Serum insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3, leptin concentrations and insulin resistance in benign and malignant epithelial ovarian tumors in postmenopausal women.

AIMS: The aims of the present study were to determine the serum concentrations of insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and leptin and insulin resistance in benign and malignant epithelial ovarian tumors, and to discuss the use of these markers in benign-malignant tumor differentiation. METHODS: Forty-seven postmenopausal women with ovarian tumor and 31 age-matched, postmenopausal, healthy controls were included in this study. Insulin resistance index by homeostasis model assessment (HOMA score) and fasting blood glucose (FBG), serum IGF-I, IGFBP-3, leptin and CA-125 concentrations were determined in all patients preoperatively. The results were evaluated according to postoperative histopathology results. RESULTS: According to postoperative histopathology results, the patients were divided into malignant (n = 23), benign (n = 24) and control (n = 31) groups. There were no differences among the groups in relation to age, body mass index, FBG and HOMA score (p > 0.05). Serum concentrations of CA-125 were elevated in the malignant group compared with the benign ovarian tumor and control groups (p < 0.05). In contrast, serum IGF-I concentrations were significantly decreased in patients with malignant and benign ovarian tumors compared with controls (p < 0.05). Serum IGFBP-3 concentrations were also found to be lower in women with malignant ovarian tumors than in women with benign tumors (p < 0.05). Serum leptin did not differ among patients with malignant-benign tumors and controls (p > 0.05). CONCLUSION: Serum leptin and HOMA score have not been found to be valid indicators in ovarian tumors. However, the present data suggest that low concentrations of IGF-I and IGFBP-3 could be a reliable marker to differentiate benign from malignant ovarian tumors. Further experimental studies are warranted to understand the impact of the IGF-I system in ovarian carcinogenesis.     

Serum insulin-like growth factor (IGF)-I,IGF binding protein (IGFBP)-3, leptin concentrations and insulin resistance in benign and malignant epithelial ovarian tumors in postmenopausal women

Aims. The aims of the present study were to determine the serum concentrations of insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and leptin and insulin resistance in benign and malignant epithelial ovarian tumors, and to discuss the use of these markers in benign–malignant tumor differentiation.

Methods. Forty-seven postmenopausal women with ovarian tumor and 31 age-matched, postmenopausal, healthy controls were included in this study. Insulin resistance index by homeostasis model assessment (HOMA score) and fasting blood glucose (FBG), serum IGF-I, IGFBP-3, leptin and CA-125 concentrations were determined in all patients preoperatively. The results were evaluated according to postoperative histopathology results.

Results. According to postoperative histopathology results, the patients were divided into malignant (n = 23), benign (n = 24) and control (n = 31) groups. There were no differences among the groups in relation to age, body mass index, FBG and HOMA score (p > 0.05). Serum concentrations of CA-125 were elevated in the malignant group compared with the benign ovarian tumor and control groups (p < 0.05). In contrast, serum IGF-I concentrations were significantly decreased in patients with malignant and benign ovarian tumors compared with controls (p < 0.05). Serum IGFBP-3 concentrations were also found to be lower in women with malignant ovarian tumors than in women with benign tumors (p < 0.05). Serum leptin did not differ among patients with malignant–benign tumors and controls (p > 0.05).

Conclusion. Serum leptin and HOMA score have not been found to be valid indicators in ovarian tumors. However, the present data suggest that low concentrations of IGF-I and IGFBP-3 could be a reliable marker to differentiate benign from malignant ovarian tumors. Further experimental studies are warranted to understand the impact of the IGF-I system in ovarian carcinogenesis.     

Circulating insulin-like growth factor (IGF)-I and IGF binding proteins -1 and -3 and placental development in the guinea-pig

Restricting maternal nutrition before and throughout pregnancy in the guinea-pig restricts foetal growth in part by altering placental structural determinants of substrate transfer function. The insulin-like growth factors have been implicated in mediating these changes. To assess the role of IGF-I in placental adaptation to maternal undernutrition, we examined the associations of circulating IGF-I and IGF binding proteins -1, -3 and -4 in the mother with placental structural development. In both mid- and late pregnancy, maternal food restriction reduced maternal plasma IGF-I by 56 per cent (P<0.0005) and 50 per cent (P<0.0005) respectively, and plasma IGFBP-3 by 47 per cent (P=0.03) and 55 per cent (P=0.002), respectively. Maternal plasma IGFBP-4 was reduced by 45 per cent (P=0.041) in food restricted guinea-pigs in mid-pregnancy but not late in pregnancy, while IGFBP-1 was unaltered at both stages. Late in pregnancy, food restriction reduced the ratio of maternal circulating IGF-I to IGFBP-1 by 52 per cent (P=0.011) and increased the ratio of IGF-I to IGFBP-3 in maternal plasma by 10 per cent (P=0.011). The relationships between the maternal IGF axis and structural correlates of placental function were assessed using pooled data from both ad libitum fed and food restricted animals. In mid-pregnancy, the volume density of the maternal blood space in the placental labyrinth correlated positively with both maternal plasma IGF-I and IGFBP-3, while maternal blood space volume correlated negatively with maternal plasma IGFBP-1. In late pregnancy, placental weight correlated positively with both maternal plasma IGF-I and IGFBP-4, while the surface area of syncytiotrophoblast and weight of trophoblast correlated positively, and mean syncytiotrophoblast thickness negatively, with maternal plasma IGF-I. Late in pregnancy, the volume density and weight of syncytiotrophoblast, the surface density and total surface area of trophoblast and the volume of the maternal blood space each correlated positively, and syncytiotrophoblast thickness correlated negatively with maternal plasma IGFBP-3. Concomitantly, placental weight, placental diameter, placental volume, volume density and weight of syncytiotrophoblast, weight of foetal capillaries, syncytiotrophoblast surface density and total syncytiotrophoblast surface area in the placental labyrinth, each correlated positively with the ratio of IGF-I to IGFBP-1 in maternal plasma, while syncytiotrophoblast thickness correlated negatively with this ratio. In late pregnancy therefore, increased trophoblast abundance and placental vascularity, and a reduced barrier to diffusion between maternal and foetal blood, occurs in association with increased abundance of IGF-I and its major carrier, IGFBP-3, and a reduction in that of IGFBP-1 in maternal blood in the guinea-pig. This suggests that systemic IGF-I and modulation of its bioavailability by IGFBPs -1 and -3 within the mother may influence placental growth and differentiation in an endocrine fashion, particularly when nutrition is limited.     

Oral contraceptives increase insulin-like growth factor binding protein-1 concentration in women with polycystic ovarian disease.

Insulin-like growth factor-I (IGF-I) stimulates ovarian androgen production. Insulin-like growth factor binding protein-1 (IGFBP-1) inhibits IGF actions in vitro. OBJECTIVE: To investigate the effect of oral contraceptive (OC) pills, given for 3 months, on serum gonadotropin, androgen, IGF-I, and IGFBP-1 concentrations, and glucose tolerance in seven women with polycystic ovarian disease (PCOD) and in five healthy control subjects. PATIENTS: Seven women with PCOD and five healthy control subjects. INTERVENTIONS: An oral glucose tolerance test (OGTT) was performed before and after treatment with OC. RESULTS: After treatment with OC, serum luteinizing hormone, androstenedione, and free testosterone levels decreased, and sex hormone-binding globulin concentration increased in the women with PCOD as well as in the control subjects. The cumulative response of serum insulin to OGTT was larger in the women with PCOD than in the control subjects both before and after treatment. Serum IGF-I concentration, which was unchanged during OGTT, decreased from basal level of 326 +/- 70 micrograms/L to 199 +/- 28 micrograms/L after treatment with OC in the women with PCOD, whereas no change was found in the control subjects (from 235 +/- 11 micrograms/L to 226 +/- 11 micrograms/L). Treatment with OC caused an increase of the mean basal IGFBP-1 concentration from 24 +/- 7 micrograms/L to 73 +/- 14 micrograms/L in the women with PCOD. This increase was constant during the OGTT. In the control subjects, treatment with OC did not result in any significant change in IGFBP-1 concentrations (from 44 +/- 11 micrograms/L to 61 +/- 9 micrograms/L). CONCLUSION: The combination of decreased total IGF-I concentration and increased IGFBP-1 concentration induced by OC may decrease ovarian androgen production in PCOD.     

Placental alkaline phosphatase de-phosphorylates insulin-like growth factor (IGF)-binding protein-1

Background

Insulin-like growth factors (IGF) regulate fetal growth through their effects on placenta. Their actions are influenced by IGF binding protein-1. Phosphorylated IGFBP-1 (pIGFBP-1) has high affinity for IGF-I and usually inhibits IGF-I activity but during pregnancy, it is de-phosphorylated to generate lower affinity isoforms and consequently, increased IGF bioavailability. Here we investigate the role of placenta in this process.

Results

Our data show that term human placental explants, but not their conditioned medium, can de-phosphorylate IGFBP-1 through the action of placental alkaline phosphatase (PLAP).

Discussion

PLAP-mediated de-phosphorylation of IGFBP-1 may provide a mechanism for controlling IGF-I bioavailability and action at the maternal/fetal interface.     

Lack of insulin-like growth factor binding protein-3 variation after follicle-stimulating hormone stimulation in women with polycystic ovary syndrome undergoing in vitro fertilization.

OBJECTIVE: To investigate serum and follicular fluid (FF) insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) behavior in superstimulated cycles in patients with polycystic ovary syndrome (PCOS). DESIGN: Controlled clinical study. SETTING: Department of Obstetrics and Gynecology, University of Naples. PATIENT(S): Thirty-two patients with regular menses and tubal and/or male factor infertility and 21 patients with PCOS undergoing IVF. INTERVENTION(S): The IVF program used leuprolide acetate suppression followed by sequential hMG in the subsequent cycle. After follicular development, hCG administration was followed 34-36 hours later by oocyte retrieval. MAIN OUTCOME MEASURE(S): E2, GH, IGF-I, and IGFBP-3 assayed by RIA and immunoradiometric assay. RESULT(S): The controls and patients with PCOS showed similar increases in E2 and GH titers in response to FSH stimulation. Serum IGF-I did not change in either group and was equivalent in the FF. Patients with PCOS had a higher FF IGFBP-3 titer and did not show the decrease in serum IGFBP-3 levels of the control group after FSH stimulation. CONCLUSION(S): The apparent failure of IGFBP-3 reduction in patients with PCOS alters IGF-I bioavailability. Increased sequestration of IGF-I affects ovarian steroidogenesis and may explain the poor response to gonadotropin stimulation.     

The regional expression of insulin-like growth factor II (IGF-II) and insulin-like growth factor binding protein-1 (IGFBP-1) in the placentae of women with pre-eclampsia

Insulin-like growth factors and their binding proteins regulate cellular proliferation, differentiation and function, and play an important role in placental development. IGF-II and IGFBP-1 are abundantly expressed by cells at the maternal-fetal interface and mediate cell-to-cell communication between trophoblasts and decidua. Placentae of pre-eclamptic pregnancies show villous cytotrophoblast proliferation, increased syncytial sprout formation and impaired trophoblast invasion. We hypothesized that the expression of IGF-II and IGFBP-1 by cells at the maternal-fetal interface is altered in pre-eclampsia. We determined the regional abundance and cellular localization of IGF-II mRNA and IGFBP-1 mRNA and protein in placentae from normotensive control and pre-eclamptic pregnancies. IGF-II mRNA was expressed in both the chorionic villi and basal plate decidua regions. Increased IGF-II mRNA abundance was observed in the intermediate trophoblasts of peri-infarct regions. IGFBP-1 expression was present only in the decidua of the basal plate and membranes, and this expression was decreased significantly in pre-eclamptic placentae. The increased IGF-II expression in the intermediate trophoblast surrounding placental infarcts suggests a role for IGF-II in placental repair or remodelling. Decreased IGFBP-1 mRNA expression in the basal plate decidua suggests that the increased concentrations of IGFBP-1 the circulation of pre-eclamptic women is not of decidual origin. The altered IGF-II and IGFBP-1 expression at the fetomaternal interface may be important in the pathophysiology of pre-eclampsia.     

Methylation of the insulin-like growth factor binding protein-3 gene and prognosis of epithelial ovarian cancer

Insulin-like growth factor binding protein-3 (IGFBP-3) is a member of the IGFBP family, which regulates the mitogenic and antiapoptotic effects of insulin-like growth factors. Hypermethylation of the IGFBP-3 promoter has been found to suppress its expression. To evaluate the role of IGFBP-3 in ovarian cancer progression, we examined the survival of 235 consecutively selected epithelial ovarian cancer patients in association with IGFBP-3 promoter methylation and IGFBP-3 expression in tumor tissue. IGFBP-3 promoter methylation was analyzed using methylation-specific polymerase chain reaction. Cytosol protein was extracted and measured using a bicinchoninic acid assay; IGFBP-3 was measured by enzyme linked immunosorbent assay. Promoter methylation of the IGFBP-3 gene was detected in 44% (104/235) of patients. IGFBP-3 promoter methylation was associated with disease progression and death after adjusting for clinical and pathologic variables. The association was more evident in patients with early-stage disease: RR = 2.87 (95% CI: 0.78-10.63) for disease progression and RR = 3.94 (95% CI: 0.91-15.78) for death. Tissue levels of IGFBP-3 did not differ by methylation status but were inversely associated with disease stage and residual tumor size. These results suggest that IGFBP-3 promoter methylation may be a useful prognostic marker for disease progression and death in early-stage ovarian cancer.     

Insulin-like growth factor-1 and insulin-like growth factor binding protein-1 and 3 in the follicular fluid of infertile patients submitted to in vitro fertilization

Purpose: In the present article we propose to evaluate IGF-1, IGFBP-1 and 3 in the follicular fluid of infertile patients submitted to in vitro fertilization.Methods: We performed a case-control study with 53 infertile patients submitted to the first in vitro fertilization attempt. We compared their follicular fluid concentration of IGF-1, IGFBP-1 and IGFBP-3 between the patients who became pregnant (n = 11) versus those nonpregnant (n = 42).Results: The clinical characteristics of patients from the two groups were similar in terms of age and body mass index. Data related to the analysis of ovulation induction was not different regarding length of induction in days, number of retrieved oocytes, fertilization rate, and number of transferred embryos. Furthermore, the number of FSH units required for ovarian induction was also similar between the studied groups.IGF-1 and IGFBP-1 were not significantly different between the groups (p > 0.05). However, those patients that became pregnant presented a lower follicular fluid concentration of IGFBP-3, 2237.10 ± 582.73 pg/ml and 2657.64 ± 584.15 ng/ml, respectively (p = 0.038).Conclusions: We demonstrated an association of a lower follicular fluid IGFBP-3 in individuals that became pregnant compared to subjects that did not after in vitro fertilization.     

Superoxide dismutase activity in human follicular fluid after controlled ovarian hyperstimulation in women undergoing in vitro fertilization

Objective: To determine the activity of superoxide dismutase (SOD) and the total protein concentration in human preovulatory ovarian follicular fluid (FF) in relation to corresponding serum levels and the fertilization capacity of oocytes.

Design: Prospective, observational study.

Setting: Academic-based center for reproductive medicine.

Patient(s): Twenty-eight female partners of infertile couples, 13 of whom were smokers, undergoing controlled ovarian hyperstimulation for IVF.

Intervention(s): Blood and follicular fluid samples were collected 34–36 hours after hCG administration.

Main Outcome Measure(s): Levels of SOD activity and total protein concentrations.

Result(s): Superoxide dismutase activity was present in all the FF studied and mean levels were statistically significantly higher than in serum. Total protein concentrations in serum were statistically significantly correlated with corresponding concentrations in FF. There was no difference in SOD activity between smokers and nonsmokers. Total protein concentrations in FF were marginally and statistically significantly lower in nonsmokers. Follicular fluid from patients whose oocytes did not become fertilized had a statistically significantly higher level of SOD activity than that from patients whose oocytes did become fertilized.

Conclusion(s): Superoxide dismutase activity is present in FF and is higher than in serum. The degree of SOD activity is variable and seems to be inversely related to the fertilization of oocytes.     

Serum insulin-like growth factor-I and insulin-like growth factor binding protein-3 in premature rupture of membranes

BACKGROUND: The aim of the study was to evaluate whether the circulating levels of insulin-like growth factor-I (IGF-I) and its major circulating binding protein, IGFBP-3, are affected in premature rupture of membranes (PROM) and preterm delivery. METHODS: The levels of IGF-I and IGFBP-3 were measured in 32 pregnant women with PROM and in 27 healthy gestational age-matched pregnant women. Statistical analyzes were performed by analysis of variance. RESULTS: All the patients with PROM had preterm delivery, at a gestational age of 31.9 +/- 0.4 weeks (mean +/- SEM). In the control subjects, pregnancy proceeded to term. In the PROM patients, the serum IGF-I and IGFBP-3 levels (289 +/- 21 ng/ml and 8248 +/- 407 ng/ml, respectively) were not statistically different from those in the control subjects (275 +/- 22 ng/ml and 7579 +/- 488 ng/ml). Seventeen patients with PROM showed a rise in serum C-reactive protein, indicating subclinical intrauterine infection. Also in this subgroup of patients the levels of serum IGF-I (281 +/- 27 ng/ml) and IGFBP-3 (9010 +/- 633 ng/ml) were not different from those in the control subjects. Before delivery, serial serum samples were available from 22 patients with PROM. No consistent changes in IGF-I or IGFBP-3 concentrations were seen during the mean follow-up period of 9 days. CONCLUSIONS: IGF-I and IGFBP-3 do not appear to play any significant role in the maintenance of pregnancy in PROM patients with preterm delivery, whether or not associated with emerging intrauterine infection.     

Concentrations of alpha-fetoprotein, insulin-like growth factor binding protein-3, c-erbB-2, and epidermal growth factor in serum of patients with endometriosis

OBJECTIVE: Endometriosis, although it is a benign disorder, shares many similarities with cancer. There is increasing levels of evidence suggesting that some circulating factors involved in gynecologic cancers, such as alpha-fetoprotein (AFP), insulin-like growth factor binding protein-3 (IGFBP-3), c-erbB-2 (HER-2/neu), and epidermal growth factor (EGF), could also play a role in endometriosis. Hence, the present study was aimed at evaluating whether the levels of these molecules are modulated in the serum of patients with endometriosis. METHODS: Levels of AFP, IGFBP-3, c-erbB-2, and EGF were determined by enzyme-linked immunosorbent assay in serum from 36 subjects with surgically confirmed endometriosis and 36 controls with no surgical evidence of the disease. In addition, information such as demographic characteristics, personal habits, menstrual characteristics, and clinical profile was collected from each participating subject. RESULTS: No significant difference was found between serum levels of AFP, IGFBP-3, c-erbB-2, and EGF in patients with endometriosis and controls, even when we adjusted for potential confounders and took into account the menstrual cycle. Moreover, no correlation was observed between the serum concentrations of these molecules and the stage of the disease. However, a correlation was detected between soluble levels of IGFBP-3 and presence of uterine leiomyoma. CONCLUSION: Although AFP, IGFBP-3, c-erbB-2, and EGF are not altered in the circulation of patients with endometriosis, their involvement in the development of endometriotic lesions cannot be excluded.     

Histochemical localization of endometrial insulin-like growth factor binding protein-1 and -3 during the luteal phase in controlled ovarian hyperstimulation cycles: a controlled study

OBJECTIVE: To determine if controlled ovarian hyperstimulation (COH) affects the endometrial expression of IGFBP-1 and IGFBP-3. DESIGN: Prospective, controlled study. SETTING: Tertiary infertility clinic. PATIENT(S): Eighteen oocyte donors undergoing COH cycles and 17 natural cycle controls. INTERVENTION(S): Controlled ovarian hyperstimulation, endometrial biopsies. MAIN OUTCOME MEASURE(S): Immunohistochemical scoring of endometrial IGFBP-1 and -3 expression, morphological endometrial dating, and serum estradiol (E(2)), LH, and progesterone (P(4)) concentrations. RESULT(S): No statistically significant difference was observed between natural and stimulated cycles in change in IGFBP-1 or -3 over standardized cycle days throughout the window of embryo implantation (days 17-24). The IGFBP-1 and -3 expression was zero or near zero for both the natural and COH cycles until day 12-13. Both IGFBPs showed increased production throughout the secretory phase. Advanced endometrial histology (>/=1 day) in glands and stroma was noted in COH cycles. Significant positive correlations of E(2) and P(4) were noted with IGFBP-1 and -3 but not with advanced endometrial morphology in the COH cycles. CONCLUSION(S): The COH cycles have no significantly increased endometrial IGFBP-1 or -3 expression throughout the implantation phase of the luteal cycle compared with normal menstrual cycles. Both IGFBPs were absent in the proliferative phase and increased throughout the secretory portion of the embryo implantation window.     

Ontogeny of expression of insulin-like growth factor (IGF) and IGF binding protein mRNAs in the guinea-pig placenta and uterus.

To determine the temporal and spatial distribution of insulin-like growth factor (IGF) and its family of binding proteins (IGFBPs), guinea-pig yolk sac and chorioallantoic placentae were collected at 15, 20, 25, 29, 44-45, 55 and 65-66 days of gestation. Messenger RNAs for IGF I, IGF II and IGFBP 1-6 were identified in tissue sections by in situ hybridization, using 35S-cRNA probes. Epithelial and mesenchymal cell types were identified by immunohistochemistry for cytokeratin and vimentin, respectively. At 15 days of gestation, IGF-II mRNA was expressed in ectoplacental mesoderm, cytotrophoblasts and syncytiotrophoblast, and IGFBP-5 mRNA was detected in the syncytiotrophoblast. In the mid-gestation placenta, IGFBP-5 mRNA was expressed in the marginal and interlobular syncytium and IGF-II mRNA in the labyrinth. Near term, when expansion of the labyrinth was complete, IGFBP-5 mRNA was coexpressed with IGF-II mRNA in the marginal and interlobular syncytium. These observations suggest that interaction between IGF-II and IGFBP-5 plays a role in the vascularization of the placenta by fetal vessels. IGF-II mRNA was not expressed in the maternal tissues at any gestational age. IGFBP-2, -3 and -5 mRNAs were expressed in the endometrial stroma at 7-12 days of gestation but, following establishment of the placenta, IGFBP mRNAs were more abundant in the myometrium than in the decidua. IGF-II mRNA was detected in trophoblasts invading the walls of maternal vessels, and the endothelium of the preplacental vessels expressed IGFBP-4 mRNA, while IGFBP-2 and IGFBP-5 mRNAs were present in the tunica media of mesometrial arteries that had not been invaded by trophoblast. These findings suggest that IGF-II produced by the trophoblast acts in an autocrine and/or paracrine fashion to promote trophoblast invasion and that this process is modulated by interaction with IGFBPs present in maternal tissues.     

Evidence supporting proteolytic cleavage of insulin-like growth factor binding protein-1 (IGFBP-1) protein in amniotic fluid

OBJECTIVE: The purpose of this study was to determine if: 1) insulin-like growth factor binding protein-1 (IGFBP-1) in amniotic fluid (AF) exhibited proteolytic cleavage in cases of intra-amniotic inflammation; and 2) if the matrix metalloproteinases (MMP-3, MMP-8, MMP-9) in AF are associated with the degradation of IGFBP-1 in AF. METHODS: AF samples (n=20) were obtained from preterm gestations with and without intra-amniotic inflammation. The form of IGFBP-1 in AF was assessed by Western blot analysis and AF MMP-8 concentration was measured by ELISA. Densitometric analysis of Western blot was performed and the fragmented/intact IGFBP-1 ratio was calculated. Proteolysis of AF IGFBP-1 by MMPs was evaluated by incubating AF with exogenous human MMP-3, MMP-8 or MMP-9, and by incubating recombinant human IGFBP-1 in AF with and without inflammation. RESULTS: 1) IGFBP-1 was present in AF without inflammation as an intact form; however, the fragmented form was dominant in AF with inflammation; 2) the ratio of fragmented/intact IGFBP-1 was significantly higher in AF with inflammation than in AF without inflammation; 3) a higher ratio of fragmented/intact IGFBP-1 was associated with a higher concentration of MMP-8; 4) in-vitro proteolysis experiments showed that AF IGFBP-1 was degraded by exogenous human MMP-3, MMP-8 and MMP-9; 5) recombinant human IGFBP-1 was fragmented in AF with inflammation, but not in AF without inflammation. CONCLUSION: The fragmented form of AF IGFBP-1 was significantly increased in AF with intra-amniotic inflammation, and MMPs produced in AF with intra-amniotic inflammation were associated with the proteolytic change of AF IGFBP-1.     

Preliminary proteomic analysis on the alterations in follicular fluid proteins from women undergoing natural cycles or controlled ovarian hyperstimulation

PurposeTo study the differences in protein expression profiles of follicular fluid (FF) between controlled ovarian hyperstimulation (COH) and natural ovulatory cycles.MethodsTwelve infertile women undergoing in vitro fertilization and embryo transfer (IVF–ET), with matched clinical information, were retrospectively recruited in the IVF center of our university hospital, including six undergoing COH and another six with natural cycles. FF was sampled from dominant follicles with mature oocytes. Protein expression profiles in each FF sample were analyzed respectively using two-dimensional gel electrophoresis. Differentially expressed proteins were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and validated by western blotting. Differentially expressed proteins were further analyzed using Ingenuity Pathway Analysis (IPA) software.ResultsTwo proteins were downregulated and 11 proteins were upregulated (change ≥1.5-fold, P < 0.05) in the COH group. We identified one down-egulated and seven upregulated proteins using MALDI-TOF MS. Four differentially expressed proteins, including transferrin, complement component C3 (C3), haptoglobin and alpha-1-antitrypsin (AAT), were further validated by rate nephelometry and western blotting analyses. The IPA analysis revealed a significant network involved in the humoral immune and inflammatory responses.ConclusionsThe eight differentially expressed proteins were related to immune and inflammatory responses in the ovary. Our results provide new insights into the influence of COH on follicular (spp) development and IVF outcomes.     

Serum levels of leptin, insulin-like growth factor-I and insulin-like growth factor binding protein-3 in women with pre-eclampsia, and their relationship to insulin resistance.

The present study was carried out to compare serum levels of leptin, insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3), homeostasis model assessment--(pancreatic beta-cell function) (HOMA-(%B)) and homeostasis model assessment--(tissue insulin sensitivity) (HOMA-(%S)) in women with mild and severe pre-eclampsia and normotensive pregnant women; and to evaluate the possible relationships between these parameters in the pathogenesis of pre-eclampsia. Seventy-three women were divided into three groups: group A consisted of 20 normotensive pregnant women (NPW); group B consisted of 25 women with mild pre-eclampsia (MPE); and group C consisted of 28 women with severe pre-eclampsia (SPE). Serum level of leptin was measured by enzyme immunoassay using a commercial kit. Serum levels of IGF-I and IGFBP-3 were measured with a two-site immunoradiometric assay. Serum level of insulin was measured by the electrochemiluminescence immunoassay method. HOMA used indices of pancreatic beta-cell function and tissue insulin sensitivity. Differences between groups were compared by one-way analyses of variance and the post hoc Tukey-HSD test for multiple comparisons; however, when a variable was not normally distributed, the Mann-Whitney U test was used. Associations between variables were tested using Pearson's coefficient of correlation. Birth weight was significantly lower (p < 0.001) in the MPE and SPE groups than in the NPW group. Serum levels of leptin and insulin in women with SPE and MPE were significantly higher (p < 0.001) than in NPW. Serum levels of IGF-I and IGFBP-3 were significantly lower in women with SPE and MPE compared with NPW (p < 0.001). The mean HOMA-(%B) level in women with SPE and MPE was significantly higher than in NPW (p < 0.001), whereas the mean HOMA-(%S) level in women with SPE and MPE was significantly lower than in NPW (p < 0.001). In the SPE group, systolic blood pressure correlated significantly with serum levels of IGF-I and leptin (r = 0.375, p < 0.05 and r = 0.495, p < 0.01, respectively). A negative correlation between mean HOMA-(%S) level and serum IGFBP-3 level was noted (r = -0.357, p < 0.05). There was a positive correlation between serum level of IGF-I and mean HOMA-(%B) level in mildly pre-eclamptic women (r = 0.541, p < 0.01). We conclude that pre-eclampsia is associated with insulin resistance; and that existing hyperinsulinemia and insulin resistance in women with pre-eclampsia seem not to correlate with leptin and birth weight, but may correlate positively with IGF-1 and IGFBP-3. Therefore we think that hyperleptinemia, low IGF-I or IGFBP-3, and insulin resistance may contribute to the pathogenesis of pre-eclampsia.     

Effects of hormone replacement therapy on insulin-like growth factor (IGF)-I, IGF-II and IGF binding protein (IGFBP)-1 to IGFBP-4: implications for cardiovascular risk.

OBJECTIVE: Hormone replacement therapy (HRT) in postmenopausal women is controversial, with an elevated cardiovascular event rate for combined estrogen-progestogen but no adverse cardiovascular effect and possible cumulative benefit for estrogen alone. Here we measured the effects of differing estrogen/progestogen combinations on the insulin-like growth factor (IGF)/IGF binding protein (IGFBP) system which has been implicated in the pathophysiological mechanisms underlying cardiovascular disease, higher IGFBP-1 levels having been linked with a reduced cardiovascular risk. DESIGN: Oral conjugated equine estrogens (CEE) alone, or in combination with the increasingly androgenic progestogens medroxyprogesterone acetate, desogestrel or norethisterone, were given in a randomized triple crossover fashion to 35 healthy postmenopausal women. Serum concentrations of IGFs and the principal circulating IGFBPs were measured. RESULTS: Circulating IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio were significantly reduced by CEE. These effects were reversed by progestogens according to their androgenicity. Plasma IGFBP-1 concentration increased from baseline to CEE alone. This rise was opposed by progestogens of increasing androgenicity. IGFBP-2 levels fell and IGFBP-4 increased with CEE, with no further change with addition of progestogens. CEE increased the proportional contribution of IGFBP-1 and IGFBP-4 to total IGFBP binding and decreased the IGFBP-3 contribution. This was reversed by progestogens. CONCLUSION: There are marked changes in molar ratios of the IGFBPs in relation to estrogen/progestogens in HRT. The effect of progestogens on IGF bioavailability could be an important determinant of the longer-term risks of specific HRT preparations by opposing the potentially beneficial effects of CEE alone on cardiovascular risk.