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PubMed1998

Generation and characterization of a polyclonal antipeptide antibody to human glycodelin.

OBJECTIVE: To develop and characterize an antiglycodelin antibody using a 15-amino acid synthetic peptide as antigen, derived from the sequence of human glycodelin. DESIGN: We have developed a chicken antiglycodelin-derived peptide antibody and have characterized the antibody with the use of endometrial and ovarian cell lines. The antibody was also tested for its ability to detect glycodelin by ELISA assay, immunocytochemistry, and by Western blot. SETTING: Various cell lines, cell culture medium, and amniotic fluid were used in the experiments. PATIENT(S): Amniotic fluid was collected from pregnant patients in their first trimester of pregnancy. INTERVENTION(S): No intervention. MAIN OUTCOME MEASURE(S): Detection of glycodelin. RESULT(S): The cell lines RL95-2 (human endometrial carcinoma cells), OVCAR-3 (human ovarian adenocarcinoma cells), HeLa (human cervical epitheloid carcinoma cells), and EM42-D (human endometrial epithelial cells) reacted with the antibody, indicating the presence of glycodelin. A specific 45-kd protein representing glycodelin was detected by Western blot in the amniotic fluid. CONCLUSION(S): Antipeptide antibodies can be successfully used to detect and quantify the presence of glycodelin in cells and fluids.

Adenocarcinoma↗
PubMed2000

Glycodelin: a pane in the implantation window.

Glycodelin is an endometrial protein with proposed immunomodulatory activity during human embryonic nidation. In this review we describe the effects of ovarian hormones on glycodelin transcription, synthesis, and secretion by human epithelial cells and focus on the importance of glycodelin in implantation. We demonstrate that glycodelin transcription, synthesis, and secretion by human epithelial cells are stimulated by progestins and antiprogestins but not by estrogen. Sequences localized within a 403-base-pair region flanking the 5' human glycodelin gene promoter appear to be responsible for transcriptional activation of this gene mediated by progesterone receptor-ligand complexes. Relaxin, purported to enhance glycodelin production in vivo and in prior in vitro studies, had no stimulatory effect on the expression of this gene in vitro in our models.

Cells, Cultured↗
PubMed2003

Zona-binding inhibitory factor-1 from human follicular fluid is an isoform of glycodelin.

Zona-binding inhibitory factor-1 (ZIF-1), a glycoprotein in human follicular fluid, reduces the binding of spermatozoa to the zona pellucida. ZIF-1 has a number of properties similar to those of glycodelin-A from human follicular fluid. The objective of this study was to compare the biochemical characteristics of these two glycoproteins. N-terminal sequencing and protease-digested peptide mapping showed that ZIF-1 and glycodelin-A have the same protein core. However, these glycoproteins differ in their oligosaccharide chains, as demonstrated by fluorophore-assisted carbohydrate electrophoresis, lectin-binding ability, and isoelectric focusing. ZIF-1 inhibited spermatozoa-zona pellucida binding slightly more than did glycodelin-A and significantly suppressed progesterone-induced acrosome reaction of human spermatozoa. Indirect immunofluorescence staining revealed specific binding of glycodelin-A and ZIF-1 to the acrosome region of human spermatozoa, where ZIF-1 produced a stronger signal than did glycodelin-A at the same protein concentration. These data suggest that ZIF-1 is a differentially glycosylated isoform of glycodelin that potently inhibits human sperm-egg interaction. Future study on the function role of ZIF-1 would provide a better understanding of the regulation of fertilization in humans.

Amino Acid Sequence↗
PubMed1998

Glycodelins.

Glycodelins are 28 to 30-kD glycoproteins synthesized in various glands, notably those of the male and female reproductive organs. Depending on the site of origin, the same protein backbone is glycosylated in different ways, yielding glycodelins with different biological actions. Thus, human endometrium-derived glycodelin-A is temporally expressed in the latter half of the menstrual cycle, consists of unique sialylated and fucosylated lacdiNAc oligosaccharide sequences, and inhibits sperm-egg binding. By contrast, glycodelin-S from seminal vesicles has no such oligosaccharide sequences and no contraceptive activity. Glycodelin-A also has potent immunosuppressive properties, and its chemically modified forms inhibit transmission of HIV in vitro. Studies are reviewed suggesting that glycoforms dictate the function of human glycodelins, and that some of the oligosaccharide recognition sites present in the human gametes and immune cells have converged.

Alpha-Globulins↗
PubMed2006

Mitogen-activated protein kinase is involved in the progesterone-mediated induction of baboon glycodelin.

In the human and non-human primate the major secretory product of the uterine glandular epithelial cells is glycodelin. The expression of glycodelin is associated with elevated progesterone levels as its production peaks during the late luteal phase of the menstrual cycle and in early pregnancy. Consistent with our previous studies, we found that the majority of the progestin responsiveness of the baboon glycodelin promoter was retained in the -20+48 region, a region devoid of progestin- and Sp1-response elements. Using serial 5' and 3' deletions of 10 basepairs of the promoter within the pGL3Basic vector, we identified the 5' and 3' limits required for progestin responsiveness as -22 and +18, respectively. When the same regions were cloned into the pGL3Promoter vector, a construct that contains the heterologous SV40 promoter, progestin did not enhance expression. Mutation of the DNA binding domain of the progesterone receptor, which disrupts its ability to activate the progesterone response element, does not obliterate its ability to induce expression via the baboon glycodelin promoter. Inhibitors of protein tyrosine kinases, genistein and AG18, blocked the progestin-mediated induction as did an inhibitor of MEK, PD98059, but not an inhibitor of p38 MAP kinase, SB202190. These findings imply that glycodelin induction in response to progestins involves a nongenomic mechanism through the ERK1/2 branch of the MAP kinase pathway. The ultimate target may be a factor involved in the initiation of glycodelin gene transcription.

Animals↗
PubMed2006

Survivin and glycodelin transcriptional activity in node-positive early breast cancer: mRNA expression of two key regulators of cell survival.

INTRODUCTION: Glycodelin and survivin are key polypeptide regulators of cellular proliferation, apoptosis and angiogenesis. In view of contradictory reports on their functional role in tumors, we studied their transcriptional levels in localized breast cancer. PATIENTS AND METHODS: Glycodelin and survivin messenger ribonucleic acid (mRNA) was isolated and amplified by quantitative reverse-trancription PCR from paraffin-embedded breast carcinomas of 275 women. A normalized score was calculated by the use of GAPDH, RPL37A reference genes and was correlated with clinicopathologic/molecular parameters and patient outcome. RESULTS: A total of 272 patients were eligible, most harbored stage III node-positive breast carcinomas larger than 2 cm. Glycodelin mRNA was expressed in 68 patients (25%), more frequently in premenopausal women (P = 0.01) and those with HER2 mRNA-positive tumors (P = 0.02). Survivin mRNA was present in 263 tumors (97%) and its levels correlated significantly with high nuclear grade, VEGF mRNA and p53 mRNA presence (P < 0.05). At a median follow-up of 64 months, neither glycodelin nor survivin mRNA expression demonstrated prognostic utility for overall or disease-free survival at univariate and multivariate analysis. CONCLUSIONS: Glycodelin and survivin transcriptional activity are associated with adverse clinicopathologic and molecular characteristics of node-positive primary breast cancer but do not predict patient outcome. Further study is needed for illumination of their functional roles in tumorigenesis.

Adult↗
PubMed2005

Glycodelin reduces carcinoma-associated gene expression in endometrial adenocarcinoma cells.

OBJECTIVE: Glycodelin is a major secretory glycoprotein of differentiated endometrial epithelium, rarely expressed in proliferative endometrium or endometrial cancer. We aimed to elucidate its role in growth and gene expression of endometrial adenocarcinoma cells, and hypothesized that glycodelin affects cell growth and tumor-associated gene expression. STUDY DESIGN: Endometrial adenocarcinoma HEC-1B cells were transfected with glycodelin cDNA in both antisense and sense orientations. Cellular morphology, cell proliferation, and gene expression were compared between native and transfected cells. RESULTS: Compared with native and antisense-transfected carcinoma cells, sense-transfected, glycodelin-producing carcinoma cells showed reduced proliferation, morphologic changes, and altered expression of cancer-related genes. Notably, anti-apoptotic Bcl-XL and MUC1 genes were down-regulated. CONCLUSION: Reduction by glycodelin transfection of carcinoma cell proliferation and expression of MUC1 and Bcl-XL is significant because these genes are often overexpressed in human cancers--MUC1 is linked to invasive growth and metastases, and both confer resistance to chemotherapy. These results suggest a novel mechanism whereby malignant growth of endometrial adenocarcinoma cells is regulated.

Adenocarcinoma↗
PubMed2006

A comparative study of glycodelin concentrations in uterine flushings in women with subseptate uteri, history of unexplained recurrent miscarriage and healthy controls.

OBJECTIVE: To compare the concentration of glycodelin in uterine flushing at the implantation window obtained from women with subseptate uteri, women with a history of recurrent first trimester miscarriage and fertile controls. STUDY DESIGN: Glycodelin concentration was assessed using Enzyme Linked Immunohistochemistry (ELISA) at The Early Pregnancy & Gynaecology Assessment Unit, King's College Hospital, London, England. Eight women with a subseptate uterus, 20 women with a history of unexplained recurrent first trimester miscarriage and 16 fertile controls had uterine cavity flushing, for glycodelin concentration, done 7 days after the luteinising hormone surge. RESULTS: Glycodelin concentrations in uterine flushing obtained from women with subseptate uteri (n=8) (median 32.9 ng/ml, range 17.1-52.4 ng/ml) and recurrent miscarriage (n=20) (median 26.8 ng/ml, range 9.7-78.5 ng/ml) were significantly lower than in the control group (n=16) (median 67.7 ng/ml, range 59.0-77.6 ng/ml) (chi(2)=19.565, p<0.001). CONCLUSION: Peri-implantation levels of glycodelin are lower in women at high risk of early pregnancy failure.

Abortion, Habitual↗
PubMed2000

Glycodelin: a reproduction-related lipocalin.

Glycodelin, a human lipocalin, is a major endometrial protein with at least two differentially glycosylated isoforms. Glycodelin-A (GdA) is purified from human mid-trimester amniotic fluid, where it is secreted from the decidualized endometrium. Glycodelin-S (GdS) is synthesized in the male reproductive tract, mainly in the seminal vesicles, and secreted into seminal plasma. These two glycodelin isoforms, glycosylated in a completely different manner, serve as a good model for studying the effects of glycosylation on protein function and physicochemical properties. We have reviewed here the structure, expression and biological functions of glycodelin.

Cell Differentiation↗
PubMed2001

IGFBP-1 and glycodelin serum levels before and after hysterectomy with and without bilateral oophorectomy in premenopausal women.

OBJECTIVES: The aim of our study was to investigate the role of the intact endometrium and ovaries for serum levels of insulin-like growth factor binding protein-1 (IGFBP-1) and glycodelin. STUDY DESIGN: In 35 premenopausal patients with a planned hysterectomy, serum measurements of IGFBP-1 and glycodelin were done before surgery and 1, 3, 5, and 10 days after surgery. Patients were divided into three groups according to the kind and time of operation: (1) hysterectomy with bilateral adnexectomy in the luteal phase and (2) hysterectomy without adnexectomy in the follicular phase or (3) the luteal phase. RESULTS: IGFBP-1-we could not show any differences in IGFBP-1 serum levels before and after hysterectomy with or without bilateral oophorectomy. Glycodelin-hysterectomized and oophorectomized patients showed decreasing serum levels up to day 3. After day 5, circulating concentrations of glycodelin increased continuously but remained below pre-operative levels. In both non-adnexectomized groups we saw a reduction up to day 5 but a rise at day 10. None of the results reached statistical significance. CONCLUSION: The results indicate that endometrium and ovary are not the only sources of IGFBP-1 and glycodelin.

Adult↗
PubMed2003

Glycodelin serum levels in women with ectopic pregnancy.

OBJECTIVE: Aim of our study was to determine circulating levels of glycodelin for biochemical monitoring of women with vaginal bleeding and/or abdominal pain in early pregnancy. The objective was, using glycodelin as a biochemical parameter, to distinguish between incomplete abortion and ectopic pregnancy in early weeks of gestation. STUDY DESIGN: In 169 women with a first trimester pregnancy, a single serum measurement of maternal glycodelin was taken. Patients were divided into groups according to the clinical and/or ultrasonografic findings at the time of hospitalisation:ectopic pregnancy, incomplete abortion and control. RESULTS: Glycodelin serum levels were significantly lower in patients with ectopic pregnancy comparable with intact pregnancy and incomplete abortion. There was no difference in serum levels between intact pregnancy and incomplete abortion. CONCLUSION: Glycodelin might represent a biochemical parameter in the differential diagnosis between ectopic pregnancies and incomplete abortion. The number of patients was too small to give reference ranges for pregnancy weeks.

Abdominal Pain↗
PubMed2002

Lysophosphatidic acid induces glycodelin gene expression in cancer cells.

Glycodelin is a glycoprotein that has been suggested to be important in normal pregnancy and in malignancy. The regulation of its synthesis has not been studied. In this study, we report the induction of glycodelin gene expression by lysophosphatidic acid (LPA). We studied the effect of LPA (5, 10 and 25 microM) on glycodelin production in breast (MDA-MB-231), cervical (Hela), endometrial (RL-95), ovarian cancer (OVCAR-3) and erythroleukemia (K562) cells. There was a dose-dependent (5-25 microM) induction of glycodelin gene and protein expression in these cell types. LPA is a mimic of phorbol myristate acetate (PMA) action and is found to be elevated in high concentrations in the serum of cancer subjects. As glycodelin is an angiogenic protein with a potential immunosuppressive role, control of LPA synthesis might offer a potential target for intervention.

Female↗
PubMed2001

Glycodelins.

Glycodelin is a major glycoprotein that is synthesized in the endometrium in response to progesterone and relaxin exposure. Endometrium-derived glycodelin-A has contraceptive and immunosuppressive properties. Glycodelin is absent from the endometrium during the fertile periovulatory phase, but is synthesized in this tissue during the peri-implantation phase and is abundant during the last week of the luteal phase. Changes in local and/or circulating glycodelin concentrations have been observed in women with reproductive disorders. The chemical modification of glycodelins has resulted in compounds with antiviral activity.

Amino Acid Sequence↗
PubMed1995

Structural analysis of the oligosaccharides derived from glycodelin, a human glycoprotein with potent immunosuppressive and contraceptive activities.

Glycodelin, also known as placental protein 14 (PP14) or progesterone-associated endometrial protein (PAEP), is a human glycoprotein with potent immunosuppressive and contraceptive activities. In this paper we report the first characterization of glycodelin-derived oligosaccharides. Using strategies based upon fast atom bombardment and electrospray mass spectrometry we have established that glycodelin is glycosylated at Asn-28 and Asn-63. The Asn-28 site carries high mannose, hybrid and complex-type structures, whereas the second site is exclusively occupied by complex-type glycans. The major non-reducing epitopes in the complex-type glycans are: Gal beta 1-4GlcNAc (lacNAc), GalNAc beta 1-4GlcNAc (lacdiNAc), NeuAc alpha 2-6Gal beta 1-4GlcNAc (sialylated lacNAc), NeuAc alpha 2-6Gal beta 1-4GlcNAc (sialylated lacdiNAc), Gal beta 1-4(Fuc alpha 1-3)GlcNAc (Lewisx), and GalNAc beta 1-4(Fuc alpha 1-3)GlcNAc (lacdiNAc analogue of Lewisx). It is possible that the oligosaccharides bearing sialylated lacNAc or lacdiNAc antennae may manifest immunosuppressive effects by specifically blocking adhesive and activation-related events mediated by CD22, the human B cell associated receptor. Oligosaccharides with fucosylated lacdiNAc antennae have previously been shown to potently block selectin-mediated adhesions and may perform the same function in glycodelin. The potent inhibitory effect of glycodelin on initial human sperm-zona pellucida binding is consistent with our previous suggestion that this cell adhesion event requires a selectin-like adhesion process. This result also raises the possibility that a convergence between immune and gamete recognition processes may have occurred in the types of carbohydrate ligands recognized in the human.

Amino Acid Sequence↗
PubMed2003

The induction of baboon glycodelin expression by progesterone is not through Sp1.

Glycodelin is a major secretory product of the uterine glandular epithelial cells of the human and non-human primate during the late luteal phase of the menstrual cycle and early pregnancy. Since progesterone levels are elevated during these periods we sought to determine how progesterone modulates glycodelin gene expression. Co-transfection of various deletions of the baboon glycodelin promoter with the progesterone receptor (PR) into Ishikawa cells, a human endometrial cell line, revealed that full progesterone responsiveness is retained within the region -119/+48. In COS-1 cells, a kidney cell line, progesterone failed to elevate luciferase levels when various deletion constructs and the PR were co-transfected. Mutation of the Sp1 site in the -67/+48 region lowered basal expression but did not affect the ability of progesterone to increase expression of the luciferase reporter in Ishikawa cells. These findings suggest that Sp1 sites are not involved in the progesterone regulation of the baboon glycodelin gene. We propose that progesterone induces a factor that regulates glycodelin gene expression in the uterus since we failed to obtain a similar response in a non-uterine cell line.

Animals↗
PubMed2005

Histone deacetylase inhibitors induce differentiation of human endometrial adenocarcinoma cells through up-regulation of glycodelin.

Histone reversible acetylation, which is controlled by histone acetyltransferases and deacetylases, plays a fundamental role in gene transcription. Histone deacetylase inhibitors (HDACIs), such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), have been characterized not only as anticancer drugs, but also as cytodifferentiation-inducing agents. In human endometrium, postovulatory production of progesterone directs estrogen-primed endometrial glandular cells to differentiate and thereby produce a number of unique bioactive substances, including glycodelin, that are critical for implantation at the secretory phase of the menstrual cycle. In this study, we show that TSA and SAHA, belonging to the hydroxamic acid group of HDACIs, can induce the phenotype of a human endometrial adenocarcinoma cell line, Ishikawa (originally derived from the glandular component of the endometrium), to differentiate to closely resemble normal endometrial epithelium in a time- and dose-dependent manner, as determined by morphological changes, synthesis of glycogen, and expression of secretory phase-specific proteins, including glycodelin. The proliferation- and differentiation-modulating effects elicited by TSA and SAHA at their optimal concentrations were comparable or more potent than those exerted by combined treatment with progesterone and estradiol. Furthermore, the gene silencing of glycodelin by small interference RNA resulted in the blockade of HDACI-induced differentiation in Ishikawa cells, suggesting the requirement for glycodelin for endometrial epithelial differentiation. Our results collectively indicate that TSA and SAHA are potent differentiation inducers for endometrial glandular cells, providing a clue for a possible therapeutic strategy to modulate endometrial function by targeting glycodelin.

Adenocarcinoma↗
PubMed2001

Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome.

We hypothesized that hyperinsulinemia contributes to early pregnancy loss in the polycystic ovary syndrome by adversely affecting endometrial function and environment. Serum glycodelin, a putative biomarker of endometrial function, is decreased in women with early pregnancy loss. Insulin-like growth factor-binding protein-1 may also play an important role in pregnancy by facilitating adhesion processes at the feto-maternal interface. We studied 48 women with polycystic ovary syndrome before and after 4 weeks of administration of 500 mg metformin (n = 26) or placebo (n = 22) 3 times daily. Oral glucose tolerance tests were performed, and serum glycodelin and insulin-like growth factor-binding protein-1 were measured during the follicular and clomiphene-induced luteal phases of menses. In the metformin group, the mean (+/-SE) area under the serum insulin curve after glucose administration decreased from 62 +/- 6 to 19 +/- 2 nmol/L.min (P < 0.001). Follicular phase serum glycodelin concentrations increased 20-fold from 150 +/- 46 to 2813 +/- 1192 pmol/L (P < 0.001), and serum insulin-like-growth factor-binding protein-1 concentrations increased from 936 +/- 152 to 2396 +/- 300 pmol/L (P < 0.001). Similarly, luteal phase serum glycodelin concentrations increased 3-fold from 3434 +/- 1299 to 10624 +/- 1803 pmol/L (P < 0.001), and serum insulin-like growth factor-binding protein-1 concentrations increased from 1220 +/- 136 to 4916 +/- 596 pmol/L (P < 0.001). Uterine vascular penetration also increased in the metformin group, as did blood flow of spiral arteries, as demonstrated by a 20% decrease in the resistance index from 0.71 +/- 0.02 to 0.57 +/- 0.03 (P < 0.001). These variables did not change in the placebo group. We conclude that insulin reduction with metformin increases follicular and luteal phase serum glycodelin and insulin-like growth factor-binding protein-1 concentrations and enhances luteal phase uterine vascularity and blood flow in the polycystic ovary syndrome. These changes may reflect an improved endometrial milieu for the establishment and maintenance of pregnancy.

Adult↗
PubMed1997

Multiple forms of messenger ribonucleic acid encoding glycodelin in male genital tract.

Glycodelin-A is a human endometrium-derived glycoprotein with contraceptive and immunosuppressive activities. Recently, we found that seminal plasma contains immunoreactive glycodelin (GdS) that is differentially glycosylated and has no contraceptive activity. We now report localization and variant forms of GdS in the male genital tract. Northern blot and reverse transcription-PCR analyses showed that GdS mRNA is expressed in the seminal vesicles and ampulla of the vas deferens. Immunohistochemical staining localized GdS to the epithelial cells and lumen of glands in the seminal vesicles and ampullary part of the vas deferens. The same tissues and cells contained glycodelin mRNA as localized by in situ hybridization. Whereas the major reverse transcription-PCR products were identical to the glycodelin-A cDNA from decidual expression library, there were also several splicing variants of GdS mRNA. Seminal plasma also contained smaller immunoreactive forms of the GdS protein. Some of them were posttranslational cleavage products of GdS, because incubation of 125I-labeled GdS in seminal plasma resulted in smaller molecular weight cleavage products. Based on these results, we concluded that multiple forms of glycodelin mRNA are expressed in the male genital tract, including those lacking the coding sequences for the glycosylation sites, and that seminal plasma has proteolytic activity that cleaves GdS.

Aged↗