dose of 0.2 mg and increased the dose at 6-month intervals to 0.4, 0.6, and, in 7 of the girls, 0.8 mg. We compared the results in these subjects with those in a matched group of 37 patients with TS in whom routine estrogen treatment had been started at similar ages and who were treated with a similar course of GH therapy. The gain in height at 2 years was 2.6 cm greater in those who were treated with depot estradiol than in those who were treated with routine estrogen. The bone age in the patients who were treated with depot estradiol increased in proportion to their chronologic age, suggesting that this difference indicates an increase in their predicted adult height. We conclude that using very low doses of systemic estradiol to induce puberty before the age of 15 years in girls with TS who are treated with GH, instead of using routine estrogen therapy, can result in increased final heights.

Adolescent↗
PubMed1997

Partial growth-hormone insensitivity: the role of growth-hormone receptor mutations in idiopathic short stature.

Mutations in the GHR locus may play a role in the cause of idiopathic short stature (ISS) by impairing growth-hormone (GH) receptor (GHR) function. At one extreme, mutations that nullify the function of the GH receptor are linked to complete GH insensitivity syndrome, or Laron syndrome, and we hypothesized that less-disruptive mutations could contribute to partial GH insensitivity syndrome. Low levels of GH binding protein may indicate mutations in the extracellular domain of the receptor, and by focusing on 14 children with ISS who had low GH binding protein and insulin-like growth factor I levels, we found three heterozygotes and one compound heterozygote for mutations in the extracellular domain of the receptor. We have since extended our study to a broader spectrum of patients, adding 76 patients with ISS who were treated with GH in a phase II study of the safety and efficacy of recombinant human GH in ISS and also adding 10 patients who were ascertained as having ISS by pediatric endocrinologists in private practice. The GHR gene has thus been analyzed in 100 patients with ISS, eight of whom were found to carry mutations: four in our original study and four with normal or elevated levels of GH binding protein. The latter group consists of three carriers of heterozygous extracellular domain mutations and one carrier of a heterozygous intracellular domain mutation. Family data suggest that the carriers of these mutations have a range of phenotypes, supporting our hypothesis that the expression of these heterozygous mutations as partial GH insensitivity syndrome depends on the genetic makeup of the person.

Body Height↗
PubMed1997

Estrogen therapy enhances calcium absorption and retention and diminishes bone turnover in young girls with Turner's syndrome: a calcium kinetic study.

Using stable tracers of calcium, we have previously shown a significant increase in calcium absorption and retention in prepubertal boys treated with exogenous testosterone. To investigate the effects of estrogen replacement on measures of calcium absorption, retention, and bone turnover, we studied a group of seven hypogonadal girls with Turner's syndrome (mean +/- SE age, 12.5 +/- 0.7 years). At baseline, 42Ca intravenously (IV) and 44Ca orally were administered, and blood and urine samples were collected for approximately 130 hours. Estrogen therapy was begun as oral ethinyl estradiol (4 or 20 micrograms/d) or intramuscular depot estradiol given over 4 weeks, after which an identical study was repeated. Analysis of calcium enrichment in blood and urine was performed using mass spectrometry methods. After estrogen therapy, there was a significant increase in calcium absorption ([Va] P = .03) and total calcium retention ([Vbal] P = .04), similar to the effects of testosterone in boys. Bone accretion (Vo+) decreased after estrogen therapy (P = .004), as did resorption ([Vo-] P = .004). The overall rate of whole-body calcium turnover (Vt) was significantly decreased after estrogen administration (P = .04). These findings were opposite of those observed in prepubertal boys treated with testosterone. The contribution of bone resorption to whole-body turnover (E) also decreased after estrogen therapy (P = .05). These changes were associated with increased levels of 1,25-dihydroxyvitamin D after therapy with estrogens (P = .05). We conclude that estrogen supplementation is significantly anabolic for calcium metabolism by markedly increasing calcium absorption and retention and diminishing the estimated whole-body calcium turnover in girls with severe hypogonadism and Turner's syndrome. Further studies assessing the dietary calcium and/or vitamin D intake and bone mineral density of hypogonadal girls whose estrogen replacement is intentionally delayed will further define the need for calcium or vitamin D supplements in the peripubertal years in this condition.

Bone Regeneration↗
PubMed1997

rhIGF-I administration in humans: differential metabolic effects of bolus vs. continuous subcutaneous delivery.

The metabolic effects of recombinant human insulin-like growth factor I (rhIGF-I) were compared using bolus vs. continuous subcutaneous infusions. Subjects (n = 5, 29 +/- 3 yr) received rhIGF-I as subcutaneous infusions by a Minimed pump (200 microg x kg(-1) x day(-1) over 16 h/day), and their data were compared with those of subjects (n = 6, 24 +/- 2 yr) who received subcutaneous 200 microg x kg(-1) x day(-1) injections twice a day. L-[1-14C]leucine and [6,6-2H2]glucose infusion studies and indirect calorimetry were performed, and total and free IGF-I, insulin, and glucose concentrations were measured before and after 5-7 days of rhIGF-I. Estimates of protein breakdown, oxidation, and synthesis did not change after pump therapy; in contrast, after bolus doses, protein oxidation decreased (P = 0.001) and whole body protein synthesis increased (P = 0.04). There was no change in lipid oxidation after pump treatment, whereas the bolus group had lower lipid oxidation (P = 0.035). Both treatment modalities increased glucose oxidation (P < 0.02) and glucose production rates (P < 0.03). Overnight fasting insulin concentrations decreased in both groups, whereas plasma glucose remained invariant in the bolus group and decreased modestly in the pump group. Total IGF-I concentrations increased comparably in both groups, but the increase in free IGF-I was greater in the bolus-treated group (P = 0.001). We conclude that, in GH-sufficient postabsorptive individuals, the metabolic effects of rhIGF-I are in part dependent on the mode of administration, with a robust protein-anabolic effect when rhIGF-I is given as twice daily bolus injections but no detectable effect on protein turnover after a continuous mode of delivery. There were higher free IGF-I levels in the bolus-treated subjects, suggesting that this form of the molecule may be important for mediating IGF-I's protein-anabolic effects at the tissue level. The data also suggest that carbohydrate metabolism is more responsive than protein metabolism to the continuous subcutaneous modality of rhIGF-I administration. Even though the mechanism of these differences in metabolic effects is not entirely clear, it should be taken into account when patients are given rhIGF-I as prolonged treatment.

Adult↗
PubMed1997

Estrogen and testosterone, but not a nonaromatizable androgen, direct network integration of the hypothalamo-somatotrope (growth hormone)-insulin-like growth factor I axis in the human: evidence from pubertal pathophysiology and sex-steroid hormone replacement.

Activation of the gonadotropic and somatotropic axes in puberty is marked by striking amplification of pulsatile neurohormone secretion. In addition, each axis, as a whole, constitutes a regulated network whose feedback relationships are likely to manifest important changes at the time of puberty. Here, we use the regularity statistic, approximate entropy (ApEn), to assess feedback activity within the somatotropic (hypothalamo-pituitary/GH-insulin-like growth factor I) axis indirectly. To this end, we studied pubertal boys and prepubertal girls or boys with sex-steroid hormone deficiency treated short-term with estrogen, testosterone, or a nonaromatizable androgen in a total of 3 paradigms. First, our cross-sectional analysis of 53 boys at various stages of puberty or young adulthood revealed that mean ApEn, taken as a measure of feedback complexity, of 24-h serum GH concentration profiles is maximal in pre- and mid-late puberty, followed by a significant decline in postpubertal adolescence and young adulthood (P = 0.0008 by ANOVA). This indicates that marked disorderliness of the GH release process occurs in mid-late puberty at or near the time of peak growth velocity, with a return to maximal orderliness thereafter at reproductive maturity. Second, oral administration of ethinyl estradiol for 5 weeks to 7 prepubertal girls with Turner's syndrome also augmented ApEn significantly (P = 0.018), thus showing that estrogen per se can induce greater irregularity of GH secretion. Third, in 5 boys with constitutionally delayed puberty, im testosterone administration also significantly increased ApEn of 24-h GH time series (P = 0.0045). In counterpoint, 5 alpha-dihydrotestosterone, a nonaromatizable androgen, failed to produce a significant ApEn increase (P > 0.43). We conclude from these three distinct experimental contexts that aromatization of testosterone to estrogen in boys, or estrogen itself in girls, is likely the proximate sex-steroid stimulus amplifying secretory activity of the GH axis in puberty. In addition, based on inferences derived from mathematical models that mechanistically link increased disorderliness (higher ApEn) to network changes, we suggest that sex-steroid hormones in normal puberty modulate feedback within, and hence network function of, the hypothalamo-pituitary/GH-insulin-like growth factor I axis.

Adolescent↗
PubMed1996

Metabolic effects of recombinant human insulin-like growth factor-I in humans: comparison with recombinant human growth hormone.

Many of the metabolic actions of growth hormone (GH) are mediated through insulin-like growth factors or somatomedins. Recombinant human insulin-like growth factor-I (rhIGF-I) has a dichotomous insulin-like and GH-like action when used in different clinical situations in humans. Its effects on carbohydrate metabolism show a prominent increase in total insulin sensitivity, causing hypoglycemia in higher doses and maintaining normal glucose homeostasis in lower doses. This polypeptide selectively stimulates whole body protein synthesis with no effect on proteolysis when given in doses of 100 micrograms/ kg subcutaneously twice daily for at least 5-7 days, effects which are indistinguishable from those of GH. This contrasts with the marked suppression of proteolysis observed when higher doses are given, similar to the effects observed with insulin. When used in combination with rhGH, rhIGF-I has a synergistic effect, improving total nitrogen retention in calorically deprived subjects, yet it does not cause any greater enhancement of whole body protein anabolism in normally fed volunteers than giving rhGH and rhIGF-I individually. This suggests a common pathway for IGF-I and GH enhancing protein anabolism in the normally fed state. rhIGF-I also stimulates linear growth in children with defects in the GH receptor. Recent data show that this potent growth factor has a potential advantage over GH in the treatment of severe protein catabolic states, particularly the glucocorticosteroid-dependent model, as it ameliorates the marked increase in protein catabolism caused by the steroids, but without a diabetogenic effect. Here, a brief overview is provided of available human data on the actions of this peptide on carbohydrate, lipid, and protein metabolism, linear growth, and its anabolic effects. rhIGF-I offers promise in the treatment of selective growth disorders and in protein catabolic and insulin-resistant states.

Growth Hormone↗
PubMed1996

Sex steroids, growth hormone, insulin-like growth factor-1: neuroendocrine and metabolic regulation in puberty.

UNLABELLED: The control of the onset of puberty involves the complex interaction of pituitary and gonadal hormones. At a preprogrammed time in a child's life there is an increase in the amplitude of GnRH pulses which triggers a cascade of events including increases in the amplitude of FSH and LH pulses, followed by marked increases in gonadal sex steroidal output, which in turn increases growth hormone (GH) and insulin-like growth factor-1 (IGF-1) production. Evidence suggests that there is an integral interaction between the endogenous opiate system and the hypothalamic-pituitary-gonadal axis, at least in the later stages of puberty in the male. Both androgenic and estrogenic hormones markedly increase GH production rates as measured by deconvolution models in the prepubertal human, and compelling data strongly suggest that it is indeed the estrogen which controls the feedback amplification of GH production during puberty even in the male. It appears that the prepubertal gonad is actively producing sex hormones which might be important in the control of GH production since early childhood. The translation of these neuroendocrine rhythms into distal metabolic actions is also reviewed. Utilizing isotopic tracer infusions of the essential amino acid leucine, studies clearly show a selective stimulation of whole body protein synthesis by both GH and IGF-1. GH, IGF-1 and androgenic hormones all increase in puberty, stimulating whole body protein anabolism during that period. However, we observed no protein-anabolic effect in the hypogonadal female given increasing doses of estrogen. The latter suggests that at least as it pertains to whole body protein effects, the action of androgens is probably mediated via the androgen and not the estrogen receptor, in clear distinction from the estrogen-mediated effects of androgens on the neuroendocrine axis. Calcium absorption and retention are also positively affected by the androgens as shown by significant increases in calcium absorption and retention after the administration of testosterone to the prepubertal male. This suggests an important role of sex steroidal hormones in the mineralization of the skeleton. IN CONCLUSION: GH, IGF-1 and sex steroids all markedly increase during puberty and their actions are amplified mutually as they control growth, increase muscle mass and affect the mineralization of the skeleton. The dichotomy of androgen and estrogen effects in the male and female may regulate the differential timing of the onset of puberty and final height in the two sexes. The synergistic actions of these anabolic hormones appear to be most significant during the finite years of puberty.

Adolescent↗
PubMed1996

The rationale for the use of recombinant human growth hormone and insulin-like growth factor-I for catabolic conditions in humans.

Patients with a variety of catabolic illnesses or conditions are subjected to protein catabolic losses which we attempt to address with traditional enteral or parenteral nutritional support. Accelerated protein catabolism and energy requirements together with inadequate intake or assimilation of exogenous amino acids are all contributing causes. Circulating glucocortico-steroids may play a significant contributing role in the redistribution and loss of body protein in acute, and possibly chronic, catabolic illnesses but such complex metabolic conditions are not easily studied. Short-term, high-dose glucocorticosteroid administration, a model for such protein catabolic condition, increases rates of whole-body proteolysis, increases amino acid oxidation, and decrease the effectiveness insulin in suppressing proteolysis. Recombinant human growth hormone (rhGH) administration alone in humans decreases amino acid oxidation and increases the estimated rate of whole body protein synthesis. The exact proteins affected by rhGH and the nutritional implications of this, remain to be determined. rhGH when given in combination with high-dose glucocorticosteroids offsets the protein catabolic effects of steroids alone. Thus, rhGH might provide a means to manipulate protein homeostasis in acute and possibly chronic catabolic conditions. Current data with the use of IGF-I is less clear and will require further investigation to clarify its potential role in such conditions. Finally, clear clinical utility of adjunctive rhGH and/or rhIGF-I therapy must be demonstrated to justify its wide applicability in specific clinical settings as a standard care.

Glucocorticoids↗
PubMed1996

Recombinant human insulin-like growth factor I, recombinant human growth hormone, and sex steroids: effects on markers of bone turnover in humans.

Sex steroids, GH, and insulin-like growth factor I (IGF-I) have all been shown to be highly anabolic in bone. Using available markers of bone formation, we measured the changes in serum concentrations of carboxy-terminal propeptide of type I collagen (PICP) and osteocalcin in five groups of subjects given different bone anabolic hormones: group I (five males and three females; mean +/- SE age, 25 +/- 2 yr) received recombinant human IGF-I (rhIGF-I) as a constant 28-h infusion i.v. (5-10 micrograms/kg.h); group II (three males and two females; 25 +/- 2 yr) received rhIGF-I (100 micrograms/kg, sc, twice daily) for 5-7 days; group III (five males; 28 +/- 2 yr) received rhGH (0.025 mg/kg.day, sc, for 7 days, alone (group IIIa) or followed by a 28-h sc infusion of rhIGF-I (10 micrograms/kg.h) in addition to rhGH (group IIIb); group IV (six prepubertal boys; 13 +/- 0.6 yr) received testosterone enanthate (100 mg, im) twice over 4 weeks; and group V (five hypogonadal girls with Turner's syndrome) received different forms of estrogen for 4 weeks. Most groups (except for III) had deoxypyridinoline concentrations (a marker of bone resorption) measured in urine as well. Each subject served as his/her own control. rhIGF-I treated subjects in group I showed a marked decrease in circulating PICP concentrations after 4 h of infusion (from 116.8 +/- 19.2 micrograms/L to 89.6 +/- 16.3; P < 0.01), followed by a marked increase at 28 h (137.6 +/- 19.7; P < 0.01) and a sustained increase 5-7 days after sc therapy (group II). This decrease followed by an increase in PICP concentrations after rhIGF-I may be secondary to the marked suppression of circulating insulin observed at 4 h followed by the establishment of an insulin-like effect of the peptide. Subjects receiving rhGH alone (group IIIa) also had comparable increases in circulating PICP (from 107.6 +/- 8.7 to 125.0 +/- 10.9; P < 0.01) and a further additive increase when rhIGF-I was coadministered (140.9 +/- 10.3; P < 0.01). These changes were accompanied by comparable increases in IGF-I concentrations in all groups (I, II, and III). Hypogonadal children had higher levels of circulating PICP than adults and showed the most significant increases after therapy [group IV, 212.2 +/- 13.8 to 429.9 +/- 52.4 micrograms/L (P < 0.001); group V, 312.8 +/- 49.0 to 355.5 +/- 44.3 (P < 0.04)]. The latter was observed despite either a modest (group IV) or no increase (group V) in circulating IGF-I concentrations. None of the groups studied showed any change in serum osteocalcin concentrations after treatment. Urinary deoxypridinoline concentrations also increased after rhIGF-I and testosterone administration. We conclude that rhIGF-I, rhGH, and sex steroid hormones all markedly increase measures of bone turnover, and that rhIGF-I and rhGH can synergize on this effect on bone. These data collectively suggest that IGF-I and sex steroid hormones (testosterone and estrogen) can impact bone formation independently, and that the actions of IGF-I, GH, sex steroid hormones (and perhaps insulin) may synergize to maximally stimulate attainment of peak bone mass in humans. PICP measurement appears to be a sensitive marker of short term anabolic hormone actions in bone.

Adult↗
PubMed1995

Estrogens do not affect whole-body protein metabolism in the prepubertal female.

The increase in bone mass, muscle bulk, and linear growth that occur during puberty are mediated, at least in part, through the action of sex steroids. By using infusions of nonradioactive tracers of leucine, we have recently shown a significant protein anabolic effect of testosterone in prepubertal boys. The present study was designed to determine whether estrogens can cause similar changes in protein metabolism in females. Seven prepubertal girls (Turner's syndrome, n = 6; hypogonadotropism, n = 1; mean age 12.2 +/- 0.3 yr) were studied. A 4-h infusion of L(-)[1-(13C)]leucine was given, and the isotopic enrichment of [13C]ketoisocaproic acid and 13CO2 were measured in plasma and in breath with use of gas chromatography/mass spectroscopy and an isotope ratio mass spectrometer, respectively. The reciprocal pool model was used for analysis of leucine kinetics. Subjects were then started on ethinyl estradiol orally (n = 5) or depot estradiol parenterally (n = 2). An identical study was repeated 4 weeks later. There were comparable changes in leucine kinetics in all girls studied, hence their data were grouped for analysis. After administration of ethinyl estradiol, there were insignificant changes in the rate of appearance of leucine, an index of proteolysis (+6% +/- 8%); leucine oxidation (-9% +/- 11%); and nonoxidative leucine disposal, an index of whole body protein synthesis (+10% +/- 8%). This is in sharp contrast to the changes found in boys studied similarly after treatment with testosterone (rate of appearance: 17 +/- 6%, P = .036; leucine oxidation -49 +/- 5%, P = 0.004; and nonoxidative leucine disposal +35 +/- 8%, P = 0.009). The lack of anabolic effect on whole-body protein in the girls reported here was observed despite significant increases in plasma insulin-like growth factor I concentrations during 4 h of sampling when comparing the 2 study days, similar to that of the prepubertal boys who were treated with testosterone. In summary, we observed that contrary to androgens, estrogens do not alter estimates of whole-body protein turnover and anabolism in prepubertal humans, despite significant increases in circulating insulin-like growth factor I concentrations. In conclusion, the impact of testosterone on protein metabolism seems to be a direct effect of androgens, independent of aromatization. These findings correlate with the significant differences in muscle bulk between the sexes as children go through puberty.

Carbon Dioxide↗
PubMed1995

Recombinant human insulin-like growth factor-I enhances whole body protein anabolism and significantly diminishes the protein catabolic effects of prednisone in humans without a diabetogenic effect.

To investigate whether recombinant human insulin-like growth factor-I (rhIGF-I) could serve as a protein-sparing nondiabetogenic agent, 21 healthy volunteers (mean age, 25 +/- 1 yr) were studied in 3 similar clinical models: rhIGF-I alone, rhIGF-I and prednisone, and prednisone alone. In study A, 6 subjects received infusions of [14C]leucine and [2H2]glucose before and after 5-7 days of rhIGF-I (100 micrograms/kg, sc, twice daily, followed by 16 h of a 10 micrograms/kg.h continuous sc infusion). The rate of appearance (Ra) of leucine, an estimate of whole body proteolysis, did not change significantly, whereas leucine oxidation decreased (-31 +/- 4%; P = 0.001), hence the nonoxidative leucine disposal (NOLD) increased significantly (P = 0.04). These effects are similar to those reported with high dose hGH. Plasma glucose concentrations did not change despite a significant reduction in circulating insulin concentrations (-58 +/- 11%; P = 0.01) and an increase in the glucose Ra (+12 +/- 5%; P = 0.04). After rhIGF-I treatment, plasma IGF-I, IGF-binding protein-1 (IGFBP-1), and IGFBP-2 all increased significantly, whereas IGFBP-3 did not change. In study B, seven subjects received rhIGF-I combined with oral prednisone (0.8 mg/kg.day) for 5 days. Group C (n = 8) received only prednisone. In group B, both the leucine Ra and oxidation increased (Ra, +7 +/- 3%; oxidation, +45 +/- 13%), but this increase was significantly less than that seen in group C (Ra, +25 +/- 5%; oxidation, 117 +/- 17%; P < 0.005 vs. group B). Group B showed no significant changes in postabsorptive glucose concentrations despite marked reductions in circulating insulin levels, in contrast to the increase in insulin and glucose concentrations observed in group C. In conclusion, 100 micrograms/g rhIGF-I, given twice daily, 1) has GH-like effects on whole body protein metabolism, 2) markedly diminishes the protein catabolic effect of glucocorticosteroids, and 3) is nondiabetogenic in prednisone-treated humans. This agent offers promise in the treatment of protein catabolic states.

Adult↗
PubMed1995

Combined recombinant human growth hormone and recombinant human insulin-like growth factor I: lack of synergy on whole body protein anabolism in normally fed subjects.

Recent data demonstrate that recombinant human insulin-like growth factor I (rhIGF-I) has GH-like effects on protein metabolism, selectively stimulating whole body protein synthesis. Additionally, recent studies suggest that the combination of recombinant human GH (rhGH) and rhIGF-I might be more anabolic than either compound alone when administered to calorically deprived subjects. To investigate whether the same is true in normally fed healthy individuals, seven healthy subjects (mean age, 26 +/- 1 yr) fed a normal weight maintenance diet (approximately 33 Cal/kg.day) with approximately 1.4 g/kg.day protein were given rhGH (0.025 mg/kg.day) and rhIGF-I (100 micrograms/kg bid daily) sc for 5 days. Whole body leucine kinetics were studied using primed 4-h infusions of [14C]leucine before and after treatment and measuring the specific activity of 14C-labeled alpha-ketoisocaproic acid and 14CO2 in plasma and breath, respectively. These data were compared with those from six additional subjects treated only with rhGH as well as with those from previously reported subjects given rhIGF-I alone. Subjects receiving combination treatment had a significant increase in plasma IGF-I concentrations (123 +/- 9 to 709 +/- 29 micrograms/L; P = 0.001). As expected, there was a significant decrease in leucine oxidation in subjects given combination therapy (P = 0.03) as well as a significant increase in leucine turnover (P = 0.018); hence the nonoxidative leucine disposal, a measure of whole body protein synthesis, was significantly increased (P = 0.018). However, when the absolute changes in all three parameters of leucine kinetics were compared in the three treatment groups (rhGH alone, rhIGF-I alone, and combined rhGH and rhIGF-I), there was no additive effect of combination treatment on whole body protein anabolism (P > 0.05, by analysis of variance). We conclude that, contrary to the calorically deprived model, in normally fed individuals, the coadministration of rhIGF-I and rhGH at these doses is not more anabolic on whole body protein than either compound given alone. This difference in observed effects in the fed and partly fasted state may be related to the difference in total insulin output and suggests a saturable capacity of the body to accumulate protein during normal substrate availability while the body is exposed to individual anabolic hormones. These data suggest a common pathway for GH and IGF-I to enhance whole body protein anabolism in the normally fed state.

Adult↗
PubMed1994

Growth hormone-binding protein levels: studies of children with short stature.

A high-affinity growth hormone-binding protein (GHBP) in serum is derived from the extracellular domain of the GH receptor. In an attempt to investigate the differences in GHBP levels in various conditions of poor growth, we measured GHBP levels by two methods--an Ultrogel chromatographic technique and a ligand-mediated immunofunctional assay (LIFA). The following three groups of children were studied: Turner's syndrome (n = 7), idiopathic and/or familial short stature ([ISS] n = 15), and organic or idiopathic hypopituitarism (n = 19). All groups were similar in age (Turner's syndrome, 10.1 +/- 0.9 years; ISS, 10.0 +/- 0.7; hypopituitarism, 11.5 +/- 1.0) and height SEM score (Turner's syndrome, -2.9 +/- 0.3; ISS, -3.0 +/- 0.4; hypopituitarism, -2.3 +/- 0.4). Their values were compared with those values of GHBP in healthy controls of similar age. Immunofunctional assay values for GHBP were as follows: Turner's syndrome, 235.4 +/- 26.0 pmol/L; ISS, 122.4 +/- 11.0; and hypopituitarism, 157.1 +/- 23.0. These results were significantly different in subjects with ISS and hypopituitarism as compared with a group of healthy controls between the ages of 9 and 12 years (N = 255; GHBP = 287.9 +/- 10.9 pMol/L; P < .001 compared with both ISS and hypopituitarism). Similar changes were found using Ultrogel chromatography. This difference in GHBP levels is still significant even when more stringent criteria are applied to define hypopituitarism (ie, peak GH responses to stimuli < 6.0 ng/mL, instead of < or = 10 ng/mL originally).(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1994

Calcium and protein kinetics in prepubertal boys. Positive effects of testosterone.

We investigated the effects of 4-6-wk administration of testosterone on calcium and protein metabolism in six healthy prepubertal short boys (mean age +/- SE = 12.9 +/- 0.6 yr). At baseline, subjects received a 4-h infusion of L-[1-13C]leucine and L-[2-15N]glutamine, and were given 42Ca intravenously, and 44Ca PO. Testosterone enanthate (approximately 3 mg/kg) was given I.M. 2 wk apart (two doses n = 5, three doses n = 1), and the study was repeated 4-5 d after the last injection. After testosterone therapy, there were significant increases in serum testosterone and mean peak and total growth hormone concentrations. Net calcium absorption (Va) and retention (Vbal) also increased (Va 13.3 +/- 2.3 vs 21.5 +/- 2.3; mg.kg-1.d-1, Vbal 8.0 +/- 2.1 vs 16.6 +/- 2.5, mg.kg-1.d-1, P < .05 both), as well as Ca's net forward flow into bone and total exchangeable pool (16 and 20%, respectively). The rate of appearance of leucine (an indicator of proteolysis) increased by 17.6 +/- 5.9%, P = 0.036. Leucine oxidation decreased by 48.6 +/- 8.0%, P = 0.004; thus, nonoxidative leucine disappearance, which estimates protein synthesis, increased significantly by 34.4 +/- 7.7%, P = 0.009. Glutamine's rate of appearance also increased (+32%), mostly through enhanced glutamine de novo synthesis (+42%). In conclusion, short term testosterone administration significantly increases calcium's retention and net forward flow into bone in prepubertal humans, as well as whole body estimates of protein and calcium anabolism. These effects may represent a pure androgen effect, an amplification of growth hormone's action or some combination of these factors.

Calcium↗
PubMed1993

Effect of human growth hormone and insulin-like growth factor I on whole-body leucine and estimates of protein metabolism.

Recombinant human growth hormone (rhGH) administration to normal volunteers increases estimates of whole-body and forearm protein synthesis but has little effect on rates of proteolysis in both the postabsorptive state and during meal absorption. In contrast, insulin decreases estimates of whole-body and forearm proteolysis while decreasing or, in the presence of infused (or ingested) amino acids, sustaining estimates of protein synthesis. We have used high-dose prednisone as a controlled model for protein catabolism in normal volunteers and demonstrated that glucocorticosteroids increase estimates of whole-body proteolysis and the oxidation of leucine with little or no effect on estimates of whole-body protein synthesis. We have recently demonstrated that high-dose rhGH together with prednisone prevents the protein-catabolic effects observed with treatment with prednisone alone, while inducing insulin resistance and increased secretion of proinsulin. GH is thought to mediate its effects via the generation of insulin-like growth factor I (IGF-I). However, high rates of infusion of rhIGF-I induce hypoglycemia and decrease estimates of whole-body proteolysis and suppress the secretion of GH, insulin and glucagon, suggesting a predominant insulin-like effect on protein and glucose metabolism. When rhIGF-I is infused at a rate that achieves plasma IGF-I concentrations similar to those observed during rhGH treatment and yet avoids hypoglycemia, estimates of proteolysis and protein synthesis were not affected in the absence or presence of prednisone treatment. When rhGH and rhIGF-I are administered simultaneously, nitrogen balance is remarkably improved. Thus, the mechanism of action of both rhGH and/or rhIGF-I on body protein metabolism remains to be elucidated.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth Hormone↗