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At least 127 records · Page 7Linked to original sources
PubMed1979

The effect of hypothyroidism on growth, serum growth hormone, the growth hormone-dependent somatomedin, insulin-like growth factor, and its carrier protein in rats.

To study the possible mechanisms involved in growth retardation associated with hypothyroidism, serum T4, GH, the GH-dependent somatomedin, insulin-like growth factor (IGF), and its carrier protein (CP) were measured in hypothyroid rats and their age-matched controls. Three groups of rats were studied: infant, immature, and adult. Marked hypothyroidism (serum T4, less than 1 microgram/dl) was produced in experimental animals by providing them with drinking water containing 0.05% propylthiouracil. Infant and immature hypothyroid rats weighed markedly less than normal controls and had significantly reduced serum levels of GH, IGF, and CP. Normal adult rats, treated with propylthiouracil for 60 days, also weighed considerably less than control animals and exhibited a significant drop in serum GH, IGF, and CP during this period. The administration of bovine GH to hypothyroid adult rats for 7 days did not restore either IGF or CP levels to normal, indicating that their decrease in serum was, in part, a direct result of hypothyroidism per se. These results indicate that serum levels of GH, IGF, and CP are at least partly under thyroid hormone control. Furthermore, these studies suggest that the growth retardation associated with hypothyroidism may be mediated through somatomedin activity.

Aging↗
PubMed1997

Changes in serum concentrations of growth hormone, insulin, insulin-like growth factor and insulin-like growth factor-binding proteins 1 and 3 and urinary growth hormone excretion during the menstrual cycle.

Few studies exist on the physiological changes in the concentrations of growth hormone (GH), insulin-like growth factors (IGF) and IGF-binding proteins (IGFBP) within the menstrual cycle, and some controversy remains. We therefore decided to study the impact of endogenous sex steroids on the GH-IGF-IGFBP axis during the ovulatory menstrual cycle in 10 healthy women (aged 18-40 years). Blood sampling and urinary collection was performed every morning at 0800 h for 32 consecutive days. Every second day the subjects were fasted overnight before blood sampling. Follicle stimulating hormone, luteinizing hormone (LH), oestradiol, progesterone, IGF-I, IGFBP-3, sex hormone-binding globulin, dihydroepiandrosterone sulphate and GH were determined in all samples, whereas insulin and IGFBP-1 were determined in fasted samples only. Serum IGF-I concentrations showed some fluctuation during the menstrual cycle, with significantly higher values in the luteal phase compared to the proliferative phase (P < 0.001). Mean individual variation in IGF-I concentrations throughout the menstrual cycle was 13.2% (SD 4.3; range 0.1-18.3%). There were no cyclic changes in IGFBP-3 serum concentrations and no differences in IGFBP-3 concentrations between the luteal and the proliferative phases. Mean individual variation in IGFBP-3 concentrations throughout the menstrual cycle was 8.8% (SD 2.7; range 3.2-14.1). IGFBP-1 concentrations were inversely associated with insulin concentrations, and showed a significant pre-ovulatory increase that returned to baseline at the day of the LH surge. Fasting insulin concentrations showed large fluctuations throughout the menstrual cycle without any distinct cyclic pattern. No cyclic changes in urinary GH excretion during menstrual cycle were detected. We conclude that, although IGF-I concentrations are dependent on the phase of the menstrual cycle, the variation in IGF-I concentrations throughout the menstrual cycle is relatively small. Therefore, the menstrual cycle does not need to be considered when evaluating IGF-I or IGFBP-3 serum values in women suspected to have GH deficiency.

Adolescent↗
PubMed1996

Effects of growth hormone and pregnancy on expression of growth hormone receptor, insulin-like growth factor-I, and insulin-like growth factor binding protein-2 and -3 genes in bovine uterus, ovary, and oviduct.

The effects of growth hormone (GH) and pregnancy on insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-2, and IGFBP-3 mRNA in reproductive tissues were studied in cattle. Lactating dairy cows were inseminated at estrus and treated with 25 mg/day GH (n = 8) or saline (n = 8) for 16 days. Corpus luteum (CL), ovary (CL removed), oviduct, endometrium, and myometrium were collected at the end of treatment. Messenger RNA for GH receptor, IGF-I, IGFBP-2, IGFBP-3, and actin were measured by nuclease protection assays. The CL contained more GH receptor mRNA than the other reproductive tissues examined. Expression of IGF-I mRNA was highest in myometrium, with lower amounts found in endometrium; the CL expressed the least amount of IGF-I mRNA. The IGFBP-2 mRNA was most abundant in endometrium and least abundant in CL. Expression of IGFBP-3 mRNA was detected in all reproductive tissues examined. However, endometrium, a tissue that expressed the most IGFBP-2 mRNA, had the lowest amount of IGFBP-3 mRNA. The GH receptor mRNA was decreased in cows treated with GH whereas the mRNA for IGF-I, IGFBP-2, or IGFBP-3 was not changed. In the reproductive tissues evaluated, cows that contained a conceptus at tissue collection (pregnant) had higher amounts of IGF-I mRNA than did nonpregnant cows. In summary, the level of mRNA encoding GH receptor, IGF-I, IGFBP-2, and IGFBP-3 varied within the tissues examined, suggesting that these genes may play a variety of roles in the bovine female reproductive tract. Supplemental GH failed to change the expression of IGF-I, IGFBP-2, and IGFBP-3 mRNA, possibly because of low GH receptor mRNA levels in tissues other than CL. A direct action of GH on IGF-I, IGFBP-2, or IGFBP-3 gene expression within cow reproductive tissues was not supported because the amount of IGF-I, IGFBP-2, or IGFBP-3 mRNA was not altered by GH.

Actins↗
PubMed1996

Critical illness is associated with low circulating concentrations of insulin-like growth factors-I and -II, alterations in insulin-like growth factor binding proteins, and induction of an insulin-like growth factor binding protein 3 protease.

OBJECTIVES: To describe the sequential changes in the circulating concentrations of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding proteins in critically ill patients. To determine whether critical illness is associated with induction of a specific protease directed against insulin-like growth factor binding protein 3 and to relate these changes to outcome. DESIGN: Prospective, descriptive study. SETTING: Intensive care unit (ICU) of a university hospital. PATIENTS: Eighteen heterogeneous critically ill patients, requiring ventilatory support. INTERVENTIONS: Serial daily blood samples were collected until death or discharge from the ICU. In five patients, samples were also obtained on the ward before discharge from the hospital. MEASUREMENTS AND MAIN RESULTS: Serum concentrations of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding proteins 1, 2, and 3 were measured by radioimmunoassay. After 5 days, insulin-like growth factor binding protein 3 concentrations were measured on alternate days. Alterations in binding of insulin-like growth factor-I to insulin-like growth factor binding protein 3 and the presence of protease activity directed against insulin-like growth factor binding protein 3 were investigated by Western ligand blotting. Circulating concentrations of insulin-like growth factor-I and insulin-like growth factor-II were low and remained low throughout the 7-day study period. Insulin-like growth factor binding protein 1 concentrations were initially increased to within the fasting range, but subsequently decreased. There was considerable variability in insulin-like growth factor binding protein 2 concentrations, but generally, concentrations were at the upper end of the normal range throughout. Insulin-like growth factor binding protein 3 concentrations were consistently low and Western ligand blotting at the nadir of the insulin-like growth factor-I concentration demonstrated the presence of a protease directed against insulin-like growth factor binding protein 3. The last recorded concentrations of insulin-like growth factor-I and insulin-like growth factor binding protein 3 were higher in survivors than in nonsurvivors (p < .05). Two patients were also studied for a prolonged period. In one patient, a survivor, insulin-like growth factor-I and insulin-like growth factor binding protein 3 were low initially, but later increased in association with recovery and cessation of protease activity over a period of 33 days. In another patient, a nonsurvivor, insulin-like growth factor-I and insulin-like growth factor binding protein 3 remained low and protease activity persisted until the patient died 38 days after admission to the ICU. CONCLUSIONS: Critical illness is associated with low circulating concentrations of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding protein 3 and these low values are associated with induction of protease activity specifically directed against insulin-like growth factor binding protein 3. In survivors, recovery is associated with increasing insulin-like growth factor-I and insulin-like growth factor binding protein 3 concentrations and cessation of protease activity. The therapeutic effects of exogenous growth factors are likely to be influenced by these changes.

Adolescent↗
PubMed1992

Expression of serum insulin-like growth factors, insulin-like growth factor-binding proteins, and the growth hormone-binding protein in heterozygote relatives of Ecuadorian growth hormone receptor deficient patients.

Recently, an isolated population of apparent GH-receptor deficient (GHRD) patients has been identified in the Loja province of southern Ecuador. These individuals presented many of the physical and biochemical phenotypes characteristic of Laron-Syndrome and are believed to have a defect in the GH-receptor gene. In this study, we have compared the biochemical phenotypes between the affected individuals and their parents, considered to be obligate heterozygotes for the disorder. Serum GH, insulin-like growth factor I and II (IGF-I and IGF-II) levels were measured by RIA Insulin-like growth factor binding proteins. (IGFBPs) were measured by Western ligand blotting (WLB) of serum samples, following separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and relative quantitation of serum IGFBPs was performed with a scanning laser densitometer. Serum GH-binding protein (GHBP) levels were measured with a ligand-mediated immunofunctional assay using a monoclonal antibody raised against the GHBP. These values were then compared to values obtained from normal, sex-matched adult Ecuadorian controls, to determine if the above parameters were abnormal in the heterozygotes. The serum IGF-I levels of the GHRD patients were less than 13% of control values for adults and 2% for children. However, the IGF-I levels of both the mothers and fathers were not significantly different from that of the control population. The serum IGF-II levels of the GHRD patients were approximately 20% of control values for adults and 12% for the children. The IGF-II levels of the mothers were reduced, but were not significantly different from that of the control population. However, IGF-II levels of the fathers were significantly lower than those of controls (64% of control male levels). WLB analysis of serum IGFBP levels of the affected subjects demonstrated increased IGFBP-2 and decreased IGFBP-3, suggesting an inverse relationship between these IGFBPs. The GHRD patients who had the lowest serum IGFBP-3 levels (as measured by WLB) demonstrated a serum protease activity that could proteolyze 125I-IGFBP-3. GHRD patients who had higher serum IGFBP-3 levels lacked this serum protease activity. There were no differences in the serum IGFBP profiles of the mothers or the fathers for either IGFBP-2 or IGFBP-3, and serum from both groups lacked the ability to significantly proteolyze 125I-IGFBP-3. While GHRD patients had very low levels of serum GHBP, some patients did have measurable GHBP levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed2002

Transforming growth factor-beta1 in fetal serum correlates with insulin-like growth factor-I and fetal growth.

OBJECTIVE: To estimate whether transforming growth factor-beta1 in fetal serum obtained by umbilical cord sampling at delivery is correlated with fetal growth. We also estimated whether transforming growth factor-beta1 is correlated with insulin-like growth factor-I and insulin-like growth factor binding protein-1, which have been shown to correlate with fetal growth. METHODS: The active form of transforming growth factor-beta1 was analyzed in serum from cord blood from 68 fetuses by the enzyme-linked immunosorbent assay technique. Of the 68 pregnant women, 12 had preeclampsia, 14 had preeclampsia and intrauterine growth restriction, 15 had intrauterine growth restriction alone, and seven had fetuses that were large for gestational age (LGA). Twenty pregnancies with fetuses appropriate for gestational age (AGA) served as controls. RESULTS: Transforming growth factor-beta1 concentrations were significantly correlated with birth weight. The average transforming growth factor-beta1 concentration in the following groups were: intrauterine growth restriction, 22.4 +/- 2.7 microg/L; intrauterine growth restriction plus preeclampsia, 22.9 +/- 2.0 microg/L; preeclampsia without intrauterine growth restriction, 28.8 +/- 2.1 microg/L; LGA, 30.3 +/- 4.3 microg/L; and AGA, 36.8 +/- 2.0 microg/L. Transforming growth factor-beta1 levels were significantly lower in pregnancies complicated by intrauterine growth restriction and showed a positive correlation with birth weight (r = 0.48, P <.001). Furthermore, there was a positive correlation between insulin-like growth factor-I levels and birth weight (r = 0.36, P <.01) and a negative correlation between insulin-like growth factor binding protein-1 and birth weight (r = -0.32, P <.01). There was also a correlation between transforming growth factor-beta1 and insulin-like growth factor-I (r = 0.29, P <.05) and between transforming growth factor-beta1 and insulin-like growth factor binding protein-1 (r = -0.25, P <.05). CONCLUSION: Transforming growth factor-beta1 might be related to fetal growth in pregnancy. The results also support previous data showing that insulin-like growth factor-I and insulin-like growth factor binding protein-1 are related to fetal growth.

Adult↗
PubMed1994

Identification of epidermal growth factor, transforming growth factor-alpha, and epidermal growth factor receptor in surgically induced pelvic adhesions in the rat and intraperitoneal adhesions in the human.

OBJECTIVE: Our purpose was to determine the presence and cellular distribution of epidermal growth factor, transforming growth factor-alpha, and epidermal growth factor receptor in surgically induced pelvic fibrous adhesions in rat uterine horns subjected to burn, crush, and debridement injury and intraperitoneal fibrous adhesions formed to various organs in the human. STUDY DESIGN: A total of 15 injured and five uninjured rats were used in this study, and fibrous adhesions and intact peritoneum were removed for processing 2 weeks after surgery. Fibrous adhesions formed to uterine, ovarian, and oviductal tissues and the peritoneal wall from eight patients who had gynecologic surgery were also collected. The tissues were processed for immunohistochemical localization of epidermal growth factor, transforming growth factor-alpha, and epidermal growth factor receptor with specific antibodies to human and rat epidermal growth factor and transforming growth factor-alpha and the extracellular binding domain of the epidermal growth factor receptor. RESULTS: All the cell types in the rat fibrous adhesion immunostained for epidermal growth factor, transforming growth factor-alpha, and epidermal growth factor receptor. The highest immunostaining intensity for epidermal growth factor was associated with inflammatory cells infiltrated into the fibrous adhesion, followed by arteriole endothelial and smooth muscle cells, fascial striated muscle, and fibroblasts of the fibrous adhesion. In the uterine tissue at the site of injuries myometrial smooth muscle cells, in addition to inflammatory cells that migrated among stromal cells, also immunostained for epidermal growth factor. Fibrous adhesions also immunostained for transforming growth factor-alpha with three separate polyclonal antibodies to the amino and carboxy termini of transforming growth factor-alpha precursor and the mature transforming growth factor-alpha, with no substantial differences in their intensity and pattern compared with epidermal growth factor. The pattern and cellular distribution of epidermal growth factor receptor was similar to that seen for epidermal growth factor and transforming growth factor-alpha. Fibrous adhesions from patients with intraperitoneal adhesions immunostained for epidermal growth factor, transforming growth factor-alpha, and epidermal growth factor receptor with a pattern and intensity similar to that observed in fibrous adhesions in the rats. CONCLUSIONS: The data suggest that epidermal growth factor and transforming growth factor-alpha may play a key role both in normal mechanism of peritoneal repair after injury and formation and maintenance of fibrous adhesions.

Animals↗
PubMedDate not supplied

Combination of platelet-derived growth factor-BB and insulin-like growth factor-I is more effective than platelet-derived growth factor-BB alone in stimulating complete healing of full-thickness wounds in "older" diabetic mice.

Platelet-derived growth factor and insulin-like growth factor-I have been shown to interact synergistically to enhance repair of skin wounds in normal healing swine. Platelet-derived growth factor alone has shown promise in treating human chronic ulcers. The objective of this study was to compare the wound healing effects of platelet-derived growth factor-BB alone with those of a combination of platelet-derived growth factor-BB and insulin-like growth factor-I in an improved model with the use of "older" animals with diabetes. Older diabetic (db/db) mice (>15 weeks of age) have less elevated insulin levels compared with young db/db mice. The serum insulin levels in the older animals is 1.0 to 2.5 times that of the nondiabetic animals, a similar increase to that which occurs in human patients with type II diabetes. Healing was evaluated in two studies involving a total of 104 animals. Treatment groups included the following: 4.0 microg/cm(2) of platelet-derived growth factor-BB, 40.0 microg/cm(2) of platelet-derived growth factor-BB, 4.0 microg/cm(2) of both platelet-derived growth factor-BB and insulin-like growth factor-I or vehicle. All growth factors were applied topically in a methylcellulose vehicle to full-thickness wounds every other day for 24 days. Efficacy end points were median and mean time to complete healing and rate of wound closure. The median time to complete healing for animals receiving the platelet-derived growth factor-BB/insulin-like growth factor-I combination was 38% and 33% faster (p < 0.001) than animals receiving 4.0 microg/cm(2) and 40.0 microg/cm(2) of platelet-derived growth factor-BB, respectively. The mean time to complete healing for platelet-derived growth factor/insulin-like growth factor-I treated animals was 31% and 29% faster (p < 0.001) than 4.0 microg/cm(2) and 40.0 microg/cm(2) platelet-derived growth factor-BB treated animals, respectively. Wounds treated with 4.0 microg/cm(2) platelet-derived growth factor-BB/insulin-like growth factor-I healed, on average, in 22 days compared with 31 days for 40.0 microg/cm(2) platelet-derived growth factor-BB alone and 38 days for vehicle. Also, platelet-derived growth factor-BB/insulin-like growth factor-I significantly improved the rate of wound closure throughout the duration of the studies compared with either dose of platelet-derived growth factor-BB alone (p < 0.005) or vehicle (p < 0.001). In conclusion, the data show that the combination of platelet-derived growth factor-BB and insulin-like growth factor-I is more effective than platelet-derived growth factor-BB alone at the doses tested or vehicle treatment in stimulating cutaneous wound healing in older, diabetic mice.

Journal Article↗
PubMed1993

The value of urinary growth hormone determination for assessment of growth hormone deficiency and compliance with growth hormone therapy.

OBJECTIVE: To compare the 24-hour integrated concentrations of plasma growth hormone with growth hormone levels in a simultaneously collected sample of urine. SETTING: Pediatric endocrine diagnostic unit. PATIENTS: Forty-six children (41 male and five female) aged 6 to 19 years underwent measurement of integrated concentrations of growth hormone and simultaneous urine collection. MEASUREMENTS AND RESULTS: Integrated concentration of plasma growth hormone was correlated with urinary growth hormone levels from both the 24-hour (r = .67; P < .0001) and 12-hour overnight (r = .52; P < .001) measurements. Peak growth hormone response to paired stimulation was not correlated with either the 24-hour (r = .26; P < .23; n = 28) or 12-hour (r = .16; P < .48; n = 28) urinary growth hormone levels. The mean 24- and 12-hour urinary growth hormone levels for the patients with normal integrated concentrations of growth hormone were significantly higher than those in patient groups having subnormal integrated concentrations of growth hormone (P < .05). However, there was considerable overlap in the 12- and 24-hour urinary growth hormone levels between the patients with normal and those with subnormal integrated concentrations of growth hormone. Only one patient who had subnormal integrated concentrations of growth hormone had a 24-hour urinary growth hormone level higher than 9 ng, and none had a 12-hour urinary growth hormone level higher than 7 ng. The mean 12- and 24-hour urinary growth hormone levels were significantly higher in patients who received growth hormone injection than in those with normal spontaneous integrated concentrations of growth hormone and had no overlap with patients who had subnormal integrated concentrations of growth hormone. CONCLUSIONS: (1) Urinary and integrated concentrations of plasma growth hormone are correlated; (2) patient diagnoses based on integrated plasma growth hormone levels exhibit a high degree of overlap of urinary growth hormone; and (3) urinary growth hormone levels can serve to monitor compliance with growth hormone therapy.

Adolescent↗
PubMed1993

Transforming growth factor-alpha expression during liver regeneration after partial hepatectomy and toxic injury, and potential interactions between transforming growth factor-alpha and hepatocyte growth factor.

Transforming growth factor-alpha and hepatocyte growth factor are important stimulators of hepatocyte proliferation. In this series of experiments we sought to measure the expression of transforming growth factor-alpha mRNA by hepatocytes in response to toxic liver injury produced by carbon tetrachloride or galactosamine and to perform a more detailed analysis of transforming growth factor-alpha expression after partial hepatectomy. We also explored the interactions of transforming growth factor-alpha and hepatocyte growth factor in their effects on hepatocytes in vitro and tested the ability of these factors to stimulate endogenous transforming growth factor-alpha production by hepatocytes. In previous work we have used oligonucleotide probes to measure transforming growth factor-alpha mRNA expression after partial hepatectomy. In this study we used a rat transforming growth factor-alpha cDNA probe and found that the level of liver transforming growth factor-alpha mRNA increases 4 hr after partial hepatectomy, shows peak expression at 18 hr and returns to the normal level by 36 to 48 hr. Measurement of the corresponding peptide in the liver by means of radioimmunoassay shows that the level of transforming growth factor-alpha rises by 12 hr, peaks at 24 hr and remains significantly increased at 48 hr compared with the levels in sham-operated rats. Carbon tetrachloride and galactosamine are known to produce different patterns of acute liver injury, with maximal hepatocyte DNA synthesis at 48 hr and 5 days, respectively. After carbon tetrachloride administration the profiles of the transforming growth factor-alpha and hepatocyte growth factor mRNA expression are similar, each showing two peaks: the first at 12 hr and the second at 48 hr. In contrast, after galactosamine-induced liver injury the expression patterns of transforming growth factor-alpha and hepatocyte growth factor mRNAs differ: hepatocyte growth factor shows a major peak at 24 hr, with a smaller increase at 5 days, whereas transforming growth factor-alpha begins to increase after 2 days, with a single peak occurring at 5 days. In primary hepatocyte cultures, transforming growth factor-alpha and hepatocyte growth factor appear to have complementary effects. The maximal hepatocyte nuclear labeling index induced by hepatocyte growth factor was 42%; the addition of transforming growth factor-alpha increased this to 74%. Exogenous transforming growth factor-alpha, but not hepatocyte growth factor, stimulates the production of the transforming growth factor-alpha peptide by hepatocytes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Growth hormone therapy in normal short children induces a transitory decrease in plasma growth hormone releasing hormone levels and in human growth hormone responsiveness to exogenous growth hormone releasing hormone.

A three-month study of the effect of growth hormone (hGH) therapy (0.1 U/kg/day sc) on plasma levels of GH releasing hormone (GHRH), somatostatin and insulin-like growth factor I (IGF-I) and on the hGH responsiveness to exogenous GHRH was carried out in 32 prepubertal short-stature children with normal GH secretion. Blood samples were collected prior to initiation of therapy, and at 5, 30 and 90 days of onset of therapy, as well as 2 and 90 days after termination of therapy. The nonconventional hGH therapy induced an increase in serum IGF-I levels which lasted as long as therapy was continued. Plasma GHRH levels showed an early transitory decrease after five days of therapy, whereas plasma somatostatin levels were unaltered. A slight suppression in hGH responsiveness to exogenous GHRH was found at 2 but not at 90 days after termination of hGH therapy. It is concluded that nonconventional hGH treatment does not cause permanent changes in physiological hGH secretion.

Adolescent↗
PubMed1984

Somatomedins (insulin-like growth factors), but not growth hormone, are mitogenic for chicken heart mesenchymal cells and act synergistically with epidermal growth factor and brain fibroblast growth factor.

Chicken, ovine or human growth hormones have no mitogenic effect on chicken heart mesenchymal cells, which are proliferatively quiescent at low culture densities in medium containing heparinized, heat-defibrinogenated rooster plasma at 10%. Sm-C/IGF-I (15 ng/ml; 2 nM), MSA/rIGF-II (50 ng/ml; 7 nM), insulin (10,000 ng/ml; 1750 nM) or proinsulin (16,000 ng/ml; 1750 nM), however, cause these cells to increase threefold in number during four days of incubation. While EGF alone at 100 ng/ml causes threefold multiplication at four days and brain FGF causes a sixfold increase, EGF acts synergistically with Sm-C/IGF-I, MSA/rIGF-II, insulin or proinsulin to cause 18-fold multiplication, and brain FGF acts synergistically with IGFs to cause 20-fold multiplication. EGF and brain FGF, however, show no mitogenic synergy. Addition to the plasma-containing culture medium of a monoclonal antibody to Sm-C/IGF-I nearly abolishes the mitogenic effect of added EGF or brain FGF but does not affect the autonomous (mitogenic hormone-independent) proliferation of RSV-infected chicken heart mesenchymal cells. These findings support the somatomedin hypothesis for growth hormone action and suggest that potentiation of the activity of other mitogenic hormones, like EGF and FGF, makes a significant contribution to control of cell proliferation by the GH/IGF axis.

Animals↗
PubMed1994

Differential effect of growth hormone and insulin-like growth factor-I, insulin-like growth factor-II, and insulin on Ig production and growth in human plasma cells.

The effect of human growth hormone (GH) and insulin-like growth factor-I (IGF-I), IGF-II, and insulin on human plasma cell responses was studied. GH enhanced Ig production and thymidine uptake in the human plasma cell lines, IM-9 and AF-10. IGF-I, but not IGF-II or insulin, also enhanced Ig production and proliferation in them. However, enhancement by GH was not mediated by IGF-I, because enhancement was blocked by anti-GH antibody (Ab), but not by Ab to IGF-I or IGF-I receptor. Conversely, the enhancement by IGF-I was blocked by either Ab to IGF-I or IGF-I receptor, but not by anti-GH Ab. GH and IGF-I also enhanced production of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, and IgM and thymidine uptake in PCA-1+ plasma cells generated in vitro. Again, enhancement by GH was specifically blocked by anti-GH Ab, whereas enhancement by IGF-I was specifically blocked by either Ab to IGF-I or IGF-I receptor. These results indicate that GH and IGF-I may play important roles in plasma cell responses.

Cell Division↗
PubMed2000

Transforming growth factor-beta1 induces transforming growth factor-beta1 and transforming growth factor-beta receptor messenger RNAs and reduces complement C1qB messenger RNA in rat brain microglia.

Transforming growth factor-beta1 is a multifunctional peptide with increased expression during Alzheimer's disease and other neurodegenerative conditions which involve inflammatory mechanisms. We examined the autoregulation of transforming growth factor-beta1 and transforming growth factor-beta receptors and the effects of transforming growth factor-beta1 on complement C1q in brains of adult Fischer 344 male rats and in primary glial cultures. Perforant path transection by entorhinal cortex lesioning was used as a model for the hippocampal deafferentation of Alzheimer's disease. In the hippocampus ipsilateral to the lesion, transforming growth factor-beta1 peptide was increased >100-fold; the messenger RNAs encoding transforming growth factor-beta1, transforming growth factor-beta type I and type II receptors were also increased, but to a smaller degree. In this acute lesion paradigm, microglia are the main cell type containing transforming growth factor-beta1, transforming growth factor-beta type I and II receptor messenger RNAs, shown by immunocytochemistry in combination with in situ hybridization. Autoregulation of the transforming growth factor-beta1 system was examined by intraventricular infusion of transforming growth factor-beta1 peptide, which increased hippocampal transforming growth factor-beta1 messenger RNA levels in a dose-dependent fashion. Similarly, transforming growth factor-beta1 increased levels of transforming growth factor-beta1 messenger RNA and transforming growth factor-beta type II receptor messenger RNA (IC(50), 5pM) and increased release of transforming growth factor-beta1 peptide from primary microglia cultures. Interactions of transforming growth factor-beta1 with complement system gene expression are also indicated, because transforming growth factor-beta1 decreased C1qB messenger RNA in the cortex and hippocampus, after intraventricular infusion, and in cultured glia. These indications of autocrine regulation of transforming growth factor-beta1 in the rodent brain support a major role of microglia in neural activities of transforming growth factor-beta1 and give a new link between transforming growth factor-beta1 and the complement system. The auto-induction of the transforming growth factor-beta1 system has implications for transgenic mice that overexpress transforming growth factor-beta1 in brain cells and for its potential role in amyloidogenesis.

Alzheimer Disease↗
PubMed1993

Expression of messenger ribonucleic acid for epidermal growth factor receptor and its ligands, epidermal growth factor and transforming growth factor-alpha, in human first- and second-trimester fetal ovary and uterus.

OBJECTIVES: The epidermal growth factor receptor, a 170 kd polypeptide with tyrosine kinase activity, is used as the common receptor by two homologous polypeptide growth factors, epidermal growth factor and transforming growth factor-alpha. The activation of the epidermal growth factor receptor results in effects including deoxyribonucleic acid synthesis and cellular differentiation. Epidermal growth factor, transforming growth factor-alpha, and the epidermal growth factor receptor are reported to be associated with adult reproduction. However, the pattern of gene expression for the epidermal growth factor receptor and its ligands in human fetal reproductive tissues has not been detailed previously. STUDY DESIGN: We studied the expression of messenger ribonucleic acid encoding three polypeptides, epidermal growth factor receptor, epidermal growth factor, and transforming growth factor-alpha, in 10-, 15-, 19-, and 22-week human fetal ovaries and uteri. Ribonucleic acid was prepared from the fetal tissues and made into complementary deoxyribonucleic acid by reverse transcription. The complementary deoxyribonucleic acid was amplified by polymerase chain reaction, using primers specific for the human epidermal growth factor receptor, epidermal growth factor, and transforming growth factor-alpha. RESULTS: We found that epidermal growth factor receptor messenger ribonucleic acid was present in all stages of ovarian and uterine tissues studied. In addition, both epidermal growth factor and transforming growth factor-alpha messenger ribonucleic acid was found in all four stages of ovarian development. Epidermal growth factor messenger ribonucleic acid was detected in all four stages of fetal uterine development. CONCLUSIONS: This is the first demonstration, to our knowledge, of epidermal growth factor receptor, epidermal growth factor, and transforming growth factor-alpha messenger ribonucleic acid expression in human first- and second-trimester uterus and ovary.

Base Sequence↗
PubMed1995

Inhibition of in vitro meningioma proliferation after growth factor stimulation by calcium channel antagonists: Part II--Additional growth factors, growth factor receptor immunohistochemistry, and intracellular calcium measurements.

We have previously reported that calcium channel antagonists can block both the growth of meningiomas in culture and the potent growth stimulation of meningioma cells by epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). This study further defines the nature of this growth inhibition. Primary meningioma cultures were established, and cells were characterized. Fibroblast growth factor or insulin-like growth factor-I growth stimulation in the presence of calcium channel antagonists was examined. In addition, the effects of ethylene glycol-bis-(aminoethylether) N,N,N',N"-tetraacetic acid and Bay K 8644, a calcium channel agonist, on the growth factors were analyzed. Growth factor receptor immunohistochemistry was performed on the original tumors and the in vitro meningioma cells. Twelve of 17 (71%) meningiomas in this study were positive for the EGF receptor, and 14 of 17 (82%) were positive for the PDGF receptor. Five of six (83%) of the culture cells were positive for the EGF receptor, and four of five (80%) were positive for the PDGF receptor. Intracellular calcium changes were quantified using the intracellular calcium-chelating, fluorescent dye, Fura-2. The growth stimulation of fibroblast growth factor and insulin-like growth factor-I on meningioma cells in culture was decreased in a dose-dependent manner by calcium channel antagonists. The growth stimulation of fibroblast growth factor and insulin-like growth factor-I was not affected by a reduction of extracellular calcium, whereas the growth stimulation of EGF and PDGF was. Interestingly, intracellular calcium was not increased after exposure to growth factors but was increased after serum stimulation. This increase could be blocked by preincubation with verapamil. Calcium channel antagonists can inhibit proliferation of meningioma cells in culture after stimulation with a number of growth factors. These drugs might disrupt intracellular calcium homeostasis or interfere with key elements of the growth factor signal transduction pathways. These mechanisms as well as the potential clinical relevance of these findings are discussed.

Adult↗
PubMed1988

Platelet-derived growth factor or basic fibroblast growth factor induce anchorage-independent growth of human fibroblasts.

Anchorage-independent growth, i.e., growth in semi-solid medium is considered a marker of cellular transformation of fibroblast cells. Diploid human fibroblasts ordinarily do not exhibit such growth but can grow transiently when medium contains high concentrations of fetal bovine serum. This suggests that some growth factor(s) in serum is responsible for anchorage-independent growth. Much work has been done to characterize the peptide growth factor requirements of various rodent fibroblast cells for anchorage-independent growth; however, the requirements of human fibroblasts are not known. To determine the peptide growth factor requirements of human fibroblasts for anchorage-independent growth, we used medium containing serum that had had its peptide growth factors inactivated. We found that either platelet-derived growth factor (PDGF) or the basic form of fibroblast growth factor (bFGF) induced anchorage-independent growth. Epidermal growth factor (EGF) did not enhance the growth induced by PDGF, or did so only slightly. Transforming growth factor beta (TGF-beta) decreased the growth induced by PDGF. EGF combined with TGF-beta induced colony formation in semi-solid medium at concentrations at which neither growth factor by itself was effective, but the combination was much less effective in stimulating anchorage-independent growth than PDGF or bFGF. This work showed that PDGF, or bFGF, or EGF combined with TGF-beta can stimulate anchorage-independent growth of nontransformed human fibroblasts. The results support the idea that cellular transformation may reduce or eliminate the need for exogenous PDGF or bFGF.

Blood↗
PubMed1997

Growth hormone secretion in HIV-positive versus HIV-negative hemophilic males with abnormal growth and pubertal development. The Hemophilia Growth and Development Study.

UNLABELLED: Growth and pubertal development in hemophilic males, age 6-19 years at baseline, were evaluated over a 3.5-year period in 207 HIV-positive and 126 HIV-negative subjects as part of the Hemophilia Growth and Development Study. METHODS: Thyroid function, insulin-like growth factor I (IGF-1) levels, bone age, cranial magnetic resonance image normality, CD4+ counts, and serum testosterone levels of study participants were measured at baseline. An extensive endocrine evaluation was performed in subjects who demonstrated declines in height for age (measurement <5th percentile with two pervious heights >10th percentile), who had not achieved Tanner stage 4 level of pubertal development by age 15 years or who had abnormal growth velocity, which included assessment of peak stimulated growth hormone response after clonidine stimulation, 12-hour growth hormone profiles, and serum beta carotene levels (triggered protocol). RESULTS: For almost the entire group (-99%), thyroid function tests were normal for age. IGF-1 levels were normal for 93% of the cohort. A total of 120 subjects, 89 HIV-positive and 31 HIV-negative, had an abnormality of growth, pubertal development, or both; 34 (11.1%) HIV-positive and 4 (3.6%) HIV-negative subjects had declines in height (p = .001), 20 (23.3%) HIV-positive and 5 (15.8%) HIV-negative subjects had not achieved Tanner stage 4 by 15 years of age (p = .372) and 59 (43.4%) HIV-positive and 23 (25.6) HIV-negative subjects had abnormal growth velocity (p < 0.001). Among subjects with abnormal height or growth velocity, the HIV-positive group had significantly lower mean age-adjusted testosterone levels than did the HIV-negative group (p = .030). Within the HIV-positive group, older subjects with abnormal height or growth velocity had significantly lower mean bone age than subjects of similar age without growth abnormalities (p = .0092). Extensive testing was done in 39 patients (32 HIV-positive, 7 HIV-negative). Half of the HIV-positive subjects had mean 12-hour growth hormone levels <3 ng/ml, 47% had peak stimulated levels <10 ng/ml, 28% had peak spontaneous values <10 ng/ml, and 38% had low levels of IGF-1. In the HIV-positive cohort, there was no difference in the rate of abnormalities of growth hormone secretion between those with CD4+ counts > or = or <200 cells/mm3 and between those subjects that met the 1987 Centers for Disease Control (CDC) surveillance definition of AIDS. In the subset of HIV-positive patients with abnormal peak growth hormone levels after clonidine stimulation, growth hormone response correlated positively with CD4+ count (r = .657, p = .0056) and beta carotene concentration (R = .596, p = .0192). CONCLUSIONS: The results of this longitudinal study suggest that abnormalities of growth and pubertal development, particularly an abnormal growth velocity, are common in HIV-infected hemophilic boys and adolescents. These abnormalities might serve as indicators of the presence of HIV infection in this at-risk population. Since thyroid function tests and IGF-1 levels were normal, the etiology of growth impairment in HIV infection does not appear to be secondary to inadequate caloric intake or acquisition, or severe illness such as that caused by recurrent or persistent infection. Rather, HIV infection appears to lead to diminished growth hormone production or release and decreased androgen secretion, even before the development of AIDS and immunocompromise. These results provide a rationale for trials of treatment with growth hormone or androgens in patients with abnormalities of endocrine function.

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