Neuroendocrine carcinoma of the endometrium concomitant with Lynch syndrome:A case report

BACKGROUND Large-cell neuroendocrine carcinoma(NEC)is an uncommon type of tumor that can occur in the endometrium.This aggressive cancer requires definitive management.Here,we describe the clinical characteristics and treatment of a postmenopausal woman with large cell NEC of the endometrium.CASE SUMMARY A 55-year-old Asian female presented with a 1-year history of postmenopausal vaginal bleeding.Transvaginal ultrasound revealed a thickened endometrium(30.2 mm)and a hypervascular tumor.Computed tomography revealed that the tumor had invaded more than half of the myometrium and spread to the pelvic lymph nodes.The tumor marker,carcinoembryonic antigen,was elevated(3.65 ng/mL).Endocervical biopsy revealed high-grade endometrial carcinoma.She underwent radical hysterectomy,bilateral salpingo-oophorectomy,omentectomy,and bilateral pelvic and para-aortic lymph node dissection.Pathological examination revealed mixed neuroendocrine and endometrioid adenocarcinoma,pT2N0M0,grade 3,and International Federation of Gynecology and Obstetrics stage 2.Immunohistochemistry showed moderate estrogen and progesterone receptor expressions(20%and 1%,respectively),focal CD56 expression(NEC marker),positive staining for vimentin,p53(wild type),and ki67(90%),and loss of expression of PMS2(Lynch syndrome marker).The patient received five cycles of cisplatin and etoposide after surgery.No recurrence was noted after 5 mo.CONCLUSION We report the characteristics and successful management of a rare case of large cell endometrial NEC concomitant with Lynch syndrome.

Analyses of circRNA profiling during the development from pre-receptive to receptive phases in the goat endometrium

Background: Recent studies have revealed that noncoding RNAs play important regulatory roles in the formation of endometrial receptivity.Circular RNAs(circRNAs) are a universally expressed noncoding RNA species that have been recently proposed to act as miRNA sponges that directly regulate expression of target genes or parental genes.Results: We used Illumina Solexa technology to analyze the expression profiles of circRNAs in the endometrium from three goats at gestational day 5(pre-receptive endometrium,PE) and three goats at gestational day 15(receptive endometrium,RE).Overall,21,813 circRNAs were identified,of which 5,925 circRNAs were specific to the RE and 9,078 were specific to the PE,which suggested high stage-specificity.Further analysis found 334 differentially expressed circRNAs in the RE compared with PE(P < 0.05).The analysis of the circRNA-miRNA interaction network further supported the idea that circRNAs act as miRNA sponges to regulate gene expression.Moreover,some circRNAs were regulated by estrogen(E2)/progesterone(P4) in endometrial epithelium cell lines(EECs) and endometrial stromal cell line(ESCs),and each circRNA molecule exhibited unique regulation characteristics with respect to E2 and P4.Conclusions: These data provide an endometrium circRNA expression atlas corresponding to the biology of the goat receptive endometrium during embryo implantation.

Expression of Eph-Ephrin A Molecules in Endometrium During Swine Embryo Implantation Examined Using Real-Time RT-PCR

Erythropoietin-producing hepatocellular receptor and its membrane-bound ligands （Eph-Ephrin） system could regulate some mammalian blastocyst attachment and spreading. In order to investigate the involvement of the Eph-Ephrin system in swine embryo attachment, mRNA expression of Eph-Ephrin molecules in endometrium was examined by real-time RT- PCR during embryo implantation in pigs. The results indicated that mRNA expressions of Eph A5, A7 and Ephrin A5 all continually increased from pregnancy day 13 to 24. Ephrin A3 mRNA expression significantly increased from day 13 to 18 and decreased from day 18 to 24, and the expression was the lowest on pregnancy day l 3 and the highest on day 18. However, Ephrin A4 mRNA expression was the lowest on pregnancy day 18 and the highest on day 24, and the expression decreased from day 13 to 18 and increased from day 18 to 24. Furthermore, mRNA expressions of Eph A5 and A7 were both found in other tissues, such as brain, muscle, intestine, stomach, etc. These findings suggest that the Eph-Ephrin system may play an important role in regulating the contact between blastocysts and endometrium during swine embryo implantation.

Predicting Endometrium Receptivity with Parameters of Spiral Artery Blood Flow

In order To evaluate whether the parameters of spiral artery blood flow, as measured by transvaginal color Doppler, may be used to assess endometrium receptivity prior to embryo transfer (ET), a retrospective study of 94 infertile women who had undergone ART treatments with different outcomes (pregnant or nonpregnant) was done. Subendometrial blood flow was evaluated. The resistance index (RI), systolic/diastolic ratio (S/D) and pulsatility index (PI) were significantly lower in those who achieved pregnancy as compared with those who did not: 0.62±0.04 vs 0.68±0.04 (P<0.001), 2.66±0.33 vs 3.19±0.39 (P<0.01) and 1.15±0.17 vs 1.34±0.22 (P<0.05), respectively. Furthermore, when RI>0.72, PI>1.6, and S/D>3.6, no pregnancy occurred. These data suggest that the parameters of spiral artery blood flow could be used as a new assay in predicting endometrial receptivity before ET.

Expression of Calbindin-d28k in Human Endometrium

Objective To investigate the expression of Calbindin-d28k （CaBP-d28k） in human endometrium. Methods Thirty-three samples of human normal endometrial tissues were divided into 6 groups： early proliferative stage （n =6）, mid proliferative stage （n =5）, late proliferative stage （n=5）, early secretory stage （n=7）, mid secretory stage （n=5） and late secretory stage （n=5）. The expression and change of CaBP-d28k protein and gene were determined by immunohistochemistry and reverse transcription polymerase chain reaction methods. Results In endometrial samples, the expression of CaBP-d28k protein was mainly observed in the cytoplasm of luminal and glandular epithelium. In the menstrual cycle, the level of CaBP-d28k protein in the epithelium was the lowest during the early and mid proliferative stages, and was the highest during the mid secretory stage, then decreased in the late secretory stage （P〈0.05）. In the stroma, the expressed type of CaBP-d28k protein was the same as in the epithelium, but was lower than that in the epithelium（P〈0.05）. The CaBP-d28k mRNA was at the lowest level in the early proliferative stage（P〈0.05）, and significantly increased in the late proliferative, and early, mid secretory stages （P〈0. 05）. Conclusion Both CaBP-d28k protein and gene were expressed in human endometrium, and their expression had cyclic changes.

Inducible overexpression of porcine homeobox A10 in the endometrium of transgenic mice

Homeobox A10 （HOXA 10） is a well-known transcription factor that plays an important role in directing endometrial differ- entiation and establishing the conditions required for implantation. Interestingly, the expression level of HOXAIO may be associated with litter size. To study the effects of the porcine HOXAIO promoter fragment on the expression of HOXAIO gene in vivo, we generated a transgenic mouse model using pronuclear microinjection, and measured the expression of HOXAIO in the endometrium. There was no difference in the expression level of HOXAIO between transgenic and wild- type mice in the absence of hormone stimulation. However, following treatment with progesterone and estradiol benzoate, the expression level of HOXAIO was significantly increased in transgenic mice compared with that of wild-type mice. Fur- thermore, the litter size of transgenic females was larger than that of wild-type females （7.02±1.73 vs. 6.48＋1.85; P=0.14）. Moreover, the difference of litter size was greater in the later parities （7.33±1.62 vs. 6.37±2.02; P=0.08） compared with the first parity （6.76±1.81 vs. 6.61v1.67; P=0.77） between transgenic and wild-type mice. Therefore, our transgenic mouse model provides exciting insights regarding the actions of HOXAIO and its hormone-inducible promoter in vivo. The present study offers valuable proof of principle to develop transgenic pigs with a hormone-inducible promoter regulating HOXAIO to alter litter size.

Clinial Implication of tThe Expression of Aurora B in Normal Endometrium and Endometrial Carcinoma

The expression of Aurora B in normal endometria and endometrial carcinomas and its relation with clinicopathologic parameters of endometrial carcinomas were investigated. Streptavidin-biotin peroxidase （SP） immunohistochemical technique was used to detect the expression of Aurora B in 10 cases of normal proliferative phase endometria, 10 cases of normal secretory phase endometria and 72 cases of endometrial carcinomas respectively. According to the 1988 International Federation of Gynecology and Obstetrics （FIGO） grade, there were 37 patients in grade 1, 23 in grade 2 and 12 in grade 3 respectively. According to the FIGO stage, there were 59 patients in stage Ⅰ-Ⅱ and 13 patients in stage Ⅲ-Ⅳ. Aurora B was expressed in both normal proliferative phase endometria, secretory phase endometria and endometrial carcinomas, but its positive labeling index （PLI） in proliferative phase endometria was significantly higher than that in secretory phase endometria （P〈0.01） and endometrial carcinomas （P〈0.01）. The PLI of Aurora B was lower in tumors with well differentiation （G1）, low surgical staging （Ⅰ-Ⅱ）, and ≤1/2 myometrial invasion than that in tumors with moderate and low differentiation （G2--G3）, higher surgical staging （Ⅲ-Ⅳ）, and 〉1/2 myometrial invasion （all P〈0.01）. Aurora B exerts its functions in the replication of normal endometrial glandular cells; Expression of Aurora B is significantly correlated with biologic behavior of endometrial carcinoma, indicating that Aurora B may be a promising prognostic factor in endometrial carcinoma.

Study on the Effects of FCu-IUD and FICu-IUD on Matrix metalloproteinases in Human Uterine Flushing and Endometrium

The activity of matrix metalloproteinases (MMPs) in the uterine flushing and endometrial tissue of normal adult women wearing FCu IUD (fixed Cu IUD) or FICu IUD (indomethacin releasing FCu IUD) was observed by using zymography on SDS PAGE containing gelatin. The results showed that the activity and kinds of MMPs in FCu IUD group were increased significantly as compared with themselves before being inserted FCu IUD. However, compared with the FCu IUD group, the activity of some kinds of MMPs in the FICu IUD group was decreased significantly. These data suggest that IUD can enhance the activity of MMPs in human endometrium, intermediated by prostaglandins, and MMPs may have relation to IUD induced menorrhagia and indomethacin reduces IUD induced menorrhagia by partly inhibiting MMPs synthesis.

Expression of TRAIL in Mouse Uterine Endometrium during Embryo Implantation

Objective To investigate the expression of TRAIL in mouse uterine endometrium during embryo implantation and its role in the apoptosis of decidual cells. Methods Expression of TRAIL in uterine endometrium of pregnant mouse from d 1 to d 8 was detected with RT-PCR and immunohistochemistry. Results The expressed level of TRAIL mRNA in uterine endometrium of pregnant mouse from d 1 to d 8 was higher during embryo implantation than that prior to embryo implantation （P〈0.05）. No expression of TRAIL protein in mouse utrine endometrium was detected through d 1 to d 3. However, TRAIL protein was found in the luminal epithelial cells to which embryos attached on d 4. Moreover, TRAIL was expressed solely in decidual cells around invadting embryos through d 5 to d 6 while in trophoblastic cells adjacent to decidua through d 7 to d 8. Conclusion Apoptosis of luminal epithelial cells of endometrium induced by TRAIL could be one of mechanisms with which embryos penertrated the epithelial barrier, and apoptosis of both decidual cells and trophoblastic cells induced by TRAIL may play an important role during accruate invasion of trophoblastic cells.

circRNA landscape of non-pregnant endometrium during the estrus cycle in dairy goats

Endometrial development is a complicated process involving numerous regulatory factors.Circular RNAs(circRNAs)have been known as a member of the naturally occurring non-coding RNA family,and are reportedly crucial for a variety of physiological processes.This study investigated the circRNA landscape of non-pregnant endometrium of dairy goats during estrus.Non-pregnant endometrial samples of goats at estrus day 5(Ed5)and estrus day 15(Ed15)were used to methodically analyze the circRNA landscape using strand-specific Ribo-Zero RNA-Seq.A total of 2331 differentially expressed(P<0.05)circRNAs(DEciRs)between Ed5 and Ed15 were discovered in the goat endometrium.It was found that Nipped-B-like(NIPBL)and calcium responsive transcription factor(CARF)may participate in the development of the endometrium by decreasing(P<0.05)the levels of their circRNA-transcript forms.Furthermore,Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analyses of DEciR host genes(hgDEciRs)revealed that tight junctions and GTPases may be involved in endometrial development during the estrus cycle.A total of 2331 DEciRs were discovered in the endometrium at Ed5 and Ed15.Based on GO and KEGG enrichment analyses,it could be inferred that tight junctions and GTPases are likely to play an important role in the development of goat endometrium during the estrus cycle.This circRNA study greatly enhances our knowledge of global trends in the development of non-pregnant endometrium during the estrus cycle in goats;these results help us to better understand the molecular regulation of endometrial development in dairy goats.

Similarity between Spatial-temporal Expression Patterning of HOXAll and Progesterone Receptor in Human Endometrium

Objective To study HOXAll expression and its correlation with that of the progesterone receptor (PR) gene in human endometriumMethods In situ hybridization and semi-quantitative RT-PCR were used. Results HOXAll mRNA was detected in both stromal and glandular cells of normal endometrium by in situ hybridization. But the expression levels in the glandular cells had a dramatic decline or even disappearance at mid-secretory stage. Semi-quantitative RT-PCR analysis, however, demonstrated that the total expression levels of HOXAll mRNA were markedly increased in the mid-secretory endometrium, which suggested that there was an increased expression in stromal cells. Similar results were obtained for PR gene expression in human endometrium by in situ hybridization and semi-quantitative RT-PCR analysis.Conclusion HOXAll gene spatial and temporal expression patterns were similar to that of PR gene in endometrium across menstrual cycle, and HOXAll was closely related to the endometrial proliferation and differentiation during menstrual cycle, especially the establishment of receptive status in implantation.

Formation of Nucleolar Channel System in Human Endometrium in vitro is Independent of Progesterone

Objective To determine whether formation of the nucleolar channel system (NCS) in human endometrium depends on the presence of progesteronal steroids. Materials & Methods Tissues of late proliferative endometrium were obtained from 5 normally cycling women of reproductive age. Half of each tissue was cultured in the DMEM medium containing diethylstilbesterol (25 μg/mL) plus medroxyprogesterone acetate (25 μg/mL) (E + P culture). As a control, the other half was cultured in the medium alone. After 100 h incubation, the tissues were assessed for the formation of NCS with transmission electron microscope.Results NCS was observed in the endometrial epithelium treated with E + P or the medium alone. Moreover, giant mitochondria and glycogen accumulation were both seen in epithelia derived from both types of cultures.Conclusion Progesterone would be not indispensable for the formation of NCS in human endometrium. Transition of proliferative endometrium to the secretory stage in vitro could occur even in the absence of both estrogen and progesterone.

The expression of Hoxa10 and its regulation by sex steroids andHB-EGF at the time of implantation in the human endometrium

Objective:The aim of this study was to determine the expression of Hoxa 10 in endometrium during the menstrual cycle and their response to sex steroids and HB-EGF.Methods:Forty endometrial samples from regularly cycling women were studied.The endometrial epithelial(EEC)and stromal(ESC)cells isolated by collagenase Ⅰ digestion and mechanical dissociation was cultured from every sample.The endometrial stromal cells(ESC)were incubated with 17-beta estradiol(10-8mol/L),medroxyprogesterone acetate(MPA)(10-6mol/L),RU486(10-8mol/L)or HB-EGF(10ng/ml)for 48 hours respectively.The expression of Hoxa10 mRNA was demonstrated by reverse transcription-polymerase chain reaction(RT-PCR).Result:Hoxa10 showed a regulated cycle phase-dependent expression pattern in stromal cells and epithelial cells.Hoxa10 expression dramatically increased during the midsecretory phase of the menstrual cycle,at the time of implantation.The expression of Hoxa10 in cultured endometrial stromal cells was stimulated by estrogen,progesterone and HB-EGF.Conclusion:The cycle phase-specific expression of Hoxa10 and up-regulated by sex steroids and HB-EGF suggests a tight regulation and establishing conditions necessary for implantation.

DNA Microarray Analysis of Gene Expression in Eutopic Endometrium from Patients with Endometriosis

Pathogenesis of the endometriosis is complex and the etiology is still unclear. The objective of this study was to examine that endometrial gene expression in late secretory phase endometrium differs between patients with and without endometriosis. Five patients with proven advanced-stage endometriosis and 5 controls underwent endometrial biopsy in the late secretory phase. Analysis of eutopic endometrial gene expression was performed using Affymetrix gene arrays and differentially expressed genes were assigned to gene ontology groups based on overrepresented analysis using Database for Annotation, Visualization, and Integrated Discovery software. Four hundred sixty two genes were identified as up-regulated such as matrix metalloproteinase 10, cytochrome P450 family 24 subfamily A polypeptide 1, matrix metalloproteinase 3, chemokine (C-C motif) ligand 20, Rho family GTPase 1, interleukin 1-beta, and insulin-like growth factor binding protein 1. Six hundred forty three genes were down-regulated in all endometriotic samples. A lot of genes related with metabolic process, cellular ketone metabolic process and ncRNA metabolic processing were included. Expression patterns of selected five genes were validated by quantitative real time PCR. The results of this analysis support that the eutopic endometrium from patients with advanced-stage endometriosis has distinct gene expression profile from eutopic endometrium of control without endometriosis.

TNF system in eutopic endometrium from women with endometriosis

The role of the tumor necrosis factor (TNF) system in endometriosis is not completely clear and therefore was the focus of this study. In eutopic endometria obtained from women with (n = 41) and without (controls;n = 34) endometriosis during laparoscopy, the subcellular location and the percentages for TNF, TNFR1, TNFR2 and CD45 positive-cells were determined (immunohistochemistry);the protein concentration (ELISA) of the soluble receptors (sTNFR1 and sTNFR2) were measured in 4h-explants culture media and the TNF concentration was performed in ex vivo endometrial homogenates. The TNF, TNFR1 and TNFR2 mRNAs were analyzed by real-time PCR. In control endometria, TNF, TNFR1 and sTNFR1 proteins increased during the late secretory phase. In endometriosis endometria, the protein highest level of TNFR1 was reached during the early and the mid secretory phases and of sTNFR1 concentration during the proliferative phase;however, during the late secretory phase, both TNFR1 and sTNFR1 protein levels were reduced compared to the control endometria (p sTNFR2 concentrations, and TNF and TNFR2 mRNAs were similar in control and endometriosis endometria. Although TNFR1 mRNA was highly expressed, no significant differences were found between control and endometriosis endometria. In summary, this study establishes that TNF and TNFR1 protein expressions and the sTNFR concentrations in eutopic endometria from women with and without endometriosis are dependent on the menstrual cycle. The differences on the TNFR1 and sTNFR1 protein pattern between both groups, mainly during the mid and late secretory phases may play a role in the lower implantation rates observed in women with endometriosis, and also could be related to the altered cell death, which favor the augmented cell viability facilitating the characteristic endometrial implantation and growth outside the uterus in this disease.

New rat to mouse xenograft transplantation of endometrium as a model of human endometriosis

Background:Endometriosis can lead to infertility.Since there is no definitive treat-ment for endometriosis,animal modelling seems necessary to examine the possible treatments.Mouse endometrium cannot be separated for endometriosis induc-tion.In addition,transplantation of uterus into the abdominal viscera to induce endometriosis causes organ damage.In this study,we defined a new model of en-dometriosis leading to separability of endometrium and a safe anatomical region for transplantation.Methods:Forty female mice were allocated to 5 groups:1,sham;2,allograft uterus transplantation of mice to anterior abdominal wall of mice;3,allograft uterus trans-plantation of mice to mesentery of mice;4,xenograft endometrial transplantation of rat to anterior abdominal wall of mice;5,xenograft endometrial transplantation of rat to mesentery of mice.Adult female rats with a previous pregnancy experience were selected and placed in the vicinity of male rats for 2 weeks to induce estrogen secre-tion and increase endometrial thickness.Results:In the 4th group of animals,compared to sham,the peritoneal concentrations of VEGF-A,TNF-α,NO,MDA,and serum levels of CA-125 and IL-37 were increased and total body weight was decreased,while weight and size of endometrial lesions were increased significantly(P<.05).Genes expression of HOXA10 and HOXA11 were decreased significantly(P<.05)in groups 2 and 4 compared to sham.Conclusions:Xenograft transplantation of endometrium from rat to anterior abdomi-nal wall of mice can potentially mimic human endometriosis morphologically,histo-logically,and genetically.

Pathological pattern of endometrial abnormalities in postmenopausal women with bleeding or thickened endometrium

BACKGROUND Postmenopausal bleeding and an endometrial thickness≥5 mm on sonograms of menopausal women can indicate the presence of endometrial lesions.Diagnostic hysteroscopy is a powerful method for endometrial diseases.AIM To investigate the pathological pattern of endometrial abnormalities in postmenopausal women with bleeding or asymptomatic thickened endometrium diagnosed by hysteroscopy.METHODS A total of 187 postmenopausal women with bleeding or asymptomatic thickened endometrium underwent diagnostic hysteroscopy.The women were subsequently divided into three groups:Postmenopausal bleeding(PMB)group(n=84),asymptomatic group(n=94),and additional group(n=9).Women in the additional group manifested abdominal pain and leukorrhagia.RESULTS Among the 187 patients examined,84(44.9%)were diagnosed with PMB and 94(50.3%)with asymptomatic thickened endometrium.Endometrial polyp was the most common endometrial abnormality,which was detected in 51.2%,76.6%and 77.8%of the PMB,asymptomatic,and additional groups,respectively.In the PMB group,7(8.3%)women had hyperplasia with atypia and 14(16.7%)had endometrial adenocarcinoma.Fewer malignant lesions were detected in the asymptomatic group.Endometrial hyperplasia without atypia was found in 8.3%of the PMB group and 7.4%of the asymptomatic group.CONCLUSION Endometrial polyp was the most common pathology in the PMB group.Diagnostic hysteroscopy is recommended for women with PMB and asymptomatic thickened endometrium.

Transcription and Translation of Dickkopf-1 in Endometrium of Pregnant Mice during the Peri-implantation Period

Summary: To study the expression of Dickkopf-1 (DKK-1) in endometrium of pregnant mice during the peri-implantation period and the role of DKK-1 during the embryo implantation in mice. Immunohistochemical technique was employed to determine the location of DKK-1 protein in endometrium, and semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) was utilized to determine the levels of DKK-1 mRNA. Our results showed that the expressions of DKK1 mRNA and protein were higher in experimental groups than in control group (P<0.01), and it increased significantly on day 3 and reached its peak on day 4, and then decreased gradually on day 5-7. The levels of DKK-1 mRNA and protein on day 4 was significantly higher than those of other groups (P<0.01). It is concluded that DKK-1 probably plays an important role in signal transudation of embryo implantation and its high expression indicates the opening of implantation window.

Expression of TWEAK on the Ectopic and Eutopic Endometrium from Women with Endometriosis

Objective To investigate the relationship between Tumor necrosis factor （TNF）-like weak inducer of apoptosis（TWEAK） and endometriosis. Methods TWEAK mRNA and protein concentrations in paired samples of eutopic endometrial tissue from women with and without endometriosis, and also of ectopic endometrial tissue from women with endometriosis were measured by Real-time PCR, immunohistochemistry and Western blotting, respectively. Results Compared with control endometrium from women without endometriosis and eutopic endometrium from women with endometriosis, TWEAK expressions were reduced on the ectopic endometrium （P〈O.05）. Moreover, the expressions of TWEAK mRNA on eutopic endometrium and control endometrium in proliferative phase were much lower than those in secretory phase. TWEAK protein was expressed in the cytoplasm of glandular cells and stromal cells of endometrium. Conclusion TWEAK is expressed on the endometrium of reproductive women, and its concentration rises in secretory phase, compared with that in proliferative phase. Patients with endometriosis had a lower expression of TWEAK on ectopic endometrium, which may lead to a decreased level of apoptosis on endometrial cells. Consequently, endometrial cells were able to survive outside uterus helping the development of endometriosis.

Expression of vascular endothelial growth factor and its two receptors in normal human endometrium

Objectives: We try to demonstrate the expression of vascular endothelial growthfactor (VEGF) and its receptors, flt-1 and KDR, in normal human emdometrium duringthe menstrual cycle.Methods: Immunohistochemical method was used to observe the expression ofVEGF and its two receptors in emdometrium throughout the normal menstrual cyclemeanwhile the isoforms of VEGF were also detected by Western blot analysis. The en-dothelial cells of micro-vessels were marked with Ⅷ factor antibody.Results: VEGF and its receptors existed in endometrial glandular, stromal and vas-cular endothelial cells of human endometrium. Their expressions were higher in the mid-secretory phase of menstrual cycle and highest at menstruation. VEGF121 and VEGF165were the predominant isoforms in normal human endometrium.Conclusion: The expression of VEGF and its two receptors showed cycle-dependentin human endometrium, probably involved in embryonic implantation and endometrialproliferation and differentiation.