What is the best method of detecting endometrial cancer in outpatients?‐endometrial sampling,suction curettage,endometrial cytology

Objective:  Office methods of endometrial sampling for outpatients with abnormal uterine bleeding should be minimally invasive. The purpose of this study was to determine the best method for detecting endometrial cancer in an outpatients setting.
Methods:  In all, 114 symptomatic women who were suspected of having endometrial disease by their local gynaecologist were enrolled in this study. After pelvic examination and transvaginal ultrasonography, endometrial cytology, suction endometrial curettage, and four-site endometrial biopsy were performed, in this order without anaesthesia in each patient. After endometrial sampling, the patient was asked to comment on the intensity of any pain experienced during each procedure. Then the final histological diagnosis made from the surgical materials was compared with the results of the three pre-operative methods.
Results:  Among the 114 consecutive patients, 56 had endometrial carcinoma, three had carcinosarcoma, six had endometrial hyperplasia, and 49 had benign conditions. The sensitivity of detecting malignancy was 88% (52/59) with endometrial cytology, 92% (54/59) with suction curettage, and 88% (52/59) with four-site biopsy. When endometrial cytology was combined with suction curettage, the sensitivity of detecting malignancy was increased from 92% to 98%, whereas the sensitivity was increased from 88% to 97%, when endometrial cytology was added to four-site biopsy. Suction curettage was significantly less painful than four-site biopsy.
Conclusion:  Our data indicated that suction curettage plus endometrial cytology was the best combination for pathological examination of outpatients with abnormal uterine bleeding.     

Trophinin-mediated cell adhesion induces apoptosis of human endometrial epithelial cells through PKC-δ

Trophinin is an intrinsic membrane protein expressed in trophectoderm cells of embryos and in uterine epithelial cells. Trophinin potentially mediates apical cell adhesion at human embryo implantation sites through trophinin-trophinin binding in these two cell types. Trophinin-mediated cell adhesion activates trophectoderm cells for invasion, whereas the effect of adhesion on maternal side is not known. We show that addition of GWRQ peptide, a previously established peptide that mimics trophinin-mediated cell adhesion, to human endometrial epithelial cells expressing trophinin induces their apoptosis. FAS involvement was excluded, as GWRQ did not bind to FAS, and FAS knockdown did not alter GWRQ-induced apoptosis. Immunoblotting analyses of protein kinases revealed an elevation of PKC-δ protein in GWRQ-bound endometrial epithelial cells. In the absence of GWRQ, PKC-δ associated with trophinin and remained cytoplasmic, but after GWRQ binding to the trophinin extracellular domain, PKC-δ became tyrosine phosphorylated, dissociated from trophinin and entered the nucleus. In PKC-δ knockdown endometrial cells, GWRQ did not induce apoptosis. These results suggest that trophinin-mediated cell adhesion functions as a molecular switch to induce apoptosis through the PKC-δ pathway in endometrial epithelial cells. Thus, trophinin-mediated induction of apoptosis of endometrial epithelial cells, which function as a barrier to embryo invasion, allows trophoblast invasion of maternal tissue and embryo implantation in humans.Key words: blastocyst, embryo implantation, apoptosis, cell adhesion, signal transduction     

Hypoxia-induced Factor-1α in endometrial carcinoma: a mini-review of current evidence

Despite the well-established role of hypoxia in cancer biology, the literature on its effects on endometrial cancer is scarce; it mainly refers to experimental settings rather than patient-derived results. Herein, an overview of the hypoxia inducible factor 1α (HIF-1α) biology, focusing on endometrial cancer, is presented. The molecular mechanisms possibly involved in endometrial cancer progression are presented, followed by a systematic approach to the current literature on immunohistochemistry evaluation of HIF-1α expression in endometrial carcinoma. Since no consensus has been made regarding HIF-1α evaluation, the evidence of possible involvement of HIF-1α in endometrial carcinoma prognosis is weak. After a consensus has been made, properly powered studies may be able to clarify whether HIF-1α can act as a prognosticator in endometrial carcinoma.     

Which bovine endometrial cells are the source of and target for lysophosphatidic acid?

The objective of the study was to examine which cultured endometrial cells are the source and which are the target for lysophosphatidic acid (LPA) in the bovine uterus. LPA concentration as well as mRNA and protein expressions of the enzymes responsible for LPA synthesis (phospholipase A2: PLA₂, autotaxin: AX) were greater in epithelial than in stromal cells (P < 0.05). In turn, mRNA and protein expression of LPA receptor (LPAR1) was lower in epithelial than in stromal cells (P < 0.05). We suggest that LPA in bovine endometrium is produced mainly by epithelial cells and affects mostly stromal cells acting via LPAR1.     

Do mares possess an intracellular endometrial inhibitor of prostaglandin synthesis during early pregnancy?

Cytosol was prepared from endometrium collected from pregnant or nonpregnant mares 14 d after ovulation and was added to a prostaglandin-generating system (bovine fetal cotyledonary microsomes). Addition of endometrial cytosol from pregnant mares suppressed microsomal synthesis of prostaglandin F, but addition of endometrial cytosol from nonpregnant mares increased microsomal synthesis of prostaglandin F. The results suggest that mares possess an intracellular inhibitor of prostaglandin F synthesis during early pregnancy.     

Cystic endometrial hyperplasia-pyometra complex in the bitch: should the two entities be disconnected?

The uteri of 26 clinically healthy bitches and 42 bitches with a clinical suspicion of pyometra were examined histologically using a computerized image analysis system. Histologic lesions were characterised mainly by thickening or atrophy of the endometrium and by varying degrees of cystic changes of the glands. These lesions were observed in most of the clinically healthy bitches as well as in all of the clinically ill animals. In most of the ill bitches a variable degree of inflammation also was found. Some bitches with clinical signs indicative for pyometra had no inflammatory reaction in the uterus. These bitches were misdiagnosed as suffering from pyometra, confirming the difficulty of diagnosing pyometra by simple clinical examination. Determination of sex hormone serum levels revealed that all dogs in both groups were either in metestrus or in anestrus. Based on the results of this study the cystic endometrial hyperplasia-pyometra complex can be divided in two entities: a cystic endometrial hyperplasia-mucometra complex and an endometritis-pyometra complex. Both entities bear many similarities with each other, except for the inflammatory reaction in the endometritis-pyometra complex. It is concluded from this study that the latter complex probably does not necessarily follow the former, but that both can arise de novo.     

Clustered integrin α5β1 ligand displays model fibronectin-mediated adhesion of human endometrial stromal cells

Progress towards endometrial tissue engineering for modelling endometrial diseases and infertility is frustrated by the inability to mimic the fibronectin (FN) extracellular matrix required by human endometrial stromal cells (EnSCs). Here we show that this is because of the requirement to present integrin α5β1 (the FN receptor) ligands in specifically oriented, polyvalent displays; by engineering controlled self-assembly of the 9th–10th type III FN domain pair (FIII9–10, the minimal integrin α5β1 ligand) immobilised in a specific orientation to cell culture surfaces. The fraction of adherent EnSCs seen to spread increased significantly for the multimeric ligand surfaces in the order: tetramer > trimer > dimer > monomer. The extent of EnSC spread morphology also increased in the same order, with the tetrameric ligand supporting a morphology most similar to that supported by FN. Our data suggest that only higher-order multimers of FIII9–10 will fully promote cell spreading mediated through integrin α5β1 binding.     

The PGC-1α-dependent pathway of mitochondrial biogenesis is upregulated in type I endometrial cancer

PGC-1α-dependent pathway of mitochondrial biogenesis was investigated for the first time in type I endometrial cancer and in normal endometrium. In cancer endometrial tissue the citrate synthase activity, the mitochondrial DNA content and the TFAM level were found doubled compared to control endometrial tissue. Moreover, a 1.6- and 1.8-fold increase, respectively, of NRF-1 and PGG-1α expression was found. This study demonstrates, for the first time, that the increased mitochondrial biogenesis in type I endometrial cancer is associated to the upregulation of PGC-1α signalling pathway.     

The membrane-bound 17β-estradiol dehydrogenase of porcine endometrial cells: purification, characterization and subcellular localization

The membrane-bound 17β-estradiol dehydrogenase of porcine endometrial cells was purified to homogeneity as judged by SDS-PAGE and silver staining of a single 32 kD band. A second, more hydrophobic product of the purification protocol contained additional bands at 45 and 80 kD. The 17β-estradiol dehydrogenase activities of both products exceeded those for 17-one reduction by more than 260-fold. Activities of 3-, 3β- and 20-dehydrogenases were absent in either fraction. Polyclonal and monoclonal antibodies raised against the 32 kD protein and the more hydrophobic product precipitated the enzymatic activity and reacted with the 32 and 80 kD bands, but not with the 45 kD band in Western blots. The subcellular localization of the enzyme was studied in sections of intact cells and of isolated organelles using gold sol coated with F(ab′)₂ fragments of monoclonal antibody F1. Gold particles were found exclusively over cytoplasmic vesicles of 120–150 nm diameter with electron-dense contents.     

Interleukin 6 promotes endometrial cancer growth through an autocrine feedback loop involving ERK–NF-κB signaling pathway

Interleukin (IL)-6 as an inflammation factor, has been proved to promote cancer proliferation in several human cancers. However, its role in endometrial cancer has not been studied clearly. Previously, we demonstrated that IL-6 promoted endometrial cancer progression through local estrogen biosynthesis. In this study, we proved that IL-6 could directly stimulate endometrial cancer cells proliferation and an autocrine feedback loop increased its production even after the withdrawal of IL-6 from the medium. Next, we analyzed the mechanism underlying IL-6 production in the feedback loop and found that its production and IL-6-stimulated cell proliferation were effectively blocked by pharmacologic inhibitors of nuclear factor-kappa B (NF-κB) and extra-cellular signal-regulated kinase (ERK). Importantly, activation of ERK was upstream of the NF-κB pathways, revealing the hierarchy of this event. Finally, we used an orthotopic nude endometrial carcinoma model to confirm the effects of IL-6 on the tumor progression. Taken together, these data indicate that IL-6 promotes endometrial carcinoma growth through an expanded autocrine regulatory loop and implicate the ERK–NF-κB pathway as a critical mediator of IL-6 production, implying IL-6 to be an important therapeutic target in endometrial carcinoma.     

Curcumin attenuates proangiogenic and proinflammatory factors in human eutopic endometrial stromal cells through the NF-κB signaling pathway

Endometriosis is a chronic gynecological inflammatory disorder in which immune system dysregulation is thought to play a role in its initiation and progression. Due to altered sex steroid receptor concentrations and other signaling defects, eutopic endometriotic tissues have an attenuated response to progesterone. This progesterone-resistance contributes to lesion survival, proliferation, pain, and infertility. The current agency-approved hormonal therapies, including synthetic progestins, GnRH agonists, and danazol are often of limited efficacy and counterproductive to fertility and cause systemic side effects due to suppression of endogenous steroid hormone levels. In the current study, we examined the effects of curcumin (CUR, diferuloylmethane), which has long been used as an anti-inflammatory folk medicine in Asian countries for this condition. The basal levels of proinflammatory and proangiogenic chemokines and cytokines expression were higher in primary cultures of stromal cells derived from eutopic endometrium of endometriosis (EESC) subjects compared with normal endometrial stromal cells (NESC). The treatment of EESC and NESC with CUR significantly and dose-dependently reduced chemokine and cytokine secretion over the time course. Notably, CUR treatment significantly decreased phosphorylation of the IKKα/β, NF-κB, STAT3, and JNK signaling pathways under these experimental conditions. Taken together, our findings suggest that CUR has therapeutic potential to abrogate aberrant activation of chemokines and cytokines, and IKKα/β, NF-κB, STAT3, and JNK signaling pathways to reduce inflammation associated with endometriosis.     

Equine endometrial biopsy: enhancement of clinical value by more extensive histopathology and application of new diagnostic techniques?

During the 1960s and 1970s, the clinical value of equine endometrial histopathology was firmly established after it was shown that fertility outcome was correlated with the presence and severity of specific microscopic lesions. The objective of this paper is to summarize reports from the veterinary literature published after the mid 1980s that describe new diagnostic methods of assessing equine uterine health using material collected by endometrial biopsy.     

Intrauterine infusion of ovine conceptus secretory proteins reduces prostaglandin F2α release without affecting endometrial oxytocin receptor concentrations

Chronically ovariectomized ewes were pretreated with progesterone and oestradiol to induce oestrus and randomly allocated into four treatment groups. Progesterone injections were given to Groups 1 and 2 on Days 1–12 and Groups 3 and 4 on Days 1–15. Ewes in Groups 2 and 4 were infused with conceptus secretory proteins (oCSP), via an intrauterine catheter, twice daily on Days 13–15. Ewes in Groups 1 and 3 were similarly infused, but with serum proteins (oSP). Endometrial oxytocin receptor (OTr) concentrations and oxytocin-induced 13,14-dihydro-15-keto-prostaglandin F_2α (PGFM) release were measured on Day 16.Progesterone concentrations in ewes receiving 12 days of progesterone treatment declined after Day 12, reaching a nadir on Day 14. In contrast, plasma progesterone concentrations remained elevated until Day 16 in ewes receiving the extended progesterone treatment. On Day 16, endometrial OTr concentrations were significantly higher in ewes given 12 days of progesterone treatment than in ewes given 15 days of progesterone irrespective of the presence of oCSP or oSP. Treatment with oCSP significantly decreased oxytocin-induced PGFM release in ewes given 12 days of progesterone treatment compared with those ewes receiving oSP infusions. The extended 15 day progesterone treatment resulted in a further decrease in oxytocin-induced PGFM release in both oCSP and oSP infused ewes.These data indicate that, in steroid treated ovariectomized ewes, intrauterine infusion of oCSP will reduce oxytocin-induced PGFM response but not OTr concentrations. Progesterone appears to play a dominant role in the regulation of OTr as well as oxytocin-induced PGFM release.