Insulin-like growth factor I (IGF-I) and growth in children undergoing hemodialysis or after successful renal transplantation

Los niños con insuficiencia renal crónica frecuentemente presentan retardo de crecimiento. Para analizar la relación entre IGF-I y crecimiento en esta situación clínica, se estudiaron 7 pacientes hemodializados y 7 pacientes transplantados con función renal normal. El IGF-I total del suero se midió por RIA luego de cromatografía ácida en columnas de OFDS silica. Los pacientes hemdializados crecían a muy baja velocidad (X1.5c,/a), y aunque los transplantados lo hacían a una velocidad significativamente mayor (X3.3 cm/a, p<0.025), 4/7 presentaban velocidades por debajo de lo normal. Todos los pacientes de ambos grupos tuvieron niveles de IGF-I dentro de los límites normales, pero la media de los transplantados fue significativamente mayor que la de los hemodializados (39.2 ñ 13.6 nM/I vs 13.4 ñ 3.0 nM/I --predialisis-- p<0.005). La medida de la desviación logarítmica de los valores de IGF-I de los pacientes hemodializados no difirió significativamente de lo normal, mientras que la media de los transplantados fue signifdicativamente mayor que lo normal (1.027 ñ 0.500, p<0.005). Estos últimos presentaban por lo tanto, como grupo, un aumento pequeño pero real de los valores de IGF-I.. Sin embargo, no se encontró una correlación estadísticamente significativa entre IGF-I y velocidad de crecimiento. Esto, junto a la ausencia de los valores de IGF-I por debajo de lo normal, indicaría que los niveles séricos de IGF-I no desempeñan un papel importante en el retardo de crecimiento de los pacientes con insuficiencia renal crónica (AU)

Insulin-like growth factor I (IGF-I) and growth in children undergoing hemodialysis or after successful renal transplantation

Los niños con insuficiencia renal crónica frecuentemente presentan retardo de crecimiento. Para analizar la relación entre IGF-I y crecimiento en esta situación clínica, se estudiaron 7 pacientes hemodializados y 7 pacientes transplantados con función renal normal. El IGF-I total del suero se midió por RIA luego de cromatografía ácida en columnas de OFDS silica. Los pacientes hemdializados crecían a muy baja velocidad (X1.5c,/a), y aunque los transplantados lo hacían a una velocidad significativamente mayor (X3.3 cm/a, p<0.025), 4/7 presentaban velocidades por debajo de lo normal. Todos los pacientes de ambos grupos tuvieron niveles de IGF-I dentro de los límites normales, pero la media de los transplantados fue significativamente mayor que la de los hemodializados (39.2 ñ 13.6 nM/I vs 13.4 ñ 3.0 nM/I --predialisis-- p<0.005). La medida de la desviación logarítmica de los valores de IGF-I de los pacientes hemodializados no difirió significativamente de lo normal, mientras que la media de los transplantados fue signifdicativamente mayor que lo normal (1.027 ñ 0.500, p<0.005). Estos últimos presentaban por lo tanto, como grupo, un aumento pequeño pero real de los valores de IGF-I.. Sin embargo, no se encontró una correlación estadísticamente significativa entre IGF-I y velocidad de crecimiento. Esto, junto a la ausencia de los valores de IGF-I por debajo de lo normal, indicaría que los niveles séricos de IGF-I no desempeñan un papel importante en el retardo de crecimiento de los pacientes con insuficiencia renal crónica

Effect of clonidine on growth and plasma somatomedin C levels of young rats

To study effects of clonidine on growth and plasma somatomedin C (SmC) lelvels, 42 male Wistar rats aged 28 days and weighing 75 to 105 g were given clonidine (1,5 microng/ml in drinking water), or filtered water alone and were weighed weekly. After 0,4 and 8 weeks, the animals were sacrificed under ether anesthesia, their length was measured and blood was collected by cardiac puncture for measurement of SmC concentration. Growth and the weigh/lengh ratio were lower, and plasma SmC levels (mean ñ SEM) were greater in the treated groups after 4 (616 ñ 44.7 vs 433.2 ñ 39.38 ng/ml, P < 0.01) and 8(595.2 28.3 vs 412.66 ñ 39.01 ng/ml, P < 0.01) weeks of treatment, suggesting that clonidine treatment increased growth hormone secretion. In other experiments, treated showed increased food intake only during the first week of treatment and decreased epididymal fat weight afther 3 weeks (1.412 ñ 0.0536 vs 1.6 ñ 0.1335 mg/100 g body weight, P < 0.01). The results suggest that clonidine acts at the level of the central nervous system involving transitory modulation of food intake, as well as on the regulation of energy metabolism

Molecular forms of serum insulin-like growth factor (IGF)-binding proteins in man: relationships with growth hormone and IGFs and physiological significance.

Insulin-like growth factor-I (IGF-I) and IGF-II are associated in the blood with specific binding proteins (BPs), forming complexes that elute in gel filtration with estimated mol wt around 40 and 150 kD. The latter appears to be under GH control. Five molecular forms of BP (41.5, 38.5, 34, 30, and 24 kD) have been identified by Western blotting using 125I-labeled IGF. All five forms are present in the smaller complexes, but only the 41.5- and 38.5-kD forms are found in the larger complexes. In this study immunoblotting showed that the 41.5- and 38.5-kD forms were recognized by antibodies directed against the GH-dependent BP purified from human plasma, and the 30-kD form was recognized by antibodies directed against the BP purified from amniotic fluid. The 34- and 24-kD forms proved to be immunologically unrelated to the other three. In sera with large quantities of the 41.5- and 38.5-kD forms, an additional band was often observed immediately ahead of the migration front of the 30 kD band. This was recognized by the anti-GH-dependent BP antibody and probably corresponds to a degradation product of the 41.5- and 38.5-kD BPs. Serum 41.5- and 38.5-kD BPs have been found to be elevated in acromegaly, where GH hypersecretion causes increased IGF-I levels, and diminished in cases of genetic or idiopathic GH deficiency and defects of the GH receptor (Laron's syndrome), where both IGF-I and IGF-II are decreased, as well as in Pygmy adults and children who have isolated IGF-I deficiency. In all of these conditions, the proportions of the 34- and 30-kD forms were inversely related to those of the 41.5- and 38.5-forms. Under treatment, the BP profiles tended to return to normal. In cases of GH deficiency caused by a tumor, the BP profiles resembled those of hypopituitary or normal serum, depending on whether IGF levels were diminished or normal. It, therefore, seems that BP synthesis is coordinated with IGF-I synthesis and may not be directly GH dependent. The results of neutral pH gel filtration analysis of hypopituitary (idiopathic and tumoral) and normal sera point to a relationship between the levels of circulating IGFs and those of the 150-kD IGF-BP complex whose binding units are the 41.5- and 38.5-kD BPs. It, therefore, seems that the 150-kD complex controls the bioavailability of IGF-I and IGF-II.(ABSTRACT TRUNCATED AT 400 WORDS)

The role of insulin-like growth factor I in growth of diabetic rats.

Insulin-deficient, streptozotocin-diabetic rats show severe metabolic disturbances and stop growing. Besides insulin, these animals also lack growth hormone and insulin-like growth factor-I. We examined whether or not growth parameters correlate with IGF-I serum levels in young rats with streptozotocin-diabetes of different severity. In the diabetic rats, blood glucose varied between 18.4 and 38.6 mmol/l (healthy controls between 6.1 and 9.3), IGF-I serum levels between 2.6 and 15.6 nmol/l (controls between 19.6 and 26.5), and serum insulin levels between 0.05 and 0.14 nmol/l (controls between 0.36 and 0.55). We found a highly significant linear correlation between IGF-I serum levels and the two investigated growth parameters, tibial epiphyseal width and longitudinal tibial bone growth. The finding that these indices of growth are strongly correlated with IGF-I serum levels in young rats with diabetes of different severity, suggests that IGF-I is a major determinant of growth. This is in keeping with our earlier demonstration that exogenously infused IGF-I promotes growth in diabetic rats.

Dietary carbohydrate content determines responsiveness to growth hormone in energy-restricted humans.

To determine if diet composition influences responses to GH, we fed 11 obese women diets containing 12 Cal/kg ideal BW (IBW) for 2 5-week study intervals. Nonprotein calories were supplied to 6 subjects as 72% carbohydrate (high carbohydrate diet), and 5 subjects received 80% of their nonprotein calories as lipid (high lipid diet). Protein intake was constant (1.0 g/kg IBW) in both groups. During 1 study interval we gave injections of GH (0.1 mg/kg IBW) every other day for 3 weeks (weeks 2-4), and in the other interval injections of vehicle were given. Subjects ingesting the high carbohydrate diet excreted significantly less urinary nitrogen [660.2 +/- 124.1 mmol/day (mean +/- SD)] than those who received high lipid (794.2 +/- 198.5 mmol/day; P less than 0.001), and GH injections reduced nitrogen excretion in the high carbohydrate subjects (532.8 +/- 123.8 mmol/day), but not in the high lipid subjects (743.7 +/- 126.6 mmol/day). The subjects receiving the high carbohydrate diet had a significant increase in serum insulin-like growth factor-I (IGF-I; from 36.2 +/- 9.7 to 55.9 +/- 6.6 nmol/L) and urinary C-peptide excretion (from 43.9 +/- 25.6 to 60.8 +/- 29.4 nmol/day) in response to GH. The IGF-I response attenuated slowly over the 3-week treatment interval. On the other hand, the high lipid group had lesser increases in IGF-I (from 31.0 +/- 6.5 to 41.7 +/- 8.8 nmol/L) and C-peptide excretion (from 24.3 +/- 28.9 to 29.8 +/- 32.8 nmol/day), and IGF-I concentrations declined to control values after only 5 days of GH injection. We believe that this initial IGF-I response was due to an antecedent 35-Cal balanced diet. The mean increment in serum FFA 4 h after GH injection was significantly less in subjects fed the high lipid diet (0.53 +/- 0.40 meq/L) than in those fed the high carbohydrate diet (0.83 +/- 0.43 meq/L). GH injections produced more body fat loss than injections of vehicle whether expressed as percent body fat lost (GH, 3.7 +/- 1.0%; vehicle, 2.8 +/- 0.7%, P less than 0.05) or as the fraction of weight lost as fat (fat loss/weight loss; GH, 0.81 +/- 0.13; vehicle, 0.64 +/- 0.08; P less than 0.005). There was an inverse correlation between the percentage of body fat lost and mean urinary C-peptide excretion during GH injections (r = -0.70; P less than 0.05), suggesting that stimulation of insulin secretion by GH might antagonize the tendency of GH to promote fat loss.(ABSTRACT TRUNCATED AT 400 WORDS)

Spinal and peripheral bone mineral densities in acromegaly: the effects of excess growth hormone and hypogonadism.

STUDY OBJECTIVE: To measure spinal and peripheral bone mineral densities in patients with acromegaly. DESIGN: Retrospective study. SETTING: Tertiary care center. SUBJECTS: Twenty-four patients with acromegaly and 24 case controls. Seventeen patients (12 eugonadal and 5 hypogonadal) had "active" disease as indicated by elevated plasma concentrations of growth hormone or somatomedin C or both at the time of the study. Seven patients (all hypogonadal) had inactive disease by these criteria. MEASUREMENTS AND MAIN RESULTS: Bone mineral was measured by single photon absorptiometry of the forearm and dual photon absorptiometry of the spine. The forearm bone mineral content of patients with active disease, regardless of gonadal status, was significantly higher than that of normal subjects (P less than 0.001) or of patients with inactive disease (P less than 0.001). The disease "activity" (17.2 +/- 3.7; CI, 9.5 to 24.9) and the sex of the patient (female, -16.6 +/- 3.4; CI, -23.7 to -9.5) were the only independent predictors of forearm measurements. Vertebral bone densities were lower in acromegalic patients than in normal subjects (P less than 0.001). Vertebral values were correlated with the gonadal status of the patients (hypogonadism, -0.126 +/- 0.056; CI, -0.244 to -0.009) and with serum calcium concentrations (0.592 +/- 0.274; CI, 0.032 to 1.153) but not with acromegalic activity. In 13 patients, forearm bone was measured before and after treatment (mean duration of follow-up, 3.4 years). Patients with persistently elevated, plasma somatomedin C concentrations at the end of the study period showed a mean annual increase of 1.5% in forearm measurements during the period of observation, whereas patients with normal concentrations showed a mean annual decrease of 1.0% (P less than 0.01 for the difference between the groups). The percent change in forearm bone mineral content per year (y) was highly correlated with residual somatomedin C activity (x): y = 2.023x - 2.75; r = 0.665. CONCLUSIONS: Forearm and vertebral bone mineral measurements change in opposite directions in acromegaly. The high forearm values are attributable to the growth-promoting action of growth hormone and somatomedin C, whereas low vertebral values are associated with hypogonadism.

Structure, specificity, and regulation of the insulin-like growth factor-binding proteins in adult rat serum.

Insulin-like growth factor-I (IGF-I), the principal IGF in adult rat serum, occurs complexed to specific binding proteins. After fractionation of serum on Sephadex G-200 at neutral pH, 62% of the immunoreactive IGF-I is recovered in the 150K region, 38% in the 40K region, and none is present as free 7.5K IGF-I. Adult rat serum also contains unoccupied binding sites for IGFs that also are predominantly (77%) located in the 150K region and have preferential binding affinity for IGF-II. IGF-binding protein components in the 150K and 40K regions were evaluated by affinity cross-linking to 125I-labeled IGFs and by ligand blotting (i.e. incubation of nitrocellulose blots of sodium dodecyl sulfate (SDS)-gels with [125I]IGFs). Affinity cross-linking of the 150K region revealed a major 43K binding protein complex and several minor covalent complexes of 97-210K that are formed during the cross-linking reaction. The 40K region of the gel filtration column contains a predominant 32K complex and smaller amounts of the 43K complex. Ligand blotting of the 150K region identifies a predominant cluster of binding components of about 40K and a smaller 29K protein. The apparent molecular masses of the 40K and 29K proteins are decreased by incubation with N-glycanase, indicating that they contain N-linked oligosaccharides. These glycoprotein components, designated gp40 and gp29, presumably combine with an acid-labile nonbinding subunit of about 100K to generate the 150K complex. The gp40 cluster represents glycosylation variants of a 34K protein; gp29 has been shown to correspond to an amino-terminal fragment of gp40. Ligand blotting of the 40K region indicates that it contains smaller amounts of gp40 and gp29, possibly representing free subunits not combined with the nonbinding subunit, as well as two proteins of apparent molecular mass 24K and 30K (p24 and p30) that are not glycosylated. Although p30 is similar in size to the binding protein from BRL-3A cells (BP-3A) that is present in fetal rat serum, immunoprecipitation and immunoblotting of whole and fractionated adult serum with an antiserum to BP-3A indicate that p30 in adult rat serum is an antigenically distinct protein. Serum levels of gp40 and gp29 are decreased by hypophysectomy and are restored by GH treatment; p24 and p30 show similar but smaller changes.

Identification of a type 1 insulin-like growth factor binding protein (IGF BP) in serum from rats with diabetes mellitus.

Circulating insulin-like growth factor binding protein (IGF BP) activity is increased in animals with streptozotocin-induced diabetes. Separation of BPs by SDS/PAGE for ligand and immunoblot analysis revealed that a 32,000 molecular weight BP is present and increased in diabetic serum. This BP is immunologically distinct from the low molecular weight fetal rat BP (rBP2) and is related to the human amniotic fluid BP (hBP1) that is increased in patients with insulin dependent diabetes mellitus.

Low somatomedin C and high growth hormone levels in newborns damaged by maternal alcohol abuse.

To study the mechanism of alcohol-induced fetal damage, we determined the somatomedin C and growth hormone (GH) concentrations of umbilical cord blood samples in 56 infants of alcohol-abusing women and in 20 infants of alcohol-abstinent women. In addition, maternal serum somatomedin C concentrations were determined 1-7 days before delivery. Twenty-five infants born to alcohol-abusing mothers were growth-retarded and also had other signs of fetal alcohol effects, but the remaining 31 infants born to the drinkers and all infants of abstinent mothers were healthy. The somatomedin C levels of infants with fetal alcohol effects (mean +/- SD 4.6 +/- 1.5 nmol/L) were lower (P less than .005) than the levels of healthy infants of drinking (6.8 +/- 4.0 nmol/L) or abstinent (7.1 +/- 3.3 nmol/L) mothers, but the levels did not correlate with infant birth weight, placental weight, or fetal GH or maternal somatomedin C levels. Alcohol drinking was not associated with any changes in maternal somatomedin C levels. The GH levels of infants with fetal alcohol effects (25.4 +/- 22.6 ng/mL) were elevated (P less than .01) when compared with those of infants of abstinent mothers (13.1 +/- 5.3 ng/mL), but did not differ from those of healthy infants of drinking mothers (19.9 +/- 15.1 ng/mL). Low somatomedin C levels and high GH levels in infants born to the drinkers suggest a disharmony in the regulation of the synthesis and/or release of these growth factors, which may be of importance in alcohol-induced fetal damage.

Alterations in the pulsatile properties of circulating growth hormone concentrations during puberty in boys.

To investigate the mechanisms subserving physiological alterations in circulating GH concentrations during puberty, we assessed the GH pulse characteristics of 60 24-h serum GH profiles obtained from healthy male volunteers of normal stature (aged 7-27 yr) whose physical development spanned the entire pubertal range. Subjects were divided into five study groups based on degree of sexual maturation. The mean 24-h concentration of GH was greater in late pubertal boys than in all other groups (P less than 0.001). This elevation primarily reflected a greater size, rather than number, of GH pulses, whether assessed as mean GH pulse area (P = 0.004 vs. all other groups), mean GH pulse amplitude (P = 0.001), or sum of the GH pulse areas (P less than 0.001). GH pulse frequency was indistinguishable among all groups (P greater than 0.05). However, circadian GH rhythms varied significantly in amplitude and mean values (but not in phase) throughout puberty. Plasma insulin-like growth factor-I levels were greatest in the late pubertal boys (1.98 +/- 0.15 U/mL) and remained elevated in the postpubertal group (1.44 +/- 0.18). The mean value for the adult men (0.74 +/- 0.06) was indistinguishable from that of prepubertal boys (0.90 +/- 0.13). In addition, all assessed characteristics of GH pulses and circadian rhythms in adults were equal to or less than corresponding values in prepubertal boys. We conclude that circulating GH concentrations transiently increase during mid- to late puberty in normal boys, primarily through augmentation of the size of GH pulses, but return to or below prepubertal levels during early adulthood.

Significance of abnormal serum binding of insulin-like growth factor II in the development of hypoglycemia in patients with non-islet-cell tumors.

We reported that serum and tumor from a hypoglycemic patient with a fibrosarcoma contained insulin-like growth factor II (IGF-II), mostly in a large molecular form designated "big IGF-II." We now describe two additional patients with non-islet-cell tumor with hypoglycemia (NICTH) whose sera contained big IGF-II. Removal of the tumor eliminated most of the big IGF-II from the sera of two patients. Because specific IGF-binding proteins modify the bioactivity of IGFs, the sizes of the endogenous IGF-binding protein complexes were determined after neutral gel filtration through Saphadex G-200. Normally about 75% of IGFs are carried as a ternary complex of 150 kDa consisting of IGF, a growth hormone (GH)-dependent IGF-binding protein, and an acid-labile complexing component. The three patients with NICTH completely lacked the 150-kDa complex. IGF-II was present as a 60-kDa complex with variable contributions of smaller complexes. In the immediate postoperative period, a 110-kDa complex appeared rather than the expected 150-kDa complex. Abnormal IGF-II binding may be important in NICTH because the 150-kDa complexes cross the capillary membrane poorly. The smaller complexes present in our patients' sera would be expected to enter interstitial fluid readily, and a 4- to 5-fold increase in the fraction of IGFs reaching the target cells would result.

Normal growth hormone (GH) response to GH-releasing hormone in children with thalassemia major before puberty: a possible age-related effect.

The plasma GH response to a single iv bolus dose of 2 micrograms/kg BW synthetic GHRH-(1-44)NH2 was evaluated in 13 prepubertal children with thalassemia major (mean age, 7.6 +/- 0.8 yr) with growth retardation and in 15 prepubertal children with nonendocrine short stature. All of the patients showed a significant increase in plasma GH concentration, with a mean peak of 31.4 +/- 4.5 micrograms/L at 15 min (P less than 0.001 vs. basal values; range, 18.4-65 micrograms/L) after GHRH, which was not different from that of the control group of idiopathic short stature children (40.1 +/- 3.4 micrograms/L; range, 21-65.4 micrograms/L). All but 1 of the thalassemic patients had a normal GH response to the arginine-insulin stimulation test. The mean plasma insulin-like growth factor-I level was low (0.12 +/- 0.05 U x 10(3)/L; range, less than 0.02-0.61 U x 10(3)/L). Analysis of these results as well as previously reported data indicating that older thalassemic patients have an impaired GH response indicates that there may be an age-related pituitary and/or hypothalamic dysfunction in thalassemic children. This study also confirms that the insulin-like growth factor-I decrease occurs before any alteration in GH secretion. These changes might play a role in the early growth retardation that occurs in these patients.

Prolonged fasting or clonidine can restore the defective growth hormone secretion in old dogs.

Age-related changes in GH secretion were studied in dog. In preliminary experiments, administration of GH-releasing hormone (GHRH-40, 2 micrograms/kg, iv) or the alpha 2-adrenoceptor agonist clonidine (4 micrograms/kg, iv) elicited significantly higher plasma GH rises in 3 to 4 years old than in 10 to 14 years old beagle dogs. The pulsatile patterns of GH secretion in both young and old dogs under baseline conditions and after prolonged fasting or clonidine administration were studied. Samples were taken every 10 min from 09.00 to 15.00 h from five young and five old dogs of both sexes. Under baseline conditions, GH peak frequency, total peak area, and integrated GH secretion were significantly lower in old than in young dogs. In old dogs, 5-day complete fasting or 14-day clonidine administration (75 micrograms/dog, po, twice daily) increased the frequency and amplitude of spontaneous GH bursts, the total peak area, and the integrated GH secretion. After either stimulus, the GH secretory pattern was quantitatively and qualitatively indistinguishable from that of young dogs under baseline conditions. Similarly, the foregoing indices were significantly increased in young dogs by either stimulus, except for the inability of clonidine to affect peak frequency. These data demonstrate that the defective GH secretion in old dogs is not irreversible, since it is normalized when old dogs are exposed to central nervous system-directed stimuli.

Changes in basal and stimulated TSH and other parameters of thyroid function in acromegaly after transsphenoidal surgery.

T1 and T3 levels, TSH response to TRH and somatomedin-C levels in 63 patients with acromegaly, were measured before transsphenoidal surgery and during a 4-year follow-up period. Criteria for cure were: mean GH level less than 5 mU/l, suppression of GH by oral glucose tolerance test below 2.5 mU/l and normalization of paradoxical GH reaction to TRH. Nine patients underwent radioiodine studies to assess the renal and thyroid clearance of iodide, plasma inorganic iodine level and absolute iodine uptake. Among the patients 40% had goitre, with a male preponderance. T1 and T3 levels were in the normal range both before and after surgery. A transient decrease in T3 levels was found in the immediate postoperative period. Before treatment a diminished or absent TSH response to TRH was exhibited by 64% of the goitre patients and 34% of the non-goitre groups (p less than 0.05). Despite normalization of GH and somatomedin-C levels and normal T4 and T3 levels no improvement of the TSH response was found during follow-up. No correlation between the incremental response of TSH to TRH and circulating T4 or T3 levels, basal TSH, GH or tumour size was found. There was, however, a negative correlation (r = -0.765, p less than 0.05) between the incremental TSH response to TRH and somatomedin-C levels for females with goitre. Somatomedin-C levels were higher in patients with goitre than in those without goitre (95 +/- 26 vs 75 +/- 30 nmol/l; mean +/- SD, p = 0.05). Radioiodine studies showed an increased renal clearance of iodide which was related to the increase in creatinine clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Caloric restriction and 7,12-dimethylbenz(a)anthracene-induced mammary tumor growth in rats: alterations in circulating insulin, insulin-like growth factors I and II, and epidermal growth factor.

Caloric restriction (CR) inhibits many neoplastic diseases in rodents, yet the biochemical mechanism(s) for these effects are poorly understood. We have examined the effects of ad libitum (AL) feeding with 25 or 40% CR on the promotion of 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis in virgin female Sprague-Dawley rats. Further, we have also studied the influence of chronic CR on temporal alterations in circulating insulin, insulin-like growth factor I/somatomedin C, insulin-like growth factor II/multiplication-stimulating activity, and epidermal growth factor levels at 0, 1, 3, 5, 11, and 20 weeks in carcinogen- and vehicle-treated animals. Tumor incidence and multiplicity were markedly inhibited (P less than 0.05) with increasing CR. Fasting serum insulin-like growth factor I/somatomedin C levels exhibited a significant acute decline with CR at 1 and 3 weeks, but were comparable to AL-fed controls throughout the remainder of the 5-month study, despite continued differences in weight gain between AL and CR rats. Levels of insulin-like growth factor II/multiplication-stimulating activity exhibited no discernible pattern in relation to CR. Serum insulin levels showed age-dependent increases, but were affected by increasing CR at all time points. Insulin levels were significantly (P less than 0.05) reduced in 40% CR rats from 3 weeks onward compared to controls, while 25% CR resulted in nonsignificant (P less than 0.07) reductions throughout the study. No significant differences in growth factor levels were observed between 7,12-dimethylbenz(a)anthracene- and vehicle-treated rats. Circulating epidermal growth factor was not detectable in any treatment group regardless of the nature or duration of the dietary regimen, time of blood collection, or subsequent tumor-bearing status. These data suggest that decreased serum insulin-like growth factor I/somatomedin C and insulin levels with CR and their complex interactions in vivo may play a role in the inhibition of mammary tumor promotion by CR.

The effects of altered nutritional status upon insulin-like growth factors and their binding proteins in neonatal rats.

To investigate the role of nutrition in the regulation of IGFs during the perinatal period, 10-d-old rats were infused intravenously with various concentrations of nutrients for 24 h. Breast-fed litter mates served as controls. The effect of caloric intake on concentrations of IGF-I and IGF-II as well as IGF-binding proteins in serum, liver, and brain of neonatal rats was studied. A total of 45 rats from 10 litters was infused with solutions ranging from a caloric intake of 0 (saline) to 75% (glucose, amino acids, and lipids) of the estimated intake of control rats. In serum, both IGF-I and -II concentrations fell markedly in response to fasting. Serum IGF-II levels were linearly related to caloric intake in the pooled data from all groups. Concentrations of IGF-II, but not IGF-I, in liver and brain were depressed by caloric restriction. In contrast to the fall in IGF concentrations, activity of IGF-associated binding proteins rose in serum and in liver cytosol 2- to 4-fold in response to decreased nutrient intake. In serum, but not liver, the rise in binding protein activity was inversely related to to caloric intake. In liver, cytosol, but not serum, the rise in binding protein activity was inversely related to total serum amino acid concentration. Thus, IGF concentrations in preweanling rats change in response to alterations of nutrient intake. The fasting induced decrements in IGF levels, as well as the elevations in IGF-associated binding protein activity, may serve as a protective mechanism to depress growth in times of caloric restriction.

Measurement of nocturnal urinary growth hormone values.

Nocturnal urinary growth hormone values were measured by a sensitive enzyme immunoassay in normal adults, patients with GH deficiency, patients with Turner's syndrome, normal but short children who had normal plasma GH responses to provocative tests, and patients with acromegaly. The mean nocturnal urinary GH values in patients with acromegaly were significantly greater than those in normal adults (1582.3 +/- 579.8 vs 53.5 +/- 8.6 pmol/mmol creatinine (+/- SEM); p less than 0.05). In the normal but short children and patients with Turner's syndrome, the mean nocturnal urinary GH values were 83.1 +/- 5.2 and 79.8 +/- 29.5 pmol/mmol creatinine, respectively. In patients with GH deficiency, the nocturnal urinary GH values were undetectable (less than 5.3 pmol/mmol creatinine) except in one patient where the value was 6.3 pmol/mmol creatinine. The nocturnal urinary GH values of the patients with GH deficiency were significantly lower than those of the other groups (p less than 0.05). In normal but short children, the nocturnal urinary GH values correlated significantly with mean plasma nocturnal GH concentrations (r = 0.76, p less than 0.001), and 24-hour urinary GH values (r = 0.84, p less than 0.001), respectively. In 4 patients with GH deficiency who had circulating anti-hGH antibody, the urinary GH values were also undetectable. These data indicate that nocturnal urinary GH value reflects endogenous GH secretion during collection time, and that measurement of the nocturnal urinary GH values is a useful method for screening of patients with GH deficiency and acromegaly.

Pituitary adenocarcinoma in an acromegalic patient: response to bromocriptine and pituitary testing: a review of the literature on 36 cases of pituitary carcinoma.

There are 36 reported cases of metastatic pituitary carcinoma and almost half (44%) of these were associated with syndromes of hormonal hypersecretion. The case of a 56-year-old acromegalic man with cervical lymphatic and spinal metastases from a primary pituitary carcinoma is described. Elevated basal levels of plasma growth hormone (GH) and insulin growth factor-1/Somatomedin C (IGF-1/SmC) were found. GH levels did not increase after TRH or LHRH administration but decreased after L-Dopa and glucose. Immunostaining of the metastatic tumor for GH and electron microscopy findings confirmed the diagnosis of pituitary GH-secreting carcinoma. Striking clinical improvement and a 46% decrease in plasma GH levels were observed with bromocriptine treatment, although IGF-1/SmC levels increased during therapy. The clinical course of most reported cases of pituitary adenocarcinoma has been one of progressive intracranial expansion of a pituitary neoplasm. In only 25% were metastatic lesions discovered antemortem, and disabling symptomatology caused by metastases was rare. Only four previously reported patients of 36 with pituitary carcinoma had acromegaly.