Bridging the Diagnostic Gap between Histopathologic and Hysteroscopic Chronic Endometritis with Deep Learning Models.

Chronic endometritis (CE) is an inflammatory pathologic condition of the uterine mucosa characterized by unusual infiltration of CD138(+) endometrial stromal plasmacytes (ESPCs). CE is often identified in infertile women with unexplained etiology, tubal factors, endometriosis, repeated implantation failure, and recurrent pregnancy loss. Diagnosis of CE has traditionally relied on endometrial biopsy and histopathologic/immunohistochemistrical detection of ESPCs. Endometrial biopsy, however, is a somewhat painful procedure for the subjects and does not allow us to grasp the whole picture of this mucosal tissue. Meanwhile, fluid hysteroscopy has been recently adopted as a less-invasive diagnostic modality for CE. We launched the ARCHIPELAGO (ARChival Hysteroscopic Image-based Prediction for histopathologic chronic Endometritis in infertile women using deep LeArninG mOdel) study to construct the hysteroscopic CE finding-based prediction tools for histopathologic CE. The development of these deep learning-based novel models and computer-aided detection/diagnosis systems potentially benefits infertile women suffering from this elusive disease.

Construction of deep learning-based convolutional neural network model for automatic detection of fluid hysteroscopic endometrial micropolyps in infertile women with chronic endometritis.

OBJECTIVE(S): Chronic endometritis (CE) is a localized mucosal inflammatory disorder associated with female infertility of unknown etiology, endometriosis, tubal factors, repeated implantation failure, and recurrent pregnancy loss, along with atypical uterine bleeding and iron deficiency anemia. Diagnosis of CE has traditionally relied on endometrial biopsy and detection of CD138(+) endometrial stromal plasmacytes. To develop a less invasive diagnostic system for CE, we aimed to construct a deep learning-based convolutional neural network (CNN) model for the automatic detection of endometrial micropolyps (EMiP), a fluid hysteroscopy (F-HSC) finding recognized as tiny protrusive lesions that are closely related to this disease. STUDY DESIGN: This is an in silico study using archival images of F-HSC performed at an infertility center in a private clinic. A total of 244 infertile women undergoing F-HSC on the days 6-12 of the menstrual cycle between April 2019 and December 2021 with histopathologically-confirmed CE with the aid of immunohistochemistry for CD138 were utilized. RESULTS: The archival F-HSC images of 208 women (78 with EMiP and 130 without EMiP) who met the inclusion criteria were finally subjected to analysis. Following preprocessing of the images, half a set was input into a CNN architecture for training, whereas the remaining images were utilized as the test set to evaluate the performance of the model, which was compared with that of the experienced gynecologists. The sensitivity, specificity, accuracy, precision, and F1-score of the CNN model-aided diagnosis were 93.6 %, 92.3 %, 92.8 %, 88.0 %, and 0.907, respectively. The area under the receiver operating characteristic curves of the CNN model-aided diagnosis (0.930) was at a similar level (p > .05) to the value of conventional diagnosis by three experienced gynecologists (0.927, 0.948, and 0.906). CONCLUSION: These findings indicate that our deep learning-based CNN is capable of recognizing EMiP in F-HSC images and holds promise for further development of the computer-aided diagnostic system for CE.

Precision Medicine for Chronic Endometritis: Computer-Aided Diagnosis Using Deep Learning Model.

Chronic endometritis (CE) is a localized mucosal infectious and inflammatory disorder marked by infiltration of CD138(+) endometrial stromal plasmacytes (ESPC). CE is drawing interest in the field of reproductive medicine because of its association with female infertility of unknown etiology, endometriosis, repeated implantation failure, recurrent pregnancy loss, and multiple maternal/newborn complications. The diagnosis of CE has long relied on somewhat painful endometrial biopsy and histopathologic examinations combined with immunohistochemistry for CD138 (IHC-CD138). With IHC-CD138 only, CE may be potentially over-diagnosed by misidentification of endometrial epithelial cells, which constitutively express CD138, as ESPCs. Fluid hysteroscopy is emerging as an alternative, less-invasive diagnostic tool that can visualize the whole uterine cavity in real-time and enables the detection of several unique mucosal findings associated with CE. The biases in the hysteroscopic diagnosis of CE; however, are the inter-observer and intra-observer disagreements on the interpretation of the endoscopic findings. Additionally, due to the variances in the study designs and adopted diagnostic criteria, there exists some dissociation in the histopathologic and hysteroscopic diagnosis of CE among researchers. To address these questions, novel dual immunohistochemistry for CD138 and another plasmacyte marker multiple myeloma oncogene 1 are currently being tested. Furthermore, computer-aided diagnosis using a deep learning model is being developed for more accurate detection of ESPCs. These approaches have the potential to contribute to the reduction in human errors and biases, the improvement of the diagnostic performance of CE, and the establishment of unified diagnostic criteria and standardized clinical guidelines for the disease.

Commonalities and Disparities between Endometriosis and Chronic Endometritis: Therapeutic Potential of Novel Antibiotic Treatment Strategy against Ectopic Endometrium.

Chronic endometritis (CE) is a local mucosal inflammatory disorder of the uterine lining, which is histopathologically recognized as the unusual infiltration of CD138(+) plasmacytes into the endometrial stromal compartment. Accumulating body of research documented that CE is associated with female infertility and several obstetric/neonatal complications. The major cause of CE is thought to be intrauterine infection represented by common bacteria (Escherichia coli, Enterococcus faecalis, Streptococcus, and Staphylococcus), Mycoplasma/Ureaplasma, and Mycobacterium. Additionally, local dysbiosis in the female reproductive tract may be involved in the onset and development of CE. Antibiotic treatments against these microorganisms are effective in the elimination of endometrial stromal plasmacytes in the affected patients. Meanwhile, endometriosis is a common female reproductive tract disease characterized by endometriotic tissues (ectopic endometrium) growing outside the uterus and potentially causes chronic pelvic symptoms (dysmenorrhea, dyspareunia, dyschezia, and dysuria), infertility, and ovarian cancers. Endometriosis involves endocrinological, genetic, and epigenetic factors in its etiology and pathogenesis. Recent studies focus on immunological, inflammatory, and infectious aspects of endometriosis and demonstrate several common characteristics between endometriosis and CE. This review aimed to better understand the immunological and microbial backgrounds underlying endometriosis and CE and look into the therapeutic potential of the novel antibiotic treatment strategy against endometriosis in light of endometrial infectious disease.

Challenges in Clinical Diagnosis and Management of Chronic Endometritis.

Chronic endometritis (CE) is a local mucosal infectious and inflammatory disorder characterized by unusual filtration of CD138(+) endometrial stromal plasmacytes. CE is attracting attention due to its potential association with infertility of unknown etiology, repeated implantation failure, recurrent pregnancy loss, and several maternal/neonatal complications. Due to the variance in study design among researchers, universal diagnostic criteria remain to be established for the clinical diagnosis and management of CE. This review article aims to summarize current knowledge and provide insights into unsolved questions on CE to establish clinical guidelines for the disease from the viewpoint of human reproduction.

Chronic Endometritis: Potential Cause of Infertility and Obstetric and Neonatal Complications.

Chronic endometritis (CE) is a local inflammatory disease characterized by unusual plasmacyte infiltration in the endometrial stromal areas. CE has been neglected in gynecologic practice, as it is a less symptomatic benign disease that requires demanding and time-consuming histopathologic examinations for the definite diagnosis. Recent studies, however, suggest the association of CE with infertility and obstetric and neonatal complications. In this review article, we aimed to update the knowledge on epidemiology, etiology, and pathogenesis of CE as well as discuss its clinical management from diagnosis to treatment.

Unusual inflammation in gynecologic pathology associated with defective endometrial receptivity.

Human cycling endometrium displays a series of periodic transitions unique to this mucosal tissue, which includes rapid proliferation, secretory transformation, physiological angiogenesis, interstitial edema, and menstrual shedding. Among these properties of the endometrium are the inflammatory changes that occur dynamically across the menstrual cycle. Immunocompetent cell composition and inflammatory gene expression pattern in the human endometrium drastically fluctuate from the proliferative phase to the secretory phase, particularly at the time of ovulation. These local immune responses are fine-tuned by the direct or indirect action of two representative ovarian steroids, estradiol and progesterone, and are essential for successful blastocyst implantation. Meanwhile, studies have been accumulating the evidence that such physiological endometrial inflammatory status is altered in the presence of certain gynecologic pathologies. Given that blastocysts are semi-allografts for maternal tissue, even subtle alterations in endometrial immunity potentially have a negative impact on implantation process. In this article, we aimed to review and discuss the physiological and pathological mucosal inflammatory conditions that can affect endometrial receptivity.

Regulatory role of membrane-bound form interleukin-15 on human uterine microvascular endothelial cells in circulating CD16(-) natural killer cell extravasation into human endometrium.

Interleukin (IL)-15 plays a major role in accumulation of unique CD16(-) natural killer (NK) cells in the human endometrium, partly via selective extravasation of peripheral blood (PB) counterparts from local microvascular circulation. While IL-15 exhibits a chemotactic activity for PB CD16(-) NK cells, IL-15 attenuates their binding capacity to dermatan sulfate, the major CD62L ligand expressed on human uterine microvascular endothelial cells (HUtMVECs). These findings suggest that premature action of IL-15 interferes with CD62L-dependent tethering/rolling of PB CD16(-) NK cells on HUtMVECs, which is an early critical process of leukocyte extravasation. In this study, we investigated the mechanisms underlying the IL-15 regulation in the initial CD62L-dependent contact between PB CD16(-) NK cells and HUtMVECs. Unlike other candidate molecules, recombinant IL-15 downregulated CD62L expression on freshly isolated PB CD16(-) NK cells. IL-12 and IL-10, the two known upregulators of CD62L on CD16(-) NK cells, were not detectable in HUtMVECs and endometrial perivascular stromal cells. Binding to immobilized dermatan sulfate increased surface IL-15 receptor-alpha chain expression on CD16(-) NK cells. Under ovarian steroid stimulation, IL-15 was detectable on the surface, but not in the supernatant, of cultured HUtMVECs. Ovarian steroid-induced IL-15 expression on HUtMVECs was not attenuated by chondroitinase ABC (which degrades chondroitin sulfate-A and -C and dermatan sulfate) or sodium acetate buffer (which dissociates cytokines from their cognate receptors). These results suggest that HUtMVECs secrete a less soluble form of IL-15 into local microcirculation. Instead, HUtMVECs bear a membrane-bound form IL-15 under the influence of ovarian steroids, which may be favorable for preventing downregulation of CD62L on PB CD16(-) NK cells and facilitating their initial contact with HUtMVECs.

Inter-observer and intra-observer variability in immunohistochemical detection of endometrial stromal plasmacytes in chronic endometritis.

Chronic endometritis (CE) is an unusual endometrial inflammation characterized by stromal plasmacyte infiltration. CE is easily missed due to its subtle symptoms and demanding histopathological examinations. Although the immunohistochemistry for the plasmacyte marker CD138 has facilitated the detection of endometrial stromal plasmacytes, the accuracy and biases of this method for CE diagnosis remain poorly understood. The aim of this study was to investigate the inter- and intra-observer variability in the immunohistochemical detection of stromal plasmacytes in the human endometrium. A total of 80 CE and 20 non-pathological archival hematoxylin-stained endometrial preparations with or without immunostaining for CD138 were evaluated independently by two experienced observers and two inexperienced observers. Endometrial stromal plasmacytes in unit areas were counted in the hematoxylin-stained and CD138-immunostained preparations. Each preparation was subdivided into 11 categories by every five plasmacyte counts. The second evaluation was performed four weeks after the first evaluation. The immunohistochemical detection method was superior to conventional histopathological evaluation in both the inter- and intra-observer agreement, irrespective of the experience level of the observers. The linear weighted κ coefficient for intra-observer agreement was higher in the experienced observers than in the inexperienced observers. The inter-observer agreement among the four observers by the immunohistochemical detection method was similarly good between the first and second evaluation. There was no significant inter- or intra-observer variability in the paired comparison of the individual samples. These findings validate the use of immunohistochemistry for CD138 as an accurate and less biased diagnostic tool for CE.

Premature delivery due to intrauterine Candida infection that caused neonatal congenital cutaneous candidiasis: a case report.

Congenital cutaneous candidiasis is a very rare disease with less than 100 cases published in the medical literature. Neonates having this disease present with systemic skin lesions caused by intrauterine Candida infections. We present a case of threatened premature delivery due to Candida chorioamnionitis, which caused both maternal postpartum endometritis and neonatal congenital cutaneous candidiasis. A 34-year-old woman who was admitted for fetal membrane bulging at 20 weeks of gestation underwent McDonald cervical cerclage. We diagnosed threatened premature delivery due to intrauterine infection; therefore, we terminated the gestation by cesarean section at 24 weeks of gestation. Fungi-like yeast was detected in infantile gastric juice. Histopathological findings of the placenta revealed that Candida albicans mycelium invaded the placenta, chorioamniotic membrane and umbilical cord.

Diverse functions of uterine proteoglycans in human reproduction (review).

Proteoglycans (PGs) are a group of heavily glycosylated proteins that are present throughout the mammalian body and are involved in a wide variety of biological phenomena, including structural maintenance, tissue remodeling, molecular presentation, cell adhesion and signal transmission. Previous studies have revealed an increasing number of roles for PGs in human reproduction. Several PGs are currently utilized or regarded as biomarkers for the diagnosis of certain pathological uterine conditions associated with infertility and obstetrical complications. The aim of this review was to discuss the involvement of PGs in the human uterus in reproductive biology and pathophysiology.

Immunohistochemistrical and clinicopathological characterization of chronic endometritis.

PROBLEM: Chronic endometritis is an elusive entity that is often asymptomatic and undetectable by conventional endometrial biopsy and histological examination. Using immunohistochemistry for full-thickness endometrium, we sought for its clinicopathological features. METHOD OF STUDY: Two hundred and thirty-four archival endometrial specimens obtained by hysterectomy were immunostained for the plasmacyte marker syndecan-1 to identify chronic endometritis. Endometrial morphology was dated by the standard criteria. The immunoreactive cells were enumerated in 10 non-overlapping endometrial stromal areas. The clinical parameters were obtained from the medical charts. RESULTS: Chronic endometritis was identified in 11.1% of the samples examined. Its occurrence was similar between the proliferative phase and secretory phase. A total of 23.1% of the cases were asymptomatic. Stromal plasmacyte infiltration and morphological delay were more prominent in symptomatic chronic endometritis than in asymptomatic counterpart. CONCLUSIONS: Chronic endometritis is a common gynecological pathological condition and more often asymptomatic than ever expected. There was no menstrual cycle-dependent fluctuation in its occurrence.

Progesterone induction of chondroitin sulfate proteoglycan aggrecan expression in human endometrial epithelial cells.

Chondroitin sulfate (CS) is the most abundant glycosaminoglycan species in the human endometrium, but the expression profile of CS proteoglycans (PGs) in this mucosal tissue remains fully undetermined. In this study, we aimed to clarify the expression of CSPGs including aggrecan, neurocan, melanoma-associated CSPG, neuroglycan C, and brevican in the human cycling endometrium. By reverse transcription-polymerase chain reaction, the gene transcripts for aggrecan core protein were detected in all samples examined, while other CSPGs were not. Western blotting showed the immunoreactivity for aggrecan core protein at approximately 370 kDa size after enzymatic digestion of CS-A and CS-C side chains. The expression level of aggrecan core protein was significantly higher in the secretory phase than in the proliferative phase. The immunostaining for aggrecan was detected in the endometrial microvascular endothelium throughout the menstrual cycle. The immunostaining in the glandular epithelium was faint during the proliferative and early secretory phase, but distinct during the mid-to-late-secretory phase. Progesterone, but not 17ß-estradiol, induced aggrecan core protein expression in cultured endometrial epithelial cells. The endometrial expression pattern of aggrecan was distinct from that of other known CSPGs, suggesting the unique role of this proteoglycan at the implantation site.

Aberrant expression of selectin E, CXCL1, and CXCL13 in chronic endometritis.

Chronic endometritis is often identified in the patients with unexplained infertility, and is histopathologically characterized by infiltration of plasmacytes within the endometrial stroma. In parallel with stromal plasmacyte infiltration, the endometrial functional layer in chronic endometritis is invaded by B cells, which are a rare leukocyte subset residing within the basal layer in the nonpathological endometrium. In this study, we investigated the molecular expression underlying this unusual increase of B cells in chronic endometritis. Twenty-two out of 76 infertile patients were diagnosed with chronic endometritis from the stromal plasmacyte infiltration, and the endometrium contained numerous stromal B-cell aggregates and glandular single B cells. However, the other major leukocyte subsets, including T cells, natural killer cells, macrophages, and neutrophils were comparable in densities in chronic endometritis and nonpathological endometrium. The microvascular endothelium showed immunoreactivity to adhesion molecule selectin E and chemokine CXCL13 along with immunoreactivity to CXCL1 in the glandular epithelium in chronic endometritis, but not in the nonpathological endometrium. Lipopolysaccharide significantly induced surface selectin E expression and CXCL13 secretion in uterine microvascular endothelial cells, and CXCL1 secretion in endometrial epithelial cells in vitro. These findings indicated that the aberrant local microenvironment triggered possibly by bacterial infection has a role in selective extravasation of circulating B cells in chronic endometritis.

Leukocyte density and composition in human cycling endometrium with uterine fibroids.

In this study, we evaluated the leukocyte density and composition in the human cycling endometrium with uterine fibroids (UF). The endometrium with neighboring nodule (NN group, n = 62), autologous endometrium without NN (non-NN group, n = 62), and allogeneic endometrium without UF (non-UF group, n = 24) were immunostained for the leukocyte common and subset-specific antigens. The immunoreactive cells in the unit areas were enumerated under a light microscope. The stromal pan-leukocyte density in the proliferative phase was significantly higher in the endometrium in the NN group than in the non-NN group. The macrophage density was higher in the NN group than in the non-NN group throughout the menstrual cycle. The NK cell density in the mid-to-late secretory phase was lower in the NN group than in the non-NN group. The T cell density in the midsecretory phase was higher in the non-NN group than in the non-UF group. The neutrophil density in the proliferative phase was higher in the non-NN group than in the non-UF group. The leukocyte density and composition in the endometrium with UF are different from those without UF, suggesting their local effects on endometrial leukocyte population.

Effect of ovarian steroids on gene expression profile in human uterine microvascular endothelial cells.

OBJECTIVE: To examine the effect of the ovarian steroids on the gene expression profile in human uterine microvascular endothelial cells. DESIGN: An experimental study. SETTING: University hospital and research laboratory. PATIENT(S): Eighteen premenopausal women with proven fertility undergoing hysterectomy for cervical carcinoma in situ or cervical dysplasia. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The effect of E(2) and P on gene expression profile in pooled human uterine microvascular endothelial cells was examined with cDNA microarray analysis and confirmed with quantitative real-time reverse transcriptase polymerase chain reaction. In vivo endometrial endothelial expression of the proteins encoded by the genes significantly regulated by E(2) and/or P was examined with Western blotting analysis and immunohistochemistry. RESULT(S): The genes steadily up-regulated by E(2) and/or P included angiogenic factors, water transporters, immunomodulators, binding proteins, electron transporters, amino acid transporter, signal transduction proteins, and blood pressure regulation factors. The proteins encoded by IL1RL1, WAS, and NPPA were detected in endometrial microvascular endothelial cells. CONCLUSION(S): Progesterone (alone or in combination with E(2)) can induce the genes involved in angiogenesis, edematous change, and leukocyte recruitment in human uterine microvascular endothelial cells. Ovarian steroids may contribute to endometrial differentiation via the action on local microvessels.

Dermatan sulfate proteoglycan biglycan as a potential selectin L/CD44 ligand involved in selective recruitment of peripheral blood CD16(-) natural killer cells into human endometrium.

Unique CD16(-) NK cells acutely increase in the human uterine endometrium after ovulation. The origin of these NK cells remains unknown, but they may be recruited selectively from the circulation. Proteoglycans and their glycosaminoglycan side-chains expressed on endometrial microvascular endothelial cells play a key role in lymphocyte tethering/rolling, the initial step of lymphocyte extravasation. In this study, we sought for the potential proteoglycans involved in tethering/rolling of peripheral blood CD16(-) NK cells on endometrial microvascular endothelial cells. As compared with CD16(+) NK cells and non-NK cells, enriched peripheral blood CD16(-) NK cells bound preferably to immobilized glycosaminoglycans except for keratan sulfate. CD16(-) NK cells bound maximally to dermatan sulfate (DS), which was diminished by enzymatic pretreatment with dermatanase and chondroitinase ABC, but not with chondroitinase ACII. The binding capacity of CD16(-) NK cells to DS was attenuated by blocking antibodies against selectin L and CD44 or pretreatment of CD16(-) NK cells with IL-15. Of three known DS proteoglycans, biglycan and decorin but not epiphycan were expressed in the human cycling endometrium. In the endometrial microvessels, the immunoreactivity for biglycan was greater in the secretory phase than in the proliferative phase, and there was little, if any, immunoreactivity for decorin throughout the menstrual cycle. The ovarian steroid progesterone enhanced biglycan expression in cultured human uterine microvascular endothelial cells. These findings demonstrated that DS proteoglycan biglycan is a potential selectin L/CD44 ligand involved in tethering/rolling of peripheral blood CD16(-) NK cells on endometrial microvascular endothelial cells.

Possible role of hematopoietic CD44/chondroitin sulfate interaction in extravasation of peripheral blood CD16(-) natural killer cells into human endometrium.

Unique CD16(-) natural killer (NK) cells appear in the human cycling endometrium. Although their origin remains undetermined, one possible explanation is extravasation of circulating peripheral blood CD16(-) NK cells. Hematopoietic CD44 (CD44H) is an adhesion molecule expressed on leukocytes and plays a role in the initial step of leukocyte extravasation (leukocyte tethering/rolling). Recent studies have shown that CD44H binds to chondroitin sulfate (CS). To test the hypothesis that peripheral blood CD16(-) NK cells extravasate using the CD44H/CS interaction, we have compared the binding capacity of CD44H to immobilized CS among peripheral blood lymphocyte subsets, as well as determined the menstrual cycle-dependent expression of CD44H. Additionally, we have investigated the expression of the CS proteoglycan serglycin in human endometrial endothelial cells. CD44H expression on peripheral blood CD16(-) NK cells was higher compared with other lymphocyte subsets throughout the menstrual cycle. Peripheral blood CD16(-) NK cells bound preferentially to immobilized CS-A and CS-C compared with other lymphocyte subsets. The binding was significantly reduced by function-blocking anti-CD44H antibody. Serglycin expression in the human endometrial endothelial cells was greater in the secretory phase than in the proliferative phase. Progesterone (10(-7) M to 10(-8) M) significantly increased serglycin core protein expression in cultured human uterine microvascular endothelial cells, whereas 17beta-estradiol had no effect. These results indicate that the interaction between CD44H on peripheral blood CD16(-) NK cells and CS on endometrial endothelial cells may play a role in extravasation of these NK cells into human endometrium. Serglycin may be a potential CS proteoglycan involved in this phenomenon.

Genes regulated by interferon-gamma in human uterine microvascular endothelial cells.

Interferon (IFN)-gamma plays a critical role in murine uterine spiral artery remodeling for successful pregnancy. The effect of IFN-gamma on human uterine microvasculature, however, remains poorly understood. The aim of this study was to identify the genes regulated by IFN-gamma in human uterine microvascular endothelial cells. The effect of IFN-gamma on the gene expression profile in human uterine microvascular endothelial cells was evaluated by cDNA microarray analysis and quantitative real-time reverse transcriptase-polymerase chain reaction for the selected genes of interest. In vivo expression of the protein encoded by some of these genes in human uterine microvascular endothelial cells was evaluated by Western blotting and immunohistochemistry. Treatment with 10 ng/ml IFN-gamma for 4 h induced a significant > or =2-fold change in 29 genes in pooled human uterine microvascular endothelial cells; a total of 20 genes were up-regulated, whereas nine genes were down-regulated. The genes significantly up-regulated included chemokines (CXCL9, CXCL10, CCL8, IL15RA, and CCL5), enzymes (GBP5, TAP1, CYP27B1, SOD2, MX1, CASP1, and PTGES), and transcription factors (TFAP2C, IRF1, NFE2L3). The genes significantly down-regulated following IFN-gamma treatment included cytokines/cytokine receptors (CSF2, IL1R2, and SPP1), and insulin-like growth factor binding proteins (WISP2 and IGFBP3). The results of the cDNA microarray analysis were confirmed by quantitative real-time reverse transcriptase-polymerase chain reaction for the selected 17 genes of interest. The immunoreactivity for the proteins encoded by IL15RA, IFI30, and MX1 was detected in human uterine microvascular endothelial cells in vivo, whereas the immunoreactivity for CCNA1 and NQO1 was not detectable. These results suggest that IFN-gamma regulates the gene expression involved in natural killer cell recruitment, embryo and trophoblast migration, endometrial decidualization, angiogenesis, angiostasis, and anti-viral infection in human uterine microvascular endothelial cells.