epidermal-growth-factor and Polycystic-Ovary-Syndrome

Knowledgement on ovary function regulation is advancing. Classic concept about endocrine regulation by sexual hormones and gonadotrophin has turning to an hypothesis: autocrine and paracrine factors as intra-ovarian regulators. Follicular growth and steroidogenesis are mainly driven by follicle stimulating hormone (FSH), luteine hormone (LH) and steroids. On the other hand, the presence of intra-ovarian growth factors have an important role in modulation of gonadotrophin effects on ovarian functions. The influence of this factors on follicle growth are described.

Topics: Apoptosis; Epidermal Growth Factor; Female; Humans; Ovarian Follicle; Polycystic Ovary Syndrome; Transforming Growth Factor alpha

The etiology of polycystic ovary syndrome (PCOS) has not yet been fully elucidated but involves a disruption of normal ovarian function and multisystem sequelae. A combination of abnormally functioning genes whose expression is influenced by environmental, extra-ovarian factors determines the symptoms. Growth factors are heavily involved in the pathophysiology, either contributing to or as a consequence of the arrested development of follicles, abnormal steroidogenesis and hyperinsulinemia. Hyperactivity of a--transforming growth factor (TGFa) and epidermal growth factor (EGF) may block stimulation of aromatase and attenuate apoptosis of follicles and other factors may interface with the insulin-like growth factor (IGF) system preventing arrested follicles from becoming atretic and preventing the selection of a dominant follicle. IGF-binding protein concentrations are decreased by insulin, freeing biologically active IGF-I which augments the action of luteinizing hormone (LH) by inducing LH receptors, hyperactivating the enzymes P450c17a and 17,20 lyase resulting in hyperandrogenism. Growth hormone itself may be involved in the pathophysiology, as in normoinsulinemic PCOS patients it is hypersecreted and its actions on growth factors and their binding proteins are similar to those of insulin.

Topics: Androgens; Epidermal Growth Factor; Female; Growth Substances; Humans; Insulin Resistance; Ovarian Follicle; Polycystic Ovary Syndrome; Somatomedins; Transforming Growth Factor alpha

The mechanism of the ovarian dysfunction in polycystic ovary syndrome, the most common cause of anovulatory infertility, remains obscure. Clinical data suggest that follicle stimulating hormone (FSH) action may be inhibited at the ovarian level by paracrine factors derived, presumably, from interstitial cells. The greater responsiveness to FSH of granulosa cells isolated from polycystic ovaries (PCO) compared with that seen in cells derived from normal ovaries, provides some support for this hypothesis and we present data which suggests that epidermal growth factor, or more likely transforming growth factor alpha, could be a candidate for this inhibitor. It should be emphasized, however, that the cardinal biochemical feature of the PCO is hypersecretion of androgens by interstitial cells. Stromal tissue from the PCO will secrete significant quantities of androstenedione in response to LH, whereas there is a negligible response in stroma from normal ovaries. It remains to be determined whether androgens have a direct inhibitory effect on FSH-induced oestradiol production in the human follicle, or whether they might exert an indirect effect by activating inhibitory polypeptide growth factors.

Topics: Cells, Cultured; Epidermal Growth Factor; Estradiol; Female; Follicle Stimulating Hormone; Granulosa Cells; Growth Substances; Humans; Polycystic Ovary Syndrome; Somatomedins

Polycystic ovary syndrome is the most important cause of chronic anovulation. In women who fail to respond to clomiphene, low-dose FSH given in a step-wise fashion can induce normal follicular growth and ovulation. The failure of the action of endogenous FSH in these women may be related to reduced biological activity of circulating FSH, but may also involve inhibition of its action at follicular level by polypeptide growth factors such as EGF.

Topics: Androgens; Anovulation; Clomiphene; Epidermal Growth Factor; Female; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Ovarian Follicle; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy

The aim of this study was to find underlying genes and their interaction mechanism crucial to the polycystic ovarian syndrome (PCOS) by analyzing differentially expressed genes (DEGs) between PCOS and non-PCOS subjects.. Gene expression data of PCOS and non-PCOS subjects were collected from gene expression omnibus (GEO) database. GEO2R were used to calculating P value and logFC. The screening threshold of DEGs was P < .05 and | FC | ≥ 1.2. GO annotation and Kyoto encyclopedia of genes and genomes (KEGG) signaling pathway enrichment analysis was performed by using DAVID (2021 Update). The protein-protein interaction (PPI) network of DEGs was constructed by using the STRING database, and the hub genes were recognized through Hubba plugin of Cytoscape software.. PCOS and non-PCOS subjects shared a total of 174 DGEs, including 14 upregulated and 160 downregulated genes. The GO biological processes enriched by DEGs mainly involved actin cytoskeleton organization, positive regulation of NF-κB signaling pathway, and positive regulation of canonical Wnt signaling pathway. The DEGs were significantly enriched in cytoplasm, nucleus and cytosol. Their molecular functions mainly focused on protein binding, calmodulin binding and glycerol-3-phosphate dehydrogenase activity. The PI3K/Akt signaling pathway and glycosaminoglycan biosynthesis were highlighted as critical pathways enriched by DEGs. 10 hub genes were screened from the constructed PPI network, of which EGF, FN1 and TLR4 were mainly enriched in the PI3K/Akt signaling pathway.. In this study, a total of 174 DEGs and 10 hub genes were identified as new candidate targets for insulin resistance (IR) in PCOS individuals, which may provide a new direction for developing novel treatment strategies for PCOS.

Topics: Calmodulin; Computational Biology; Epidermal Growth Factor; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Ontology; Glycerolphosphate Dehydrogenase; Glycosaminoglycans; Humans; NF-kappa B; Phosphatidylinositol 3-Kinases; Polycystic Ovary Syndrome; Proto-Oncogene Proteins c-akt; Toll-Like Receptor 4

Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder with complex pathogenesis. This study aimed to analyze the expression of platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and insulin-like growth factor-II (IGF-II) in patients with PCOS and its correlation with pregnancy outcomes.. A total of 104 PCOS patients admitted to the Cangzhou Central Hospital from January 2015 to February 2018 were selected as the PCOS group, and 92 healthy pregnant women who received health examinations in the hospital during the same period were selected as the control group. Levels of PDGF, EGF, and IGF-II in serum were detected. The expression of PDGF, EGF, and IGF-II in different populations were compared. Age at pregnancy, body mass index (BMI), waist-to-hip ratio before pregnancy, parity, family history of hypertension, family history of diabetes, and serological indicators of pregnant women in the PCOS group were collected, such as follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), fasting insulin (INS), and free testosterone index (FTI). Multivariate logistic regression was used to analyze the risk factors that affect the pregnancy outcomes of PCOS patients.. The expression levels of PDGF, EGF, and IGF-II in the PCOS group were significantly higher than those in the control group (P<0.05). Among 76 pregnant PCOS patients, 34 cases had adverse pregnancy outcomes and 42 did not. Age at pregnancy, BMI before pregnancy, waist-to-hip ratio before pregnancy, LH, INS, FTI, PDGF, EGF, and IGF-II expression levels were positively correlated with the pregnancy outcome of PCOS patients (P<0.05). The BMI before pregnancy, waist-to-hip ratio before pregnancy, INS, FTI, and expression levels of PDGF, EGF, and IGF-II were revealed as independent risk factors that affect the pregnancy outcomes of PCOS patients (P<0.05).. The expression levels of PDGF, EGF, and IGF-II are high in PCOS patients. The BMI, waist-to-hip ratio before pregnancy, INS, FTI, and the expression levels of PDGF, EGF, IGF-II are independent risk factors that affect the pregnancy outcomes of PCOS patients. Corresponding measures should be actively taken for PCOS patients with high-risk factors to improve both maternal and infant outcomes.

Topics: Epidermal Growth Factor; Female; Humans; Insulin-Like Growth Factor II; Platelet-Derived Growth Factor; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Outcome

Oocyte developmental competence is altered in patients with polycystic ovary syndrome (PCOS); is gene expression in cumulus cells (CCs) from mature metaphase II oocytes of patients with PCOS altered as well?. Compared with CCs from non-PCOS patients, the gene expression profile of CCs isolated from mature oocytes of patients with PCOS present alterations that could explain the abnormal folliculogenesis and reduced oocyte competence in such patients.. Abnormal mRNA expression of several members of the insulin-like growth factor (IGF) family in CCs from PCOS patients was previously reported. Moreover, the whole transcriptome has been investigated in cultured CCs from PCOS patients.. This retrospective study included six PCOS patients diagnosed following the Rotterdam Criteria and six non-PCOS patients who all underwent ICSI for male infertility in the assisted reproduction technique (ART) Department of Montpellier University Hospital, between 2009 and 2011.. CCs from PCOS and non-PCOS patients who underwent controlled ovarian stimulation (COS) were isolated mechanically before ICSI. Gene expression profiles were analysed using the microarray technology and the Significance Analysis of Microarray was applied to compare the expression profiles of CCs from PCOS and non-PCOS patients.. The gene expression profile of CCs from patients with PCOS was significantly different from that of CCs from non-PCOS patients. Specifically, CCs from women with PCOS were characterized by abnormal expression of many growth factors, including members of the epidermal growth factor-like (EGFR, EREG and AREG) and IGF-like families (IGF1R, IGF2R, IGF2BP2 and IGFBP2), that are known to play a role in oocyte competence. In addition, mRNA transcripts of factors involved in steroid metabolism, such as CYP11A1, CYP1B1, CYP19A1 and CYP2B7P1, were deregulated in PCOS CCs, and this could explain the abnormal steroidogenesis observed in these women. Functional annotation of the differentially expressed genes suggests that defects in the transforming growth factor β and estrogen receptors signalling cascades may contribute to the reduced oocyte developmental competence in patients with PCOS.. Owing to the strict selection criteria (similar age, weight and reasons for ART), this study included a small sample size (six cases and six controls), and thus, further investigations using a large cohort of patients are needed to confirm these results.. This study opens a new perspective for understanding the pathogenesis of PCOS.. This work was partially supported by a grant from the Ferring Pharmaceutical. The authors of the study have no competing interests to report.. Not applicable.

Topics: Adult; Cumulus Cells; Epidermal Growth Factor; Female; Humans; Male; Metaphase; Oocytes; Ovulation Induction; Polycystic Ovary Syndrome; Protein Array Analysis; Retrospective Studies; Signal Transduction; Sperm Injections, Intracytoplasmic; Steroids; Transcriptome; Vascular Endothelial Growth Factors

To investigate the regulation of MMP-9, TIMP-1, and progesterone via three signal transduction pathways in luteinized granulosa cells from normal ovulatory and PCOD women.. In vitro study.. Laboratory for Research in Reproductive Sciences, Department of Obstetrics and Gynecology, Ha'Emek Hospital, Afula, Israel.. Ten normal ovulatory and 10 women with polycystic ovary disease (PCOD) treated in an assisted reproduction program.. Cultured cells were exposed to phorbol 12-myristate 13-acetate (TPA), acting via protein kinase C (PKC), to epidermal growth factor (EGF), acting via protein tyrosine kinase (PTK), and to forskolin, acting via protein kinase A (PKA).. Secretion of MMP-9, TIMP-1, and progesterone.. Phorbol 12-myristate 13-acetate elicited an increase in MMP-9 and TIMP-1 secretion in both groups and apparently did not affect progesterone secretion. Epidermal growth factor did not change significantly neither MMP-9 nor TIMP-1 secretion but dose dependently decreased MMP-9-TIMP-1 ratio and increased progesterone secretion in the PCOD group. Forskolin inhibited MMP-9 activity and increased TIMP-1 and progesterone secretion in both groups. Progesterone production was inversely related to the ratio of MMP-9-TIMP-1 regardless of cell origin.. In this preliminary study, similar and divergent patterns have emerged in the regulation of MMP-9 and TIMP-1 in human luteinized granulosa cells. Repressing MMP-9-TIMP-1 ratio may have an important modulatory effect on progesterone secretion.

Topics: Adult; Blotting, Western; Colforsin; Cyclic AMP-Dependent Protein Kinases; Epidermal Growth Factor; Female; Granulosa Cells; Humans; Luteinization; Matrix Metalloproteinase 9; Polycystic Ovary Syndrome; Progesterone; Protein Kinase C; Protein-Tyrosine Kinases; Signal Transduction; Tetradecanoylphorbol Acetate; Tissue Inhibitor of Metalloproteinase-1

We investigated aromatization and the mechanism of action of epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha) on oestradiol biosynthesis in freshly prepared granulosa cells from polycystic ovaries. Freshly prepared granulosa cells from polycystic ovaries incubated for only 3 h under basal conditions secreted significantly (P< 0.001) greater amounts of oestradiol-17beta than that of granulosa cells from normal ovaries. 8-Bromo-cyclic adenosine monophosphate (8-Br-cAMP), but not follicle stimulating hormone (FSH) or luteinizing hormone (LH), further enhanced this activity. Both EGF and TGFalpha inhibited gonadotrophinor 8-Br-cAMP-stimulated, but not basal, oestradiol production. LH receptor (LHR) binding, estimated by immunolabelling the bound LH, was significantly (P< 0.001) reduced in granulosa cells from polycystic ovaries when compared with cells from normal ovaries. EGF or TGFalpha significantly reduced the binding in cultured cells from all patient groups (P< 0.05). More interestingly, a further increase of the inhibitory effect was seen in granulosa cells from polycystic ovaries (P < 0.001). In conclusion, granulosa cells from polycystic ovaries contain high levels of basal aromatase activity in vitro, which is probably inherited from the in-vivo condition. EGF and TGFalpha suppress oestradiol synthesis at a step beyond the production of cAMP and also LHR binding with more effect in granulosa cells from polycystic ovaries.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Adult; Aromatase; Cells, Cultured; Epidermal Growth Factor; Estradiol; Female; Follicle Stimulating Hormone; Granulosa Cells; Humans; Luteinizing Hormone; Polycystic Ovary Syndrome; Receptors, LH; Transforming Growth Factor alpha

It has previously been suggested that epidermal growth factor (EGF) plays a role in the function of the ovary. We administered systemic EGF to assess the influence of EGF receptor stimulation on the morphology of the ovaries.. Forty-eight female Wistar rats were allocated to five groups receiving EGF treatment (150 microgram/kg/day) for 0 (controls), 1, 2, 3 and 4 weeks. All rats were exactly 8 weeks at the start of the experiment and 12 weeks at sacrifice. The EGF was administered in the weeks prior to sacrifice. At sacrifice, the perfusion-fixed ovaries were removed and weighed, and the volumes of tissue components were quantified using stereology.. EGF administration increased the total weight of the ovaries from 129 +/- 18 mg in the controls to 158 +/- 29 mg (p<0.05) after one week. In subsequent weeks the total weight increased to 230 +/- 73 mg (p<0.001). The weight gain after one week of treatment was exclusively due to a fourfold increase in follicular cyst volume (p<0.01). In subsequent weeks the cyst volume was increased up to eightfold. After 2, 3 and 4 weeks of treatment the quantity of luteinizing cells was likewise increased by 70% (p<0.01).. EGF administration causes the follicular cells to produce cysts and increases the quantity of luteinizing cells.

Topics: Animals; Corpus Luteum; Epidermal Growth Factor; Female; Ovarian Follicle; Ovary; Polycystic Ovary Syndrome; Rats; Rats, Wistar; Reference Values; Time Factors

To investigate intrafollicular insulin-like growth factor II (IGF-II) in patients affected with polycystic ovary syndrome (PCOS) in comparison with normal women.. Insulin-like growth factor-II was determined in 103 follicular fluids (FF) from normally ovulating women and in 102 FF from patients with PCOS. Ribonucleic acid was extracted from granulosa cells of follicles obtained from control and PCOS patients and from tissue from polycystic ovaries.. Procedures were performed in a university laboratory.. Twenty-nine normally ovulating women and 19 patients with PCOS underwent ovulation induction for IVF-ET with LH-releasing hormone (LH-RH) analog and gonadotropins. Eleven of them, 4 to 8 months later, underwent ovulation induction with approximately the same dosage of gonadotropins plus a standard dosage of GH.. Intrafollicular IGF-II, IGF-I, epidermal growth factor (EGF), transforming growth factor beta 2, (TGF-beta 2), inhibin, and steroids were evaluated by appropriate RIA, immunoenzymatic assay (EIA), and ELISA assays. The expression of the gene encoding IGF-II was analyzed by Northern blot.. Intrafollicular IGF-II was lower in PCOS than in controls. Accordingly, IGF-II messenger RNA expression was lower in PCO than in normal granulosa cells. Several differences in FF IGF-I, EGF, inhibin, and TGF-beta 2 concentrations were observed between PCOS and controls.. Both IGF-II and IGF-I were reduced in PCOS, confirming a possible role of an IGF imbalance in the development of this disease.

Topics: Adult; Case-Control Studies; Epidermal Growth Factor; Estradiol; Female; Follicular Fluid; Granulosa Cells; Humans; Inhibins; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Ovulation; Polycystic Ovary Syndrome; Progesterone; RNA, Messenger; Transforming Growth Factor beta

Topics: Epidermal Growth Factor; Female; Gonadotropins; Growth Hormone; Humans; Insulin-Like Growth Factor I; Ovarian Follicle; Ovulation Induction; Polycystic Ovary Syndrome

Follicular fluid sex-steroids, insulin-like growth factor-I (IGF-I), IGF-I binding protein (IGF-I-BP) and epidermal growth factor were investigated in patients with polycystic ovaries and normally ovulating women, following ovulation induction with gonadotrophins or growth hormone plus gonadotrophins. Growth hormone supplementation enhanced the ovarian response to gonadotrophins, and significantly increased follicular fluid IGF-I in both groups, without affecting follicular fluid epidermal growth factor; growth hormone supplementation significantly decreased follicular fluid androstenedione in both groups.

Topics: Adult; Androstenedione; Carrier Proteins; Drug Synergism; Epidermal Growth Factor; Estradiol; Female; Follicular Fluid; Gonadotropins; Growth Hormone; Humans; Infertility, Female; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Ovulation; Ovulation Induction; Polycystic Ovary Syndrome; Progesterone

The follicular fluid (FF) content of androgens, estrogens and epidermal growth factor (EGF) has been evaluated in a group of patients with policystic ovary disease (PCO) and in one of normally-ovulating infertile women (NOW) in an IVF/ET program. The in vitro response to follicle-stimulating hormone (FSH) has been also evaluated in granulosa luteal cells from the same patients. PCO patients showed significantly higher FF androstenedione (delta 4) and testosterone (T) and similar FF estrone (E1) and 17 beta-estradiol (E2) levels compared to controls. In vitro production of E1 and E2 by granulosa luteal cells from PCO patients and from controls were overlapping and their response to FSH was similar. These data indicate a normal intrinsic potential aromatase activity in ovaries from PCO patients stimulated with gonadotropins and suggest that PCOs do not derive from inherent ovarian aromatase deficiency. Increased FF androgen content following gonadotropin stimulation may result from theca cell hyperactivity and androgen accumulation in the follicular antrum of rescued hyperandrogenic follicles as well as from inhibitory factors that may inhibit aromatase activation in vivo, partially counteracting the effect of gonadotropins. FF EGF levels were significantly higher in the group of PCO patients compared to those of NOW. EGF may play a role in blunting the in vivo response of granulosa cells to gonadotropins.

Topics: Androstenedione; Cells, Cultured; Embryo Transfer; Epidermal Growth Factor; Estradiol; Estrogens; Estrone; Female; Fertilization in Vitro; Follicular Fluid; Gonadal Steroid Hormones; Granulosa Cells; Humans; Luteal Cells; Polycystic Ovary Syndrome; Testosterone

Anovulation in women with polycystic ovary syndrome results from a disorder of FSH-mediated follicular maturation which may involve paracrine modulation of FSH action by intra-ovarian factors. Epidermal growth factor (EGF) is a potent inhibitor of FSH-stimulated oestradiol production in the rat and has also been shown to inhibit aromatase activity in human granulosa cells obtained after superovulation. The purpose of this study was to investigate the action of EGF on granulosa cell function in human ovaries which had not been previously exposed to treatment with exogenous gonadotrophins and to compare the responses in tissue obtained from normal and from polycystic ovaries. Granulosa cells were obtained from antral follicles less than 10 mm in diameter after dissection of unstimulated normal or polycystic ovaries (PCO). Cells were pooled, washed, plated and incubated for 48h in the presence of 10(-7) M testosterone and various doses of human FSH. FSH dose responses were obtained with or without the addition of purified EGF (50 pg/ml). Testosterone in the absence of FSH resulted in a fourfold (range 2-7.5) increase in oestradiol accumulation in the medium after incubation of granulosa cells from both normal and polycystic ovaries. This increase was reversed by addition of EGF. FSH treatment stimulated a dose-related increase in oestradiol regardless of the origin of the granulosa cells. The peak E2 response to FSH, obtained at a dose of 1-2.5 ng/ml was a 20-fold increase above testosterone alone (range 4-55) in cells from PCO compared to sixfold (2.5-13) in cells from normal ovaries.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Cells, Cultured; Depression, Chemical; Dose-Response Relationship, Drug; Epidermal Growth Factor; Estradiol; Female; Follicle Stimulating Hormone; Granulosa Cells; Humans; Polycystic Ovary Syndrome; Testosterone

Thirty-three samples of follicular fluid (FF) were collected from 14 patients with the polycystic ovary (PCO) syndrome and matched for FF-volume with small follicles collected from subjects with normal ovaries. The median (range) FF concentration of insulin-like growth factor 1 (IGF1) in the group with PCO, 0.42 (0.13-1.20) U/ml was significantly higher than that of the controls, 0.33 (0.04-0.59) U/ml. All samples tested had less than 1 ng/ml of FF-epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha). The patients with PCO syndrome (PCOS) had similar FF-testosterone (T) and FF-progesterone (P) concentrations to volume matched controls, but significantly higher levels of FF-androstenedione (AD) and lower FF-oestradiol (E2). These results suggest that the granulosa cells within the polycystic follicle have a functional defect in their aromatase enzyme complex.

Topics: Adult; Androstenedione; Epidermal Growth Factor; Estradiol; Female; Follicular Fluid; Gonadal Steroid Hormones; Growth Substances; Humans; Insulin-Like Growth Factor I; Polycystic Ovary Syndrome; Progesterone; Radioimmunoassay; Testosterone; Transforming Growth Factors