Regulation of IGF binding proteins by FSH in human luteinizing granulosa cells

Objectives To evaluate the regulation of the secretion of insulin-like growth factor (IGF) binding proteins (IGFBPs) by FSH in human luteinizing granulosa cells.Design and Results Luteinizing granulosa cells were incubated with and without FSH. Levels of IGFBP-1 and -3 in the medium were measured by EIA and RIA, respectively and binding activities of these IGFBP were evaluated by Western ligand blot. FSH inhibited the secretion of IGFBP-1 dose dependently. FSH did not inhibit the secretion of immunoreactive IGFBPS, but inhibited the binding activity of IGFBP-3. To assess the protease activity,¹²⁵ I-IGFBP-3 was incubated with the cultured medium.¹²⁵ I-IGFBP-3 degraded into small fragments when it was incubated with the cultured medium treated with FSH.Conclusions FSH enhances the action of IGF-I in human granulosa cells by inhibiting the secretion of IGFBP-1 and the binding activity of IGFBP-3 by stimulating the proteolysis of IGFBPS-3.Presented at the IXth World Congress on In Vitro Fertilization and Alternate Assisted Reproduction, April 3–7, 1995, Vienna, Austria.     

Spatial and temporal patterns of expression of messenger RNA for insulin-like growth factors and their binding proteins in the placenta of man and laboratory animals

To better understand the role of the insulin-like growth factors (IGF-I and -II) and their binding proteins (IGFBPs 1-6) in placental development and function, it is important to review similarities and differences between species in expression of the respective mRNAs. In human placenta, IGF-II mRNA is expressed in chorionic mesoderm and first trimester villous cytotrophoblast, but not in syncytiotrophoblast. In contrast, in rhesus monkey placenta, IGF-II mRNA is expressed in syncytiotrophoblast but not in chorionic mesoderm. IGFBP-3 mRNA is present in the chorionic mesoderm of placental villi from both these species and may modulate IGF-II action through a paracrine mechanism. In rodent placentae, IGF-II mRNA is expressed both in fetal mesoderm and in the trophoblast of the placental labyrinth. In guinea pig, where IGFBP-5 mRNA is expressed in the marginal and interlobular syncytium and IGF-II mRNA in the labyrinth, interaction between IGF-II and IGFBP-5 mRNA may be involved in vascularization of the placenta by fetal vessels. In sheep placenta, IGF-II mRNA is expressed, not in the trophoblast layer, but in the fetal mesoderm immediately adjacent to it. In the basal plate of human, rhesus monkey and baboon placentae, extravillous trophoblasts express IGF-II mRNA and uterine decidual cells IGFBP 1-6 mRNAs. The inference is that there is interaction between IGF-II and IGFBPs at the maternal-fetal interface of the primate placenta during trophoblast invasion and decidualization. IGFBP-1 expressed by the decidua may also interact with alpha(5)beta(1)integrin expressed by the extravillous trophoblast. The placentae of rodents are also of the invasive type. Glycogen cells of the mouse placenta are analogous with human extravillous trophoblast and express IGF-II mRNA. However, expression of IGFBP mRNAs in the mouse, as in the guinea pig, is confined to non-decidualized endometrium and myometrium. IGF-II mRNA is strongly expressed by trophoblasts invading uterine vessels in human and guinea pig placentae. Interactions probably occur between IGF-II expressed by these trophoblasts and IGFBPs expressed in the vessel walls. However, it is possible that IGFBPs expressed by maternal vessels are associated with processes that are independent of trophoblast invasion. Thus, IGFBP-3 mRNA is highly expressed in the maternal blood vessels of the non-deciduate sheep placenta. Findings to date highlight the diversity in the expression of the IGF system among placentae of man and different laboratory animals, and even between closely related species. Comparative studies will continue to be required to understand the functional role of IGFs and IGFBPs in each species.     

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.     

Immunohistochemical Analysis of Insulin-like Growth Factor–Binding Proteins -1, -2, and -3 in Implantation Sites of the Mouse

Purpose: Our purpose was to analyze potential interactions between the embryo and the maternal endometrial interface in vivo by analyzing immunolocalization of insulin-like growth factor–binding proteins (IGFBPs) -1, -2, and -3 in implantation sites of the mouse. Methods: Six-week-old B ₆ D ₂ F ₁ female mice underwent superovulation followed by mating and sacrifice at timed intervals. Formalin-fixed paraffin-embedded tissue was used for avidin–biotin immunocytochemical localization of IGFBPs utilizing standard methodology. Results: Immunostaining at 1.5 days post coitum revealed light staining in the epithelial glandular cells and faint staining in decidual stroma for both IGFBP-1 and IGFBP-2. At 7.5–10.5 days post coitum, there was moderate–dense immunostaining in the decidualized stromal cells at the implantation site for all three IGFBPs, whereas light immunostaining was seen in nonimplantation site decidua. Conclusions: Compartmentalization of immunostaining for IGFBP-1, -2, and -3 within decidualized stroma suggests that these proteins may be regulated by trophoblastic and/or embryonic signals.     

Mitogenic Activity of Growth Factors in the Human Endometrial Adenocarcinoma Cell Lines HEC-1-A and KLE

Endometrial adenocarcinoma is the most common gynecologic malignancy occurring in the United States. Evidence is accumulating that links peptide growth factors with malignant proliferation. Epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) are known mitogens for endometrial adenocarcinoma in vitro. However, the biological activity of other growth factors in this malignancy is unclear. This study was undertaken to determine the influence of growth factors on the mitogenic activity of the human endometrial adenocarcinoma cell lines HEC-1-A and KLE. Incubation with EGF, IGF-I, insulin-like growth factor II (IGF-II), or insulin stimulated a time-dependent mitogenic response in both cell lines, with the peak response occurring at 24 hr for HEC-1-A and 48 hr for KLE. After two doubling intervals, the number of HEC-1-A cells was increased 3.5-fold by EGF (100 ng/ml), 2.7-fold by IGF-I (100 ng/ml), 2.3-fold by IGF-II (100 ng/ml), and 2.2-fold by insulin (1000 ng/ml) when compared to untreated controls (P < 0.05). The number of KLE cells was increased 2.6-fold by EGF (100 ng/ml), 2.3-fold by IGF-I (100 ng/ml), 2.1-fold by IGF-II (100 ng/ml), and 2.0-fold by insulin (1000 ng/ml) when compared to untreated controls (P < 0.05). Similar results were obtained when DNA content was measured. PDGF failed to stimulate any mitogenic response in either cell line at all concentrations tested (0.1-100 ng/ml). These findings suggest that EGF, IGF-I, IGF-II, and insulin may play a regulatory role in the proliferation of endometrial adenocarcinoma.     

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.     

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.     

The expression of insulin-like growth factor and insulin-like growth factor binding protein mRNAs in mouse placenta

Insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) are paracrine regulators of tissue growth and development, and are expressed at the sites of biological action. To study the role of the IGFs and IGFBPs in mouse placental development, we determined the temporal and spatial expression patterns of the mRNAs at embryonic days 10.5 to 18.5 by in situ hybridization. IGF-II mRNA was expressed strongly in mesoderm and fetal blood vessels of early placenta and in labyrinthine trophoblast of later placenta. In the junctional zone, IGF-II mRNA was expressed first in spongiotrophoblasts, later strongly in glycogen cells and variably in giant cells. IGFBP-2 mRNA was expressed weakly in spongiotrophoblasts and glycogen cells. IGFBP-2, -5 and -6 mRNAs were detected in the stroma of the metrial gland. Myometrium expressed IGFBP-2 mRNA strongly, IGFBP-6 mRNA moderately and IGFBP-5 mRNA weakly. The endothelium of maternal blood vessels in decidua expressed IGFBP-3 and -5 mRNAs, and some deeper vessels expressed IGFBP-4 mRNA. In the yolk sac, IGF-II mRNA was expressed in endoderm and mesoderm, whereas IGFBP-1, -2 and -4 mRNAs were expressed only in endoderm, and IGFBP-4 mRNA in mesoderm. Strong expression of IGF-II mRNA in glycogen cells suggests a role in the autocrine/paracrine regulation of invasion. Similar to rat and guinea pig, but in contrast to man and primates, IGFBP mRNAs, except IGFBP-4, were not expressed in mouse decidua. However, IGFBP-3, -4 and -5 mRNAs were expressed in endothelium of maternal blood vessels, and IGFBP-2 and -6 mRNAs in myometrium, where IGFBPs may play a critical role in regulating trophoblast invasion. These findings suggest possible biological roles of the peptides at the feto-maternal interface.     

Production of insulin-like growth factor binding proteins (IGFBPS) by human endometrial stromal cells is stimulated by the presence of embryos

Purpose To identify IGFBPs among endometrial secretory products and study their role in implantation and early embryo development.Methods Two-cell CB ₆ F ₁ mouse embryos were cultured alone or with human endometrial stromal cells in RPMI 1640 plus 10% fetal calf serum (FCS) with or without addition of IGF-I (20 g/ml), IGF receptor antibody (0.1 g/ml), progesterone (P) (20 ng/ml) and relaxin (R) (20 g/ml). On the designated day, the medium was changed to protein-free RPMI and incubated for 16 h. Both conditioned medium and conditioned protein-free medium were then collected for protein analysis and immunoradiometric assay. Cells were fixed with 4% paraformaldehyde for immunohistochemical staining.Results IGFBP1 (31 kDa), IGFBP2 (36 kDa), IGFBP3 (45 kDa and 50 kDa) and an unknown IGFBP (25 kDa) were identified in conditioned medium of human endometrial stromal cells cultured alone or cocultured with mouse embryos. Secretion of IGFBPs by endometrial stromal cells was stimulated in the presence of mouse embryos as well as by P and R. IGFBP3 appears to be more responsive to embryonic signals. On the other hand, the secretion of IGFBP1 was greatly stimulated by P and R. Immunolocalization revealed that all three BPs were present in both embryonic and endometrial cells and their immunological staining was heavily increased by P and R.Conclusions Endometrial stromal cells were able to synthesize and secrete IGFBPs to modify IGF action on embryo development. Secretion of IGFBPs was stimulated by embryonic signals and was hormonally dependent. The fact that IGFBP3 was more responsive to embryonic signals suggests that it may be important in early implantation. On the other hand, IGFBP1 production was highly responsive to both P and R, suggesting that it may be important throughout pregnancy. In addition, the fact that IGFBPs were located in endometrial and embryonic cells may suggest that these secretory products have autocrine and/or paracrine effects on both types of cells. Presented at the 50th Annual Meeting of the American Fertility Society, San Antonio, Texas, November 5–10, 1994.     

胰岛素样生长因子及胰岛素样生长因子结合蛋白-3与胎儿生长受限的关系

目的　探讨胰岛素样生长因子 (IGF) Ⅰ、IGF Ⅱ和IGF结合蛋白 3(IGFBP 3)与胎儿生长的关系 ,以及IGF在胎儿生长受限 (FGR)发病中的作用。方法　选取 2 0例分娩FGR胎儿 (FGR组 )、10例分娩巨大儿 (巨大儿组 )及 2 0例分娩正常儿 (对照组 )的产妇 ,抽取 3组产妇分娩后肘静脉血及其新生儿脐静脉血 ,分离血清。采用放射免疫法和免疫放射法测定 3组产妇及其新生儿血清中IGF Ⅰ、IGF Ⅱ及IGFBP 3的水平。结果　 (1)FGR组产妇血清IGF Ⅰ、IGF Ⅱ及IGFBP 3水平分别为(130 5± 2 6 0 ) μg/L、(2 40± 0 42 ) μg/L及(5 5 79± 848) μg/L ;新生儿脐血清IGF Ⅰ、IGF Ⅱ及IGFBP 3水平分别为 (6 6± 1 7) μg/L、(1 5 4± 0 31) μg/L及 (86 9± 183) μg/L。 (2 )巨大儿组产妇血清IGF Ⅰ、IGF Ⅱ及IGFBP 3水平分别为 (30 9 7± 44 6 ) μg/L、(2 43± 0 2 5 ) μg/L及(5 5 6 2± 742 ) μg/L ;新生儿脐血清IGF Ⅰ、IGF Ⅱ及IGFBP 3水平分别为 (6 9 6± 2 3 9) μg/L、(2 19± 0 2 9) μg/L及(16 82± 130 )μg/L。(3)对照组产妇血清IGF Ⅰ、IGF Ⅱ及IGFBP 3水平分别为 (30 7 9± 70 7) μg/L、(2 41± 0 36 )μg/L及 (5 5 86± 6 78) μg/L ;新生儿脐血清IGF Ⅰ、IGF Ⅱ及IGFBP 3水平分别为 (6 8 9     

Effects of platelet activating factor on mouse embryo implantation in vitro

Purpose Our purpose was to assess the role of platelet activating factor (PAF) in embryo implantation, we examined the effects of PAF and a PAF antagonist on the in vitro implantation of mouse embryos, using an in vitro embryo culture system in the absence of the endometrium.Methods BDF1 mouse pronuclear-stage embryos were cultured until they developed to the two-cell, the four- to eight-cell, or the morula stage in the absence of PAF or its antagonist CV6209. The medium was then changed and supplemented with PAF or CV6209 at various concentrations. We also examined the reversible effects of PAF addition to the media containing the PAF antagonist.Results The addition of PAF to the culture from the two-cell stage significantly (P <0.05) increased the rates of embryo implantation in vitro (control, 69.8%; 10 ^–10 MPAF, 90.1%; 10 ^–9 MPAF, 95.5%). Similarly, the addition of PAF to the cultures from the four- to eight-cell and morula stage also significantly (P <0.05) increased their rates of implantation in vitro. In contrast, the addition of CV6209 to the culture significantly (P <0.01) decreased the rates of embryo implantation in vitro. CV6209 also decreased the rate of blastocyst formation. The degree of inhibition by CV6209 decreased with the advancing stage of embryos. The addition of PAF to media containing CV6209 reversed the inhibition and restored the implantation rate in vitro.Conclusions These results suggest that PAF may act directly on the mouse embryo and favor its implantation like an autocrine activating factor, irrespective of the presence or absence of the endometrium.     

Follicular Fluid Insulin-like Growth Factor-I and Insulin-like Growth Factor–Binding Protein-1 and -3 Vary as a Function of Ovarian Reserve and Ovarian Stimulation

Purpose: Follicular fluid concentrations of insulin-like growth factor (IGF)-I, IGF-II, IGF-binding protein (BP)-1, and IGFBP-3 in 57 women undergoing in vitro fertilization and embryo transfer were examined to determine whether levels reflected differences in patients' exposure to gonadotropin stimulation and a diminished ovarian reserve. Methods: Preovulatory follicular fluid was obtained from both gonadotropin-stimulated and unstimulated cycles. Subjects were grouped according to normal or decreased ovarian reserve and whether or not they received gonadotropin stimulation. Results: The mean follicular fluid concentrations of IGF-I and IGFBP-1 were significantly lower in the decreased ovarian reserve group compared with the normal ovarian reserve group, with no change in estradiol or IGF-II levels. This resulted in a decreased molar IGF-I: BP ratio and an increased molar IGF-II:IGFBP-1 ratio. In unstimulated cycles, mean follicular fluid concentrations of IGFs did not differ significantly compared with those in stimulated cycles, whereas concentrations of IGFBP-1 and IGFBP-3 were significantly lower, leading to higher molar ratios of the IGFs to the binding proteins. Conclusions: Follicular fluid IGF and binding proteins vary as a function of ovarian reserve and gonadotropin stimulation. This may reflect either differences in oocyte quality or a suboptimal follicular fluid environment.     

The pregnancy-associated plasma protein A and insulin-like growth factor system in response to cigarette smoking

Objective: Maternal smoking during pregnancy is associated with a reduction in birth size but the mechanism by which this occurs still remains unclear. The purpose of this study was to evaluate the effect of tobacco smoking on concentrations of pregnancy-associated plasma protein A (PAPP-A), insulin-like growth factor I (IGF-I), II (IGF-II) and binding proteins BP-3 and BP-4 in pregnant women and correlations between these parameters. Methods: Sixty healthy pregnant women were divided into smoking and tobacco-abstinent group according to results of serum cotinine concentration. The current smokers were defined as those who had smoked five or more cigarettes per day during pregnancy. Results: The mean serum concentrations of PAPP-A, IGF-I and IGF–II were significantly lower in smoking than in non-smoking pregnant women (p < 0.01). The level of PAPP-A correlated positively with the IGF-II concentration in both studied group (non-smoking: r = 0.54; p < 0.001; smoking: r = 0.40; p < 0.05). In tobacco-abstinent group negative correlation between IGF-II and IGFBP-4 concentrations was found (r = ?0.35; p < 0.05). Conclusion: Tobacco smoking during pregnancy decreases the pregnancy-associated plasma protein A and insulin growth factors I and II levels. The correlation between PAPP-A and IGF-II may suggest function of this protein as a protease and regulator in the IGF system.     

Enhanced embryo development of rabbit oocytes fertilized in vitro with platelet activating factor (PAF)-treated spermatozoa

Purpose The purpose of this study was to determine the effects of PAF treatment of rabbit spermatozoa on in vitro fertilization and subsequent blastocyst formation. Rabbit spermatozoa were exposed to PAF (10 ^–7 M), lyso-PAF (10 ^–7 M), or HIS (385 mOsm/kg) for 15 min prior to insemination of ovulated oocytes. Fertilized oocytes were cultured to the hatched blastocyst stage. Results Fertilization rates with PAF were significantly higher than those of fresh (P <0.001), lyso-PAF-treated (P <0.01), HIS-treated (P <0.05) spermatozoa. Two-cell embryos produced from oocytes inseminated with PAF-treated spermatozoa had significantly higher hatched blastocysts than oocytes inseminated with fresh (P <0.01), lyso-PAF-treated (P <0.05), or HIS-treated (P <0.05) spermatozoa. Conclusion We conclude that PAF treatment of spermatozoa increases fertilization rates and subsequent embryonic development.     

Serum and follicular fluid levels of IGF-II,IGF-binding protein-4 and pregnancy-associated plasma protein-A in controlled ovarian hyperstimulation cycle between polycystic ovarian syndrome (PCOS) and non-PCOS women

Objective.?To investigate the difference of serum and follicular expression patterns for IGFα, IGFBP4 and PAPP-A in COH cycle between PCOS and non-PCOS women.

Methods.?COH was performed for total 30 sterile women (20 with PCOS and 10 with normal ovarian function). The serum and follicular fluid (FF)from dominant follicles levels of IGFα, IGFBP4 and PAPP-A before COH, day of hCG, and were measured using an ELISA.

Results.?The PCOS women had significantly higher day 3 serum PAPP-A, day of hCG serum IGFBP-4, and ff IGF-II levels compared to the normoovulatory subjects. Serum levels of IGF-II and IGFBP-4 in PCOS women had increased after gonadotropins stimulation, and yet PAPP-A was decreased. Within the PCOS women, day of hCG serum IGFBP-4 was strongly correlated with BMI (r?=?0.777; P?=?0.000), day of hCG IGF II (r?=??0.573, p?=?0.008), ff IGF II (r?=??0.573, p?=?0.008) and ff PAPP-A (r?=??0.461, p?=?0.041) was inversely related to diameter >16?mm follicle number and day 3 PAPP-A correlated to diameter?>16?mm follicle number (r?=?0.474; p?=?0.035).

Conclusions.?Ovarian IGF system on the gonadotropin response to differences in the PCOS and non-PCOS women in COH cycle, and may indicate a inordinate IGF system that might disturb folliculogenesis in PCOS women.