Insulin and insulin-like growth factor-I responsiveness in polycystic ovarian syndrome.

OBJECTIVE: To assess insulin and insulin-like growth factor I (IGF-I) action in women with polycystic ovarian syndrome (PCOS). DESIGN: Hyperinsulinemia was determined by measuring the insulin responses during a 2-hour oral glucose tolerance test (OGTT). Quantification of in vivo insulin action was determined by a frequently sampled intravenous (IV) OGTT with minimal modeling analysis. In vitro sensitivity to insulin at physiological and supraphysiological concentrations and to IGF-I was assessed by examining colony formation of two hematopoietic cell populations, burst-forming units of the erythroid line (BFU-E) and human leukemia virus immortalized T-cell lines. (The proliferative responses of BFU-E, a primary tissue explant, are presumably conditioned by factors in the immediate blood-borne environment, whereas proliferative responses of T-cell lines are presumed to reflect intrinsic target-cell hormone sensitivity.) SETTING: Tertiary care research institution. PATIENTS: Eight patients (4 obese and 4 nonobese) with PCOS and three healthy women for reference controls. RESULTS: Nonobese (P less than 0.04) and obese patients with PCOS (P less than 0.01) both demonstrated significant hyperinsulinemia after OGTT. In vivo insulin resistance was observed in both nonobese (P less than 0.03) and obese PCOS subjects (P less than 0.01) using frequently sampled IV OGTT. Both nonobese (P less than 0.03) and obese patients with PCOS (P less than 0.01) had blunted in vitro clonal responses of BFU-E, with normal T-cell line clonal responsiveness to physiological levels of insulin and normal BFU-E and T-cell line clonal responses to IGF-I. CONCLUSIONS: These findings demonstrate the following in both nonobese and obese patients with PCOS: (1) there is in vivo hyperinsulinemia and resistance to insulin action on glucose disposal; (2) with BFU-E, there is in vitro resistance to the mitogenic action of insulin but normal responsiveness to IGF-I; and (3) there is normal in vitro mitogenic responsiveness of T-cell lines to both insulin and IGF-I. The intrinsically normal mitogenic responsiveness to insulin and, especially to IGF-I, whether or not under the influence of the bloodborne milieu, provides a mechanism whereby hyperinsulinemia could directly contribute to the ovarian abnormalities that characterize PCOS.     

Effect of naloxone on plasma insulin, insulin-like growth factor I, and its binding protein 1 in patients with polycystic ovarian disease.

Insulin and insulin-like growth factors (IGFs) stimulate ovarian steroidogenesis, and hyperinsulinemia is often accompanied by hyperandrogenemia in women with polycystic ovarian disease (PCOD). Because opioid peptides are involved in the regulation of insulin secretion, we studied the effect of naloxone-induced opiate receptor blockade on the circulating levels of insulin, IGF-I, and IGF binding protein 1 (IGFBP-1) in 13 nonobese and 7 obese PCOD patients and in 6 healthy subjects. In obese PCOD patients, the mean basal insulin concentration was significantly higher and the IGFBP-1 concentration lower than in nonobese PCOD patients. Plasma IGF-I levels were elevated both in obese and nonobese PCOD patients. After an intravenous bolus of 10 mg naloxone, no significant changes were found in the circulating insulin or IGF-I levels, whereas IGFBP-1 levels decreased in nonobese PCOD patients and remained low in obese PCOD patients. No significant decrease was found in healthy subjects. These results suggest that, in addition to insulin, endogenous opioids are involved in the regulation of serum IGFBP-1 level.     

Decreased 34K insulin-like growth factor binding protein in polycystic ovarian disease

Insulin and insulin-like growth factor I (IGF-I) have been implicated in ovarian androgen production. Insulin is closely related to IGF-I and cross-reacts with its receptor. The 34K IGF-binding protein (34K IGF-BP) has been shown to inhibit the binding of IGF-I to its receptor. The authors evaluated the role of insulin in the regulation of serum levels of 34K IGF-BP in patients with polycystic ovarian disease (PCOD). 34K IGF-BP levels during an oral glucose tolerance test (OGTT) were measured in 15 PCOD (8 obese and 7 nonobese) patients and in 10 healthy control subjects. The fasting level of 34K IGF-BP was decreased in nonobese PCOD patients (2.4 +/- 0.3 micrograms/l) (mean +/- standard error) (P = 0.02) and obese PCOD patients (0.59 +/- 0.2 micrograms/l) (P less than 0.001) as compared with healthy controls (4.8 +/- 0.9 micrograms/l). Both nonobese PCOD patients and normal controls demonstrated a significant decrease in 34K IGF-BP following OGTT. An insulin-related decrease in 34K IGF-BP may allow an increased pool of IGF-I able to bind to its receptor. This would provide a mechanism for increased ovarian androgen production via IGF-I stimulation of its receptor.     

Vascular endothelial growth factor and insulin-like growth factor-1 in polycystic ovary syndrome and their relation to ovarian blood flow

OBJECTIVES: (1) To determine the serum levels of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) in women with polycystic ovary syndrome (PCOS). (2) To study Doppler blood flow changes within the ovarian stroma of women with PCOS. (3) To evaluate the relationship between VEGF and IGF-1 and Doppler indices as well as hormonal profile. SETTING: Department of Obstetrics and Gynecology, and Department of Biochemistry, Faculty of Medicine, Assiut University, Egypt. DESIGN: Cross-sectional study. PATIENTS AND METHODS: Fifty infertile women with PCOS diagnosed by ultrasound examination and a history of oligomenorrhea, hirsutism and obesity were studied. Serum levels of vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1) and hormonal profile were measured. Doppler blood flow velocity waveforms analysis in both right and left intraovarian arteries was done. Twenty healthy and fertile women with regular menstrual cycles served as a comparison group were similarly studied at the third day of the cycle. RESULTS: The serum levels of VEGF, IGF-1 (4.79 +/- 0.91, 253.15 +/- 70.07 versus 2.39 +/- 0.42, 186.65 +/- 42.7) were significantly elevated (P <0.001 and P <0.01, respectively) in women with PCOS compared with control. Doppler indices, PI (2.01 +/- 0.77, 2.66 +/- 1.00 versus 2.98 +/- 0.77, 3.75 +/- 0.98) and RI (0.77 +/- 0.12, 0.82 +/- 0.09 versus 0.87 +/- 0.09, 0.89 +/- 0.09) in both right and left intraovarian vessels were significantly lower in the patients than controls. The VEGF and IGF-1 levels were negatively correlated with RI and PI in the uterine and intraovarian arteries. VEGF level was positively correlated with IGF-1 (r=0.41, P <0.05) in women with PCOS. CONCLUSIONS: Higher serum levels of VEGF and IGF-1 in PCOS women may be related to the increased vascularity that underlies the increased blood flow demonstrated by Doppler blood flow measurements in these women.     

Vascular endothelial growth factor and basic fibroblast growth factor in polycystic ovary syndrome during controlled ovarian hyperstimulation.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that causes anovulation and consequent subfertility. It is well established that increased ovarian mass, supported by new blood vessel proliferation in stroma and theca, is a key feature of PCOS. Recent studies suggest a role for angiogenetic factors in this phenomenon. AIM: To evaluate of levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in serum and follicular fluid of PCOS patients during a controlled ovarian hyperstimulation. METHODS: In 52 patients undergoing in vitro fertilization treatments, 26 PCOS patients and 26 controls, serum VEGF and bFGF levels were assessed before starting administration of follicle-stimulating hormone (FSH) (day 0), on the day of administration of human chorionic gonadotropin (hCG) and on the day of oocyte retrieval. Follicular fluid levels of the two growth factors were detected on the day of oocyte retrieval. RESULTS: PCOS patients showed higher serum VEGF levels than controls before starting FSH administration, on the day of hCG administration and on the day of oocyte retrieval. Serum VEGF levels showed a rise after hCG administration only in the PCOS patients. In addition, serum bFGF levels were higher in PCOS patients than in controls on the day of hCG administration and the day of oocyte retrieval. Furthermore, on the day of hCG administration, serum bFGF levels were directly correlated to the amount of FSH previously administered (p < 0.0001). In follicular fluid, higher VEGF and bFGF levels were found in PCOS patients than in controls. Furthermore, follicular-fluid bFGF concentrations were inversely correlated with the percentage of mature oocytes collected (p < 0.05). CONCLUSIONS: The present study revealed elevated levels of VEGF and bFGF in serum and follicular fluid in PCOS patients compared with controls. bFGF seems to be an FSH-dependent growth factor and its levels in follicular fluid are inversely correlated with the percentage of mature oocytes collected.     

Association between serum adipocyte factor level and insulin resistance in polycystic ovarian syndrome

The relationship between serum adipocytokines level and insulin resistance (IR) in polycystic ovary syndrome (PCOS) is unclear. Sixty-one patients with PCOS were divided into an IR group (n?=?31) and a non-IR group (n?=?30) using homeostasis model assessment (HOMA). Serum levels of luteinizing hormone, follicle-stimulating hormone, estradiol, progesterone, total testosterone, insulin, glucose, and adipocytokines were measured by radioimmunoassay or enzyme-linked immunosorbent assay. The serum adiponectin level in women with PCOS and IR was lower than that of non-IR PCOS patients (P?<?0.05); however, there were no significant differences between the two groups with regard to resistin, leptin, and leptin receptor levels (P?>?0.05). And the levels of adipocytokines and IR are significantly correlated; consequently, adipocytokines may be involved in the development of IR in PCOS patients.     

胰岛素样生长因子Ⅰ及胰岛素与胎儿宫内发育迟缓发病的关系

目的 探讨胰岛素样生长因子１（ＩＧＦ－Ｉ）及胰岛素与胎儿宫内发育迟缓（ＩＵＧＲ）发病的关系。方法 应用放射免疫分析法和酶联免疫吸附试验,分别测定１７例ＩＵＧＲ患儿,孕妇（ＩＵＧＲ组）血清及羊水中Ｉｎｓ和ＩＧＦ－Ｉ水平,同期住院的正常晚期妊娠妇女３８例（正常妊娠组）作为对照。     

多囊卵巢综合征胰岛素抵抗相关基因研究进展

多囊卵巢综合征是一种以内分泌紊乱为主,多种代谢异常导致的异质性临床综合征,胰岛素抵抗是一个重要环节,本文对多囊卵巢综合征胰岛素抵抗相关基因的研究现状进行综述。     

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.     

Screening for insulin resistance in women with polycystic ovarian syndrome.

INTRODUCTION: Insulin resistance is implicated in the pathogenesis of polycystic ovarian syndrome (PCOS). Insulin-sensitizing agents are increasingly used in the treatment of infertility and hirsutism in PCOS. However, not all women with PCOS are insulin-resistant. OBJECTIVE: To assess the degree of insulin resistance within a clinic population of women referred for treatment of oligomenorrhoea or infertility. DESIGN: We evaluated 25 consecutive PCOS outpatients referred for treatment of menstrual dysfunction/infertility and a matched control group. All underwent a standard oral glucose tolerance test (OGTT) with serial insulin measurements. Insulin sensitivity was calculated using homeostasis model assessment (HOMA). RESULTS: Five of the 25 clinic patients had abnormal glucose handling (two had previously unknown type 2 diabetes and three had impaired glucose tolerance). Fasting and 2-h insulin levels were significantly higher in the PCOS women. Mean HOMA-S (insulin sensitivity) was even lower for PCOS women with normal GTT status (mean (95% confidence interval): 0.53 (0.34-0.72)) than for controls (0.94 (0.84-1.04)) (F = 4.2, p < 0.001). HOMA-B (pancreatic beta-cell function) was nearly tripled for normal GTT status PCOS women at 273 (205-342) versus 105 (70-139) for controls (F = 6.8, p < 0.001). CONCLUSIONS: The results suggest a role for routine measurement of HOMA-S in identifying women with PCOS with insulin resistance with a view to targeting them with insulin-sensitizing agents.     

Determination of insulin and insulin-like growth factors in the ovarian circulation

Recent in vitro studies implicate the ovary as an extra-hepatic source of insulin-like growth factors (IGFs) with production regulated by gonadotropins and local steroids. Because previous studies have failed to show any significant variations in IGF levels in peripheral blood during the menstrual cycle, we measured the concentrations of IGF-I, IGF-II, and insulin in ovarian and peripheral venous blood samples obtained simultaneously from nine women undergoing abdominal hysterectomy to obtain more detailed data on the ovarian contribution. A significant decreased ovarian gradient was found for IGF-II but not for IGF-I or insulin. Although there was no significant ovarian vein insulin gradient, insulin levels were higher in follicular than in luteal phase ovarian samples. These data suggest that IGF-II may be locally regulated by the ovary. Both insulin and IGFs may regulate ovarian function in vivo.     

Hyperprolactinemia and polycystic ovarian syndrome.

Prolactin and pituitary gonadotropin levels were studied in eight patients with polycystic ovarian syndrome. All women were of reproductive age and had had menstrual disorders since menarche. Three patients had hyperprolactinemia with or without galactorrhea and tomograms of the sella turcica revealed pituitary microadenomas. The remaining five patients with normal baseline prolactin levels had a prolactin stimulation test which used 25 mg of thorazine per os, and a prolactin suppression test using l-dopa 500 mg per os. Analysis of the results of these tests and a comparison with tests performed in five normal individuals used as controls showed significantly different responses in the two groups of women. The preliminary information obtained indicates that an abnormal prolactin secretion status may exist in the polycystic ovarian syndrome.     

Evaluation of the correlation between insulin like factor 3, polycystic ovary syndrome,and ovarian maldescent

The aim of this study was to investigate a proposed correlation between the incidentally discovered undescended ovaries and their confirmed diagnosis as a polycystic ovary disease (PCOD) for all cases included, and to evaluate the role of estimated insulin like factor 3 (INSL3) circulating level in the pathogenesis of both abnormal findings. The study group (A) comprised 35 women whose ovaries had been incidentally found to be undescended during the routine laparoscopy for infertility causes, and all had been diagnosed as PCOD. The control category included two subgroups; subgroup (B) included 35 women group, diagnosed as PCOD but with normally allocated ovaries in the true pelvis, and subgroup (C) included 35 healthy women with regular menses and no signs of hyperandrogenism. Correlations between the level of INSL3 and other PCOD relevant biochemical tests: [e.g. BMI, waist-to-hip ratio (WHR), LH, FSH, androstendione (A), total and free testosterone (T &; Ft), DHEA-S, and SHBG] had been also investigated. INSL3 levels were significantly higher in PCOD groups (A) and (B) compared to the healthy fertile control subgroup (C) (80.5?±?29.4, 65.11?±?15.6, and 41.11?±?10.2?pg/mL, respectively), and was highest in group (A). Moreover, we identified a strong correlation between INSL3 and androstenedione (r?=?0.42, p?=?0.0012), and free (r?=?0.42, p?=?.0123) and total testosterone (r?=?0.41, p?=?.004) in the PCOD (A) and (B) subgroup compared to the levels in subgroup (C). LH was significantly higher in all PCOD women in groups (A&;B) (12. 3?±?3.4, and 11.2?±?1.4 mIU/L, respectively) compared to those in group (A) (5.7?±?2.5 mIU/L), with a fair correlation with INSL3. However, there was no statistically significant correlation between INSL3 and FSH, DHEA-S, glucose, basal insulin concentration or HOMA-IR in all PCOD women. The strong positive correlation between INSL3, and high ovarian androgens levels in all PCOD women, which appeared clearly in undescended polycystic ovaries could support the proposed syndrome hypothesis between those abnormal findings.     

The effect of obesity on ovarian function. I. Serum insulin and insulin dependent protein concentrations in obese patients with polycystic ovary syndrome

OBJECTIVES: The aim of the present study was to estimate the role of insulin in the pathogenesis of polycystic ovary syndrome. DESIGN: The study was carried out in 21 obese women with PCO, 18 obese women without menstrual disturbances and 9 normal-weight healthy women. MATERIALS AND METHODS: In all patients antropomethric parameters: weight, height, % of body fat, waist and hip girths were measured and than BMI and WHR were calculated. Oral glucose tolerance test after 75 g glucose was done after overnight fast. Plasma glucose and insulin were measured in 0 min, 60 min and 120 min of the test. The concentrations of IGF-I, IGFBP-1, SHBG, LH, FSH, testosterone, cortisol, PRL, estradiol, were estimated. RESULTS: There was statistical significant difference between plasma insulin concentrations in obese patients with PCO in comparison to obese women with normal menstrual cycle (p < 0.05) and control group (p < 0.001). The concentrations of IGFBP-1 and SHBG were similar in both groups of obese patients and differ markedly in comparison to the control group. There were significant correlation between plasma insulin and % body fat, BMI and waist girth in all studied groups. CONCLUSIONS: We conclude that in obese women with PCO insulin influence ovarian androgen production and decreases the serum SHBG and IGFBP-1 which could contribute in the augmentation of the symptoms of PCO.     

Screening for insulin resistance in women with polycystic ovarian syndrome

Introduction Insulin resistance is implicated in the pathogenesis of polycystic ovarian syndrome (PCOS). Insulin-sensitizing agents are increasingly used in the treatment of infertility and hirsutism in PCOS. However, not all women with PCOS are insulin-resistant.

Objective To assess the degree of insulin resistance within a clinic population of women referred for treatment of oligomenorrhoea or infertility.

Design We evaluated 25 consecutive PCOS outpatients referred for treatment of menstrual dysfunction/infertility and a matched control group. All underwent a standard oral glucose tolerance test (OGTT) with serial insulin measurements. Insulin sensitivity was calculated using homeostasis model assessment (HOMA).

Results Five of the 25 clinic patients had abnormal glucose handling (two had previously unknown type 2 diabetes and three had impaired glucose tolerance). Fasting and 2-h insulin levels were significantly higher in the PCOS women. Mean HOMA-S (insulin sensitivity) was even lower for PCOS women with normal GTT status (mean (95% confidence interval): 0.53 (0.34–0.72)) than for controls (0.94 (0.84–1.04)) (F?=?4.2, p?<?0.001). HOMA-B (pancreatic β-cell function) was nearly tripled for normal GTT status PCOS women at 273 (205–342) versus 105 (70–139) for controls (F?=?6.8, p?<?0.001).

Conclusions The results suggest a role for routine measurement of HOMA-S in identifying women with PCOS with insulin resistance with a view to targeting them with insulin-sensitizing agents.     

Metformin therapy increases insulin-like growth factor binding protein-1 in hyperinsulinemic women with polycystic ovary syndrome

OBJECTIVES: Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism, insulin resistance, compensatory hyperinsulinemia, and increased levels of free insulin-like growth factor-I (IGF-I), presumably due to a decline in IGF binding protein 1 (IGFBP-1). This study was designed to evaluate effects of metformin therapy on serum levels of IGFBP-1 and IGF-I. STUDY DESIGN: Twenty-seven obese, hyperandrogenic PCOS women with elevated fasting insulin were treated for 12 weeks with metformin (500 mg p.o., t.i.d.). Serum levels of insulin, testosterone, sex hormone binding globulin (SHBG), IGF-I, and IGFBP-1 were measured before and after treatment. Body mass index (BMI) and waist-to-hip ratio (WHR) were assessed at baseline and at the end of therapy. RESULTS: Metformin therapy significantly increased IGFBP-1 concentration by 38% (P = 0.05) but had no demonstrable effect on the total IGF-I levels. Fasting insulin levels declined by 38% (P = 0.0001) while the glucose/insulin ratio increased by 72% (P = 0.0001) and quantitative insulin sensitivity check index (QUICKI) increased by 8% (P = 0.0001). Metformin treatment also significantly decreased testosterone (by 37%, P = 0.0001) and increased SHBG concentration (by 16%, P = 0.04). Multiple linear regression analysis revealed that baseline IGFBP-1 levels correlated inversely and independently with two baseline parameters: WHR (P = 0.003) and free testosterone index (P = 0.04). CONCLUSIONS: The present study shows that metformin therapy not only restores normal levels of insulin and testosterone, but also decreases the pool of free-bioactive IGF-I by increasing the levels of circulating IGFBP-1. We provide further arguments in favor of metformin therapy in hyperinsulinemic women with PCOS.     

胰岛素样生长因子1受体与卵巢癌SKOV3细胞顺铂耐药相关性的研究

目的:探讨胰岛素样生长因子1受体(IGF-1R)与卵巢癌SKOV3细胞顺铂耐药的相关性。方法:建立人卵巢癌细胞系SKOV3异种移植瘤模型,其中部分用顺铂处理;由此模型获得细胞分为SKOV3-P组(未化疗组)和SKOV3-R组(化疗组)。采用免疫细胞化学法和流式细胞术检测瘤细胞中IGF-1和IGF-1R的表达差异;MTT法和流式细胞术分别检测不同浓度顺铂(0、1、5、10、15、20μg/ml)和IGF-1R抑制剂NVP-AEW541(0、1、5、10、20μmol/L)单独及联合应用对瘤细胞的增殖及凋亡的影响。结果:SKOV3-P组、SK-OV3-R组细胞中均表达IGF-1和IGF-1R,且SKOV3-R组细胞的表达均显著高于SKOV3-P组细胞(P<0.05);NVP-AEW541对SKOV3-P组、SKOV3-R组细胞均表现增殖抑制,呈现剂量-时间依赖关系;NVP-AEW541联合顺铂作用瘤细胞时抑制作用显著增强,移植瘤细胞的顺铂敏感性显著增加(P<0.05);流式细胞术检测联合用药组细胞(10μmol/LNVP-AEW541+10μg/ml顺铂)凋亡率明显高于对照组和单独用药组(10μmol/L NVP-AEW541),且SKOV3-P组细胞的抑制率和凋亡率均显著高于SKOV3-R组细胞(P<0.05)。结论:IGF-1R参与了化疗耐药过程,通过NVP-AEW541抑制IGF-1R可能逆转卵巢癌细胞的顺铂耐药。