Recent Insights into Insulin-Like Growth Factor Binding Protein 2 Transcriptional Regulation

Insulin-like growth factor binding proteins (IGFBPs) are major regulators of insulin-like growth factor bioavailability and activity in metabolic signaling. Seven IGFBP family isoforms have been identified. Recent studies have shown that IGFBPs play a pivotal role in metabolic signaling and disease, including the pathogenesis of obesity, diabetes, and cancer. Although many studies have documented the various roles played by IGFBPs, transcriptional regulation of IGFBPs is not well understood. In this review, we focus on the regulatory mechanisms of IGFBP gene expression, and we summarize the findings of transcription factor activity in the IGFBP promoter region.

Antepartal insulin-like growth factor concentrations indicating differences in the metabolic adaptive capacity of dairy cows

Cows with different Insulin-like Growth Factor-I (IGF-I) concentrations showed comparable expression levels of hepatic growth hormone receptor (GHR). Suppressor of cytokine signaling 2 (SOCS2), could be responsible for additional inhibition of the GHR signal cascade. The aims were to monitor cows with high or low antepartal IGF-I concentrations (IGF-I(high) or IGF-I(low)), evaluate the interrelationships of endocrine endpoints, and measure hepatic SOCS2 expression. Dairy cows (n = 20) were selected (240 to 254 days after artificial insemination (AI)). Blood samples were drawn daily (day -17 until calving) and IGF-I, GH, insulin, thyroid hormones, estradiol, and progesterone concentrations were measured. Liver biopsies were taken (day 264 +/- 1 after AI and postpartum) to measure mRNA expression (IGF-I, IGFBP-2, IGFBP-3, IGFBP-4, acid labile subunit (ALS), SOCS2, deiodinase1, GHR1A). IGF-I concentrations in the two groups were different (p 0.05). Thyroxine levels and ALS expression were higher in the IGF-I(high) cows compared to IGF-I(low) cows. Estradiol concentration tended to be greater in the IGF-I(low) group (p = 0.06). It was hypothesized that low IGF-I levels are associated with enhanced SOCS2 expression although this could not be decisively confirmed by the present study.

Expression of the Insulin-like Growth Factor Binding Proteins (IGFBPs) in Colon Cancer

PURPOSE: The purpose of this study was to demonstrate the hypothesis that tussue IGFBP-2,-3, and -4 levels would differ between colon cancer tissue and adjacent normal tissue and to determine whether these factors could affect the clinicopathologic characteristics such as age, tumor stage, differentiation, serosal invasion, and CEA in patients with colon cancer. METHODS: This study group consisted of 102 patients with colorectal cancer who under went operations between January 2004 and December 2006. Postoperative colon cancer specimens and adjacent normal colon tissues were obtained immediately. Histopathologic examinations were made by on pathologist for each specimen. The gene expressions of IGFBP-2,-3,-4 in cancer and normal tissues were measured using a reverse transcriptase-polymerase chain reaction (RT-PCR). In additional, the various clinic-opathologic factors were evaluated for both tissues by comparing the IGFBP-2, -3, -4 expression densities. RESULTS: No significant difference was found in the expression of IGFBP-3, -4 between colon cancer and normal colon tissues. A statistically significant expression of IGFBP-2 was detected in the cancer specimens compared with the normal colon tissues. IGFBP-3 was significantly associated with pathologic N stage. CONCLUSIONS: This is a rare report comparing colon cancer with normal colon tissue for IGFBP expression by means of a systemical evaluation of colon cancer patients. Our data suggest that IGFBP-2 may be intimately associated with malignant phenotypes, and may confer some growth advantage on tumor cells, which means that IGFBP-2 shows a high sensitivity for colorectal cancer. Interestingly, IGFBP-3 was strongly associated with the pathologic N stage. We think further studies are needed to understand this phenomenon.

Exploring upregulated genes during osteogenic differentiation of hMSCs

Human bone marrow mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to lineages of mesenchymal tissues, including bone, cartilage, fat, tenden, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells could be isolated from marrow aspirates of human and animals. This study was designed to identify and characterize genes specifically expressed by osteogenic supplements-treated cells by suppression subtractive hybridization(SSH) method. The results were as follows: 1. 2 genes were upregulated genes in osteogenic diffeentiation of hMSCs, which is further proved by Northern blot analysis. 2. IGFBP-2 has been identified playing an important role in bone formation. 3. HF1 was also upregulated during osteogenic differentiation, but its role in bone formation is not clear yet.

Influence of Tumor Necrosis Factor-alpha on Expression of Insulin-like Growth Factor-II, Insulin-like Growth Factor Binding Protein-1, 2, 3, 5 in Cultured Human Luteinized Granulosa Cells / 대한산부인과학회지

OBJECTIVE: To investigate the influence of tumor necrosis factor (TNF)-alpha on the expression of insulin-like growth factor (IGF)-II, insulin-like growth factor binding protein (IGFBP)-1, 2, 3, and 5 mRNA in cultured human luteinized granulosa cells. METHODS: Human luteinized granulosa cells were obtained from the follicular fluid by transvaginal oocyte aspiration from infertile patients undergoing controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF). The cells were cultured for 72 hours with TNF-alpha at concentrations of 1.0, 10.0, and 100.0 ng/mL, respectively. The cells not treated with TNF-alpha were served as control. Riverse transcription-polymerase chain reaction (RT-PCR) had been used to examine the expression of IGF-II, IGFBP-1, 2, 3, and 5 mRNA. Results were analyzed with Kolmogorov-Smirnov test and analysis of variance (ANOVA) and statical significance was defined as p<0.05. RESULTS: The expressions of IGF-II mRNA in 10.0 and 100.0 ng/mL of TNF-alpha groups were significantly lower than the control group (p<0.05, p<0.05, respectively). The expressions of IGFBP-2 mRNA were seemed to be decreased in 10.0 and 100.0 ng/mL of TNF-alpha groups than the control group (p=0.05, p=0.06, respectively). The expression of IGFBP-3 mRNA was seemed to be increased in 100.0 ng/mL of TNF-alpha group than the control group (p=0.08). There were no statistically significant differences in the expressions of IGFBP-1 and 5 in all groups. CONCLUSION: TNF-alpha might play a role as a regulator of human ovarian physiology by modulating the expression of IGF-II in luteinized granulosa cells.

Evaluation of Serum Insulin-Like Growth Factor(IGF)-I, Insulin-Like Growth Factor Binding Protein(IGFBP)-2 and IGFBP-3 Levels in Healthy Korean Children / 소아과

PURPOSE: We performed this study to evaluate the mean serum levels of insulin-like growth factor (IGF)-I, insulin-like growth factor binding protein(IGFBP)-2 and IGFBP-3 in healthy Korean children according to age and sex. METHODS: Ninety two healthy children, consisting of 42 boys and 50 girls, were classified into five groups according to age:neonate; infancy; early childhood; late childhood; and adolescence. We measured serum levels of IGF-I, IGFBP-2 and IGFBP-3 by enzyme-linked immunosorbent assay(ELISA) and analysed the serum levels according to sex and age group. RESULTS: For boys, the mean serum levels of IGF-I(ng/mL) in neonate, infancy, early childhood, late childhood and adolescence were 41.1+/-3.6, 70.9+/-33.7, 103.5+/-97.2, 89.8+/-46.5 and 51.4+/-27.8, respectively. Those of IGFBP-2(ng/mL) were 8.2+/-3.4, 5.8+/-0.4, 9.3+/-4.0, 9.5+/-1.1 and 7.0+/-0.5, respectively. Those of IGFBP-3(ng/mL) were 559.2+/-215.2, 1,333.3+/-692.5, 2,254.6+/-1,513.8, 2,447.1+/-1,464.2, 1,533.6+/-807.4, respectively. For girls, the mean serum levels of IGF-I(ng/mL) according to five age groups were 53.3+/-9.5, 99.3+/-45.8, 69.6+/-51.1, 106.2+/-67.0 and 145.1+/-127.8, respectively. Those of IGFBP-2 (ng/mL) were 9.1+/-7.4, 5.3+/-0.9, 6.9+/-2.0, 10.5+/-3.0 and 7.9+/-1.3, respectively. Those of IGFBP-3(ng/ mL) were 858.2+/-433.4, 1,834.8+/-851.3, 1,404.3+/-570.2, 2,203.5+/-899.4 and 2,029.3+/-1,316.7, respectively. There were significant positive correlations observed between IGF-I and IGFBP-3 levels(r=0.589, P= 0.000). CONCLUSION: IGF-I and IGFBP-3 levels increased as children get older. The peak level of IGFBP-3 was observed in late childhood for both boys and girls, suggesting a current trend of children reaching peak growth velocity before adolescence. The IGFBP-2 level was higher in neonates compare to infancy, suggesting that IGFBP-2 is an important substance for fetal growth.

Study of the Mechanism for the Growth Inhibitory Effects of Conjugated Linoleic Acid on Caco-2 Colon Cancer Cells

Conjugated linoleic acid (CLA) is a group of positional and geometric isomers of linoleic acid (LA) and exhibits anticarcinogenic activity in a variety of animal models. We have previously observed that CLA inhibited the growth of Caco-2 cells, a human colon adenocarcinoma cell line. The present study was performed to determine whether the growth inhibitory effect of CLA is related to change in secretion of IGF- II and/or IGF-binding proteins (IGFBPs) that have been shown to regulate Caco-2 cell proliferation by an autocrine mechanism. Cells were incubated in serum-free medium with various concentrations of CLA or linoleic acid (LA). Immunoblot analysis of 24-hours, serum-free, conditioned medium using a monoclonal anti-IGF-IIantibody revealed that Caco-2 cells secreted both mature 6,500 Mr and higher Mr forms of pro IGF-II. The levels of pro IGF-II and mature IGF-IIwere decreased by 43+/-2% and 53+/-6%, respectively by treatment with 50 micrometer CLA. LA slightly increased pro IGF- II levels. Results from Northern blot analysis showed that CLA decreased IGF-II mRNA levels at 50 micrometer concentration suggesting that CLA regulation of IGF-II protein expression occurs partly at the transcriptional level. Ligand blot analysis of conditioned media using 1251-IGF-II revealed that CLA slightly decreased IGFBP-2 levels and increased IGFBP-4 levels. We confirmed our previous results that CLA inhibited cell growth in a dose-dependent manner but LA slightly increased cell growth. Exogenous IGF-II mitigated the growth inhibitory effect of CLA. These results indicate that the growth inhibitory effect of CLA may be at least in part mediated by decreasing IGF-II and IGFBP-2 secretion and increasing IGFBP-4 secretion in Caco-2 cells.

The Pattern of Differentially Expressed Genes in Biliary Atresia

Biliary atresia is a progressive obliterative cholangiopathy, but the etiology of this disorder remains uncertain. Identifying genes specifically expressed in biliary atresia and analyzing the pattern of expression may lead to a better understanding of the pathogenesis. Liver tissues were taken from a recipient with biliary atresia and a normal donor during liver transplantation. Total RNA was extracted from each sample and reversely transcribed to cDNA. Then radiolabeled cDNA probe pools were made by random primed DNA labeling method and used for screening of differentially expressed genes by hybridizing with expressed sequence tags (EST) dot blot panel. Northern blot hybridization was done to confirm that these genes are also differentially expressed in other liver tissues. Among 1,730 EST clones, 26 cDNA clones were significantly overexpressed in biliary cirrhosis, while 2 clones were significantly decreased in biliary atresia. By Northern blot hybridization, the results of tissue inhibitor of metalloproteinase (TIMP)-1 and IGFBP-2 were well correlated with differential EST screening (DES). This study identified the pattern of differentially expressed genes in the biliary cirrhosis due to biliary atresia using DES technique.

Influence of Activin and Follistatin on Expression of Insulin-like Growth Factor (IGF)-I, II, Insulin-like Growth Factor Binding Protein (IGFBP)-1, 2, and 3 mRNA in Cultured Mouse Granulosa Cells / 대한산부인과학회잡지

OBJECTIVE: To investigate the influence of activin and follistatin on the expression of IGF (insulin-like growth factor)-I, II, IGFBP (insulin-like growth factor binding protein)-1, 2, and 3 mRNA in cultured mouse granulosa cells MATERIALS AND METHODS: The granulosa cells were obtained from the mouse and cultured for 6 days with 10 ng/ml of activin, 10 ng/ml of follistatin, and 10 ng/ml of activin with 10 ng/m of follistatin, respectively. The cells not treated with activin or follistatin served as control. Reverse transcription-polymerase chain reaction (RT-PCR) has been used to examine the expression of IGF-I, II, IGFBP-1, 2, and 3 mRNA. Results were analyzed with Kolmogorov-Smirnov test and analysis of variance (ANOVA) and statistical significance was defined as p<0.05. RESULTS: The expression of IGF-I and II mRNA were not different significantly. However, the expression of IGFBP-3 mRNA was significantly increased in the follistatin group compared to the control group (p<0.05) and significantly decreased in the activin with follistatin group compared to the control group (p<0.05). The expression of IGFBP-1 mRNA was seemed to be increased in the activin group and decreased in the follistatin group compared to the control group, respectively (p=0.07, p=0.07). The expression of IGFBP-2 and 3 mRNA were seemed to be decreased in the activin group compared to the control group (p=0.06, p=0.07, respectively). CONCLUSION: Activin and follistatin might play a role as regulators of mouse ovarian physiology by modulating the IGF system, especially IGFBPs.

The Expression of Insulin-like Growth Factor (IGF), IGF- Binding Protein (IGFBP) and the Role of IGFBP-3 in the Korean Gastric Cancer Cell Lines / 대한암학회지

PURPOSE: Insulin-like growth factor (IGF)-I and II are potent mitogens, postulated to exert autocrine and paracrine effects on growth regulation in human gastric cancer. In this study, we evaluated the expression of IGF-I, -II and IGFBPs in a panel of human gastric cancer cell lines. We also evaluated whether high expression of IGFBP-3 in human gastric cancer cells may increase the sensitivity to the anti-proliferative agents. MATERIALS AND METHODS: 10 human korean gastric cancer ceIl lines and 1 Caucacian gastric adenocarcinoma cell line were used for this study. IGF and IGFBP expressions were evaluated by RT-PCR. IGFBP proteins in conditioned media were detected by Western Ligand Blot. Cell survival after treatment of anti-proliferative agents was assessed by MTT assay. RESULTS: IGF-I and II were expressed in all gastric cancer cell lines. In addition, IGF-I and II stimulated the proliferation of gastric cancer cells. The expression of IGFBP-2 was found in all gastric cancer cell lines. IGFBP-4 was expressed in the most of cell lines. IGFBP-3, -4 and -6 were expressed in about 50% of cell lines. The growth inhibition of IGFBP-3 expressing cells by anti- proliferative agents was more significant than that of IGFBP-3 nonexpressing cells. Cell growth inhibition with treatment of these agents was accompanied by increased IGFBP-3 mRNA level. CONCLUSION: These data confirm that IGF-I, -II, and certain IGFBPs were expressed in gastric cancer cells, and gastric cancer cells show the differential growth inhibition by anti-proliferative agents. The differential growth inhibitory effect of anti-proliferative agents is, at least in part, mediated through up-regulation of IGFBP-3 expression.

The relationship between serum insulin - like growth factor binding proteins profiles and bone mineral density in women without ovarian function / 대한산부인과학회잡지

The insulin-like growth factor(IGF)s are believed to play an important role in the maintenance of bone mass. The IGFs are found complexed with high affinity to a family of IGF-binding protein(IGFBP)s in the circulation. It is known that IGFBPs are involved in the transport of IGFs to tissues and modulate IGFs actions at local tissue The purposes of this study were to compare serum IGFBPs profiles in natural menopausal women with and without osteoporosis and in osteoporotic and nonosteoporotic women with premature menopause and to evaluate the relationship between serum IGFBPs profiles and bone mineral density(BMD) in women without ovarian function. Serum IGFBPs were measured by western ligand blot and immunoradiometric assay. The relative levels and proportions of serum IGFBP-2 measured by western ligand blot in natural menopausal women with osteoporosis(n=20) significantly increased compared to nonosteoporotic women(n= 20), whereas relative levels of serum IGFBP-3 in natural menopausal women with osteoporosis decreased. No significant differences in the relative levels of serum IGFBPs between osteoporotic(n=8) and nonosteoporotic women(n=10) with premature menopause were noted. The IGFBP-3 levels determined by immunoradiometric assay in women without ovarian function(n= 69) showed a similiar trend. The relative proportions of serum IGFBP-2 in osteoporotic women without ovarian function were signifcantly higher than those in nonosteoporotic women whereas relative levels of serum IGFBP-3 in osteoporotic women with natural menopause decreased. The relative levels and proportions of serum IGFBP-2 in women without ovarian function correlated negatively with BMD of lumbar spine, trochanter and Ward's triangle but there were significant positive correlations between levels and relative proportions of serum IGFBP-3 and BMD of above sites. No significant correlations between relative levels and proportions of serum IGFBP-1, IGFBP-2 and BMD were noted. Our data indicate that serum IGFBP profiles might be useful in identifying women without ovarian funcion at risk for osteoporosis,

Serum insulin-like growth factor (IGF)-I and IGF-binding proteins in lung cancer patients

Many studies have shown that insulin-like growth factors (IGF-I & IGF-II) are implicated in the autocrine and paracrine growth of various tumors. Alterations in serum IGFs and IGF-binding proteins (IGFBPs) profiles have been reported in lung cancer. In this study, we measured serum levels of IGF-I and IGFBPs in 41 patients with lung cancer (small cell lung cancer, SCLC, 9; non-small cell lung cancer, NSCLC, 32) by radioimmunoassay and Western ligand blot (WLB). The serum IGF-I level in patients with lung cancer was significantly lower than in controls (207.9+/-62.6 vs 281.3+/-53.9 ng/mL, p0.05). The concentration of IGFBP-3 in lung cancer was 48% of that found in controls by WLB. The serum level of IGFBP-2 was markedly elevated in patients with lung cancer compared with controls (1303.7+/-618.0 vs 696.2+/-300.5, p<0.01). However, there was no significant difference between SCLC and NSCLC groups. This result showed that serum level of IGF-I/IGFBPs may be useful markers for diagnosing and identifying tumor types in lung cancer and further studies are needed.

Factores de crecimiento insulino símiles: estructura, bioactividad y métodos de ensayo / Insulin-like growth factors: structure, bioativity and methods of assay

El sistema de los factores de crecimiento insulino-símiles (IGF) se halla involucrado en diferentes aspectos de la regulación celular y tisular, como así también en el desarrollo y el crecimiento corporal. Este sistema depende de la interacción entre ligandos (IGF-I, IGF-II), receptores (Tipo I, Tipo II), proteínas ligadoras o transportadoras (IGFBP-1 a -6), y proteasas específicas para las IGFBPs. La acción de los IGFs se encuentra regulada por diferentes factores y estímulos, tales como la hormona de crecimiento, que actúan a diversos niveles. El desarrollo de nuevos métodos para analizar los diferentes componentes del sistema de los IGFs ha aportado elementos adicionales para la evaluación, diagnóstico y seguimiento de pacientes con alteraciones del crecimiento

Alteration of Serum Insulin-like Growth Factor(IGF)-I and IGF-Binding Protein-2 in Healthy Population with Aging / 대한소아내분비학회지

PURPOSE:Insulin-like growth factors, IGF- I and IGF-II, are proteins that promote cellular growth and differentiation of the various organs including the kidney. These peptides circulate in serum bound to specific carrier proteins, called IGF binding proteins(IGFBPs). The IGFs are produced in most organs but liver is believed to be the principal source of circulating IGF-I. We studied the correlation of serum IGF-I and IGFBP-2 pattern with aging. METHODS:Sera were collected from 320 healthy population who were grouped according to age. IGF-I was seperated from IGFBPs by Sephadex G-50 acid chromatography. We measured serum IGF-I and IGFBP-2 by using radioimmuno-assay (RIA) and immunoradiometric assay (IRMA) respectively. RESULTS:Serum IGF-I levels were quite low in early childhood, rising slowly and reaching a peak during puberty and a significant decline(P<00.01) during adulthood. The age-dependent pattern of serum IGFBP-2 levels shows a pattern opposite to that of IGF-I which are high at birth, decline by late puberty and increase again with aging. CONCLUSION: Our results demonstrate the alteration of serum IGF-I and IGFBP- 2 pattern with aging. These data suggests that when these tests are performed in the clinic, their interpretation should be based upon age specific criteria.

The Effect of Sex Steroid Hormone on the Expression of Insulin-Like Growth Factor Binding Preteins mRNA in the Explant Cultured from Human Uterine Myoma and Adjacent Normal Myometrium / 대한내분비학회지

BACKGROUND: Sex steroid hormones are believed to play an important role in the genesis and growth of uterine myoma. Several studies suggest a possible role of insulin-like growth factor(IGF) as a mediator of estradiol in uterine myama. We have recently demonstrated that some IGF binding proteins(IGFRPs) messenger ribonucleic acid(mRNA) expressions in myoma are dependent on the in vivo esttogen status. The purposes of this study are to evaluate the in vitro effects of sex steroid hormones including estrogen on the IGFBPs gene expression in tissues from uterine myoma and adjacent normal myometrium. METHODS: Tissues from myoma and adjacent normal myometrium of patients with uterine myoma during early proliferative phase of menstrual cycle were cultured in the absence(control) and presence of 17b-estradiol(10M/L) or/and progesterone(10M/L) for 3 days. The IGFBPs mRNA expressions in these explants were analyzed by Nothern blot using specific human complementary deoxyribonucleic acid(cDNA) probes. RESULTS: The addition of 17b-estradiol, progesterone alone and in combination to conditioned media of explants from myoma and adjacent normal myornetrium did not result in any changes in the expression of IGFBP-2, IGFBP-4, IGFBP-5, and IGFBP-6 mRNA. With progesterone addtion, lGFBP-3 rnRNA expression was significantly reduced in myoma explant but not in adjacent ncemal myometrium explant. There was no significant change in the IGFBP-3 mRNA expression with 17b-estradiol and with the combination of both 17b-estradiol and progesterone. CONCLUSION: 17b-estradiol does not affect IGFBPs gene expression in the myoma and adjacent normal myometrium explant regardless of the presence of progesterone in vitro. However progesterone alone induces a decrease in IGFBP-3 synthesis in myoma explant.

Insulin-like Growth Factor Binding Proteins(IGFBPs) Profiles in CordSera of Appropriate-for gestational Age, Small-for-gestational Age,Large-for-gestational Age Infant and Preterm Infant / 대한산부인과학회잡지

The insulin-like growth factor(IGF) system consists of IGFs, their receptor and binding proteins(IGFBPs). The IGFs are important growth factors in the regulation of fetal growth. Since IGFBPs control IGF actions, the IGFBPs themselves may also be important in fetal growth and development. The goals of this study are to investigate the profiles of IGFBPs in cord sera of appropriate-for-gestatinal age(AGA, n=27), small-for-gestatinal age(SGA, n=14), large-for-gestatinal age(LGA, n=10) infants and preterm(PT, n=14) infants and to evaluate the relationship between these IGFBP levels and gestational weeks and birth weight and between total IGFBP levels in cord sera and paired maternal sera(n=65). The IGFBPs were analyzed by Western ligand blot and immunoprecipitation. In cord sera of AGA infants IGFBPs with molecular weight with 37/43 kilocatons(kDa; IGFBP-3), 31 kDa(IGFBP-2), 26 kDa(IGFBP-1), 24 kDa(IGFBP-4) were detected. In cord sera of LGA infants there was a significant increase in IGFBP-3 levels and a reduction of IGFBP-1 and IGFBP-4 levels compared with those in AGA infants. SGA infants had significantly higher IGFBP-1 and IGFBP-2 levels in cord sera than AGA infants. There was a similiar trend in IGFBP-1 levels in cord sera of PT infants. The relative proportion of IGFBP-4 in cord sera of SGA and PT infants was significantly higher than that of AGA infants. There was no significant correlation beween total IGFBP levels in cord sera and paired maternal sera. The ratios of total IGFBP in cord sera to that in maternal sera to that in maternal sera were significantly higher in SGA and PT infants than in AGA infants. The IGFBP-1 and IGFBP-2 levels correlated with birth weight but did not correlate with gestational weeks. These data suggest that there is an unique profile of IGFBPs in cord sera of infants according to their weight, and that IGFBPs may play a major role in the control of fetal growth.

Insulin-Like Growth Factors and Their Bindign Proteins in Uterine Leiomyoma Pretreated with Gonadtropin Releasing Hormone Agonist / 대한내분비학회지

BACKGROUND: Uterine leiomyoma is the most common pelvic tumor, occurring in 20-25% of women in reproductive age. Gonadotropin releasing hormone agonist (GnRHa) has been reognized as a temporary medical management for this disorder. The etiology of these tumors is unknown but it has been shown that the insulin-like growth factors (IGF-I, IGF-II) are promoters of growth in nongynecologic tumors. Several recent studies have suggested the possible role of IGFs in human leiomyoma growth. The IGF binding proteins (IGFBPs) are believed to modulate actions of IGF and to have IGF-independent actions. The purpose of this study was to evaluate the type of IGF and IGFBP which may be involved in leiomyoma growth and to investigate a possible IGF related mechanism of action of GnRHa. METHOD: The IGFs and IGFBPs were measured by double antibody radioimmunoassay, western ligand blot and immunoprecipitation in the tissue cytosols of normal uterine myometria (n=15), nontumorous myometria adjacent to a leiomyoma and leiomyoma from patients nontreated (n=15) and treated (n=10) with GnRHa. RESULTS: The mean IGF-I and IGF-II level were significantly higher in leiomyoma from untreated patients than in the adjacent myometrium and normal myometrium but no significant differences in these IGF levels between normal myometrium and adjacent myometrium were noted. The IGFBP-2, IGFBP-3 and 26kDa IGFBP were detected variably but IGFBP-4 was consistently present in all tissues. There were no significant differences in the relative intensity for IGFBP-4 and the frequency of IGFBPs between leiomyoma, adjacent myometrium and normal myometrium from untreated patients. The IGF-I, IGF-II levels and the relative intensity of IGFBP-4 in leiomyoma from GnRHa-treated patients were significantly lower than those in untreated patients, but these levels in the adjacent myometrium were comparable. The frequency of each IGFBP in leiomyoma and the adjacent myornetrium from GnRHa-treated patients did not significantly differ from untreated patients. CONCLUSION: Both IGF-I and IGF-II are involved in the growth of leiomyoma and GnRHa may in part act to decrease size of leiomyoma by regulating the local levels of IGF-I, IGF-II and IGFBP-4.

The Effects of a Gonadotropin Releasing Hormone agonist on Insulin-like Growth Factor Binding Proteins(IGFBPs) Production in Explant Cultures of Human Uterine Myoma and Normal Myometrium / 대한산부인과학회잡지

Gonadotropin releasing hormone agonist(GnRHa) has been used as a temporaruy medical management for uterine myoma. Insulin-like growth factors(IGFs) has been supposed to play an etiological role in myoma growth and their action is modulated by IGF-binding proteins(IGFBPs). The purpose of this study is to evaluate the effects of GnRHGa on the IGFBPs production in the explant culture of adjacent myometrium and uterine myoma. The adjacent myometrium and myoma explants from patients treated(n=10) and nontreated(n=16) with GnRHa were cultured under serum free condition.Some explants from untreated patients were also cultured in the presence of GnRHa(10(-7) M/L). Western ligand blot and immunoprecipitation showed the presence of 276 kilodalton IGFBP, IGFBP-2, IGFBP-3 and IGFBP-4 in culture media of these explants and IGFBP-4 only was consistently present in culture media of all explants. There were no significant differences in the frequency of each IGFBP between adjacent myometrium and myoma explant cultures regardless of the type of GnRHa exposure. The relative IGFBP-4 level in explant cultures of myoma from patients treated with GnRHa was significantly higher than that from untreated patients.Addition of GnrHa in the media of myoma explants did not result in an significant change in the relative IGFBP-4 level compared with in vitro untreated explant cultures. Our data suggest that Gnrha may act through indirect involvement in the EGFBP-4 production in myoma tissue.

The Effects of a Gonadotropin Releasing Hormone agonist on Insulin-like Growth Factor Binding Proteins(IGFBPs) Production in Explant Cultures of Human Uterine Myoma and Normal Myometrium / 대한산부인과학회잡지

Gonadotropin releasing hormone agonist(GnRHa) has been used as a temporaruy medical management for uterine myoma. Insulin-like growth factors(IGFs) has been supposed to play an etiological role in myoma growth and their action is modulated by IGF-binding proteins(IGFBPs). The purpose of this study is to evaluate the effects of GnRHGa on the IGFBPs production in the explant culture of adjacent myometrium and uterine myoma. The adjacent myometrium and myoma explants from patients treated(n=10) and nontreated(n=16) with GnRHa were cultured under serum free condition.Some explants from untreated patients were also cultured in the presence of GnRHa(10(-7) M/L). Western ligand blot and immunoprecipitation showed the presence of 276 kilodalton IGFBP, IGFBP-2, IGFBP-3 and IGFBP-4 in culture media of these explants and IGFBP-4 only was consistently present in culture media of all explants. There were no significant differences in the frequency of each IGFBP between adjacent myometrium and myoma explant cultures regardless of the type of GnRHa exposure. The relative IGFBP-4 level in explant cultures of myoma from patients treated with GnRHa was significantly higher than that from untreated patients.Addition of GnrHa in the media of myoma explants did not result in an significant change in the relative IGFBP-4 level compared with in vitro untreated explant cultures. Our data suggest that Gnrha may act through indirect involvement in the EGFBP-4 production in myoma tissue.

Serum Insulin-like Growth Factor-1(IGF-1) and Insulin-like Growth Factor Binding Proteins in Hyperthyroidism and Hypothyroidism / 대한내분비학회지

Backgrounds: Thyroid hormones play a fundamental role in the initiation and maintenance of somatic growth in mammalian species, and the insulin-like growth factors(IGFs) occupy a position of central importance in the growth of all tissues. To evaluate the changes in serum insulin-like growth factor-I(IGF-I) and insulin-like growth factor binding proteins in hyperthyroid and hypothyroid patients, sera was obtained from 19 hyperthyroid patients, 9 hypothyroid patients, and 10 healthy volunteers. Methods: IGF-I concentration was determined by radioimmunoassay, and changes in IGFBPs were assesed by Western Ligand Blotting. To evaluate the binding pattern of IGF-I & IGFBPs, autoradiographs were obtained. Results & Conclusion: IGF-I levels were increased significantly in hyperthyroid patients(mean ±SE, 267.88±9.80 ng/ml, p<0.05) and decreased significantly in hypothyroid patients(154.81±1.43 ng/ml, p<0.01) compaired to healthy control group(209.45±.60 ng/ml). Autoradiograph of serum IGFBPs from patients with hyperthyroidism and hypothyroidism did not show any change in the intensity of IGFBP-3 bands(40-45 KD) and IGFBP-1 bands, but in hyperthyroid patients, it showed increased intensity of IGFBP-2 band compared to healthy control group and hypothyroid patients.