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Sample records for endometrial progesterone resistance

  1. Progesterone Receptor Action in Leiomyoma and Endometrial Cancer

    PubMed Central

    Kim, J. Julie; Sefton, Elizabeth C.; Bulun, Serdar E.

    2013-01-01

    Progesterone is a key hormone in the regulation of uterine function. In the normal physiological context, progesterone is primarily involved in remodeling of the endometrium and maintaining a quiescent myometrium. When pathologies of the uterus develop, specifically, endometrial cancer and uterine leiomyoma, response to progesterone is usually altered. Progesterone acts through mainly two isoforms of the progesterone receptor (PR), PRA and PRB which have been reported to exhibit different transcriptional activities. Studies examining the expression and function of the PRs in the normal endometrium and myometrium as well as in endometrial cancer and uterine leiomyoma are summarized here. The clinical use of progestins and the transcriptional activity of the PR on genes specific to endometrial cancer and leiomyoma are described. An increased understanding of the differential expression of PRs and response to progesterone in these two diseases is critical in order to develop more efficient and targeted therapies. PMID:20374701

  2. Progesterone Action in Endometrial Cancer, Endometriosis, Uterine Fibroids, and Breast Cancer

    PubMed Central

    Kim, J. Julie; Kurita, Takeshi

    2013-01-01

    Progesterone receptor (PR) mediates the actions of the ovarian steroid progesterone, which together with estradiol regulates gonadotropin secretion, prepares the endometrium for implantation, maintains pregnancy, and differentiates breast tissue. Separation of estrogen and progesterone actions in hormone-responsive tissues remains a challenge. Pathologies of the uterus and breast, including endometrial cancer, endometriosis, uterine fibroids, and breast cancer, are highly associated with estrogen, considered to be the mitogenic factor. Emerging evidence supports distinct roles of progesterone and its influence on the pathogenesis of these diseases. Progesterone antagonizes estrogen-driven growth in the endometrium, and insufficient progesterone action strikingly increases the risk of endometrial cancer. In endometriosis, eutopic and ectopic tissues do not respond sufficiently to progesterone and are considered to be progesterone-resistant, which contributes to proliferation and survival. In uterine fibroids, progesterone promotes growth by increasing proliferation, cellular hypertrophy, and deposition of extracellular matrix. In normal mammary tissue and breast cancer, progesterone is pro-proliferative and carcinogenic. A key difference between these tissues that could explain the diverse effects of progesterone is the paracrine interactions of PR-expressing stroma and epithelium. Normal endometrium is a mucosa containing large quantities of distinct stromal cells with abundant PR, which influences epithelial cell proliferation and differentiation and protects against carcinogenic transformation. In contrast, the primary target cells of progesterone in the breast and fibroids are the mammary epithelial cells and the leiomyoma cells, which lack specifically organized stromal components with significant PR expression. This review provides a unifying perspective for the diverse effects of progesterone across human tissues and diseases. PMID:23303565

  3. Progesterone receptor gene variants and risk of endometrial cancer

    PubMed Central

    O'Mara, Tracy A.; Fahey, Paul; Ferguson, Kaltin; Marquart, Louise; Lambrechts, Diether; Despierre, Evelyn; Vergote, Ignace; Amant, Frederic; Hall, Per; Liu, Jianjun; Czene, Kamila; Rebbeck, Timothy R.; Ahmed, Shahana; Dunning, Alison M.; Gregory, Catherine S.; Shah, Mitul; Webb, Penelope M.; Spurdle, Amanda B.

    2011-01-01

    Prolonged excessive estrogen exposure unopposed by progesterone is widely accepted to be a risk factor for endometrial cancer development. The physiological function of progesterone is dependent upon the presence of its receptor [progesterone receptor (PGR)] and several studies have reported single nucleotide polymorphisms (SNPs) in the PGR gene to be associated with endometrial cancer risk. We sought to confirm the associations with endometrial cancer risk previously reported for four different PGR polymorphisms. A maximum of 2888 endometrial cancer cases and 4483 female control subjects from up to three studies were genotyped for four PGR polymorphisms (rs1042838, rs10895068, rs11224561 and rs471767). Logistic regression with adjustment for age, study, ethnicity and body mass index was performed to calculate odds ratios (ORs) and associated 95% confidence intervals (CIs) and P-values. Of the four SNPs investigated, only rs11224561 in the 3′ region of the PGR gene was found to be significantly associated with endometrial cancer risk. The A allele of the rs11224561 SNP was associated with increased risk of endometrial cancer (OR per allele 1.31; 95% CI 1.12–1.53, P = 0.001, adjusted for age and study), an effect of the same magnitude and direction as reported previously. We have validated the endometrial cancer risk association with a tagSNP in the 3′ untranslated region of PGR previously reported in an Asian population. Replication studies will be required to refine the risk estimate and to establish if this, or a correlated SNP, is the underlying causative variant. PMID:21148628

  4. Inverse Relationship between Progesterone Receptor and Myc in Endometrial Cancer

    PubMed Central

    Dai, Donghai; Meng, Xiangbing; Thiel, Kristina W.; Leslie, Kimberly K.; Yang, Shujie

    2016-01-01

    Endometrial cancer, the most common gynecologic malignancy, is a hormonally-regulated disease. Response to progestin therapy positively correlates with hormone receptor expression, in particular progesterone receptor (PR). However, many advanced tumors lose PR expression. We recently reported that the efficacy of progestin therapy can be significantly enhanced by combining progestin with epigenetic modulators, which we term “molecularly enhanced progestin therapy.” What remained unclear was the mechanism of action and if estrogen receptor α (ERα), the principle inducer of PR, is necessary to restore functional expression of PR via molecularly enhanced progestin therapy. Therefore, we modeled advanced endometrial tumors that have lost both ERα and PR expression by generating ERα-null endometrial cancer cell lines. CRISPR-Cas9 technology was used to delete ERα at the genomic level. Our data demonstrate that treatment with a histone deacetylase inhibitor (HDACi) was sufficient to restore functional PR expression, even in cells devoid of ERα. Our studies also revealed that HDACi treatment results in marked downregulation of the oncogene Myc. We established that PR is a negative transcriptional regulator of Myc in endometrial cancer in the presence or absence of ERα, which is in contrast to studies in breast cancer cells. First, estrogen stimulation augmented PR expression and decreased Myc in endometrial cancer cell lines. Second, progesterone increased PR activity yet blunted Myc mRNA and protein expression. Finally, overexpression of PR by adenoviral transduction in ERα-null endometrial cancer cells significantly decreased expression of Myc and Myc-regulated genes. Analysis of the Cancer Genome Atlas (TCGA) database of endometrial tumors identified an inverse correlation between PR and Myc mRNA levels, with a corresponding inverse correlation between PR and Myc downstream transcriptional targets SRD5A1, CDK2 and CCNB1. Together, these data reveal a

  5. Photoaffinity labeling of the progesterone receptor from human endometrial carcinoma

    SciTech Connect

    Clarke, C.L.; Satyaswaroop, P.G.

    1985-11-01

    A nude mouse model for the growth of human endometrial carcinoma and hormonal modulation of the progesterone receptor (PR) was established previously. This study describes the effect of 17 beta-estradiol and tamoxifen (TAM) on growth rate and PR concentration in a hormonally responsive human endometrial tumor (EnCa 101) grown in this experimental system and presents the first characterization of human endometrial carcinoma PR. EnCa 101 was transplanted subcutaneously into ovariectomized, BALB/c, nu/nu athymic mice and grown under 17 beta-estradiol-stimulated, TAM-stimulated, and control conditions. Both 17 beta-estradiol and TAM increased the growth rate of EnCa 101 in nude mice, and a parallel increase in the cytosol PR concentration was observed. PR was partially purified by phosphocellulose and DEAE cellulose chromatography, and the DEAE eluate was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and photoaffinity labeling with (17 alpha-methyl-TH)promegestone ((TH)R5020). Two PR-negative tumors (EnCa K and EnCa V) were also examined in parallel. Photolabeling and sodium dodecyl sulfate-polyacrylamide gel electrophoresis of EnCa 101 grown in the presence of 17 beta-estradiol or TAM revealed incorporation of (3H)R5020 into proteins of molecular weight approximately 116,000 and 85,000. Labeled proteins of molecular weight 66,000, 45,000, and 35,000 were also observed. No incorporation of (TH)R5020 was observed in EnCa 101 grown in the absence of estrogen, nor was any observed in EnCa K or EnCa V.

  6. Endometrial changes from short-term therapy with CDB-4124, a selective progesterone receptor modulator.

    PubMed

    Ioffe, Olga B; Zaino, Richard J; Mutter, George L

    2009-03-01

    Selective progesterone receptor modulators are a class of drugs with progesterone antagonist activity that may confer therapeutic benefit for reproductive disorders in premenopausal women. Endometrial structure, which is dynamically controlled by circulating sex hormones, is likely to be perturbed by progesterone receptor modulators through their progesterone antagonist properties. We examined endometrial histology in 58 premenopausal women treated with the progesterone receptor modulator CDB-4124 (also known as Proellex) for endometriosis or uterine leiomyomata in two clinical trials. Endometrial biopsies obtained after 3 or 6 months with doses of 12.5, 25, or 50 mg daily oral CDB-4124 were reviewed independently by three pathologists. Consensus diagnoses using the World Health Organization hyperplasia scoring system, comments on specific histologic features, and clinical annotation were collected and analyzed. The majority of the endometrial biopsies (103 of 174 biopsies) contained histologic changes that are not seen during normal menstrual cycles. The histology of CDB-4124-treated patients was generally inactive or atrophic, and less frequently, proliferative or secretory, superimposed upon which were novel changes including formation of cystically dilated glands, and secretory changes coexisting with mitoses and apoptotic bodies. With increasing treatment dose and duration, the cysts became predominant and their lining inactive or atrophic. Cystic glands in the CDB-4124-treated subjects correlated with increased endometrial thickness by ultrasound. None of the CDB-4124-treated patients developed endometrial carcinoma or hyperplasia while on therapy. CDB-4124 therapy for 3-6 months produces histologic changes that are sufficiently novel that they might easily be misinterpreted by pathologists, particularly as disordered proliferative or hyperplastic endometrium. Knowledge of the constellation of endometrial changes associated with this agent and other

  7. The progesterone antagonist onapristone retards the advanced endometrial transformation after gonadotropin stimulation in rabbits.

    PubMed

    Krusche, C A; Herrler, A; Classen-Linke, I; Beier, H M

    2000-01-01

    Ovarian stimulation with gonadotropins (GN) during human in vitro fertilization and embryo transfer (IVF/ET) therapy alters the ovarian steroid output, especially that of progesterone. As a consequence, endometrial transformation is advanced, and embryo implantation is hampered. This study used the rabbit model to determine if the application of the progesterone antagonist (PA) onapristone (ONA) could retard endometrial development after GN-stimulation. Rabbits were GN-stimulated twice daily with 5 IU FSH and 5 IU LH on 3 consecutive days with a) hMG (n = 10) or b) with a mixture of recombinant FSH and LH (n = 10). The animals were then mated, and hCG was injected i.v. to ensure ovulation. This day is designated as day 0 post coitum (d 0 p.c.). On day 2 p.c., five animals of each group were treated with 20 mg ONA/kg body weight and five with vehicle for control. On d 5 p.c. endometrial transformation was analyzed by morphology, uteroglobin (Ugl)-mRNA expression, and proliferation. Embryos were flushed from the uteri. Their number and morphology was evaluated. The endometrium of GN-stimulated control animals demonstrated very long endometrial glands and narrow stromal septa. Ugl-mRNA expression was restricted to the cells at the bottom of the gland. 17.0 +/- 4.6% (mean +/- SD) of glandular cells and 6.0 +/- 5.3% of luminal epithelial cells proliferated. In ONA-treated animals, endometrial glands were significantly shorter, and the pattern of arborization was less pronounced. Endometrial gland cells and luminal epithelial cells expressed Ugl-mRNA. Furthermore, glandular and luminal cells proliferated with high intensity (38.6 +/- 6.8% and 36.4 +/- 9.3%, respectively). These results indicate that the status of endometrial differentiation was retarded after ONA-treatment. Nevertheless, the embryos of these ONA-treated animals were well developed. In conclusion, after GN-stimulation, ONA treatment retarded the advanced endometrial transformation in rabbits. Therefore

  8. Altered expression of genes involved in progesterone biosynthesis, metabolism and action in endometrial cancer.

    PubMed

    Sinreih, Maša; Hevir, Neli; Rižner, Tea Lanišnik

    2013-02-25

    Endometrial cancer (EC) is one of the most common gynecological malignancies worldwide. It is associated with prolonged exposure to estrogens that is unopposed by the protective effects of progesterone, which suggests that altered progesterone biosynthesis, metabolism and actions might be implicated in the development of EC. Our aim was to evaluate these processes through quantitative real-time PCR expression analysis in up to 47 pairs of EC tissue and adjacent control endometrium. First, we examined the expression of genes encoding proteins associated with progesterone biosynthesis: steroidogenic acute regulatory protein (STAR); a side chain cleavage enzyme (CYP11A1); and 3β-hydroxysteroid dehydrogenase/ketosteroid isomerase (HSD3B). There were 1.9- and 10.0-fold decreased expression of STAR and CYP11A1, respectively, in EC versus adjacent control endometrium, with no significant differences in the expression of HSD3B1 and HSD3B2. Next, we examined expression of genes encoding five progesterone metabolizing enzymes: the 3-keto and 20-ketosteroid reductases (AKR1C1-AKR1C3) and 5α-reductases (SRD5A1 and SRD5A2); and the opposing 20α-hydroxysteroid dehydrogenase (HSD17B2). These genes are expressed in EC and adjacent control endometrium. No statistically significant differences were seen in mRNA levels of AKR1C1, AKR1C2, AKR1C3 and SRD5A1. Expression of HSD17B2 was 3.0-fold increased, and expression of SRD5A2 was 3.7-fold decreased, in EC versus adjacent control endometrium. We also examined mRNA levels of progesterone receptors A and B (PGR), and separately the expression of progesterone receptor B (PR-B). Here we saw 1.8- and 2.0-fold lower mRNA levels of PGR and PR-B, respectively, in EC versus adjacent control endometrium. This down-regulation of STAR, CYP11A1 and PGR in endometrial cancer may lead to decreased progesterone biosynthesis and actions although the effects on progesterone levels should be further studied.

  9. Akt regulates Progesterone Receptor B dependent transcription and angiogenesis in endometrial cancer cells

    PubMed Central

    Lee, Irene I.; Maniar, Kruti; Lydon, John P.; Kim, J. Julie

    2016-01-01

    Progestins have long been used clinically for the treatment of endometrial cancers, however, the response rates to progestin therapy vary and the molecular mechanisms behind progestin insensitivity are poorly understood. We hypothesized that in PTEN mutated endometrial cancers, hyperactive Akt signaling downregulates Progesterone Receptor B (PRB) transcriptional activity, leading to overall impaired progestin responses. We report that inhibition of Akt with the Akt inhibitor, MK-2206 (MK), in conjunction with progestin (R5020) treatment, is sufficient to upregulate a subset of PRB target genes in Ishikawa cells stably expressing PRB (PRB-Ishikawa). Through gene ontology analysis of Akt-regulated PRB target genes, angiogenesis was found to be the principle process regulated by Akt-PRB. To further interrogate the mechanism by which Akt modulates PRB transcriptional activity, ChIP-Mass Spectrometry was performed to identify potential cofactors that differentially interact with PRB in the presence of the R5020 and MK+R5020. 14-3-3σ was identified as a protein enriched in the MK+R5020 dataset, and it was demonstrated that 14-3-3σ is required for the upregulation in PRB target gene expression following inhibition of Akt. In order to determine the ramifications of MK+R5020 treatment on angiogenesis, in vitro assays were performed and combinatorial MK+R5020 treatment significantly decreased endothelial cell invasion and tube formation more than MK or R5020 treatment alone. Furthermore, we found that combinatorial MK-2206+Progesterone treatments decreased angiogenesis and proliferation in the Ptend/d conditional mouse model of endometrial cancer. Taken together, these findings suggest that a combinatorial therapeutic approach utilizing Akt inhibitors with progestins may improve the efficacy of progestin therapy for the treatment of endometrial cancer. PMID:26996671

  10. Progesterone Receptor Transcriptome and Cistrome in Decidualized Human Endometrial Stromal Cells

    PubMed Central

    Mazur, Erik C.; Vasquez, Yasmin M.; Li, Xilong; Kommagani, Ramakrishna; Jiang, Lichun; Chen, Rui; Lanz, Rainer B.; Kovanci, Ertug; Gibbons, William E.

    2015-01-01

    Decidualization is a complex process involving cellular proliferation and differentiation of the endometrial stroma that is required to establish and support pregnancy. Progesterone acting via its nuclear receptor, the progesterone receptor (PGR), is a critical regulator of decidualization and is known to interact with certain members of the activator protein-1 (AP-1) family in the regulation of transcription. In this study, we identified the cistrome and transcriptome of PGR and identified the AP-1 factors FOSL2 and JUN to be regulated by PGR and important in the decidualization process. Direct targets of PGR were identified by integrating gene expression data from RNA sequencing with the whole-genome binding profile of PGR determined by chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) in primary human endometrial stromal cells exposed to 17β-estradiol, medroxyprogesterone acetate, and cAMP to promote in vitro decidualization. Ablation of FOSL2 and JUN attenuates the induction of 2 decidual marker genes, IGFBP1 and PRL. ChIP-seq analysis of genomic binding revealed that FOSL2 is bound in proximity to 8586 distinct genes, including nearly 80% of genes bound by PGR. A comprehensive assessment of the PGR-dependent decidual transcriptome integrated with the genomic binding of PGR identified FOSL2 as a potentially important transcriptional coregulator of PGR via direct interaction with regulatory regions of genes actively regulated during decidualization. PMID:25781565

  11. Progesterone regulation of the endometrial WNT system in the ovine uterus.

    PubMed

    Satterfield, M Carey; Song, Gwonhwa; Hayashi, Kanako; Bazer, Fuller W; Spencer, Thomas E

    2008-01-01

    WNT signalling regulates cell proliferation, differentiation, polarity and organisation. The present study investigated the effects of progesterone (P4) on the endometrial WNT system in relation to blastocyst development and growth in sheep. Ewes received daily intramuscular injections of either corn oil (CO) vehicle or 25 mg P4 from 36 h after mating (Day 0) until hysterectomy on Day 9 or 12. Another group received P4 until Day 8 and 75 mg mifepristone (RU486) from Day 8 to Day 12. Early P4 treatment increased blastocyst growth on Days 9 and 12, whereas no blastocysts were recovered from P4 + RU486-treated ewes. Levels of WNT2 mRNA in the stroma and WNT11 and WNT7A mRNAs in the endometrial luminal epithelia (LE) were reduced in P4 + RU486-treated ewes on Day 9, whereas WNT11 mRNA was reduced in the endometria of both P4- and P4 + RU486-treated ewes on Day 12. On Day 12, WNT2 mRNA was increased in the stroma, WNT7A mRNA was increased in the LE and WNT5A mRNA was increased in the LE and stroma of P4 + RU486- compared with P4-treated ewes. DKK1 mRNA was absent in the endometrial stroma of P4 + RU486-treated ewes. Expression of transcription factor 7 like-2 (TCF7L2) was transiently increased in endometrial epithelia of P4-treated ewes on Day 9, but decreased in these ewes on Day 12. MSX1 mRNA was decreased by P4 treatment on Day 9 and levels of both MSX1 and MSX2 mRNA were higher in P4 + RU486-treated ewes on Day 12. Thus, P4 modulates the endometrial WNT system and elicits a transient decline in selected WNT pathways and signalling components, which is hypothesised to alter tight and adherens junctions, thereby stimulating blastocyst growth and development. PMID:19007558

  12. Notch1 Is Regulated by Chorionic Gonadotropin and Progesterone in Endometrial Stromal Cells and Modulates Decidualization in Primates

    PubMed Central

    Afshar, Yalda; Miele, Lucio

    2012-01-01

    No other tissue in the body undergoes such a vast and extensive growth and remodeling in a relatively short period of time as the primate endometrium. Endometrial integrity is coordinated by ovarian hormones, namely, estrogens, progesterone, and the embryonic hormone chorionic gonadotropin (CG). These regulated events modulate the menstrual cycle and decidualization. The Notch family of transmembrane receptors regulate cellular proliferation, differentiation, and apoptosis, cellular processes required to maintain endometrial integrity. In two primate models, the human and the simulated pregnant baboon model, we demonstrated that Notch1 is increased during the window of uterine receptivity, concomitant with CG. Furthermore, CG combined with estrogens and progesterone up-regulate the level of Notch1, whereas progesterone increases the intracellular transcriptionally competent Notch1, which binds in a complex with progesterone receptor. Inhibition of Notch1 prevented decidualization, and alternatively, when decidualization is biochemically recapitulated in vitro, Notch1 is down-regulated. A focused microarray demonstrated that the Notch inhibitor, Numb, dramatically increased when Notch1 decreased during decidualization. We propose that in the endometrium, Notch has a dual role during the window of uterine receptivity. Initially, Notch1 mediates a survival signal in the uterine endometrium in response to CG from the implanting blastocyst and progesterone, so that menstrual sloughing is averted. Subsequently, Notch1 down-regulation may be critical for the transition of stromal fibroblast to decidual cells, which is essential for the establishment of a successful pregnancy. PMID:22535768

  13. Genetic variation in the progesterone receptor gene and risk of endometrial cancer: a haplotype-based approach

    PubMed Central

    Lee, Eunjung; Hsu, Chris; Haiman, Christopher A.; Razavi, Pedram; Horn-Ross, Pamela L.; Van Den Berg, David; Bernstein, Leslie; Le Marchand, Loic; Henderson, Brian E.; Setiawan, V. Wendy; Ursin, Giske

    2010-01-01

    Background: It is well established that estrogen increases endometrial cancer risk, whereas progesterone opposes the estrogen effects. The PROGINS allele of the progesterone receptor (PGR) gene reduces the function of PGR and has been associated with increased risk of the endometrioid type ovarian cancer. We investigated whether genetic variation in PGR is also associated with endometrial cancer risk using a haplotype-based approach. Methods: We pooled data from two endometrial cancer case–control studies that were nested within two prospective cohorts, the Multiethnic Cohort Study and the California Teachers Study. Seventeen haplotype-tagging single nucleotide polymorphisms (SNPs) across four linkage disequilibrium (LD) blocks spanning the PGR locus were genotyped in 583 incident cases and 1936 control women. Odds ratios (ORs) and 95% confidence intervals (CIs) associated with each haplotype were estimated using conditional logistic regression, stratified by age and ethnicity. Results: Genetic variation in LD block 3 of the PGR locus was associated with endometrial cancer risk (Pglobal test = 0.002), with haplotypes 3C, 3D and 3F associated with 31–34% increased risk. Among whites (383 cases/840 controls), genetic variation in all four blocks was associated with increased endometrial cancer risk (Pglobal test = 0.010, 0.013, 0.005 and 0.020). Haplotypes containing the PROGINS allele and several haplotypes in blocks 1, 3 and 4 were associated with 34–77% increased risk among whites. SNP analyses for whites suggested that rs608995, partially linked to the PROGINS allele (r2 = 0.6), was associated with increased risk (OR = 1.30, 95% CI = 1.06–1.59). Conclusions: Our results suggest that genetic variation in the PGR region is associated with endometrial cancer risk. PMID:20547493

  14. Mig-6 regulates endometrial genes involved in cell cycle and progesterone signaling

    SciTech Connect

    Yoo, Jung-Yoon; Kim, Tae Hoon; Lee, Jae Hee; Dunwoodie, Sally L.; Ku, Bon Jeong; Jeong, Jae-Wook

    2015-07-10

    Mitogen inducible gene 6 (Mig-6) is an important mediator of progesterone (P4) signaling to inhibit estrogen (E2) signaling in the uterus. Ablation of Mig-6 in the murine uterus leads to the development of endometrial hyperplasia and E2-induced endometrial cancer. To identify the molecular pathways regulated by Mig-6, we performed microarray analysis on the uterus of ovariectomized Mig-6{sup f/f} and PGR{sup cre/+}Mig-6{sup f/f} (Mig-6{sup d/d}) mice treated with vehicle or P4 for 6 h. The results revealed that 772 transcripts were significantly regulated in the Mig-6{sup d/d} uterus treated with vehicle as compared with Mig-6{sup f/f} mice. The pathway analysis showed that Mig-6 suppressed the expression of gene-related cell cycle regulation in the absence of ovarian steroid hormone. The epithelium of Mig-6{sup d/d} mice showed a significant increase in the number of proliferative cells compared to Mig-6{sup f/f} mice. This microarray analysis also revealed that 324 genes are regulated by P4 as well as Mig-6. Cited2, the developmentally important transcription factor, was identified as being regulated by the P4-Mig-6 axis. To determine the role of Cited2 in the uterus, we used the mice with Cited2 that were conditionally ablated in progesterone receptor-positive cells (PGR{sup cre/+}Cited2{sup f/f}; Cited2{sup d/d}). Ablation of Cited2 in the uterus resulted in a significant reduction in the ability of the uterus to undergo a hormonally induced decidual reaction. Identification and analysis of these responsive genes will help define the role of P4 as well as Mig-6 in regulating uterine biology. - Highlights: • We identify Mig-6- and P4-regulated uterine genes by microarray analysis. • Mig-6 suppresses cell cycle progression and epithelial cell proliferation in uterus. • We identify the Mig-6 dependent induced genes by P4. • Cited2 plays an important role for decidualization as a P4 and Mig-6 target gene.

  15. Does progesterone-induced endometrial withdrawal bleed before ovulation induction have negative effects on IUI outcomes in patients with polycystic ovary syndrome?

    PubMed Central

    Dong, Xiyuan; Zheng, Yu; Liao, Xiuhua; Xiong, Ting; Zhang, Hanwang

    2013-01-01

    Polycystic ovary syndrome is a common heterogeneous endocrine disorder in reproductive-age women, with prevalence around 4-12%. The present study was performed to investigate whether progesterone-induced endometrial bleed before ovulation induction affects pregnancy in patients with PCOS who underwent intrauterine insemination (IUI) treatment. A total of 241 IUI cycles were retrospectively analyzed. Patients enrolled in this study underwent ovulation induction with IUI treatment from Jan. 2011 to Dec. 2012. The study group consisted of 184 cycles with progesterone-withdrawal bleed before ovulation induction. The control group included 57 cycles with spontaneous menses. The clinical characteristics, ovulation induction parameters and IUI outcomes, such as pregnancy rate and live birth/ongoing pregnancy rate, were compared between the two groups. We found that patients in induced shedding group had thinner peak endometrium in ovulation induction cycles. Additionally, the ratio of peak endometrial-thickness to baseline endometrial-thickness was lower in induced menses patients. However, the pregnancy rate and live birth/ongoing pregnancy rate per cycle were similar with the control group. Excluding the peak E2 level, peak E2/number of follicles > 15mm and peak endometrial-thickness/baseline endometrial-thickness, no differences were found in ovulation induction or IUI results between patients used Letrozole or Clomiphene Citrate. In patients undergoing administration with Letrozole, those taking progesterone had thinner endometrium and lower peak endometrial-thickness/baseline endometrial-thickness. However, the pregnancy rate and live birth/ongoing pregnancy rate were not statistically different from patients with spontaneous menses. In conclusion, our study showed that progesterone exerted a negative effect on endometrial development, which seemed to be associated with reduced pregnancy results in ovulation induction with IUI cycles. PMID:23696936

  16. Differences in estrogen and progesterone receptor expression in endometrial polyps and atrophic endometrium of postmenopausal women with and without exposure to tamoxifen

    PubMed Central

    LEÃO, ROGERIO BARROS FERREIRA; ANDRADE, LILIANA; VASSALO, JOSE; ANTUNES, ARMANDO; PINTO-NETO, AARÃO; COSTA-PAIVA, LUCIA

    2013-01-01

    Postmenopausal women who use tamoxifen present with an increased incidence of endometrial alterations, such as polyps and hyperplasia, in addition to a higher risk of malignant endometrial neoplasms. Among these endometrial changes, polyps are the most common, with a pathogenesis associated with hormonal influence. The objective of this study was to compare the expression of estrogen receptors (ERs) and progesterone receptors (PRs) in endometrial polyps from tamoxifen users with that in endometrial polyps and the atrophic endometrium of postmenopausal tamoxifen non-users. Among women undergoing surgical hysteroscopy, 84 tamoxifen users with benign endometrial polyps were selected. This group was compared to 84 samples of atrophic endometrium and to 252 benign polyps from postmenopausal women who were not treated with tamoxifen. The expression of ER/PR was assessed by immunohistochemical analysis, according to the percentage of stained cells, intensity of nuclear staining and final score. The polyps from tamoxifen users exhibited a higher expression of ER and PR in the glandular epithelium and stroma compared to the atrophic endometrium (P<0.0001). Compared to the polyps from women not treated with tamoxifen, tamoxifen users exhibited a higher PR expression in the epithelium (P=0.0014) and stroma (P=0.0056), with no difference in the expression of ER. In conclusion, endometrial polyps frequently exhibit an increase in ER expression, regardless of tamoxifen use. High levels of PR expression appear to be consistent with the estrogen agonist effects of tamoxifen. PMID:24649292

  17. Immunocytochemical assay of progesterone receptors in paraffin-embedded specimens of endometrial carcinoma and hyperplasia: a preliminary evaluation.

    PubMed

    Brustein, S; Fruchter, R; Greene, G L; Pertschuk, L P

    1989-09-01

    An immunohistochemical method for the detection of progesterone receptors (PgR) using the monoclonal anti-PgR antibody KD 68 was utilized to study paraffin-embedded tissue sections from women with endometrial carcinoma and hyperplasia. Stromal as well as myometrial nuclear PgR were nearly always apparent. In carcinoma, 11/24 (46%) of cases showed epithelial positivity, whereas in hyperplasia 8/9 (89%) were PgR-positive (P less than 0.05). Initial biochemical PgR assays by the dextran-coated charcoal method were compared with results of PgR-immunocytochemical assays (ICA) in the paraffin-embedded tissue and were in concordance in 92%. In the one discordant specimen, PgR-ICA-negative tumor cells were seen infiltrating PgR-ICA-positive myometrium, and the biochemical assay was thus felt to be falsely positive. Twelve additional cases of endometrial carcinoma were also studied for estrogen receptor (ER) by immunocytochemistry. Two were positive for both ER and PgR, while five were negative for both receptors. The immunocytochemical methods described allow for analysis of routinely fixed, paraffin-embedded specimens, thus permitting analysis of very small specimens and archival material.

  18. Progesterone-Dependent Induction of Phospholipase C-Related Catalytically Inactive Protein 1 (PRIP-1) in Decidualizing Human Endometrial Stromal Cells

    PubMed Central

    Muter, Joanne; Brighton, Paul J.; Lucas, Emma S.; Lacey, Lauren; Shmygol, Anatoly; Quenby, Siobhan; Blanks, Andrew M.

    2016-01-01

    Decidualization denotes the transformation of endometrial stromal cells into specialized decidual cells. In pregnancy, decidual cells form a protective matrix around the implanting embryo, enabling coordinated trophoblast invasion and formation of a functional placenta. Continuous progesterone (P4) signaling renders decidual cells resistant to various environmental stressors, whereas withdrawal inevitably triggers tissue breakdown and menstruation or miscarriage. Here, we show that PLCL1, coding phospholipase C (PLC)-related catalytically inactive protein 1 (PRIP-1), is highly induced in response to P4 signaling in decidualizing human endometrial stromal cells (HESCs). Knockdown experiments in undifferentiated HESCs revealed that PRIP-1 maintains basal phosphoinositide 3-kinase/Protein kinase B activity, which in turn prevents illicit nuclear translocation of the transcription factor forkhead box protein O1 and induction of the apoptotic activator BIM. By contrast, loss of this scaffold protein did not compromise survival of decidual cells. PRIP-1 knockdown did also not interfere with the responsiveness of HESCs to deciduogenic cues, although the overall expression of differentiation markers, such as PRL, IGFBP1, and WNT4, was blunted. Finally, we show that PRIP-1 in decidual cells uncouples PLC activation from intracellular Ca2+ release by attenuating inositol 1,4,5-trisphosphate signaling. In summary, PRIP-1 is a multifaceted P4-inducible scaffold protein that gates the activity of major signal transduction pathways in the endometrium. It prevents apoptosis of proliferating stromal cells and contributes to the relative autonomy of decidual cells by silencing PLC signaling downstream of Gq protein-coupled receptors. PMID:27167772

  19. Oestrogen and Progesterone Receptors and COX-2 Expression in Endometrial Biopsy Samples During Maternal Recognition of Pregnancy in Llamas (Lama glama).

    PubMed

    Bianchi, C P; Meikle, A; Benavente, M A; Álvarez, M A; Trasorras, V L; Miragaya, M H; Rodríguez, E; Aba, M A

    2015-12-01

    Endometrial expression of oestrogen receptor-α (ERα), progesterone receptor (PR) and cyclooxigenase-2 (COX-2) was evaluated in non-pregnant and pregnant llamas during the period when luteolysis/maternal recognition of pregnancy is expected to occur. Females (n = 28) were divided into two groups: non-pregnant llamas were induced to ovulate with a Buserelin injection, and endometrial biopsies were obtained on day 8 (n = 5) or 12 (n = 5) post-induction of ovulation. Animals of the pregnant group (n = 18) were mated with a fertile male. Pregnancy was confirmed by the visualization of the embryo collected by transcervical flushing in 5 of 9 animals on day 8 post-mating and by progesterone profile on day 12 post-mating in 4 of 9 animals, when endometrial biopsies were obtained. An immunohistochemical technique was used to evaluate receptors population and COX-2 expression. Pregnant llamas showed a higher percentage of positive cells and stronger intensity for ERα than for non-pregnant llamas in stroma on day 8 and in the luminal epithelium on day 12 post-induction of ovulation, while a deep decrease in endometrial PR population was reported in pregnant llamas on that day in luminal and glandular epithelia and stroma. In the luminal epithelium, COX-2 expression was lower in pregnant than in non-pregnant animals. Briefly, the increase of ERα in pregnant llamas gives further support to the hypothesis that oestrogens are involved in the mechanism of maternal recognition of pregnancy. Endometrial PR decrease in pregnant llamas might be a necessary event to allow the expression of proteins involved in conceptus attachment, a mechanism widely accepted in other species. Moreover, embryo seems to attenuate maternal PGF(2α) secretion during early pregnancy by decreasing the endometrial expression of COX-2 in the luminal epithelium of pregnant llamas. PMID:26446171

  20. Oestrogen and Progesterone Receptors and COX-2 Expression in Endometrial Biopsy Samples During Maternal Recognition of Pregnancy in Llamas (Lama glama).

    PubMed

    Bianchi, C P; Meikle, A; Benavente, M A; Álvarez, M A; Trasorras, V L; Miragaya, M H; Rodríguez, E; Aba, M A

    2015-12-01

    Endometrial expression of oestrogen receptor-α (ERα), progesterone receptor (PR) and cyclooxigenase-2 (COX-2) was evaluated in non-pregnant and pregnant llamas during the period when luteolysis/maternal recognition of pregnancy is expected to occur. Females (n = 28) were divided into two groups: non-pregnant llamas were induced to ovulate with a Buserelin injection, and endometrial biopsies were obtained on day 8 (n = 5) or 12 (n = 5) post-induction of ovulation. Animals of the pregnant group (n = 18) were mated with a fertile male. Pregnancy was confirmed by the visualization of the embryo collected by transcervical flushing in 5 of 9 animals on day 8 post-mating and by progesterone profile on day 12 post-mating in 4 of 9 animals, when endometrial biopsies were obtained. An immunohistochemical technique was used to evaluate receptors population and COX-2 expression. Pregnant llamas showed a higher percentage of positive cells and stronger intensity for ERα than for non-pregnant llamas in stroma on day 8 and in the luminal epithelium on day 12 post-induction of ovulation, while a deep decrease in endometrial PR population was reported in pregnant llamas on that day in luminal and glandular epithelia and stroma. In the luminal epithelium, COX-2 expression was lower in pregnant than in non-pregnant animals. Briefly, the increase of ERα in pregnant llamas gives further support to the hypothesis that oestrogens are involved in the mechanism of maternal recognition of pregnancy. Endometrial PR decrease in pregnant llamas might be a necessary event to allow the expression of proteins involved in conceptus attachment, a mechanism widely accepted in other species. Moreover, embryo seems to attenuate maternal PGF(2α) secretion during early pregnancy by decreasing the endometrial expression of COX-2 in the luminal epithelium of pregnant llamas.

  1. The Regulation of Embryo Implantation and Endometrial Decidualization by Progesterone Receptor Signaling

    PubMed Central

    Large, Michael J.; DeMayo, Francesco J.

    2011-01-01

    During the early stages of pregnancy, fertilized embryos must attach to the uterine epithelium, invade into the underlying uterine stroma, and the stroma must then differentiate in a process termed decidualization in order for a successful pregnancy to be initiated. The steroid hormone progesterone (P4) is an integral mediator of these early pregnancy events, exerting its effects via the progesterone receptor (PR). Insights gained from the use of mouse models and genomic profiling has identified many of the key molecules enlisted by PR to execute the paradigm of early pregnancy. This review describes several of the molecules through which the PR exerts its pleiotropic effects including ligands, receptors, chaperones, signaling proteins and transcription factors. Understanding these molecules and their concatenation is of vital importance to our ability to clinically treat reproductive health problems like infertility and endometriosis. PMID:21821095

  2. Progesterone acts via progesterone receptors A and B to regulate breast cancer resistance protein expression.

    PubMed

    Vore, Mary; Leggas, Markos

    2008-03-01

    The breast cancer resistance protein (BCRP; ABCG2) is an ATP-dependent efflux multidrug transporter that belongs to the G family of half-transporters that consist of six transmembrane-spanning domains and must homodimerize to form the active membrane transporter. It is expressed in the apical plasma membrane domain of the small intestine, endothelium, and liver, where it has been shown to play an important role in limiting drug absorption and distribution and in enhancing drug clearance, respectively. BCRP is also expressed in the apical membrane of mammary alveolar epithelia, where it mediates efflux of substrates into milk, and in the placental syncytiotro-phoblasts, where it reduces fetal exposure to these substrates. BCRP substrates include numerous drugs (topotecan, nitrofurantoin, cimetidine) as well as food carcinogens (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) and the vitamins riboflavin and folic acid. BCRP expression is regulated by a number of nuclear transcription factors, including the peroxisome proliferator-activated receptor-gamma and Hif-1. This issue of Molecular Pharmacology includes a study (p. 845) now conclusively demonstrating that progesterone acts via the progesterone A and B receptors to regulate BCRP expression in a placental cell line.

  3. Oestrogen, progesterone and oxytocin receptors and COX-2 expression in endometrial biopsy samples from the induction of ovulation to luteolysis in llamas (Lama glama).

    PubMed

    Bianchi, C P; Meikle, A; Alvarez, M A; Benavente, M A; Cavilla, M V; Rodríguez, E; Aba, M A

    2013-08-01

    Endometrial expression of oestrogen (ERα), progesterone (PR) and oxytocin receptor (OR) and cyclooxygenase-2 (COX-2) was evaluated from the induction of ovulation to luteolysis in llamas. Ovarian activity was daily assessed by ultrasonography in five females. Ovulation was induced immediately after the detection of an ovulatory follicle by a GnRH injection (Day 0). Endometrial samples were obtained by transcervical biopsies from the left and right horns on day 0 and days 4, 8, 10 and 12 post-GnRH. Blood samples were collected daily for progesterone and estradiol-17β determinations by RIA. An immunohistochemical technique was used to study receptors population and COX-2 expression which were then evaluated by two independent observers. The expression of ERα and PR was highest on day 0 in the luminal epithelium and stroma in association with high plasma estradiol-17β concentrations. Thereafter, a decrease in ERα population was registered on day 4 and a new increase of its expression was observed between days 8 and 12 in those cell types. Conversely, PR population was gradually down-regulated until its lowest expression was reached on day 10 post-GnRH in the luminal epithelium. Content of OR was similar throughout the study in all cell types. The expression of COX-2 was highest from day 8 to 12 post-GnRH in the luminal epithelium, in relation to the time of maximal PGF2α release. Both steroid receptors populations and COX-2 expression were similar between horns. Meanwhile, OR expression was higher in the right than in the left uterine horn. In summary, this study showed that the loss of endometrium sensitivity to progesterone by days 8-10 post-induction of ovulation and the concomitant increase of COX-2 expression could play a key role in the mechanism of luteolysis and somehow be related to the short corpus luteum lifespan of llamas.

  4. Progestins Upregulate FKBP51 Expression in Human Endometrial Stromal Cells to Induce Functional Progesterone and Glucocorticoid Withdrawal: Implications for Contraceptive- Associated Abnormal Uterine Bleeding

    PubMed Central

    Guzeloglu Kayisli, Ozlem; Kayisli, Umit A.; Basar, Murat; Semerci, Nihan; Schatz, Frederick; Lockwood, Charles J.

    2015-01-01

    Use of long-acting progestin only contraceptives (LAPCs) offers a discrete and highly effective family planning method. Abnormal uterine bleeding (AUB) is the major side effect of, and cause for, discontinuation of LAPCs. The endometria of LAPC-treated women display abnormally enlarged, fragile blood vessels, decreased endometrial blood flow and oxidative stress. To understanding to mechanisms underlying AUB, we propose to identify LAPC-modulated unique gene cluster(s) in human endometrial stromal cells (HESCs). Protein and RNA isolated from cultured HESCs treated 7 days with estradiol (E2) or E2+ medroxyprogesterone acetate (MPA) or E2+ etonogestrel (ETO) or E2+ progesterone (P4) were analyzed by quantitative Real-time (q)-PCR and immunoblotting. HSCORES were determined for immunostained-paired endometria of pre-and 3 months post-Depot MPA (DMPA) treated women and ovariectomized guinea pigs (GPs) treated with placebo or E2 or MPA or E2+MPA for 21 days. In HESCs, whole genome analysis identified a 67 gene group regulated by all three progestins, whereas a 235 gene group was regulated by E2+ETO and E2+MPA, but not E2+P4. Ingenuity pathway analysis identified glucocorticoid receptor (GR) activation as one of upstream regulators of the 235 MPA and ETO-specific genes. Among these, microarray results demonstrated significant enhancement of FKBP51, a repressor of PR/GR transcriptional activity, by both MPA and ETO. q-PCR and immunoblot analysis confirmed the microarray results. In endometria of post-DMPA versus pre-DMPA administered women, FKBP51 expression was significantly increased in endometrial stromal and glandular cells. In GPs, E2+MPA or MPA significantly increased FKBP51 immunoreactivity in endometrial stromal and glandular cells versus placebo- and E2-administered groups. MPA or ETO administration activates GR signaling and increases endometrial FKBP51 expression, which could be one of the mechanisms causing AUB by inhibiting PR and GR-mediated transcription

  5. Stromal Clues in Endometrial Carcinoma: Loss of Expression of β-Catenin, Epithelial-Mesenchymal Transition Regulators, and Estrogen-Progesterone Receptor

    PubMed Central

    Sayar, Ilyas; Ceyran, Ayse B.; Ibiloglu, Ibrahim; Akalin, Ibrahim; Firat, Ugur; Kosemetin, Duygu; Engin Zerk, Pinar; Aydin, Abdullah

    2016-01-01

    Epithelial-stroma interactions in the endometrium are known to be responsible for physiological functions and emergence of several pathologic lesions. Periglandular stromal cells act on endometrial cells in a paracrine manner through sex hormones. In this study, we immunohistochemically evaluated the expression of epithelial-mesenchymal transition regulators (SNAIL/SLUG, TWIST, ZEB1), adhesion molecules (β-catenin and E-cadhenin), estrogen (ER)-progesterone (PR) receptor and their correlation with each other in 30 benign, 148 hyperplastic (EH), and 101 endometrioid-type endometrial carcinoma (EC) endometria. In the epithelial component, loss of expression in E-cadherin, ER and PR, and overexpression of TWIST and ZEB1 were significantly higher in EC than in EH (P<0.01). In the periglandular stromal component, β-catenin and SNAIL/SLUG expression were significantly higher in normal endometrium and simple without atypical EH compared with complex atypical EH and EC (P<0.01). In addition, periglandular stromal TWIST expression was significantly higher in EH group compared with EC (P<0.05). There was significantly negative correlation between β-catenin and ER, TWIST and ER, and TWIST and PR in hyperplastic and carcinomatous glandular epithelium, whereas there was a significantly positive correlation between β-catenin and SNAIL-SLUG, β-catenin and TWIST, β-catenin and ER, β-catenin and PR, SNAIL-SLUG and ER, SNAIL-SLUG and PR, TWIST and ER, TWIST and PR, in periglandular/cancer-associated stromal cells (P<0.01). In conclusion, the pattern of positive and negative correlations in the expression of epithelial-mesenchymal transition regulators (SNAIL-SLUG and TWIST), sex hormone receptors (ER and PR), and β-catenin between ECs and hyperplasia, as well as between epithelium and stroma herein, is suggestive of a significant role for these proteins and their underlying molecular processes in the development of endometrial carcinomas. PMID:26367784

  6. MiR-125b regulates endometrial receptivity by targeting MMP26 in women undergoing IVF-ET with elevated progesterone on HCG priming day

    PubMed Central

    Chen, Cheng; Zhao, Yue; Yu, Yang; Li, Rong; Qiao, Jie

    2016-01-01

    On the women undergoing IVF-ET with elevated progesterone on human chorionic gonadotrophin priming, the assisted reproductive technology outcome is poor. But, due to the unknown mechanism of this process, no effective method has been found to overcome this difficulty. Here, we investigated the roles of miR-125b and its target gene, MMP26, in endometrial receptivity (ER) in these women. The expression of miR-125b was significantly up-regulated in EECs in women with elevated progesterone during the window of implantation, and it showed a progesterone-dependent effect in vitro. Similarly, the expression of miR-125b was significantly up-regulated in the preimplantation period, and was down-regulated in the implantation period and the post-implantation period in mouse EECs. In addition, miR-125b showed a greater decrease at implantation sites than it did at interimplantation sites. The luciferase report assay demonstrated that MMP26 is a target gene of miR-125b. And the expression profile of MMP26 showed an inverse relationship with miR-125b in vivo and in vitro. Overexpression of miR-125b in human EECs inhibited cell migration and invasion. Gain-of-function of miR-125b induced a significant decrease in the number of implantation sites. In conclusion, these data shed new light on how miR-125b triggers ER decline through the regulation of MMP26 function. PMID:27143441

  7. Immunohistochemical localization of estradiol and progesterone receptors in human uterus throughout pregnancy: expression in endometrial blood vessels.

    PubMed

    Perrot-Applanat, M; Deng, M; Fernandez, H; Lelaidier, C; Meduri, G; Bouchard, P

    1994-01-01

    Although progesterone and estrogens are essential to maintain human pregnancy after implantation, the localization of their specific receptors in different uterine cell types during pregnancy has not been investigated. We studied uteri (n = 40) obtained during the first 3 months of pregnancy (n = 21) and in late pregnancy (n = 9) as well as from women 5-14 weeks pregnant (n = 10) who had received the antiprogestagen RU 38486 (Roussel-UCLAF) to induce cervical dilation. Frozen tissues were processed for indirect immunocytochemical staining with specific monoclonal antibodies against estrogen receptors (ER; Abbott Laboratories) and progesterone receptors (PR; Li 417). Specific staining for steroid receptors was only detected in the nucleus. In the endometrium, PR staining remained fairly constant throughout pregnancy, whereas ER staining was initially weak and then undetectable. PR was widely expressed in stromal cells and in spiral arterial wall cells, whereas ER was expressed in scattered stromal cells and arterial cells. Both PR and ER were absent from glandular epithelium, contrasting with the secretory activity during the first trimester. Spiral arteries of the endometrium and myometrial smooth muscle cells showed intense PR and moderate ER staining in early pregnancy. The progesterone antagonist RU 38486 (mifepristone), given in early pregnancy at a dose of 200 mg, caused a marked increase in ER staining and a smaller increase in PR staining in stromal cells, whereas the glandular epithelium remained negative for both ER and PR (except for one and two specimens, respectively). We conclude the following. 1) Stromal cells retain PR despite the high progesterone levels during pregnancy, in keeping with the role of progesterone in stromal decidualization. The absence of PR from the secretory glandular epithelium suggests a paracrine link between decidualized stromal cells and epithelial cells. 2) Significant PR down-regulation by progesterone during pregnancy

  8. Inflammation influences steroid hormone receptors targeted by progestins in endometrial stromal cells from women with endometriosis.

    PubMed

    Grandi, Giovanni; Mueller, Michael D; Papadia, Andrea; Kocbek, Vida; Bersinger, Nick A; Petraglia, Felice; Cagnacci, Angelo; McKinnon, Brett

    2016-09-01

    Endometriosis is an estrogen-dependent disease characterised by the growth of endometrial epithelial and stromal cells outside the uterus creating a chronic inflammatory environment that further contributes to disease progression. The first choice treatment for endometriosis is currently progestin mediated hormone modulation. In addition to their progestogenic activity however, progestins also have the potential to bind to other nuclear receptors influencing their local activity on endometriotic cells. This local activity will be dependent on the steroid hormone receptor expression that occurs in endometrial cells in a chronic inflammatory environment. We therefore aimed to quantify receptors targeted by progestins in endometrial stromal cells after exposure to inflammation. Using primary endometrial stromal cells isolated from women with endometriosis we examined the mRNA and protein expression of the progesterone receptors A and B, membrane progesterone receptors 1 and 2, androgen receptors, mineralocorticoid receptors and glucocorticoid receptors after exposure to the inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β). The results indicate that both cytokines reduced the expression of progesterone receptors and increased the expression of the glucocorticoid receptors in the endometrial stromal cells. The change in expression of progestin targets in endometrial stromal cells in an inflammatory environment could contribute to the progesterone resistance observed in endometriotic cells and ultimately influence the design of hormonal therapies aimed at treating this disease. PMID:27371899

  9. Abiraterone Treatment in Castration-Resistant Prostate Cancer Selects for Progesterone Responsive Mutant Androgen Receptors

    PubMed Central

    Chen, Eddy J.; Sowalsky, Adam G.; Gao, Shuai; Cai, Changmeng; Voznesensky, Olga; Schaefer, Rachel; Loda, Massimo; True, Lawrence D.; Ye, Huihui; Troncoso, Patricia; Lis, Rosina L.; Kantoff, Philip W.; Montgomery, Robert B.; Nelson, Peter S.; Bubley, Glenn J.; Balk, Steven P.; Taplin, Mary-Ellen

    2014-01-01

    Purpose The CYP17A1 inhibitor abiraterone markedly reduces androgen precursors and is thereby effective in castration-resistant prostate cancer (CRPC). However, abiraterone increases progesterone, which can activate certain mutant androgen receptors (ARs) identified previously in flutamide-resistant tumors. Therefore, we sought to determine if CYP17A1 inhibitor treatment selects for progesterone activated mutant ARs. Experimental Design AR was examined by targeted sequencing in metastatic tumor biopsies from 18 CRPC patients who were progressing on a CYP17A1 inhibitor (17 on abiraterone, 1 on ketoconazole), alone or in combination with dutasteride, and by whole exome sequencing in residual tumor in one patient treated with neoadjuvant leuprolide plus abiraterone. Results The progesterone-activated T878A mutant AR was present at high allele frequency in 3 of the 18 CRPC cases. It was also present in one focus of resistant tumor in the neoadjuvant treated patient, but not in a second clonally related resistant focus which instead had lost one copy of PTEN and both copies of CHD1. The T878A mutation appeared to be less common in the subset of CRPC patients treated with abiraterone plus dutasteride, and transfection studies showed that dutasteride was a more potent direct antagonist of the T878A versus the wildtype AR. Conclusions These findings indicate that selection for tumor cells expressing progesterone-activated mutant ARs is a mechanism of resistance to CYP17A1 inhibition. PMID:25320358

  10. Lipocalin 2 Enhances Migration and Resistance against Cisplatin in Endometrial Carcinoma Cells

    PubMed Central

    Kashima, Hiroyasu; Yamada, Yasushi; Kobara, Hisanori; Asaka, Ryoichi; Ando, Hirofumi; Higuchi, Shotaro; Ida, Koichi; Mvunta, David Hamisi; Shiozawa, Tanri

    2016-01-01

    Purpose Lipocalin 2 (LCN2) is a secretory protein that is involved in various physiological processes including iron transport. We previously identified LCN2 as an up-regulated gene in endometrial carcinoma, and found that the overexpression of LCN2 and its receptor, SLC22A17, was associated with a poor prognosis. However, the functions and mechanism of action of LCN2 currently remain unclear. Methods The LCN2-overexpressing endometrial carcinoma cell lines, HHUA and RL95-2, and LCN2-low-expressing one, HEC1B, were used. The effects of LCN2 on cell migration, cell viability, and apoptosis under various stresses, including ultraviolet (UV) irradiation and cisplatin treatment, were examined using the scratch wound healing assay, WST-1 assay, and Apostrand assay, respectively. Results LCN2-silencing using shRNA method significantly reduced the migration ability of cells (p<0.05). Cytotoxic stresses significantly decreased the viability of LCN2-silenced cells more than that of control cells. In contrast, LCN2 overexpression was significantly increased cisplatin resistance. These effects were canceled by the addition of the iron chelator, deferoxamine. After UV irradiation, the expression of phosphorylated Akt (pAkt) was decreased in LCN2-silenced cells, and the PI3K inhibitor canceled the difference induced in UV sensitivity by LCN2. The cisplatin-induced expression of pAkt was not affected by LCN2; however, the expression of p53 and p21 was increased by LCN2-silencing. Conclusions These results indicated that LCN2 was involved in the migration and survival of endometrial carcinoma cells under various stresses in an iron-dependent manner. The survival function of LCN2 may be exerted through the PI3K pathway and suppression of the p53-p21 pathway. These functions of LCN2 may increase the malignant potential of endometrial carcinoma cells. PMID:27168162

  11. Endometrial ablation

    MedlinePlus

    Hysteroscopy-endometrial ablation; Laser thermal ablation; Endometrial ablation-radiofrequency; Endometrial ablation-thermal balloon ablation; Rollerball ablation; Hydrothermal ablation; Novasure ablation

  12. Homeostasis imbalance in the endometrium of women with implantation defects: the role of estrogen and progesterone.

    PubMed

    Lessey, Bruce A; Young, Steven L

    2014-09-01

    Embryo implantation is regulated by an inflammatory process in response to sequential exposure to estrogen and progesterone, followed by resolution and repair. The actions of estrogen and progesterone on these inflammatory processes are tightly and reciprocally controlled through regulated expression of steroid receptors, cofactors, chaperone proteins, and downstream signaling components. In endometriosis, the inflammatory cascades, normally seen at menstruation, are prematurely activated and endogenous endometrial mechanisms of inflammation resolution appear defective. The temporally abnormally inflammation is also associated with an imbalance between estrogen and progesterone actions; the normal luteal-phase dominance of progesterone action appears to be lost and is replaced by progesterone resistance and estrogen dominance. In this review, we examine these relationships in greater detail and argue that estrogen action is a prime target for future therapeutic solutions to endometriosis and implantation failure that result from this chronic, inflammatory disease. PMID:24959818

  13. Hormones and endometrial carcinogenesis.

    PubMed

    Kamal, Areege; Tempest, Nicola; Parkes, Christina; Alnafakh, Rafah; Makrydima, Sofia; Adishesh, Meera; Hapangama, Dharani K

    2016-02-01

    Endometrial cancer (EC) is the commonest gynaecological cancer in the Western World with an alarmingly increasing incidence related to longevity and obesity. Ovarian hormones regulate normal human endometrial cell proliferation, regeneration and function therefore are implicated in endometrial carcinogenesis directly or via influencing other hormones and metabolic pathways. Although the role of unopposed oestrogen in the pathogenesis of EC has received considerable attention, the emerging role of other hormones in this process, such as androgens and gonadotropin-releasing hormones (GnRH) is less well recognised. This review aims to consolidate the current knowledge of the involvement of the three main endogenous ovarian hormones (oestrogens, progesterone and androgens) as well as the other hormones in endometrial carcinogenesis, to identify important avenues for future research. PMID:26966933

  14. Progesterone receptor (PR) isoforms PRA and PRB differentially regulate expression of the breast cancer resistance protein in human placental choriocarcinoma BeWo cells.

    PubMed

    Wang, Honggang; Lee, Eun-Woo; Zhou, Lin; Leung, Peter C K; Ross, Douglas D; Unadkat, Jashvant D; Mao, Qingcheng

    2008-03-01

    Breast cancer resistance protein (BCRP) plays a significant role in drug disposition and in conferring multidrug resistance in cancer cells. Previous studies have shown that steroid hormones such as 17beta-estradiol and progesterone can affect BCRP expression in cancer cells. In this study, we investigated the molecular mechanism by which BCRP expression in human placental choriocarcinoma BeWo cells is regulated by progesterone. Transfection of the progesterone receptor (PR) isoforms PRA and PRB resulted in a similarly increased expression of PRA and PRB, respectively. However, progesterone significantly increased BCRP expression and activity only in PRB-transfected cells. This stimulatory effect of progesterone was abrogated by the PR antagonist mifepristone (RU-486). Consistently, transcriptional activity of the BCRP promoter was induced 2- to 6-fold by 10(-8) to 10(-5) M progesterone in PRB-transfected cells. Progesterone had little effect on BCRP expression and activity and transcriptional activity of the BCRP promoter in PRA-transfected cells; however, cotransfection of PRA and PRB significantly decreased the progesterone-response compared with that in cells transfected with only PRB. Mutations in a novel progesterone response element (PRE) identified between -243 to -115 bp of the BCRP promoter region significantly attenuated the progesterone-response in PRB-transfected cells, and deletion of the PRE nearly completely abrogated the progesterone effect. Specific binding of both PRA and PRB to the BCRP promoter through the identified PRE was confirmed using the electrophoretic mobility shift assay. Collectively, progesterone induces BCRP expression in BeWo cells via PRB but not PRA. PRA represses the PRB activity. Thus, PRA and PRB differentially regulate BCRP expression in BeWo cells.

  15. Upregulation of TrkB promotes epithelial-mesenchymal transition and anoikis resistance in endometrial carcinoma.

    PubMed

    Bao, Wei; Qiu, Haifeng; Yang, Tingting; Luo, Xin; Zhang, Huijuan; Wan, Xiaoping

    2013-01-01

    Mechanisms governing the metastasis of endometrial carcinoma (EC) are poorly defined. Recent data support a role for the cell surface receptor tyrosine kinase TrkB in the progression of several human tumors. Here we present evidence for a direct role of TrkB in human EC. Immunohistochemical analysis revealed that TrkB and its secreted ligand, brain-derived neurotrophic factor (BDNF), are more highly expressed in EC than in normal endometrium. High TrkB levels correlated with lymph node metastasis (p<0.05) and lymphovascular space involvement (p<0.05) in EC. Depletion of TrkB by stable shRNA-mediated knockdown decreased the migratory and invasive capacity of cancer cell lines in vitro and resulted in anoikis in suspended cells. Conversely, exogenous expression of TrkB increased cell migration and invasion and promoted anoikis resistance in suspension culture. Furthermore, over-expression of TrkB or stimulation by BDNF resulted in altered the expression of molecular mediators of the epithelial-to-mesenchymal transition (EMT). RNA interference (RNAi)-mediated depletion of the downstream regulator, Twist, blocked TrkB-induced EMT-like transformation. The use of in vivo models revealed decreased peritoneal dissemination in TrkB-depleted EC cells. Additionally, TrkB-depleted EC cells underwent mesenchymal-to-epithelial transition and anoikis in vivo. Our data support a novel function for TrkB in promoting EMT and resistance to anoikis. Thus, TrkB may constitute a potential therapeutic target in human EC. PMID:23936232

  16. Endometrial polyps

    MedlinePlus

    Uterine polyps ... one knows exactly why some women get endometrial polyps. They tend to grow when there is more ... the hormone estrogen in the body. Most endometrial polyps are not cancerous. About 5% can be cancerous ...

  17. [Endometrial imaging].

    PubMed

    Lemercier, E; Genevois, A; Dacher, J N; Benozio, M; Descargues, G; Marpeau, L

    2000-12-01

    The diagnostic value of endovaginal sonography in benign or malignant endometrial pathology is high, increased by sonohysterography. Sonohysterography is useful in the diagnosis of endometrial thickness and to determine further investigations. MRI is accurate in the uterine adenomyosis diagnosis and is the imaging modality of choice for the preoperative endometrial cancer staging. PMID:11173754

  18. The effect of progesterone treatment after ovarian induction on endometrial VEGF gene expression and its receptors in mice at pre-implantation time

    PubMed Central

    Boroujeni, Mandana Beigi; Boroujeni, Nasim Beigi; Gholami, Mohammadreza

    2016-01-01

    Objective(s): Progestrone is a prequisite for pre-implantation angiogenesis and induce decidual angiogenesis. It is unknown the effect of progestrone administration on the endometrium of hyperstimulated mice at pre-implantation time. Material and Methods: Adult female NMRI mice were divided in three groups [control group, ovarian stimulated group and progestrone treated mice after ovarian stimulation]. Uterine horn samples removed at pre-implantation time in each group. Motic image Plus 2 software was used to assess the quantitative vascular parameters of endometrium. Gene expression was determined for vascular endothelial growth factor (VEGF), FMS-like tyrosine kinase (FLT) and Kinase insert domain protein receptor (FLK) genes using the real time PCR method. Data analysis was done with LinReg PCR and Rest-RG software. Results: Comparison between progestrone treated mice after ovarian stimulation with control group showed that increase in rate of VEGF gene expression [0.775] and decrease in rate of FLK [6.072] and FLT [1.711] gene expression. Analysis of the data on quantitative vascular parameters were indicated remarkable increase in quantitative vascular parameters of progestrone treated mice compare to control group. Conclusion: Biological effect of progestrone on the vascular changes after ovarian stimulation resulted in an increase in VEGF receptors experession, it seems that induced angiogenesis by progesterone could result in better condition for implantation. PMID:27114794

  19. Endometrial Hyperplasia

    MedlinePlus

    ... the first part of the cycle, the hormone estrogen is made by the ovaries. Estrogen causes the lining to grow and thicken to ... a fertilized egg. If pregnancy does not occur, estrogen and progesterone levels decrease. The decrease in progesterone ...

  20. Insulin-like growth factor 1 regulates growth of endometrial carcinoma through PI3k signaling pathway in insulin-resistant type 2 diabetes

    PubMed Central

    Dai, Congwei; Li, Na; Song, Guangyao; Yang, Yanyan; Ning, Xiaoran

    2016-01-01

    Previous studies have shown that insulin-like growth factor 1 (IGF-1) may be responsible for the higher risk for developing endometrial carcinoma (EMC) in insulin-resistant type 2 diabetes mellitus (T2DM) patients. However, the underlying mechanisms are not understood. Here, we compared T2DM patients with or without EMC. We did not find difference in the serum levels of IGF-1, insulin-like growth factor 2 (IGF-2), IGF-1 binding protein 3, as well as the activation of IGF-1 receptor (IGF1R) in endometrial cells between T2DM patients with or without EMC. However, the levels of IGF2R activation and activation of PI3k, an IGF1R downstream factor, were significantly higher in endometrial cells in T2DM patients with EMC. In vitro analyses of activation of IGF1R, IGF2R, PI3k and CCND1 in EMC cells or IGF2R-overexpressing EMC cells by IGF-1 or IGF-2 suggest that increases in IGF2R in endometrial cells in T2DM may increase PI3k/CCND1-dependent cell growth through loss of competitive binding of IGF-2 to IGF1R, as a possible explanation for the higher risk for developing EMC in T2DM.

  1. Insulin-like growth factor 1 regulates growth of endometrial carcinoma through PI3k signaling pathway in insulin-resistant type 2 diabetes

    PubMed Central

    Dai, Congwei; Li, Na; Song, Guangyao; Yang, Yanyan; Ning, Xiaoran

    2016-01-01

    Previous studies have shown that insulin-like growth factor 1 (IGF-1) may be responsible for the higher risk for developing endometrial carcinoma (EMC) in insulin-resistant type 2 diabetes mellitus (T2DM) patients. However, the underlying mechanisms are not understood. Here, we compared T2DM patients with or without EMC. We did not find difference in the serum levels of IGF-1, insulin-like growth factor 2 (IGF-2), IGF-1 binding protein 3, as well as the activation of IGF-1 receptor (IGF1R) in endometrial cells between T2DM patients with or without EMC. However, the levels of IGF2R activation and activation of PI3k, an IGF1R downstream factor, were significantly higher in endometrial cells in T2DM patients with EMC. In vitro analyses of activation of IGF1R, IGF2R, PI3k and CCND1 in EMC cells or IGF2R-overexpressing EMC cells by IGF-1 or IGF-2 suggest that increases in IGF2R in endometrial cells in T2DM may increase PI3k/CCND1-dependent cell growth through loss of competitive binding of IGF-2 to IGF1R, as a possible explanation for the higher risk for developing EMC in T2DM. PMID:27648123

  2. Thalidomide in Treating Patients With Recurrent or Persistent Endometrial Cancer

    ClinicalTrials.gov

    2013-01-23

    Endometrial Adenoacanthoma; Endometrial Adenocarcinoma; Endometrial Adenosquamous Cell Carcinoma; Endometrial Clear Cell Carcinoma; Endometrial Papillary Serous Carcinoma; Recurrent Endometrial Carcinoma

  3. Endometrial Ablation

    MedlinePlus

    ... a thin layer of the lining of the uterus and stops the menstrual flow in many women. ... medical conditions, including the following: • Disorders of the uterus or endometrium • Endometrial hyperplasia • Cancer of the uterus • ...

  4. Endometrial Cancer

    MedlinePlus

    Member Login Join Pay Dues Follow us: Women's Health Care Physicians Contact Us My ACOG ACOG Departments Donate ... and is best made in consultation with your health care team. What happens after treatment for endometrial cancer? ...

  5. Progesterone Alleviates Endometriosis via Inhibition of Uterine Cell Proliferation, Inflammation and Angiogenesis in an Immunocompetent Mouse Model

    PubMed Central

    Kannan, Athilakshmi; Davila, Juanmahel; Zhao, Yuechao; Nowak, Romana A.; Bagchi, Milan K.; Bagchi, Indrani C.; Li, Quanxi

    2016-01-01

    Endometriosis, defined as growth of the endometrial cells outside the uterus, is an inflammatory disorder that is associated with chronic pelvic pain and infertility in women of childbearing age. Although the estrogen-dependence of endometriosis is well known, the role of progesterone in development of this disease remains poorly understood. In this study, we developed a disease model in which endometriosis was induced in the peritoneal cavities of immunocompetent female mice, and maintained with exogenous estrogen. The endometriosis-like lesions that were identified at a variety of ectopic locations exhibited abundant blood supply and extensive adhesions. Histological examination revealed that these lesions had a well-organized endometrial architecture and fibrotic response, resembling those recovered from clinical patients. In addition, an extensive proliferation, inflammatory response, and loss of estrogen receptor alpha (ERα) and progesterone receptor (PR) expression were also observed in these lesions. Interestingly, administration of progesterone before, but not after, lesion induction suppressed lesion expansion and maintained ERα and PR expressions. These progesterone-pretreated lesions exhibited attenuation in KI67, CD31, and pro-inflammatory cytokine expression as well as macrophage infiltration, indicating that progesterone ameliorates endometriosis progression by inhibiting cell proliferation, inflammation and neovascularization. Our studies further showed that suppression of global DNA methylation by application of DNA methyltransferase inhibitor to female mice bearing ectopic lesions restrained lesion expansion and restored ERα and PR expression in eutopic endometrium and ectopic lesions. These results indicate that epigenetic regulation of target gene expression via DNA methylation contributes, at least in part, to progesterone resistance in endometriosis. PMID:27776183

  6. Megestrol Acetate or Levonorgestrel-Releasing Intrauterine System in Treating Patients With Atypical Endometrial Hyperplasia or Endometrial Cancer

    ClinicalTrials.gov

    2014-09-09

    Atypical Endometrial Hyperplasia; Endometrial Adenocarcinoma; Recurrent Endometrial Carcinoma; Stage IA Endometrial Carcinoma; Stage IB Endometrial Carcinoma; Stage II Endometrial Carcinoma; Stage IIIA Endometrial Carcinoma; Stage IIIB Endometrial Carcinoma; Stage IIIC Endometrial Carcinoma; Stage IVA Endometrial Carcinoma; Stage IVB Endometrial Carcinoma

  7. Endometrial cancer

    MedlinePlus

    ... before age 12) Starting menopause after age 50 Tamoxifen, a drug used for breast cancer treatment Women ... without progesterone therapy or women who have taken tamoxifen for more than 2 years. Frequent pelvic exams, ...

  8. Endometrial haemostasis and menstruation.

    PubMed

    Davies, Joanna; Kadir, Rezan A

    2012-12-01

    Under normal physiological circumstances menstruation is a highly regulated, complex process that is under strict hormonal control. During normal menstruation, progesterone withdrawal initiates menstruation. The cessation of menstrual bleeding is achieved by endometrial haemostasis via platelet aggregation, fibrin deposition and thrombus formation. Local endocrine, immunological and haemostatic factors interact at a molecular level to control endometrial haemostasis. Tissue factor and thrombin play a key role locally in the cessation of menstrual bleeding through instigation of the coagulation factors. On the other hand, fibrinolysis prevents clot organisation within the uterine cavity while plasminogen activator inhibitors (PAI) and thrombin-activatable fibrinolysis inhibitors control plasminogen activators and plasmin activity. Abnormalities of uterine bleeding can result from imbalance of the haemostatic factors. The most common abnormality of uterine bleeding is heavy menstrual bleeding (HMB). Modern research has shown that an undiagnosed bleeding disorder, in particular von Willebrand disease (VWD) and platelet function disorders, can be an underlying cause of HMB. This has led to a change in the approach to the management of HMB. While full haemostatic assessment is not required for all women presenting with HMB, menstrual score and bleeding score can help to discriminate women who are more likely to have a bleeding disorder and benefit from laboratory haemostatic evaluation. Haemostatic agents (tranexamic acid and DDAVP) enhance systemic and endometrial haemostasis and are effective in reducing menstrual blood loss in women with or without bleeding disorders. Further research is required to enhance our understanding of the complex interactions of haemostatic factors in general, and specifically within the endometrium. This will lead to the development of more targeted interventions for the management of abnormal uterine bleeding in the future.

  9. Endometrial thickness and risk of breast and endometrial carcinomas in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

    PubMed Central

    Felix, Ashley S.; Weissfeld, Joel L.; Pfeiffer, Ruth M.; Modugno, Francesmary; Black, Amanda; Hill, Lyndon M.; Martin, Jerry; Sit, Anita S.; Sherman, Mark E.; Brinton, Louise A.

    2013-01-01

    Postmenopausal women with higher circulating estrogen levels are at increased risk of developing breast and endometrial carcinomas. In the endometrium, excess estrogen relative to progesterone produces a net proliferative stimulus, which may result in endometrial thickening. Therefore, we tested the hypothesis that endometrial thickness is a biological marker of excess estrogen stimulation that is associated with risk of breast and endometrial carcinomas. Endometrial thickness was measured in 1,272 postmenopausal women, aged 55–74, who underwent transvaginal ultrasound (TVU) screening as part of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Serial endometrial thickness measurements were available for a subset of women at one (n=1,018), two (n=869) and three years (n=641) after baseline. We evaluated associations between endometrial thickness and breast (n=91) and endometrial (n=14) carcinoma by estimating relative risks (RRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression with age as the time metric. Models incorporating baseline endometrial thickness and as a time-varying covariate using all measurements were examined. Median follow-up among study participants was 12.5 years (range: 0.3–13.8 years). Compared to baseline endometrial thickness of 1.0 – 2.99 mm, women with baseline endometrial thickness greater than or equal to 5.0 mm had an increased risk of breast (RR: 2.00, 95% CI 1.15, 3.48) and endometrial (RR: 5.02, 95% CI 0.96, 26.36) carcinomas in models adjusted for menopausal hormone use and BMI. Our data suggest that increased endometrial thickness as assessed by TVU was associated with increased risk of breast and endometrial carcinomas. PMID:23907658

  10. Androgen Receptor Increases CD133 Expression and Progenitor-Like Population That Associate With Cisplatin Resistance in Endometrial Cancer Cell Line

    PubMed Central

    Chen, Lumin; Chang, Wei-Chun; Hung, Yao-Ching; Chang, Ying-Yi; Bao, Bo-Yin; Huang, Hsin-Ching; Chung, Wei-Min; Shyr, Chih-Rong

    2014-01-01

    Endometrial cancer (EMC) is a sex steroid hormone-related female malignancy. Androgen and androgen receptor (androgen/AR) signals have been implicated in EMC progression. Cancer stem/progenitor cells (CSPCs) are suspected to link to chemoresistance in patients with EMC. In this study, we examined the androgen/AR roles in cisplatin resistance and CSPC population. We found AR expression increased naive EMC side population, CSPC population, cell migration, and epithelial–mesenchymal transition. Meanwhile, it decreased cisplatin cytotoxic effect on EMC cells. Collaterally, endogenous AR expressions in EMC cells were upregulated in the cisplatin-resisting state. Moreover, AR expression could further enhance CD133 expression, CSPC-related markers, and drug-resistance gene messenger RNA expression in EMC cells. Finally, the AR-associated gene expression might go through indirect regulation. This is the first report revealing AR function on EMC cells’ CSPC and cisplatin resistance. PMID:23962788

  11. EGFR- and AKT-mediated reduction in PTEN expression contributes to tyrphostin resistance and is reversed by mTOR inhibition in endometrial cancer cells.

    PubMed

    Li, Tian; Yang, Yuebo; Li, Xiaomao; Xu, Chengfang; Meng, Lirong

    2012-02-01

    Loss or mutation of the PTEN (phosphatase and tensin homologue deleted on chromosome 10) gene is associated with resistance to epidermal growth factor receptor (EGFR) inhibitors. However, the mechanism underlying remains elusive. In this study, we aimed to explore whether sensitivity to the EGFR tyrosine kinase inhibitor (TKI) is affected by PTEN status in endometrial cancer cells. PTEN siRNA and the PTEN gene were transfected into HEC-1A and Ishikawa endometrial cancer cells using lentiviral vectors. Cells were treated under various concentrations of RG14620 and rapamycin, which are EGFR and mammalian target of rapamycin (mTOR) inhibitors, respectively. The IC(50) of RG16420 was determined by using the MTT method. Cell apoptosis and the cell cycle were studied, and activation of EGFR, AKT, and p70S6 were detected by Western blot analysis. Loss of PTEN promoted cell proliferation and led to significant increases in the levels of EGFR, phospho-EGFR, AKT, phospho-AKT, and phospho-mTOR proteins. Ishikawa and HEC-1A(PTENkd) cells that displayed loss and inactivation of PTEN function were resistant to RG14620. HEC-1A and Ishikawa(PTEN) cells with intact PTEN were sensitive to RG14620. The combination of two inhibitors was more effective than both monotherapies, particularly in carcinoma cells with PTEN dysfunction. Decreased phospho-EGFR protein expression was observed in all cell lines that were sensitive to RG14620. Decreased phospho-AKT and phospho-p70S6 protein expression was observed in PTEN-intact cells that were sensitive to RG14620. PTEN loss results in resistance to EGFR TKI, which was reversed by PTEN reintroduction or mTOR inhibitor treatment. The combined treatment of EGFR TKI and the mTOR inhibitor provided a synergistic effect by promoting cell death in PTEN-deficient and PTEN-intact endometrial cancer cells, particularly in PTEN-deficient carcinoma cells with up-regulated EGFR activation.

  12. The important application of thioridazine in the endometrial cancer

    PubMed Central

    Meng, Qiong; Sun, Xiao; Wang, Jing; Wang, Yudong; Wang, Lihua

    2016-01-01

    Background: Endometrial cancer (ECa) is one of the serious healthy burden for female worldwide. The treatments of ECa focus on the application of endocrine therapy and aberrant signaling proteins expression recently years. Medroxyprogesterone acrtate (MPA) plays crucial role in the endocrine therapy for ECa patients. However, the outcomes are still not ideal in the advanced stage tumor, especially in the progesterone-resistant ECa. Thioridazine (THIO) is an anti-psychotic agent, which has been reported to suppress the development of several human cancers. In this study, we aimed at to explore the clinical significant of THIO in the treatment of ECa. Methods: Two ECa cell lines (ISK and KLE) were enrolled in this study, and were grouped into fore groups based on the treatment with different agents. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay was used to analyze the viability of ECa cell lines. The apoptosis of ECa cells was examined by using the flow cytometer. To investigate the expression of important proteins, we applied the quantitative real-time RT-PCR (qRT-PCR) method and western blot analysis. Results: The viability of ECa cells was downregulated, and the apoptosis of ECa cells was upregulated after treating with the THIO plus MPA. The expression of progesterone receptor B (PRB) and dopamine receptor D2 (DRD2) were increased, and epidermal growth factor receptor (EGFR) and p-AKT were decreased in the THIO+MPA group. All these results suggested that the THIO could promote MPA to inhibit the growth of cells in ECa, especially in the progesterone-resistant ECa. Conclusion: Taken together, all the data in the present study suggested that the THIO plus MPA might act as the suppressor of tumor growth in ECa by inhibiting the PI3K/AKT signal transduction pathway, which was mediated by PRB, DRD2 and EGFR. PMID:27398159

  13. Effects of adipocyte-secreted factors on decidualized endometrial cells: modulation of endometrial receptivity in vitro.

    PubMed

    Gamundi-Segura, Silvia; Serna, Jose; Oehninger, Sergio; Horcajadas, Jose A; Arbones-Mainar, Jose M

    2015-09-01

    Obesity is defined as an excessive accumulation of adipose tissue that may lead to health complications. Mounting evidence indicates that obesity has a negative impact on fertility. Yet, the link between adipose tissue biology and infertility remains unclear. We aimed to investigate the communication between the adipose tissue and the reproductive system and the importance of this cross talk for the development of a receptive endometrium. To that end, we generated an in vitro model with endometrial and adipocyte cell lines. Sexual hormones, progesterone and estradiol, were used to decidualize endometrial cells and sensitize adipocytes. Decidualization produced a simultaneous increase of adipokine receptors in endometrial cells paralleling changes in their receptivity status. Furthermore, sensitization of 3T3-L1 adipocytes increased mRNA levels of leptin and resistin and decreased the expression of adiponectin and chemerin levels. This was accompanied by increased isoproterenol-induced lipolysis and reduced insulin-stimulated glucose uptake. Lastly, conditioned culture medium of those sensitized adipocytes was used to feed endometrial cells. This treatment resulted in (i) upregulation of genes previously identified as positive regulators of endometrial receptivity, such as leukemia inhibitory factor and glutathione peroxidase 3, and (ii) downregulation of interleukin-15 and mucin1, both genes negatively related with endometrial receptivity. Our results indicate that the endocrine communication between adipose tissue and the reproductive system is bidirectional and stress the importance of the adipose tissue to modulate the reproductive fitness.

  14. Effects of interferon-tau and steroids on cytochrome P450 activity in bovine endometrial epithelial cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective of the current study was to examine cyclooxygenase (COX), cytochrome P450 1A (CYP1A) and 2C (CYP2C) activity in bovine endometrial cell cultures following exposure to oxytocin (OT), interferon-t (IFN), estradiol (E2) and/or progesterone (P4). Bovine endometrial epithelial cells were tr...

  15. Is the pineal gland involved in the pathogenesis of endometrial carcinoma.

    PubMed

    Sandyk, R; Anastasiadis, P G; Anninos, P A; Tsagas, N

    1992-01-01

    The pathogenesis of endometrial carcinoma, which is the most common malignant neoplasm of the female genital tract, is unknown. It is believed that a prolonged period of increased estrogenic exposure unopposed by progesterone may underlie the malignant transformation of the endometrial cells. In the following communication, we propose that deficient melatonin functions may be an additional endocrine factor implicated in the pathogenesis of endometrial carcinoma. This hypothesis is based on the observations that: (a) melatonin has antiestrogenic properties; (b) melatonin stimulates progesterone production which opposes the action of estrogens; (c) an increased rate of endometrial hyperplasia, a premalignant condition, has been noted during the winter, a time of year associated with diminished melatonin secretion; (d) an increased incidence of anovulatory cycles, which is a risk factor for endometrial carcinoma, occurs in the winter; (e) melatonin secretion decreases sharply during the menopause, a period associated with an increased risk of endometrial carcinoma; (f) obesity, which is a major risk factor for endometrial carcinoma, is associated with impaired circadian melatonin secretion; (g) diabetes mellitus, which is an additional risk factor for endometrial carcinoma, is associated with decreased melatonin secretion and an increased rate of pineal calcification; and (h) the prevalence of endometrial carcinoma is lower in the black population compared to the white population. Similarly, the incidence of pineal calcification, which reflects the secretory activity of the gland, is significantly lower in the African and American black populations as compared to the white population.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1342018

  16. Is the pineal gland involved in the pathogenesis of endometrial carcinoma.

    PubMed

    Sandyk, R; Anastasiadis, P G; Anninos, P A; Tsagas, N

    1992-01-01

    The pathogenesis of endometrial carcinoma, which is the most common malignant neoplasm of the female genital tract, is unknown. It is believed that a prolonged period of increased estrogenic exposure unopposed by progesterone may underlie the malignant transformation of the endometrial cells. In the following communication, we propose that deficient melatonin functions may be an additional endocrine factor implicated in the pathogenesis of endometrial carcinoma. This hypothesis is based on the observations that: (a) melatonin has antiestrogenic properties; (b) melatonin stimulates progesterone production which opposes the action of estrogens; (c) an increased rate of endometrial hyperplasia, a premalignant condition, has been noted during the winter, a time of year associated with diminished melatonin secretion; (d) an increased incidence of anovulatory cycles, which is a risk factor for endometrial carcinoma, occurs in the winter; (e) melatonin secretion decreases sharply during the menopause, a period associated with an increased risk of endometrial carcinoma; (f) obesity, which is a major risk factor for endometrial carcinoma, is associated with impaired circadian melatonin secretion; (g) diabetes mellitus, which is an additional risk factor for endometrial carcinoma, is associated with decreased melatonin secretion and an increased rate of pineal calcification; and (h) the prevalence of endometrial carcinoma is lower in the black population compared to the white population. Similarly, the incidence of pineal calcification, which reflects the secretory activity of the gland, is significantly lower in the African and American black populations as compared to the white population.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. miR-200 Regulates Endometrial Development During Early Pregnancy.

    PubMed

    Jimenez, Patricia T; Mainigi, Monica A; Word, R Ann; Kraus, W Lee; Mendelson, Carole R

    2016-09-01

    For successful embryo implantation, endometrial stromal cells must undergo functional and morphological changes, referred to as decidualization. However, the molecular mechanisms that regulate implantation and decidualization are not well defined. Here we demonstrate that the estradiol- and progesterone-regulated microRNA (miR)-200 family was markedly down-regulated in mouse endometrial stromal cells prior to implantation, whereas zinc finger E-box binding homeobox-1 and -2 and other known and predicted targets were up-regulated. Conversely, miR-200 was up-regulated during in vitro decidualization of human endometrial stromal cells. Knockdown of miR-200 negatively affected decidualization and prevented the mesenchymal-epithelial transition-like changes that accompanied decidual differentiation. Notably, superovulation of mice and humans altered miR-200 expression. Our findings suggest that hormonal alterations that accompany superovulation may negatively impact endometrial development and decidualization by causing aberrant miR-200 expression. PMID:27533790

  18. What Is Endometrial Cancer?

    MedlinePlus

    ... endometrial adenocarcinomas. These types tend to be more aggressive than most endometrial cancers. They tend to grow ... forming glands. Grade 3 cancers tend to be aggressive and have a poorer outlook than lower-grade ...

  19. Novel Roles for Hypoxia and Prostaglandin E2 in the Regulation of IL-8 During Endometrial Repair

    PubMed Central

    Maybin, Jacqueline A.; Hirani, Nikhil; Jabbour, Henry N.; Critchley, Hilary O.D.

    2011-01-01

    The endometrium has a remarkable capacity for efficient repair; however, factors involved remain undefined. Premenstrual progesterone withdrawal leads to increased prostaglandin (PG) production and local hypoxia. Here we determined human endometrial expression of interleukin-8 (IL-8) and the roles of PGE2 and hypoxia in its regulation. Endometrial biopsy specimens (n = 51) were collected. Endometrial cells and explants were exposed to 100 nmol/L of PGE2 or 0.5% O2. The endometrial IL-8 concentration peaked during menstruation (P < 0.001) and had a significant proangiogenic effect. IL-8 was increased by PGE2 and hypoxia in secretory but not proliferative explants, which suggests that exposure to progesterone is essential. In vitro progesterone withdrawal induced significant IL-8 up-regulation in proliferative explants primed with progestins, but only in the presence of hypoxia. Epithelial cells treated simultaneously with PGE2 and hypoxia demonstrated synergistic increases in IL-8. Inhibition of HIF-1 by short hairpin RNA abolished hypoxic IL-8 induction, and inhibition of NF-κB by an adenoviral dominant negative inhibitor decreased PGE2-induced IL-8 expression (P > 0.05). Increased menstrual IL-8 is consistent with a role in repair. Progesterone withdrawal, hypoxia, and PGE2 regulate endometrial IL-8 by acting via HIF-1 and NF-κB. Hence, progesterone withdrawal may activate two distinct pathways to initiate endometrial repair. PMID:21356375

  20. Copanlisib in Treating Patients With Persistent or Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2016-10-25

    Endometrial Endometrioid Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Undifferentiated Carcinoma; Metastatic Endometrioid Adenocarcinoma; Recurrent Uterine Corpus Carcinoma

  1. Role of nuclear progesterone receptor isoforms in uterine pathophysiology

    PubMed Central

    Patel, Bansari; Elguero, Sonia; Thakore, Suruchi; Dahoud, Wissam; Bedaiwy, Mohamed; Mesiano, Sam

    2015-01-01

    BACKGROUND Progesterone is a key hormonal regulator of the female reproductive system. It plays a major role to prepare the uterus for implantation and in the establishment and maintenance of pregnancy. Actions of progesterone on the uterine tissues (endometrium, myometrium and cervix) are mediated by the combined effects of two progesterone receptor (PR) isoforms, designated PR-A and PR-B. Both receptors function primarily as ligand-activated transcription factors. Progesterone action on the uterine tissues is qualitatively and quantitatively determined by the relative levels and transcriptional activities of PR-A and PR-B. The transcriptional activity of the PR isoforms is affected by specific transcriptional coregulators and by PR post-translational modifications that affect gene promoter targeting. In this context, appropriate temporal and cell-specific expression and function of PR-A and PR-B are critical for normal uterine function. METHODS Relevant studies describing the role of PRs in uterine physiology and pathology (endometriosis, uterine leiomyoma, endometrial cancer, cervical cancer and recurrent pregnancy loss) were comprehensively searched using PubMed, Cochrane Library, Web of Science, and Google Scholar and critically reviewed. RESULTS Progesterone, acting through PR-A and PR-B, regulates the development and function of the endometrium and induces changes in cells essential for implantation and the establishment and maintenance of pregnancy. During pregnancy, progesterone via the PRs promotes myometrial relaxation and cervical closure. Withdrawal of PR-mediated progesterone signaling triggers menstruation and parturition. PR-mediated progesterone signaling is anti-mitogenic in endometrial epithelial cells, and as such, mitigates the tropic effects of estrogen on eutopic normal endometrium, and on ectopic implants in endometriosis. Similarly, ligand-activated PRs function as tumor suppressors in endometrial cancer cells through inhibition of key

  2. CD82 expression alters with human endometrial cycles and affects the uterine endometrial receptivity in vitro.

    PubMed

    Wei, Xiaowei; Liu, Shuai; Wang, Xiaoqi; Yan, Qiu

    2012-03-01

    Embryo implantation is a process that requires both temporal and spatial synchronization of the uterine endometrium and the embryo, and the endometrium becomes receptive to the embryo during the window of implantation. Although the expression patterns of many implantation-related molecules change dynamically during this process, the impact of CD82 on endometrial receptivity has not been elucidated. By immunohistochemical staining, we found that CD82 levels rose from the proliferative phase to the secretory phase in human endometrium. Specifically, the highest level appeared in mid- and late-secretory phases. Consistently, RL95-2 cells, representative of high-receptive endometrial epithelium, expressed higher levels of CD82 than did HEC-1A cells, which are representative of low-receptive endometrial epithelium, as detected by reverse transcription-polymerase chain reaction, Western blot and immunofluorescence. Furthermore, progesterone up-regulated the expression of CD82 in both epithelial cell lines. Down-regulation of CD82 in RL95-2 cells by either CD82 siRNA transfection or treatment with a CD82 antibody significantly decreased the adhesion of human embryonic JAR cells to RL95-2 cell monolayers (P < 0.01) and inhibited the phosphorylation of focal adhesion kinase (FAK). In contrast, up-regulation of CD82 in HEC-1A cells by CD82 cDNA transfection promoted embryonic JAR cell adhesion to HEC-1A monolayers (P < 0.05) and activated the phosphorylation of FAK. In conclusion, the expression of CD82 increases in endometrial tissues during the window of embryo implantation, CD82 expression affects endometrial receptivity of the uterine epithelial cells in vitro, and the FAK signaling pathway may be involved in this phenomenon. The correlation between CD82 and endometrial receptivity suggests that CD82 may serve as a potential marker of endometrial function. PMID:22393164

  3. Comparison of estrogen receptor-α, progesterone receptor and calponin expression in gonadotrophin-releasing hormone agonist-sensitive and -resistant uterine fibroids

    PubMed Central

    Kim, Eun Hee; Kim, Joo Young; Lee, Yoon Hee; Chong, Gun Oh; Park, Ji Young

    2014-01-01

    Objective This study was aimed to compare immunohistochemical expression of estrogen receptor (ER)-α, progesterone receptor (PR), and calponin in gonadotrophin-releasing hormone agonist (GnRH-a)-sensitive and -resistant uterine fibroids. Methods We collected data retrospectively. The sensitive group consisted of women who had reduction in uterine volume greater than 40% following GnRH-a treatment. Uterine volume was either reduced by less than 10%, or was increased in the resistant group. A tissue microarray was constructed using formalin-fixed, paraffin-embedded tissues, 31 and 26 patients for the sensitive and resistant groups, respectively. Tissue sections were immunostained with antibodies against ER-α, PR, and calponin. The intensity and area of the immunohistochemical reactions were evaluated using a semi-quantitative scoring system. The Mann-Whitney U-test, Fisher's exact test, and Spearman's rank correlation test were used for analysis of data. Results PR (P = 0.04) and calponin (P = 0.03) showed a significantly higher staining intensity in the resistant group than in the sensitive group. Both groups showed comparable expression of ER-α (P = 0.23). In correlation analysis between changes in uterine volume after GnRH-a therapy and clinicopathological factors, the immunohistochemical intensity of PR (P = 0.04) and calponin (P = 0.03) was significantly correlated with changes in uterine volume. Conclusion This study shows that GnRH-a resistance of uterine fibroids is not related to ER-α content, but the expression of PR and calponin is related with GnRH-a resistance. PMID:24678488

  4. In vitro release of ovarian progesterone is decreased during the oestrous cycle and pregnancy of swine with obesity/leptin resistance.

    PubMed

    Astiz, S; Gonzalez-Bulnes, A; Perez-Solana, M L; Sanchez-Sanchez, R; Torres-Rovira, L

    2013-06-01

    Previous studies indicate that reproductive prolificacy of obese swine breeds is markedly influenced by embryo losses in early pregnancy. In such period, adequate secretion of progesterone (P4) by the ovary is essential for pregnancy success. This study analyses the luteal functionality during the oestrous cycle and early pregnancy of Iberian sows and Large White x Landrace females, in terms of P4 secretion after in vitro culture of luteal tissue stimulated or not with luteinizing hormone (LH). The secretion of progesterone (expressed in ng/mg of luteal tissue or ng/mgLT) of the corpora lutea of obese Iberian swine was always hampered when compared to lean genotypes, either during early oestrous cycle (110.7 ± 37.8 vs 259.7 ± 10.2 ng/mgLT; p < 0.0001), late oestrous cycle (49.0 ± 3.5 vs 75.92 ± 7.14 ng/mgLT; p < 0.0001) or early pregnancy (38.4 ± 2.1 vs 70.7 ± 5.3 ng/mgLT; p < 0.0001). The differences in basal P4 secretion remained after stimulation with LH. Finally, P4 secretion during early pregnancy of Iberian sows decreased with age and, hence, with obesity features (46.6 ± 4.2 vs 65.5 ± 4.8 ng/mgLT; p < 0.001). In conclusion, the results of the present study provide convincing evidence of a reduced luteal function during oestrous cycle and early pregnancy of sows with obesity/leptin resistance like Iberian sows, which may contribute to the low reproductive efficiency reported in this breed.

  5. Trebananib in Treating Patients With Persistent or Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2016-02-10

    Endometrial Adenocarcinoma; Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Endometrioid Adenocarcinoma, Variant With Squamous Differentiation; Endometrial Serous Adenocarcinoma; Endometrioid Stromal Sarcoma; Recurrent Uterine Corpus Carcinoma

  6. Trametinib With or Without GSK2141795 in Treating Patients With Recurrent or Persistent Endometrial Cancer

    ClinicalTrials.gov

    2016-08-24

    Endometrial Adenocarcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Undifferentiated Carcinoma; Recurrent Uterine Corpus Carcinoma

  7. Distinction of endometrial stromal sarcomas from 'hemangiopericytomatous' tumors using a panel of immunohistochemical stains.

    PubMed

    Bhargava, Rohit; Shia, Jinru; Hummer, Amanda J; Thaler, Howard T; Tornos, Carmen; Soslow, Robert A

    2005-01-01

    Endometrial stromal sarcomas are low-grade malignant tumors that may pose a diagnostic challenge, especially when they are present in an extrauterine site. Owing to the presence of an arborizing vasculature and cells with an undifferentiated appearance, endometrial stromal sarcomas can be confused with several soft-tissue neoplasms. We studied 17 endometrial stromal sarcomas, eight hemangiopericytomas, 14 solitary fibrous tumors, and 16 synovial sarcomas immunohistochemically, detecting the following antigens: CD10, estrogen receptor, progesterone receptor, bcl-2, CD34, smooth muscle antigen, epithelial membrane antigen and cytokeratin (AE1/AE3). Most endometrial stromal sarcomas stained positively for CD10 (16/17), estrogen receptor (17/17), progesterone receptor (15/17), and bcl-2 (17/17). Staining with antismooth muscle antigen was seen in 11 of 17 cases of endometrial stromal sarcoma, with more intense staining seen in areas showing smooth muscle differentiation. Staining with AE1/3 was seen in four of 17 endometrial stromal sarcomas, with two of the positive cases containing epithelioid cells. None of the endometrial stromal sarcomas expressed epithelial membrane antigen or CD34. More than half of the hemangiopericytomas (4/8) and solitary fibrous tumors (9/14) cases demonstrated CD10 expression either focally or in a patchy cytoplasmic and membranous pattern. Hemangiopericytomas, solitary fibrous tumors, and synovial sarcomas did not express estrogen receptor. Four of eight hemangiopericytomas and seven of 14 solitary fibrous tumors also showed patchy progesterone receptor expression. CD34 expression was identified in six of eight hemangiopericytomas and 13 of 14 solitary fibrous tumors, but we did not find expression of CD34 in synovial sarcoma. Differences between endometrial stromal sarcoma and other soft-tissue tumors were detected for all of the immunohistochemical markers (P<0.05), except anti-bcl-2 and AE1/3. Antibodies against CD10 mark a substantial

  8. Integrated genomic characterization of endometrial carcinoma.

    PubMed

    Kandoth, Cyriac; Schultz, Nikolaus; Cherniack, Andrew D; Akbani, Rehan; Liu, Yuexin; Shen, Hui; Robertson, A Gordon; Pashtan, Itai; Shen, Ronglai; Benz, Christopher C; Yau, Christina; Laird, Peter W; Ding, Li; Zhang, Wei; Mills, Gordon B; Kucherlapati, Raju; Mardis, Elaine R; Levine, Douglas A

    2013-05-01

    We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.

  9. Decidualization and syndecan-1 knock down sensitize endometrial stromal cells to apoptosis induced by embryonic stimuli.

    PubMed

    Boeddeker, Sarah Jean; Baston-Buest, Dunja Maria; Fehm, Tanja; Kruessel, Jan; Hess, Alexandra

    2015-01-01

    Human embryo invasion and implantation into the inner wall of the maternal uterus, the endometrium, is the pivotal process for a successful pregnancy. Whereas disruption of the endometrial epithelial layer was already correlated with the programmed cell death, the role of apoptosis of the subjacent endometrial stromal cells during implantation is indistinct. The aim was to clarify whether apoptosis plays a role in the stromal invasion and to characterize if the apoptotic susceptibility of endometrial stromal cells to embryonic stimuli is influenced by decidualization and Syndecan-1. Therefore, the immortalized human endometrial stromal cell line St-T1 was used to first generate a new cell line with a stable Syndecan-1 knock down (KdS1), and second to further decidualize the cells with progesterone. As a replacement for the ethically inapplicable embryo all cells were treated with the embryonic factors and secretion products interleukin-1β, interferon-γ, tumor necrosis factor-α, transforming growth factor-β1 and anti-Fas antibody to mimic the embryo contact. Detection of apoptosis was verified via Caspase ELISAs, PARP cleavage and Annexin V staining. Apoptosis-related proteins were investigated via antibody arrays and underlying signaling pathways were analyzed by Western blot. Non-decidualized endometrial stromal cells showed a resistance towards apoptosis which was rescinded by decidualization and Syndecan-1 knock down independent of decidualization. This was correlated with an altered expression of several pro- and anti-apoptotic proteins and connected to a higher activation of pro-survival Akt in non-differentiated St-T1 as an upstream mediator of apoptotis-related proteins. This study provides insight into the largely elusive process of implantation, proposing an important role for stromal cell apoptosis to successfully establish a pregnancy. The impact of Syndecan-1 in attenuating the apoptotic signal is particularly interesting in the light of an already

  10. A murine uterine transcriptome, responsive to steroid receptor coactivator-2, reveals transcription factor 23 as essential for decidualization of human endometrial stromal cells.

    PubMed

    Kommagani, Ramakrishna; Szwarc, Maria M; Kovanci, Ertug; Creighton, Chad J; O'Malley, Bert W; Demayo, Francesco J; Lydon, John P

    2014-04-01

    Recent data from human and mouse studies strongly support an indispensable role for steroid receptor coactivator-2 (SRC-2)-a member of the p160/SRC family of coregulators-in progesterone-dependent endometrial stromal cell decidualization, an essential cellular transformation process that regulates invasion of the developing embryo into the maternal compartment. To identify the key progesterone-induced transcriptional changes that are dependent on SRC-2 and required for endometrial decidualization, we performed comparative genome-wide transcriptional profiling of endometrial tissue RNA from ovariectomized SRC-2(flox/flox) (SRC-2(f/f) [control]) and PR(cre/+)/SRC-2(flox/flox) (SRC-2(d/d) [SRC-2-depleted]) mice, acutely treated with vehicle or progesterone. Although data mining revealed that only a small subset of the total progesterone-dependent transcriptional changes is dependent on SRC-2 (∼13%), key genes previously reported to mediate progesterone-driven endometrial stromal cell decidualization are present within this subset. Along with providing a more detailed molecular portrait of the decidual transcriptional program governed by SRC-2, the degree of functional diversity of these progesterone mediators underscores the pleiotropic regulatory role of SRC-2 in this tissue. To showcase the utility of this powerful informational resource to uncover novel signaling paradigms, we stratified the total SRC-2-dependent subset of progesterone-induced transcriptional changes in terms of novel gene expression and identified transcription factor 23 (Tcf23), a basic-helix-loop-helix transcription factor, as a new progesterone-induced target gene that requires SRC-2 for full induction. Importantly, using primary human endometrial stromal cells in culture, we demonstrate that TCF23 function is essential for progesterone-dependent decidualization, providing crucial translational support for this transcription factor as a new decidual mediator of progesterone action.

  11. A Murine Uterine Transcriptome, Responsive to Steroid Receptor Coactivator-2, Reveals Transcription Factor 23 as Essential for Decidualization of Human Endometrial Stromal Cells1

    PubMed Central

    Kommagani, Ramakrishna; Szwarc, Maria M.; Kovanci, Ertug; Creighton, Chad J.; O'Malley, Bert W.; DeMayo, Francesco J.; Lydon, John P.

    2014-01-01

    ABSTRACT Recent data from human and mouse studies strongly support an indispensable role for steroid receptor coactivator-2 (SRC-2)—a member of the p160/SRC family of coregulators—in progesterone-dependent endometrial stromal cell decidualization, an essential cellular transformation process that regulates invasion of the developing embryo into the maternal compartment. To identify the key progesterone-induced transcriptional changes that are dependent on SRC-2 and required for endometrial decidualization, we performed comparative genome-wide transcriptional profiling of endometrial tissue RNA from ovariectomized SRC-2flox/flox (SRC-2f/f [control]) and PRcre/+/SRC-2flox/flox (SRC-2d/d [SRC-2-depleted]) mice, acutely treated with vehicle or progesterone. Although data mining revealed that only a small subset of the total progesterone-dependent transcriptional changes is dependent on SRC-2 (∼13%), key genes previously reported to mediate progesterone-driven endometrial stromal cell decidualization are present within this subset. Along with providing a more detailed molecular portrait of the decidual transcriptional program governed by SRC-2, the degree of functional diversity of these progesterone mediators underscores the pleiotropic regulatory role of SRC-2 in this tissue. To showcase the utility of this powerful informational resource to uncover novel signaling paradigms, we stratified the total SRC-2-dependent subset of progesterone-induced transcriptional changes in terms of novel gene expression and identified transcription factor 23 (Tcf23), a basic-helix-loop-helix transcription factor, as a new progesterone-induced target gene that requires SRC-2 for full induction. Importantly, using primary human endometrial stromal cells in culture, we demonstrate that TCF23 function is essential for progesterone-dependent decidualization, providing crucial translational support for this transcription factor as a new decidual mediator of progesterone action. PMID

  12. Ultrastructural and histochemical markers of endometrial secretion induction in habitual miscarriage.

    PubMed

    Ilizarova, N A; Marinkin, I O; Ageeva, T A; Bgatova, N P; Kuleshov, V M; Aidagulova, S V

    2009-10-01

    Biphasic hormone therapy at the stage of pre-gestation treatment of patients with habitual miscarriages stimulates the expression of progesterone receptors in the endometrium during the secretory phase of the menstrual cycle with full-value ultrastructural rearrangement of the endometrial glandular components in comparison with the patients receiving metabolic therapy alone. PMID:20396766

  13. Rethinking progesterone regulation of female reproductive cyclicity

    PubMed Central

    Kubota, Kaiyu; Cui, Wei; Dhakal, Pramod; Wolfe, Michael W.; Rumi, M. A. Karim; Vivian, Jay L.; Roby, Katherine F.; Soares, Michael J.

    2016-01-01

    The progesterone receptor (PGR) is a ligand-activated transcription factor with key roles in the regulation of female fertility. Much has been learned of the actions of PGR signaling through the use of pharmacologic inhibitors and genetic manipulation, using mouse mutagenesis. Characterization of rats with a null mutation at the Pgr locus has forced a reexamination of the role of progesterone in the regulation of the female reproductive cycle. We generated two Pgr mutant rat models, using genome editing. In both cases, deletions yielded a null mutation resulting from a nonsense frame-shift and the emergence of a stop codon. Similar to Pgr null mice, Pgr null rats were infertile because of deficits in sexual behavior, ovulation, and uterine endometrial differentiation. However, in contrast to the reported phenotype of female mice with disruptions in Pgr signaling, Pgr null female rats exhibit robust estrous cycles. Cyclic changes in vaginal cytology, uterine histology, serum hormone levels, and wheel running activity were evident in Pgr null female rats, similar to wild-type controls. Furthermore, exogenous progesterone treatment inhibited estrous cycles in wild-type female rats but not in Pgr-null female rats. As previously reported, pharmacologic antagonism supports a role for PGR signaling in the regulation of the ovulatory gonadotropin surge, a result at variance with experimentation using genetic ablation of PGR signaling. To conclude, our findings in the Pgr null rat challenge current assumptions and prompt a reevaluation of the hormonal control of reproductive cyclicity. PMID:27035990

  14. Fenretinide: A Novel Treatment for Endometrial Cancer

    PubMed Central

    Mittal, Navdha; Malpani, Saurabh; Dyson, Matthew; Ono, Masanori; Coon, John S.; Kim, Julie J.; Schink, Julian C.; Bulun, Serdar E.; Pavone, Mary Ellen

    2014-01-01

    Resistance to progestin treatment is a major hurdle in the treatment of advanced and reoccurring endometrial cancer. Fenretinide is a synthetic retinoid that has been evaluated in clinical trials as a cancer therapeutic and chemo-preventive agent. Fenretinide has been established to be cytotoxic to many kinds of cancer cells. In the present study, we demonstrate that fenretinide decreased cell viability and induced apoptosis in Ishikawa cells, which are an endometrial cancer cell line, in dose dependent manner in-vitro. This effect was found to be independent of retinoic acid nuclear receptor signaling pathway. Further, we have shown that this induction of apoptosis by fenretinide may be caused by increased retinol uptake via STRA6. Silencing of STRA6 was shown to decrease apoptosis which was inhibited by knockdown of STRA6 expression in Ishikawa cells. Results of an in-vivo study demonstrated that intraperitoneal injections of fenretinide in endometrial cancer tumors (created using Ishikawa cells) in mice inhibited tumor growth effectively. Immunohistochemistry of mice tumors showed a decrease in Ki67 expression and an increase in cleaved caspase-3 staining after fenretinide treatment when compared to vehicle treated mice. Collectively, our results are the first to establish the efficacy of fenretinide as an antitumor agent for endometrial cancer both in-vitro and in-vivo, providing a valuable rationale for initiating more preclinical studies and clinical trials using fenretinide for the treatment of endometrial cancer. PMID:25340777

  15. Endometrial pneumatosis (emphysematous endometritis).

    PubMed

    Chua, Yee Jia; Meharry, Suzanne; Harding, Steven; Stewart, Colin J R

    2014-09-01

    Endometrial pneumatosis, also referred to as pneumopolycystic or emphysematous endometritis, is a rare condition reported only twice previously in the literature and only once as an isolated finding. We report a case of endometrial pneumatosis in a 43-yr-old patient who underwent hysterectomy and bilateral salpingectomy for treatment of a symptomatic uterine leiomyoma. No predisposing factors towards pneumatosis were identified and in particular there was no evidence of immune impairment, diabetes mellitus, uterine infection, or prior surgical intervention. Endometrial pneumatosis remains an enigmatic condition of uncertain etiology but it appears to be self-limited with no known pathologic sequelae. PMID:25083968

  16. Cystic endometrial hyperplasia and pyometra in three captive African hunting dogs (Lycaon pictus).

    PubMed

    Jankowski, Gwen; Adkesson, Michael J; Langan, Jennifer N; Haskins, Samantha; Landolfi, Jamie

    2012-03-01

    Pyometra and cystic endometrial hyperplasia are common in domestic canids and are suspected to develop as a consequence of elevated progesterone levels. Reports of uterine pathology in exotic canids are limited, with some speculating of association with contraception. This report describes pyometra, cystic endometrial hyperplasia, and ovariohysterectomy in three African hunting dogs (Lycaon pictus). Ovarian corpora lutea were detected in two of the dogs, suggesting endogenous progesterone production. One dog had a uterine adenocarcinoma and two had ovarian granulosa cell tumors. Clinical signs included anorexia, lethargy, vulvar discharge, polyuria, polydipsia, and abdominal distention. Diagnosis was based on clinical signs, physical examination, bloodwork, radiography, and ultrasonography, with confirmation through histopathologic evaluation of tissues. Cystic endometrial hyperplasia, pyometra, and uterine neoplasia have rarely been diagnosed in exotic canids; however, they should be considered as differential diagnoses in intact bitches that present with suspected reproductive disease. PMID:22448515

  17. Endometrial Cancer Risk Factors

    MedlinePlus

    ... Women with a condition called polycystic ovarian syndrome (PCOS) have abnormal hormone levels, such as higher androgen ( ... increase a woman's chance of getting endometrial cancer. PCOS is also a leading cause of infertility in ...

  18. Life-style and metformin for the prevention of endometrial pathology in postmenopausal women.

    PubMed

    Campagnoli, Carlo; Abbà, Chiara; Ambroggio, Simona; Brucato, Tiziana; Pasanisi, Patrizia

    2013-02-01

    In western women, the endometrium is frequently exposed, even after menopause, to the endogenous hormonal stimulation. Such a stimulation increases the risk of pathologic conditions such as endometrial hyperplasia and type I (endometrioid) endometrial adenocarcinoma. Metabolic syndrome, obesity, insulin resistance and type II diabetes promote the endometrial stimulation, and are recognized risk factors for endometrial cancer. Furthermore, chronic hyperinsulinemia linked both to obesity and metabolic syndrome influences endometrial proliferation through direct and indirect actions. Intentional weight loss, calorie restriction and physical activity are associated with a reduced risk of the endometrial pathology. Biological mechanisms include reduction in insulin and sex steroid hormone levels. In addition to life-style modifications, the antidiabetic metformin may be proposed as preventive agent. Metformin reduces the metabolic syndrome, lowers insulin and testosterone levels in postmenopausal women, and it is a potent inhibitor of endometrial cancer cell proliferation.

  19. Squamous morules are functionally inert elements of premalignant endometrial neoplasia.

    PubMed

    Lin, Ming-Chieh; Lomo, Lesley; Baak, Jan P A; Eng, Charis; Ince, Tan A; Crum, Christopher P; Mutter, George L

    2009-02-01

    Squamous morules are a common component of premalignant glandular lesions that are followed by glandular, rather than squamous, carcinomas. We tested the hypothesis that the appearance of glands associated with morules predicts cancer risk, and undertook molecular testing to determine the clonal and hormonal response properties of admixed squamous and glandular elements. A total of 66 patients with squamous morules in an index endometrial biopsy had follow-up clinical data (average follow-up: interval 31 months, 2.5 biopsies) showing development of carcinoma in 11% (7/66) of cases. The histological appearance of morule-associated glands in the index biopsy was significantly associated with this clinical outcome, with the majority (71%, 5/7) of cancer occurrences following an overtly premalignant lesion (endometrial intraepithelial neoplasia) with squamous morules. Eight endometrial intraepithelial neoplasias with squamous morules were examined by immunohistochemistry for estrogen and progesterone receptors and mitotic activity (Ki-67 antigen percent stained). Glandular components had abundant estrogen and progesterone receptors, and high levels of mitotic activity in all cases. In sharp contrast, all squamous morules were devoid of sex hormone receptors and had undetectable or extremely low-proliferation rates. When mutated, the same specific PTEN mutation was detected in squamous and glandular elements, indicating that both are of common lineage. The clinical and laboratory data are consistent with a model of morule biology in which squamous morules are a hormonally incompetent subpopulation of endometrial glandular lesions. Isolated morules might result from artifactual displacement from their native glandular context, or selective hormonally induced regression of the glandular but not squamous components over time. Subsequent cancer risk, as promoted by estrogens, is greatest when the glandular component has the appearance of endometrial intraepithelial

  20. Squamous Morules Are Functionally Inert Elements of Premalignant Endometrial Neoplasia

    PubMed Central

    Lin, Ming-Chieh; Lomo, Lesley; Baak, Jan P. A.; Eng, Charis; Ince, Tan A.; Crum, Christopher P.; Mutter, George L.

    2008-01-01

    Squamous morules are a common component of premalignant glandular lesions that are followed by glandular, rather than squamous, carcinomas. We tested the hypothesis that the appearance of glands associated with morules predicts cancer risk, and undertook molecular testing to determine the clonal and hormonal response properties of admixed squamous and glandular elements. 66 patients with squamous morules in an index endometrial biopsy had followup clinical data (average followup: interval 31 months, 2.5 biopsies) showing development of carcinoma in 11% (7/66) of cases. The histological appearance of morule-associated glands in the index biopsy was significantly associated with this clinical outcome, with the majority (71%, 5/7) of cancer occurrences following an overtly premalignant lesion (Endometrial Intraepithelial Neoplasia) with squamous morules. Eight endometrial intraepithelial neoplasias with squamous morules were examined by immunohistochemistry for estrogen and progesterone receptors and mitotic activity (Ki-67 antigen percent stained). Glandular components had abundant estrogen and progesterone receptors, and high levels of mitotic activity in all cases. In sharp contrast, all squamous morules were devoid of sex hormone receptors and had undetectable or extremely low proliferation rates. When mutated, the same specific PTEN mutation was detected in squamous and glandular elements, indicating that both are of common lineage. The clinical and laboratory data are consistent with a model of morule biology in which squamous morules are a hormonally incompetent subpopulation of endometrial glandular lesions. Isolated morules might result from artifactual displacement from their native glandular context, or selective hormonally induced regression of the glandular but not squamous components over time. Subsequent cancer risk, as promoted by estrogens, is greatest when the glandular component has the appearance of endometrial intraepithelial neoplasia. Even

  1. General Information About Endometrial Cancer

    MedlinePlus

    ... Research Endometrial Cancer Treatment (PDQ®)–Patient Version General Information About Endometrial Cancer Go to Health Professional Version ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  2. Follicular progesterone elevations with ovulation induction for IVF.

    PubMed

    Kasum, Miro; Simunić, Velimir; Vrčić, Hrvoje; Stanić, Patrik; Orešković, Slavko; Beketić-Orešković, Lidija

    2014-08-01

    The purpose of this review is to analyse the sources and effects of follicular progesterone elevations during ovarian stimulation, with the underlying mechanisms and preventive strategies on the in vitro fertilisation pregnancy outcome. In the early follicular phase, a flare-up effect of gonadotrophin releasing hormone (GnRH) agonists and incomplete luteolysis in GnRH antagonist regimens can result in significant elevations of progesterone. In the late follicular phase, progesterone elevations in GnRH analogue cycles are the result of the ovarian stimulation itself, driven by high follicle stimulating hormone dosage, estradiol levels, the number of follicles and oocytes. It seems that progesterone elevations (> or = 1.5 ng/mL or 4.77 nmol/L) have a detrimental effect on the outcome of pregnancy, accelerating the endometrial maturation. The most appropriate choice to avoid the negative effects of follicular progesterone elevations is to cancel fresh embryo transfer and to transfer frozen-thawed embryos in natural cycles. To prevent follicular phase elevations it might be preferable to use milder stimulation protocols, earlier trigger of ovulation in high responders and single-blastocyst transfer on day 5. The optimal GnRH analogue protocols during the entire stimulation period appear to be the long agonist as well as "long" and long GnRH antagonist regimens.

  3. Elevated Progesterone Levels on the Day of Oocyte Maturation May Affect Top Quality Embryo IVF Cycles

    PubMed Central

    Huang, Bo; Ren, Xinling; Wu, Li; Zhu, Lixia; Xu, Bei; Li, Yufeng; Ai, Jihui; Jin, Lei

    2016-01-01

    In contrast to the impact of elevated progesterone on endometrial receptivity, the data on whether increased progesterone levels affects the quality of embryos is still limited. This study retrospectively enrolled 4,236 fresh in vitro fertilization (IVF) cycles and sought to determine whether increased progesterone is associated with adverse outcomes with regard to top quality embryos (TQE). The results showed that the TQE rate significantly correlated with progesterone levels on the day of human chorionic gonadotropin (hCG) trigger (P = 0.009). Multivariate linear regression analysis of factors related to the TQE rate, in conventional IVF cycles, showed that the TQE rate was negatively associated with progesterone concentration on the day of hCG (OR was -1.658, 95% CI: -2.806 to -0.510, P = 0.005). When the serum progesterone level was within the interval 2.0–2.5 ng/ml, the TQE rate was significantly lower (P <0.05) than when the progesterone level was < 1.0 ng/ml; similar results were obtained for serum progesterone levels >2.5 ng/ml. Then, we choose a progesterone level at 1.5ng/ml, 2.0 ng/ml and 2.5 ng/ml as cut-off points to verify this result. We found that the TQE rate was significantly different (P <0.05) between serum progesterone levels < 2.0 ng/ml and >2.0 ng/ml. In conclusion, the results of this study clearly demonstrated a negative effect of elevated progesterone levels on the day of hCG trigger, on TQE rate, regardless of the basal FSH, the total gonadotropin, the age of the woman, or the time of ovarian stimulation. These data demonstrate that elevated progesterone levels (>2.0 ng/ml) before oocyte maturation were consistently detrimental to the oocyte. PMID:26745711

  4. Brivanib Alaninate in Treating Patients With Recurrent or Persistent Endometrial Cancer

    ClinicalTrials.gov

    2016-03-16

    Endometrial Adenocarcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Mucinous Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Squamous Cell Carcinoma; Endometrial Transitional Cell Carcinoma; Endometrial Undifferentiated Carcinoma; Recurrent Uterine Corpus Carcinoma

  5. The Promyelocytic Leukemia Zinc Finger Transcription Factor Is Critical for Human Endometrial Stromal Cell Decidualization.

    PubMed

    Kommagani, Ramakrishna; Szwarc, Maria M; Vasquez, Yasmin M; Peavey, Mary C; Mazur, Erik C; Gibbons, William E; Lanz, Rainer B; DeMayo, Francesco J; Lydon, John P

    2016-04-01

    Progesterone, via the progesterone receptor (PGR), is essential for endometrial stromal cell decidualization, a cellular transformation event in which stromal fibroblasts differentiate into decidual cells. Uterine decidualization supports embryo implantation and placentation as well as subsequent events, which together ensure a successful pregnancy. Accordingly, impaired decidualization results not only in implantation failure or early fetal miscarriage, but also may lead to potential adverse outcomes in all three pregnancy trimesters. Transcriptional reprogramming on a genome-wide scale underlies progesterone dependent decidualization of the human endometrial stromal cell (hESC). However, identification of the functionally essential signals encoded by these global transcriptional changes remains incomplete. Importantly, this knowledge-gap undercuts future efforts to improve diagnosis and treatment of implantation failure based on a dysfunctional endometrium. By integrating genome-wide datasets derived from decidualization of hESCs in culture, we reveal that the promyelocytic leukemia zinc finger (PLZF) transcription factor is rapidly induced by progesterone and that this induction is indispensable for progesterone-dependent decidualization. Chromatin immunoprecipitation followed by next generation sequencing (ChIP-Seq) identified at least ten progesterone response elements within the PLZF gene, indicating that PLZF may act as a direct target of PGR signaling. The spatiotemporal expression profile for PLZF in both the human and mouse endometrium offers further support for stromal PLZF as a mediator of the progesterone decidual signal. To identify functional targets of PLZF, integration of PLZF ChIP-Seq and RNA Pol II RNA-Seq datasets revealed that the early growth response 1 (EGR1) transcription factor is a PLZF target for which its level of expression must be reduced to enable progesterone dependent hESC decidualization. Apart from furnishing essential insights

  6. The Promyelocytic Leukemia Zinc Finger Transcription Factor Is Critical for Human Endometrial Stromal Cell Decidualization

    PubMed Central

    Kommagani, Ramakrishna; Szwarc, Maria M.; Vasquez, Yasmin M.; Peavey, Mary C.; Mazur, Erik C.; Gibbons, William E.; Lanz, Rainer B.; DeMayo, Francesco J.; Lydon, John P.

    2016-01-01

    Progesterone, via the progesterone receptor (PGR), is essential for endometrial stromal cell decidualization, a cellular transformation event in which stromal fibroblasts differentiate into decidual cells. Uterine decidualization supports embryo implantation and placentation as well as subsequent events, which together ensure a successful pregnancy. Accordingly, impaired decidualization results not only in implantation failure or early fetal miscarriage, but also may lead to potential adverse outcomes in all three pregnancy trimesters. Transcriptional reprogramming on a genome-wide scale underlies progesterone dependent decidualization of the human endometrial stromal cell (hESC). However, identification of the functionally essential signals encoded by these global transcriptional changes remains incomplete. Importantly, this knowledge-gap undercuts future efforts to improve diagnosis and treatment of implantation failure based on a dysfunctional endometrium. By integrating genome-wide datasets derived from decidualization of hESCs in culture, we reveal that the promyelocytic leukemia zinc finger (PLZF) transcription factor is rapidly induced by progesterone and that this induction is indispensable for progesterone-dependent decidualization. Chromatin immunoprecipitation followed by next generation sequencing (ChIP-Seq) identified at least ten progesterone response elements within the PLZF gene, indicating that PLZF may act as a direct target of PGR signaling. The spatiotemporal expression profile for PLZF in both the human and mouse endometrium offers further support for stromal PLZF as a mediator of the progesterone decidual signal. To identify functional targets of PLZF, integration of PLZF ChIP-Seq and RNA Pol II RNA-Seq datasets revealed that the early growth response 1 (EGR1) transcription factor is a PLZF target for which its level of expression must be reduced to enable progesterone dependent hESC decidualization. Apart from furnishing essential insights

  7. Stages of Endometrial Cancer

    MedlinePlus

    ... mellitus . Taking tamoxifen for breast cancer or taking estrogen alone (without progesterone) can increase the risk of ... menstrual bleeding) as soon as possible. Women taking estrogen (a hormone that can affect the growth of ...

  8. Therapeutic options for management of endometrial hyperplasia

    PubMed Central

    2016-01-01

    Endometrial hyperplasia (EH) comprises a spectrum of changes in the endometrium ranging from a slightly disordered pattern that exaggerates the alterations seen in the late proliferative phase of the menstrual cycle to irregular, hyperchromatic lesions that are similar to endometrioid adenocarcinoma. Generally, EH is caused by continuous exposure of estrogen unopposed by progesterone, polycystic ovary syndrome, tamoxifen, or hormone replacement therapy. Since it can progress, or often occur coincidentally with endometrial carcinoma, EH is of clinical importance, and the reversion of hyperplasia to normal endometrium represents the key conservative treatment for prevention of the development of adenocarcinoma. Presently, cyclic progestin or hysterectomy constitutes the major treatment option for EH without or with atypia, respectively. However, clinical trials of hormonal therapies and definitive standard treatments remain to be established for the management of EH. Moreover, therapeutic options for EH patients who wish to preserve fertility are challenging and require nonsurgical management. Therefore, future studies should focus on evaluation of new treatment strategies and novel compounds that could simultaneously target pathways involved in the pathogenesis of estradiol-induced EH. Novel therapeutic agents precisely targeting the inhibition of estrogen receptor, growth factor receptors, and signal transduction pathways are likely to constitute an optimal approach for treatment of EH. PMID:26463434

  9. DNA Methylation Machinery in the Endometrium and Endometrial Cancer.

    PubMed

    Caplakova, Veronika; Babusikova, Eva; Blahovcova, Eva; Balharek, Tomas; Zelieskova, Maria; Hatok, Jozef

    2016-09-01

    During the normal menstrual cycle, endometrial tissue undergoes many biochemical and morphological changes which are under the control of steroid hormone levels. DNA methylation plays a key role in gene expression regulation and influences functional changes in endometrial tissue. Eliminating senescent cells from the functional layer of the endometrium is mediated by apoptotic cell death, which helps maintain cellular homeostasis. Aberrant DNA methylation changes result in deregulation of important apoptotic proteins during endometrial carcinogenesis and thus apoptosis resistance development. Evading apoptosis is still a major problem in the successful treatment of endometrial cancer patients with advanced disease. Despite intensive study of the cancer epigenome, there is missing information about disrupted apoptotic gene regulation in DNA methylation levels. Therefore, it is necessary to spread our knowledge in the field of epigenetics to help us differentiate normal and cancer tissues and detect the early stages of cancer disease. PMID:27630276

  10. Compartmentalized gene expression profiling of receptive endometrium reveals progesterone regulated ENPP3 is differentially expressed and secreted in glycosylated form

    PubMed Central

    Boggavarapu, Nageswara Rao; Lalitkumar, Sujata; Joshua, Vijay; Kasvandik, Sergo; Salumets, Andres; Lalitkumar, Parameswaran Grace; Gemzell-Danielsson, Kristina

    2016-01-01

    The complexity of endometrial receptivity at the molecular level needs to be explored in detail to improve the management of infertility. Here, differential expression of transcriptomes in receptive endometrial glands and stroma revealed Ectonucleotide Pyrophosphatase/Phosphodiesterase 3 (ENPP3) as a progesterone regulated factor and confirmed by various methods, both at mRNA and protein level. The involvement of ENPP3 in embryo attachment was tested in an in vitro model for human embryo implantation. Interestingly, there was high expression of ENPP3 mRNA in stroma but not protein. Presence of N-glycosylated ENPP3 in receptive phase uterine fluid in women confirms its regulation by progesterone and makes it possible to use in a non-invasive test of endometrial receptivity. PMID:27665743

  11. Genetic strain and reproductive status affect endometrial fatty acid concentrations.

    PubMed

    Meier, S; Peterson, A J; Mitchell, M D; Littlejohn, M; Walker, C G; Roche, J R

    2009-08-01

    Poor reproductive performance limits cow longevity in seasonal, pasture-based dairy systems. Few differences in ovarian dynamics have been reported in different strains of Holstein-Friesian cows, implying that the uterine environment may be a key component determining reproductive success. To test the hypothesis that the uterine environment differs among genetic strains of the Holstein-Friesian cow, endometrial fatty acids (FA) were analyzed from New Zealand (NZ), and North American (NA) Holstein-Friesian cows. The effect of reproductive status was also investigated, with cows from both Holstein-Friesian strains slaughtered on either d 17 of the estrous cycle (termed cyclic) or d 17 of pregnancy (after embryo transfer; termed pregnant). Endometrial tissues were collected from 22 cows (NZ pregnant, n = 6; NZ cyclic, n = 4; NA pregnant, n = 6; NA cyclic, n = 6), and FA composition was analyzed. Daily plasma progesterone concentrations, milk production, milk FA composition, body weight, and body condition score were determined. Milk yield (4% fat-corrected milk) was similar for the NZ (28.5 kg/d) and NA (29.3 kg/d; SE 2.07 kg/d) cows, but NZ cows had a greater mean milk fat percentage. Mean plasma progesterone concentrations were significantly greater in NZ cows. Plasma progesterone concentrations were similar in the pregnant and cyclic groups. Mean length of the trophoblast recovered from the pregnant cows (NZ: 20.8 +/- 2.84 cm; NA: 27.9 +/- 10.23 cm) was not affected by genetic strain. Endometrial tissues from NZ cows contained greater concentrations of C17:0, C20:3n-3, and total polyunsaturated FA. The endometria from pregnant cows contained greater concentrations of C17:0, C20:2, and C20:3n-6, and less C20:1, C20:2, C20:5n-3. The observed changes in endometrial FA between Holstein-Friesian cows of different genetic origins or reproductive states may reflect differences in endometrial function and may affect reproductive function.

  12. Cancer Statistics: Endometrial Cancer

    MedlinePlus

    ... at a Glance Show More At a Glance Estimated New Cases in 2016 60,050 % of All New Cancer Cases 3.6% Estimated Deaths in 2016 10,470 % of All Cancer ... of This Cancer : In 2013, there were an estimated 635,437 women living with endometrial cancer in ...

  13. Endometrial transcriptome analysis indicates superiority of natural over artificial cycles in recurrent implantation failure patients undergoing frozen embryo transfer.

    PubMed

    Altmäe, Signe; Tamm-Rosenstein, Karin; Esteban, Francisco J; Simm, Jaak; Kolberg, Liis; Peterson, Hedi; Metsis, Madis; Haldre, Kai; Horcajadas, José A; Salumets, Andres; Stavreus-Evers, Anneli

    2016-06-01

    Little consensus has been reached on the best protocol for endometrial preparation for frozen embryo transfer (FET). It is not known how, and to what extent, hormone supplementation in artificial cycles influences endometrial preparation for embryo implantation at a molecular level, especially in patients who have experienced recurrent implantation failure. Transcriptome analysis of 15 endometrial biopsy samples at the time of embryo implantation was used to compare two different endometrial preparation protocols, natural versus artificial cycles, for FET in women who have experienced recurrent implantation failure compared with fertile women. IPA and DAVID were used for functional analyses of differentially expressed genes. The TRANSFAC database was used to identify oestrogen and progesterone response elements upstream of differentially expressed genes. Cluster analysis demonstrated that natural cycles are associated with a better endometrial receptivity transcriptome than artificial cycles. Artificial cycles seemed to have a stronger negative effect on expression of genes and pathways crucial for endometrial receptivity, including ESR2, FSHR, LEP, and several interleukins and matrix metalloproteinases. Significant overrepresentation of oestrogen response elements among the genes with deteriorated expression in artificial cycles (P < 0.001) was found; progesterone response elements predominated in genes with amended expression with artificial cycles (P = 0.0052).

  14. Endometrial metastasis of colorectal cancer with coincident endometrial adenocarcinoma

    PubMed Central

    Colling, Richard; Lopes, Tito; Das, Nagiindra; Mathew, Joe

    2010-01-01

    Metastasis to the uterine corpus is uncommon and secondary colorectal tumours of the endometrium are rare. We describe a uterine tumour with components of both primary endometrial and metastatic colorectal carcinomata. In this case, a 72-year-old obese woman presented with a 2-week history of postmenopausal bleeding per vaginum and weight loss. She had an abdominoperineal resection 3 years previously for a Dukes stage B rectal carcinoma. A transvaginal ultrasonography showed a thickened endometrium. Histology immunophenotyping showed a CK7+, CK20+, CA125− and CEA+ colorectal metastasis (a profile consistent with her previous cancer) associated with a primary CK7+, CK20−, CA125+ and CEA− endometroid endometrial adenocarcinoma. We conclude this represents endometrial metastasis of colorectal carcinoma with coincident primary endometrial adenocarcinoma. We speculate as to whether the endometrial carcinoma arose de novo or was induced by the colorectal metastasis, or whether the primary endometrial tumour provided a fertile site for the colorectal metastasis. PMID:22791861

  15. Progesterone Receptor Signaling Mechanisms.

    PubMed

    Grimm, Sandra L; Hartig, Sean M; Edwards, Dean P

    2016-09-25

    Progesterone receptor (PR) is a master regulator in female reproductive tissues that controls developmental processes and proliferation and differentiation during the reproductive cycle and pregnancy. PR also plays a role in progression of endocrine-dependent breast cancer. As a member of the nuclear receptor family of ligand-dependent transcription factors, the main action of PR is to regulate networks of target gene expression in response to binding its cognate steroid hormone, progesterone. This paper summarizes recent advances in understanding the structure-function properties of the receptor protein and the tissue/cell-type-specific PR signaling pathways that contribute to the biological actions of progesterone in the normal breast and in breast cancer. PMID:27380738

  16. Radiation Therapy With or Without Cisplatin in Treating Patients With Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2016-10-26

    Endometrial Adenocarcinoma; Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Endometrioid Adenocarcinoma, Variant With Squamous Differentiation; Endometrial Serous Adenocarcinoma; Recurrent Uterine Corpus Carcinoma

  17. Krüppel-Like Factor 13 Deficiency in Uterine Endometrial Cells Contributes to Defective Steroid Hormone Receptor Signaling but Not Lesion Establishment in a Mouse Model of Endometriosis.

    PubMed

    Heard, Melissa E; Velarde, Michael C; Giudice, Linda C; Simmen, Frank A; Simmen, Rosalia C M

    2015-06-01

    Krüppel-like Factor (KLF) 13 and the closely related KLF9 are members of the Sp/KLF family of transcription factors that have collectively emerged as essential regulators of tissue development, differentiation, proliferation, and programmed cell death. Steroid hormone-responsive tissues express multiple KLFs that are linked to progesterone receptor (PGR) and estrogen receptor (ESR) actions either as integrators or as coregulators. Endometriosis is a chronic disease characterized by progesterone resistance and dysregulated estradiol signaling; nevertheless, distinct KLF members' contributions to endometriosis remain largely undefined. We previously demonstrated promotion of ectopic lesion establishment by Klf9 null endometrium in a mouse model of endometriosis. Here we evaluated whether KLF13 loss of expression in endometrial cells may equally contribute to lesion formation. KLF13 transcript levels were lower in the eutopic endometria of women with versus women without endometriosis at menstrual midsecretory phase. In wild-type (WT) mouse recipients intraperitoneally administered WT or Klf13 null endometrial fragments, lesion incidence did not differ with donor genotype. No differences were noted for lesion volume, number, proliferation status, and apoptotic index as well. Klf13 null lesions displayed reduced total PGR and ESR1 (RNA and immunoreactive protein) and altered expression of several PGR and ESR1 target genes, relative to WT lesions. Unlike for Klf9 null lesions, changes in transcript levels for PGR-A, ESR1, and Notch/Hedgehog-associated pathway components were not observed for Klf13 null lesions. Results demonstrate lack of a causative relationship between endometrial KLF13 deficiency and lesion establishment in mice, and they support the broader participation of multiple signaling pathways, besides those mediated by steroid receptors, in the pathology of endometriosis. PMID:25904015

  18. Krüppel-Like Factor 13 Deficiency in Uterine Endometrial Cells Contributes to Defective Steroid Hormone Receptor Signaling but Not Lesion Establishment in a Mouse Model of Endometriosis.

    PubMed

    Heard, Melissa E; Velarde, Michael C; Giudice, Linda C; Simmen, Frank A; Simmen, Rosalia C M

    2015-06-01

    Krüppel-like Factor (KLF) 13 and the closely related KLF9 are members of the Sp/KLF family of transcription factors that have collectively emerged as essential regulators of tissue development, differentiation, proliferation, and programmed cell death. Steroid hormone-responsive tissues express multiple KLFs that are linked to progesterone receptor (PGR) and estrogen receptor (ESR) actions either as integrators or as coregulators. Endometriosis is a chronic disease characterized by progesterone resistance and dysregulated estradiol signaling; nevertheless, distinct KLF members' contributions to endometriosis remain largely undefined. We previously demonstrated promotion of ectopic lesion establishment by Klf9 null endometrium in a mouse model of endometriosis. Here we evaluated whether KLF13 loss of expression in endometrial cells may equally contribute to lesion formation. KLF13 transcript levels were lower in the eutopic endometria of women with versus women without endometriosis at menstrual midsecretory phase. In wild-type (WT) mouse recipients intraperitoneally administered WT or Klf13 null endometrial fragments, lesion incidence did not differ with donor genotype. No differences were noted for lesion volume, number, proliferation status, and apoptotic index as well. Klf13 null lesions displayed reduced total PGR and ESR1 (RNA and immunoreactive protein) and altered expression of several PGR and ESR1 target genes, relative to WT lesions. Unlike for Klf9 null lesions, changes in transcript levels for PGR-A, ESR1, and Notch/Hedgehog-associated pathway components were not observed for Klf13 null lesions. Results demonstrate lack of a causative relationship between endometrial KLF13 deficiency and lesion establishment in mice, and they support the broader participation of multiple signaling pathways, besides those mediated by steroid receptors, in the pathology of endometriosis.

  19. Selective progesterone receptor modulators (SPRMs): progesterone receptor action, mode of action on the endometrium and treatment options in gynecological therapies

    PubMed Central

    Wagenfeld, Andrea; Saunders, Philippa T.K.; Whitaker, Lucy; Critchley, Hilary O.D.

    2016-01-01

    ABSTRACT Introduction: The progesterone receptor plays an essential role in uterine physiology and reproduction. Selective progesterone receptor modulators (SPRMs) have emerged as a valuable treatment option for hormone dependent conditions like uterine fibroids, which have a major impact on women’s quality of life. SPRMs offer potential for longer term medical treatment and thereby patients may avoid surgical intervention. Areas covered: The authors have reviewed the functional role of the progesterone receptor and its isoforms and their molecular mechanisms of action via genomic and non-genomic pathways. The current knowledge of the interaction of the PR and different SPRMs tested in clinical trials has been reviewed. The authors focused on pharmacological effects of selected SPRMs on the endometrium, their anti-proliferative action, and their suppression of bleeding. Potential underlying molecular mechanisms and the specific histological changes in the endometrium induced by SPRMs (PAEC; Progesterone receptor modulator Associated Endometrial Changes) have been discussed. The clinical potential of this compound class including its impact on quality of life has been covered. Expert Opinion: Clinical studies indicate SPRMs hold promise for treatment of benign gynecological complaints (fibroids, heavy menstrual bleeding; HMB). There however remains a knowledge gap concerning mechanism of action. PMID:27138351

  20. Influence of VEGFR and LHCGR on endometrial adenocarcinoma

    PubMed Central

    Kölbl, Alexandra C.; Birk, Amelie E.; Kuhn, Christina; Jeschke, Udo; Andergassen, Ulrich

    2016-01-01

    Endometrial adenocarcinoma is a common gynecological malignancy that is usually treated by surgical resection followed by radiation. However, the frequency of remote metastasis is high. The present study aimed to investigate whether patients with endometrial adenocarcinoma exhibited a positive response to treatment with a gonadotropin-releasing hormone analogue or inhibitors of neoangiogenesis, which are applied for the treatment of other malignancies. Immunohistochemical analyses were performed using 203 paraffin-embedded tissue samples of endometrial adenocarcinomas from patients who had undergone surgery at the Department of Obstetrics and Gynecology of the Ludwig Maximilians University of Munich, Germany. The tissues were incubated with antibodies against luteinizing hormone/choriogonadotropin receptor (LHCGR) and vascular endothelial growth factor receptor 2 (VEGFR2), and evaluated by bright field microscopy. The staining was categorized according to the Immune-Reactive-Score (IRS). The IRS scores were then statistically associated with various tumor traits, including tumor size, lymph node status, metastasis, grade, expression of steroid hormone receptors and patient survival. There was a significant association between VEGFR2 expression and tumor grading and estrogen receptor-α (ERα). For LHCGR, a correlation was observed with ERα and progesterone receptor (PR). No correlations were identified between VEGFR2 or LHCGR expression and the other examined tumor traits or patient survival. The associations between VEGFR2 and ERα, and between LHCGR and ERα or PR, may be explained by the interaction of these signal transduction molecules in the regulation of cellular growth and differentiation. These mechanisms also have an important role in the formation of remote metastases, which is the main cause for tumor-associated mortality. The results of the present study suggested that patients with endometrial adenocarcinoma may benefit from treatment with inhibitors

  1. Influence of VEGFR and LHCGR on endometrial adenocarcinoma

    PubMed Central

    Kölbl, Alexandra C.; Birk, Amelie E.; Kuhn, Christina; Jeschke, Udo; Andergassen, Ulrich

    2016-01-01

    Endometrial adenocarcinoma is a common gynecological malignancy that is usually treated by surgical resection followed by radiation. However, the frequency of remote metastasis is high. The present study aimed to investigate whether patients with endometrial adenocarcinoma exhibited a positive response to treatment with a gonadotropin-releasing hormone analogue or inhibitors of neoangiogenesis, which are applied for the treatment of other malignancies. Immunohistochemical analyses were performed using 203 paraffin-embedded tissue samples of endometrial adenocarcinomas from patients who had undergone surgery at the Department of Obstetrics and Gynecology of the Ludwig Maximilians University of Munich, Germany. The tissues were incubated with antibodies against luteinizing hormone/choriogonadotropin receptor (LHCGR) and vascular endothelial growth factor receptor 2 (VEGFR2), and evaluated by bright field microscopy. The staining was categorized according to the Immune-Reactive-Score (IRS). The IRS scores were then statistically associated with various tumor traits, including tumor size, lymph node status, metastasis, grade, expression of steroid hormone receptors and patient survival. There was a significant association between VEGFR2 expression and tumor grading and estrogen receptor-α (ERα). For LHCGR, a correlation was observed with ERα and progesterone receptor (PR). No correlations were identified between VEGFR2 or LHCGR expression and the other examined tumor traits or patient survival. The associations between VEGFR2 and ERα, and between LHCGR and ERα or PR, may be explained by the interaction of these signal transduction molecules in the regulation of cellular growth and differentiation. These mechanisms also have an important role in the formation of remote metastases, which is the main cause for tumor-associated mortality. The results of the present study suggested that patients with endometrial adenocarcinoma may benefit from treatment with inhibitors

  2. Intracrine Androgens Enhance Decidualization and Modulate Expression of Human Endometrial Receptivity Genes.

    PubMed

    Gibson, Douglas A; Simitsidellis, Ioannis; Cousins, Fiona L; Critchley, Hilary O D; Saunders, Philippa T K

    2016-01-01

    The endometrium is a complex, steroid-dependent tissue that undergoes dynamic cyclical remodelling. Transformation of stromal fibroblasts (ESC) into specialised secretory cells (decidualization) is fundamental to the establishment of a receptive endometrial microenvironment which can support and maintain pregnancy. Androgen receptors (AR) are present in ESC; in other tissues local metabolism of ovarian and adrenal-derived androgens regulate AR-dependent gene expression. We hypothesised that altered expression/activity of androgen biosynthetic enzymes would regulate tissue availability of bioactive androgens and the process of decidualization. Primary human ESC were treated in vitro for 1-8 days with progesterone and cAMP (decidualized) in the presence or absence of the AR antagonist flutamide. Time and treatment-dependent changes in genes essential for a) intra-tissue biosynthesis of androgens (5α-reductase/SRD5A1, aldo-keto reductase family 1 member C3/AKR1C3), b) establishment of endometrial decidualization (IGFBP1, prolactin) and c) endometrial receptivity (SPP1, MAOA, EDNRB) were measured. Decidualization of ESC resulted in significant time-dependent changes in expression of AKR1C3 and SRD5A1 and secretion of T/DHT. Addition of flutamide significantly reduced secretion of IGFBP1 and prolactin and altered the expression of endometrial receptivity markers. Intracrine biosynthesis of endometrial androgens during decidualization may play a key role in endometrial receptivity and offer a novel target for fertility treatment. PMID:26817618

  3. Pseudo-placentational endometrial cysts in a bitch.

    PubMed

    Bartel, C; Schönkypl, S; Walter, I

    2010-02-01

    Cystic alterations of the canine endometrium compromise reproduction and fertility of the bitch and may lead to life-threatening diseases, such as pyometra. Even without clinical evidence, reduction of the uterine lumen by cysts implicates disturbances during migration, nidation and development of the embryo. Several studies point to the high variability of morphology of uterine endometrial cysts but they lack detailed analyses of alterations. In the present study, immunohistochemistry was used to investigate the expression of steroid hormone receptors (oestrogen, progesterone), proliferation activity, inflammation and infection in the cystic affected tissue regions in contrast to the normal endometrium. Oestrogen receptor expression showed a high density of receptors throughout the surface epithelial cells, crypt epithelial cells, glandular epithelial cells and stromal cells of the normal endometrium as well as the cystic affected regions. Proliferation in the cysts was verified in the middle and basal cells of the crypts. Neither in the endometrium nor in the cysts inflammatory processes or evidence of infection could be detected. Furthermore, lectin histochemistry and electron microscopic methods showed that lectin binding patterns and cell morphology of internal epithelial lining and surface epithelium of the cysts can be used to characterize and distinguish different types of cystic alterations. Analogies between epithelial cells of the glandular chambers of the canine placenta and the cystic cellular morphology, steroid hormone receptor distribution as well as lectin binding patterns of the endometrial cysts, as observed in this study, suggest to introduce the term 'pseudo-placentational endometrial cysts'. PMID:19891664

  4. Unusual inflammation in gynecologic pathology associated with defective endometrial receptivity.

    PubMed

    Kitaya, Kotaro; Yasuo, Tadahiro; Tada, Yoshihiro; Hayashi, Terumi; Iwaki, Yuri; Karita, Masako; Funabiki, Miyako; Taguchi, Sagiri; Spillers, Dustin; Nakamura, Yoshitaka; Yamada, Hisao

    2014-09-01

    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. PMID:24771248

  5. A Trial for Patients With Advanced/Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2009-11-13

    Neoplasms; Neoplasms by Site; Urogenital Neoplasms; Genital Neoplasms, Female; Uterine Neoplasms; Endometrial Neoplasms; Cancer of Endometrium; Endometrial Cancer; Cancer of the Endometrium; Endometrium Cancer; Neoplasms, Endometrial

  6. Expression of Endogenous Betaretroviruses in the Ovine Uterus: Effects of Neonatal Age, Estrous Cycle, Pregnancy, and Progesterone

    PubMed Central

    Palmarini, Massimo; Gray, C. Allison; Carpenter, Karen; Fan, Hung; Bazer, Fuller W.; Spencer, Thomas E.

    2001-01-01

    The ovine genome contains 15 to 20 copies of endogenous retroviruses (enJSRVs) highly related to the oncogenic jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus. enJSRVs are highly expressed in the endometrial lumenal epithelia (LE) and glandular epithelia (GE) of the ovine uterus. The effects of neonatal age, estrous cycle, pregnancy, and progesterone on expression of enJSRVs in the ovine uterus were determined. Expression of enJSRV RNAs was absent from the uterus of ewes at birth, but enJSRV RNAs were expressed specifically in the LE and developing GE from postnatal day (PND) 7 to PND 56. In adult ewes, enJSRV RNAs were detected only in the epithelia of the uterine endometrium, as well as epithelia of the oviduct, cervix, and vagina. In cyclic ewes, endometrial enJSRV RNA abundance was lowest on day 1, increased 12-fold between days 1 and 13, and then decreased to day 15. In pregnant ewes, levels of endometrial enJSRV RNAs were high on day 11, increased to day 13, and then decreased to day 19. In day 17 and 19 conceptuses, enJSRV RNAs were also detected in binucleate cells of the trophectoderm. Immunoreactive JSRV capsid and envelope proteins were detected in the endometrial LE and GE, as well as in the binucleate cells of the conceptus. In transfection assays utilizing ovine endometrial LE cells, progesterone increased transcriptional activity of several enJSRV long terminal repeats. Collectively, these results indicate that transcription of enJSRVs in the endometrial epithelia of the ovine uterus is increased by progesterone and might support a role for enJSRVs in conceptus-endometrium interactions during the peri-implantation period and early placental morphogenesis. PMID:11689612

  7. The expression pattern of MUC1 glycoforms and other biomarkers of endometrial receptivity in fertile and infertile women.

    PubMed

    Horne, A W; Lalani, E-N; Margara, R A; Ryder, T A; Mobberley, M A; White, J O

    2005-10-01

    Changes in the surface epithelium of the endometrium, characterized in part by alterations in cell-surface molecules, sex steroid receptors and the appearance of pinopodes, coincide with the window of endometrial receptivity in the menstrual cycle. This study was performed to evaluate the usefulness of hematoxylin and eosin staining, scanning and transmission microscopy, and MUC1 glycoform, sex steroid receptor, and interleukin receptor (type 1) expression as biomarkers of endometrial receptivity using carefully characterized clinical fertile and infertile groups of women. Using a combination of immunohistochemistry and scanning electron microscopy (SEM) called scanning immunoelectron microscopy (SIM), we confirmed that MUC1 mucin was not associated with the endometrial pinopodes, which have been linked with embryo adhesion. We also showed that failure of embryo implantation was associated with an abnormal endometrial expression of MUC1 mucin, and retention of nuclear progesterone receptor (PR) particularly in epithelial cells. Hematoxylin and eosin staining, transmission electron microscopy (TEM), SEM in isolation and immunohistochemistry for interleukin receptor were not shown to be useful markers. Progesterone-dependent regulation of MUC1 appears to be an important factor in determining endometrial receptivity.

  8. Wnt antagonist DKK1 is a target of Kruppel-like factor 9 (KLF9) in endometrial stromal cells: Implications for uterine receptivity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A significant underlying cause of pregnancy loss in mammals is the inability of the uterine epithelium to enter a "state of receptivity" for embryo implantation, due partly to the dysfunctional response of endometrial cells to progesterone (P). We previously showed that mice null for the Sp1-related...

  9. Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function

    PubMed Central

    Franco, Heather L.; Rubel, Cory A.; Large, Michael J.; Wetendorf, Margeaux; Fernandez-Valdivia, Rodrigo; Jeong, Jae-Wook; Spencer, Thomas E.; Behringer, Richard R.; Lydon, John P.; DeMayo, Francesco J.

    2012-01-01

    The ovarian steroid progesterone, acting through the progesterone receptor (PR), coordinates endometrial epithelial-stromal cell communication, which is critical for its development and function. PR expression in these cellular compartments is under tight temporal and endocrine control. Although ex vivo studies demonstrated the importance of stromal PR expression, they failed to show a role for epithelial PR in uterine function. Here, the in vivo role of PR in the uterine epithelium is defined using floxed PR (PRf/f) mice crossed to Wnt7a-Cre mice. Progesterone was unable to stimulate the expression of its epithelial target genes, including Ihh, in the Wnt7a-Cre+PRf/− mice. Analysis was conducted on Ihh to determine whether PR directly regulates epithelial gene transcription. ChIP-on-chip analysis identified PR binding sites in the 5′-flanking region of Ihh. Cotransfection of the proximal Ihh promoter with PR demonstrated that PR directly regulates Ihh transcription. Female Wnt7a-Cre+PRf/− mice are infertile due to defects in embryo attachment, stromal cell decidualization, and the inability to cease estrogen-induced epithelial cell proliferation. Finally, progesterone was unable to inhibit neonatal endometrial glandular development in Wnt7a-Cre+PRf/− mice. Thus, epithelial PR is necessary for the regulation of progesterone epithelial target gene expression, as well as uterine function and development.—Franco, H. L., Rubel, C. A., Large, M. J., Wetendorf, M., Fernandez-Valdivia, R., Jeong, J.-W., Spencer, T. E., Behringer, R. R., Lydon, J. P., DeMayo, F. J. Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function. PMID:22155565

  10. The wedelolactone derivative inhibits estrogen receptor-mediated breast, endometrial, and ovarian cancer cells growth.

    PubMed

    Xu, Defeng; Lin, Tzu-Hua; Yeh, Chiuan-Ren; Cheng, Max A; Chen, Lu-Min; Chang, Chawnshang; Yeh, Shuyuan

    2014-01-01

    Estrogen and estrogen receptor (ER)-mediated signaling pathways play important roles in the etiology and progression of human breast, endometrial, and ovarian cancers. Attenuating ER activities by natural products and their derivatives is a relatively practical strategy to control and reduce breast, endometrial, and ovarian cancer risk. Here, we found 3-butoxy-1,8,9-trihydroxy-6H-benzofuro[3,2-c]benzopyran-6-one (BTB), a new derivative of wedelolactone, could effectively inhibit the 17-estradiol (E2)-induced ER transactivation and suppress the growth of breast cancer as well as endometrial and ovarian cancer cells. Our results indicate that 2.5 μM BTB effectively suppresses ER-positive, but not ER-negative, breast, endometrial, and ovarian cancer cells. Furthermore, our data indicate that BTB can modulate ER transactivation and suppress the expression of E2-mediated ER target genes (Cyclin D1, E2F1, and TERT) in the ER-positive MCF-7, Ishikawa, and SKOV-3 cells. Importantly, this BTB mediated inhibition of ER activity is selective since BTB does not suppress the activities of other nuclear receptors, including glucocorticoid receptor and progesterone receptor, suggesting that BTB functions as a selective ER signaling inhibitor with the potential to treat breast, endometrial, and ovarian cancers.

  11. Role of epigenomics in ovarian and endometrial cancers.

    PubMed

    Balch, Curtis; Matei, Daniela E; Huang, Tim H-M; Nephew, Kenneth P

    2010-06-01

    Ovarian cancer is the most lethal gynecologic malignancy and while constituting only 3% of all female cancers, it causes 14,600 deaths in the USA annually. Endometrial cancer, the most diagnosed and second-most fatal gynecologic cancer, afflicts over 40,000 US women annually, causing an estimated 7780 deaths in 2009. In both advanced ovarian and endometrial carcinomas, the majority of initially therapy-responsive tumors eventually evolve to a fully drug-resistant phenotype. In addition to genetic mutations, epigenetic anomalies are frequent in both gynecologic malignancies, including aberrant DNA methylation, atypical histone modifications and dysregulated expression of distinct microRNAs, resulting in altered gene-expression patterns favoring cell survival. In this article, we summarize the most recent hypotheses regarding the role of epigenetics in ovarian and endometrial cancers, including a possible role in tumor 'stemness' and also evaluate the possible therapeutic benefits of reversal of these oncogenic chromatin aberrations.

  12. Peroxisome proliferator-activated receptors modulate proliferation and angiogenesis in human endometrial carcinoma.

    PubMed

    Nickkho-Amiry, Mahshid; McVey, Rhona; Holland, Cathrine

    2012-03-01

    Peroxisome proliferator-activated receptors (PPAR) and retinoid X receptors (RXR) are implicated in the development of several obesity-related cancers. Little is known of either the expression or function of PPARs and RXRs in endometrial cancer although this increasingly common disease is highly associated with both obesity and insulin resistance. We investigated the expression of PPAR and RXR subtypes in human endometrial cancers and normal endometrium with immunoblotting and immunohistochemistry and subsequently showed PPAR/RXR binding preferences by coimmunoprecipitation. To determine the functions of PPARs within the endometrium, we investigated proliferation, apoptosis, PTEN expression, and secretion of vascular endothelial growth factor (VEGF) in endometrial cell lines after reducing the expression of PPARα and PPARγ with antisense RNA. The functional effects of PPAR ligands were also investigated in vitro. We identified differential expression of PPAR and RXR subtypes in endometrial cancers and discovered that PPARγ expression correlated with expression of PTEN. PPARα activation influences endometrial cell growth and VEGF secretion. PPARγ activation reduces proliferation of endometrial cells via regulation of PTEN and appears to reduce VEGF secretion. We conclude that the PPAR/RXR pathway contribute to endometrial carcinogenesis by control of PTEN expression and modulation of VEGF secretion. We propose that PPAR ligands should be considered for clinical investigation in early phase studies of women with endometrial cancer.

  13. DNA methylation in endometrial cancer

    PubMed Central

    Freudenheim, Jo L

    2010-01-01

    Endometrial cancer is the most commonly diagnosed gynecological cancer, and it has been shown to be a complex disease driven by abnormal genetic and epigenetic alterations, as well as environmental factors. Epigenetic changes resulting in aberrant gene expression are dynamic and modifiable features of many cancer types. A significant epigenetic change is aberrant DNA methylation. In this review, we review evidence on the role of aberrant DNA methylation, examining changes in relation to endometrial carcinogenesis, and report on recent advances in the understanding of the contribution of aberrant DNA methylation to endometrial cancer with the emphasis on the role of dietary/lifestyle and environmental factors, as well as opportunities and challenges of DNA methylation in endometrial cancer management and prevention. PMID:20543579

  14. Drugs Approved for Endometrial Cancer

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for endometrial cancer. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  15. Photodynamic therapy toward selective endometrial ablation

    NASA Astrophysics Data System (ADS)

    Tadir, Yona; Tromberg, Bruce J.; Krasieva, Tatiana B.; Berns, Michael W.

    1993-05-01

    Potential applications of photodynamic therapy for endometrial disease are discussed. Experimental models that may lead to diagnosis and treatment of endometriosis as well as selective endometrial ablation are summarized.

  16. 21 CFR 556.540 - Progesterone.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Progesterone. 556.540 Section 556.540 Food and... Residues of New Animal Drugs § 556.540 Progesterone. No residues of progesterone are permitted in excess of the following increments above the concentrations of progesterone naturally present in...

  17. Triclosan and bisphenol a affect decidualization of human endometrial stromal cells.

    PubMed

    Forte, Maurizio; Mita, Luigi; Cobellis, Luigi; Merafina, Verdiana; Specchio, Raffaella; Rossi, Sergio; Mita, Damiano Gustavo; Mosca, Lavinia; Castaldi, Maria Antonietta; De Falco, Maria; Laforgia, Vincenza; Crispi, Stefania

    2016-02-15

    In recent years, impaired fertility and endometrium related diseases are increased. Many evidences suggest that environmental pollution might be considered a risk factor for endometrial physiopathology. Among environmental pollutants, endocrine disrupting chemicals (EDCs) act on endocrine system, causing hormonal imbalance which, in turn, leads to female and male reproductive dysfunctions. In this work, we studied the effects of triclosan (TCL) and bisphenol A (BPA), two widespread EDCs, on human endometrial stromal cells (ESCs), derived from endometrial biopsies from woman not affected by endometriosis. Cell proliferation, cell cycle, migration and decidualization mechanisms were investigated. Treatments have been performed with both the EDCs separately or in presence and in absence of progesterone used as decidualization stimulus. Both TCL and BPA did not affect cell proliferation, but they arrested ESCs at G2/M phase of cell cycle enhancing cell migration. TCL and BPA also increased gene expression and protein levels of some decidualization markers, such as insulin growth factor binding protein 1 (IGFBP1) and prolactin (PRL), amplifying the effect of progesterone alone. All together, our data strongly suggest that TCL and BPA might alter human endometrium physiology so affecting fertility and pregnancy outcome. PMID:26604029

  18. Expression patterns of progesterone receptor membrane components 1 and 2 in endometria from women with and without endometriosis.

    PubMed

    Bunch, Kristen; Tinnemore, Deborah; Huff, Seth; Hoffer, Zachary S; Burney, Richard O; Stallings, Jonathan D

    2014-02-01

    Endometriosis is a hormone-dependent inflammatory condition associated with pain and infertility. A growing body of evidence supports attenuated secretory-phase progesterone responsiveness in women with this disease. Herein, we compare the expression of progesterone receptor membrane components (PGRMC) 1 and 2 in eutopic endometrium from 11 women with laparoscopically and/or histologically proven stage III/IV endometriosis and 23 disease-free women. Menstrual cycle phase was determined using a combination of reported cycle day, serum hormone profile, and endometrial histologic dating. The PGRMC-1 (fold change -3.3; P < .05) and PGRMC-2 (fold-change -8.8; P < .05) gene expression were significantly downregulated in secretory phase, eutopic endometrium from women with endometriosis. Immunohistochemistry demonstrated decreased PGRMC-1 and PGRMC-2 protein expression in the secretory phase endometrial stroma cells of women with endometriosis. Consistent with the preclinical work of others, our results reflect downregulation of endometrial PGRMC-1 and PGRMC-2 expression in secretory phase endometrium from women with advanced stage endometriosis. Understanding the molecular mechanisms of attenuated progesterone action in endometriosis has important diagnostic and therapeutic implications.

  19. 21 CFR 884.1100 - Endometrial brush.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Endometrial brush. 884.1100 Section 884.1100 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL... Endometrial brush. (a) Identification. An endometrial brush is a device designed to remove samples of...

  20. 21 CFR 884.1060 - Endometrial aspirator.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Endometrial aspirator. 884.1060 Section 884.1060 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED... § 884.1060 Endometrial aspirator. (a) Identification. An endometrial aspirator is a device designed...

  1. Intensity-Modulated Radiation Therapy, Cisplatin, and Bevacizumab Followed by Carboplatin and Paclitaxel in Treating Patients Who Have Undergone Surgery for Endometrial Cancer

    ClinicalTrials.gov

    2014-10-09

    Endometrial Adenocarcinoma; Endometrial Adenosquamous Cell Carcinoma; Endometrial Clear Cell Carcinoma; Endometrial Papillary Serous Carcinoma; Stage I Endometrial Carcinoma; Stage II Endometrial Carcinoma; Stage III Endometrial Carcinoma; Stage IV Endometrial Carcinoma

  2. A prospective study of dietary acrylamide intake and the risk of breast, endometrial, and ovarian cancers

    PubMed Central

    Wilson, Kathryn M.; Mucci, Lorelei A.; Rosner, Bernard A.; Willett, Walter C.

    2010-01-01

    Background Acrylamide is a probable human carcinogen formed during cooking of many common foods. Epidemiological studies of acrylamide and breast cancer risk have been null; however, positive associations with ovarian and endometrial cancers have been reported. We studied acrylamide intake and risk of breast, endometrial, and ovarian cancers in a prospective cohort study. Methods We assessed acrylamide intake among 88,672 women in the Nurses’ Health Study using food frequency questionnaires administered every four years. Between 1980 and 2006 we identified 6301 cases of invasive breast cancer, 484 cases of invasive endometrial adenocarcinoma, and 416 cases of epithelial ovarian cancer. We used Cox proportional hazards models to study the association between acrylamide and cancer risk. Results We found no association between acrylamide intake and breast cancer overall or according to estrogen and progesterone receptor status. We found an increased risk of endometrial cancer among high acrylamide consumers (adjusted relative risk [RR] for highest versus lowest quintile=1.41, 95% CI: 1.01–1.97, p-value for trend=0.03). We observed a non-significant suggestion of increased risk for ovarian cancer overall (RR 1.25, CI: 0.88–1.77, p-trend=0.12), with a significantly increased risk for serous tumors (RR 1.58, CI: 0.99–2.52, p-trend=0.04). Associations did not differ by smoking status. Conclusions We observed no association between acrylamide and breast cancer. Risk of endometrial cancer and possibly ovarian cancer was greater among high acrylamide consumers. Impact This is the second prospective study to report positive associations with endometrial and ovarian cancers. These associations should be further evaluated to inform public health policy. PMID:20693310

  3. Diagnostic value of transcervical endometrial biopsies in domestic dogs compared with full-thickness uterine sections.

    PubMed

    Christensen, B W; Schlafer, D H; Agnew, D W; Wang, C; Kozlowski, C; Asa, C S

    2012-12-01

    Transcervical endometrial biopsy is a useful tool for obtaining information about uterine health in some species. The clinical application of information gained from histopathological interpretations of endometrial biopsies in the bitch has not been validated. We hypothesized that transcervical endometrial biopsy samples would be as diagnostic as full-thickness uterine sections in identifying cystic endometrial hyperplasia (CEH), inflammation and periglandular fibrosis. Endometrial biopsies were obtained from 20 female adult dogs. Vaginal swabs, gross appearance of the vulva and vaginal tract, and serum progesterone values were used to determine the stage of the oestrous cycle at the time of sampling. The uteri were removed between 1 and 6 days after the biopsy procedure, and full-thickness sections were collected from each uterine horn and ovary and processed for histopathology. Two pathologists, blinded to the origin of each sample, compared full-thickness sections from the excised uteri to the biopsy samples collected via the transcervical technique. Pathologic features noted included: CEH, inflammation and periglandular fibrosis. Pathological diagnoses obtained from the biopsy sections were compared with those obtained from the full-thickness sections, as well as comparing diagnoses between the two pathologists, using McNemar's test. Of the 59 total biopsy samples obtained, 54 were considered diagnostic. All stages of the canine oestrous cycle were represented (anoestrus, proestrus, oestrus and dioestrus). Pyometra was not noted in any of the transcervical biopsy sections, but was noted in many of the full-thickness sections collected from dogs in dioestrus, suggesting either that biopsy is not a sensitive indicator of pyometra or that the procedure may induce pyometra in dioestrous dogs. Transcervical endometrial biopsy showed similar sensitivity as full-thickness sections in detecting CEH, inflammation and fibrosis. No differences in describing lesions were

  4. Vaginal ring delivery of selective progesterone receptor modulators for contraception

    PubMed Central

    Jensen, Jeffrey T.

    2013-01-01

    Vaginal ring delivery of selective progesterone receptor modulators (SPRMs) are under development to address limitations of current hormonal methods that affect use and effectiveness. This method would be appropriate for use in women with contraindications to, or preferences to avoid, estrogens. A contraceptive vaginal ring (CVR) also eliminates the need for daily dosing, and therefore might improve the effectiveness of contraception. The principle contraceptive effect of SPRMs is the suppression of ovulation. One limiting factor of chronic SPRM administration is the development of benign endometrial thickening characterized as PRM-associated endometrial changes. Ulipristal acetate is approved for use as an emergency contraceptive pill, but no SPRM is approved for regular contraception. The Population Council is developing an ulipristal acetate CVR for regular contraception. The CVR studied is of a matrix design composed of micronized UPA mixed in a silicone rubber matrix The target product is a ring designed for continuous use over 3 months delivering near steady-state drug levels that will suppress ovulation. Results from Phase 1–2 studies demonstrate that suppression of ovulation occurs with UPA levels above 6–7 ng/mL. PMID:23040126

  5. Vaginal ring delivery of selective progesterone receptor modulators for contraception.

    PubMed

    Jensen, Jeffrey T

    2013-03-01

    Vaginal ring delivery of selective progesterone receptor modulators (SPRMs) is under development to address the limitations of current hormonal methods that affect use and effectiveness. This method would be appropriate for use in women with contraindications to, or preferences to avoid, estrogens. A contraceptive vaginal ring (CVR) also eliminates the need for daily dosing and therefore might improve the effectiveness of contraception. The principal contraceptive effect of SPRMs is the suppression of ovulation. One limiting factor of chronic SPRM administration is the development of benign endometrial thickening characterized as PRM-associated endometrial changes. Ulipristal acetate (UPA) is approved for use as an emergency contraceptive pill, but no SPRM is approved for regular contraception. The Population Council is developing an ulipristal acetate CVR for regular contraception. The CVR studied is of a matrix design composed of micronized UPA mixed in a silicone rubber matrix The target product is a ring designed for continuous use over 3 months delivering near steady-state drug levels that will suppress ovulation. Results from Phase 1 and 2 studies demonstrate that suppression of ovulation occurs with UPA levels above 6-7 ng/mL.

  6. Treatment Option Overview (Endometrial Cancer)

    MedlinePlus

    ... mellitus . Taking tamoxifen for breast cancer or taking estrogen alone (without progesterone) can increase the risk of ... menstrual bleeding) as soon as possible. Women taking estrogen (a hormone that can affect the growth of ...

  7. Adjuvant therapy for endometrial cancer

    PubMed Central

    DeLeon, Maria C.; Ammakkanavar, Natraj R.

    2014-01-01

    Endometrial cancer is a common gynecologic malignancy typically diagnosed at early stage and cured with surgery alone. Adjuvant therapy is tailored according to the risk of recurrence, estimated based on the International Federation of Gynecology and Obstetrics (FIGO) stage and other histological factors. The objective of this manuscript is to review the evidence guiding adjuvant therapy for early stage and locally advanced uterine cancer. For patients with early stage disease, minimizing toxicity, while preserving outstanding cure rates remains the major goal. For patients with locally advanced endometrial cancer optimal combined regimens are being defined. Risk stratification based on molecular traits is under development and may aid refine the current risk prediction model and permit personalized approaches for women with endometrial cancer. PMID:24761218

  8. Immunohistochemical characterisation of molecular subtypes in endometrial cancer

    PubMed Central

    Łapińska-Szumczyk, Sylwia M; Supernat, Anna M; Majewska, Hanna I; Gulczyński, Jacek; Biernat, Wojciech; Wydra, Dariusz; Żaczek, Anna J

    2015-01-01

    Four molecular subtypes have lately been established in endometrial cancer basing on estrogen receptor (ER), progesterone receptor (PR) and HER2 status: ER+/PR+/HER2+, ER+/PR+/HER2-, ER-/PR-/HER2+ and ER-/PR-/HER2-. The subtypes have shown diversity in terms of prognosis, clinicopathological and molecular characteristics, with ER+/PR+/HER2- and ER-/PR-/HER2+ group exhibiting exceptionally benign and aggressive behavior, respectively. We have further characterized the subtypes in the context of pathways known to drive endometrial carcinogenesis: phosphatidylinositol 3-kinase (PI3K)-AKT pathway (ERBB/PI3K pathway), TP53 system, and the mismatch repair (MMR) mechanism. Analysis of tumor heterogeneity was also included. ER+/PR+/HER2+ was characterized by active ERBB/PI3K pathway occurring in 58% of cases. Subtype ER-/PR-/HER2+ was characterized by the most frequent TP53 mutations (83% of cases). Triple negative phenotype utterly lacked active ERBB/PI3K pathway. Analyzed major pathways rarely correlated with clinicopathologial data but mutated TP53 and retained MMR did correlate with shorter overall survival (both P<0.01). The presence of tumor heterogeneity was most frequent in ER-/PR-/HER2+ subtype (53% of all cases). The presented results further emphasize that the molecular subtype distinction, along with MMR and TP53 status, could be a useful diagnostic tool in guiding individualized therapy. PMID:26885170

  9. Implantation in assisted reproduction: a look at endometrial receptivity.

    PubMed

    Fatemi, H M; Popovic-Todorovic, B

    2013-11-01

    Implantation failure in assisted reproduction is thought to be mainly due to impaired uterine receptivity. With normal uterine anatomy, changes in endocrine profile during ovarian stimulation and medical conditions of the mother (i.e. thrombophilia and abnormal immunological response) could result in a non-receptive endometrium. High oestradiol concentrations during ovarian stimulation lead to premature progesterone elevation, causing endometrial advancement and hampering implantation, which can be overcome by a freeze-all approach and embryo transfer in natural cycles or by milder stimulation protocols. Patients with recurrent implantation failure (RIF) should be tested for inherited and acquired thrombophilias. Each patient should be individually assessed and counselled regarding therapy with low-molecular-weight heparin (LMWH). Empirical treatment with LMWH, aspirin or corticosteroids is not effective for women with RIF who have negative thrombophilic tests. If thrombophilic tests are normal, patients should be tested for immunological causes. If human leukocyte antigen dissimilarity is proven, treatment with intravenous immunoglobulin might be beneficial. Preliminary observational studies using intralipid infusion in the presence of increased natural killer cytotoxic activity are interesting but the proposed rationale is controversial and randomized controlled trials are needed. Hysteroscopy and/or endometrial scratching in the cycle preceding ovarian stimulation should become standard for patients with RIF.

  10. High progesterone levels in women with high ovarian response do not affect clinical outcomes: a retrospective cohort study

    PubMed Central

    2014-01-01

    Background The potentially detrimental role of progesterone during the follicular phase has been a matter of controversy for several years; however, few studies have analyzed the effects of combined raised estradiol and progesterone levels on pregnancy outcomes. The aim of the present study was to determine the influence of high progesterone levels on clinical outcomes in the context of high ovarian response. Methods We performed a retrospective cohort study that included 2850 women classified as high responders. The women were subdivided into six groups depending on their progesterone concentration on the day of human chorionic gonadotropin (hCG) administration: <0.5 ng/ml (1.81 ng/ml (>p90). Ovarian response was classified as high when > =20 oocytes were retrieved or when estradiol was > =3000 pg/ml. Clinical outcomes of each subgroup were analyzed. We also examined data from frozen-thawed embryo transfers. Results were analyzed with Student’s t- test to compare continuous variables and chi-squared test to compare proportions. A p-value of < =0.05 was considered statistically significant. Results The progesterone concentration increased with ovarian response, and elevated progesterone did not show a significant clinical impact on implantation rate and pregnancy rates. These data provide evidence that progesterone levels higher than 1.8 ng/ml do not have detrimental effect on oocyte quality or endometrial receptivity. Conclusions These data allow us to conclude that high progesterone levels correlate significantly with high estradiol levels and that in high responder women; progesterone levels do not show a significant clinical impact on results. PMID:25064138

  11. Small non-coding RNA deregulation in endometrial carcinogenesis.

    PubMed

    Ravo, Maria; Cordella, Angela; Rinaldi, Antonio; Bruno, Giuseppina; Alexandrova, Elena; Saggese, Pasquale; Nassa, Giovanni; Giurato, Giorgio; Tarallo, Roberta; Marchese, Giovanna; Rizzo, Francesca; Stellato, Claudia; Biancardi, Rossella; Troisi, Jacopo; Di Spiezio Sardo, Attilio; Zullo, Fulvio; Weisz, Alessandro; Guida, Maurizio

    2015-03-10

    Small non-coding RNAs (sncRNAs) represent a heterogeneous group of <200nt-long transcripts comprising microRNAs, PIWI-interacting RNAs (piRNAs) and small-nucleolar-RNAs (snoRNAs) involved in physiological and pathological processes such as carcinogenesis and tumor progression. Aberrant sncRNA expression in cancer has been associated with specific clinical phenotypes, grading, staging, metastases development and resistance to therapy.Aim of the present work is to study the role of sncRNAs in endometrial carcinogenesis. Changes in sncRNA expression were identified by high-throughput genomic analysis of paired normal, hyperplastic and cancerous endometrial tissues obtained by endometrial biopsies (n = 10). Using smallRNA sequencing and microarrays we identified significant differences in sncRNA expression pattern between normal, hyperplastic and neoplastic endometrium. This led to the definition of a sncRNA signature (129 microRNAs, 2 of which not previously described, 10 piRNAs and 3 snoRNAs) of neoplastic transformation. Functional bioinformatics analysis identified as downstream targets multiple signaling pathways potentially involved in the hyperplastic and neoplastic tissue responses, including Wnt/β-catenin, and ERK/MAPK and TGF-β-Signaling.Considering the regulatory role of sncRNAs, this newly identified sncRNA signature is likely to reflect the events leading to endometrial cancer, which can be exploited to dissect the carcinogenic process including novel biomarkers for early and non-invasive diagnosis of these tumors. PMID:25686835

  12. Small non-coding RNA deregulation in endometrial carcinogenesis

    PubMed Central

    Ravo, Maria; Cordella, Angela; Rinaldi, Antonio; Bruno, Giuseppina; Alexandrova, Elena; Saggese, Pasquale; Nassa, Giovanni; Giurato, Giorgio; Tarallo, Roberta; Marchese, Giovanna; Rizzo, Francesca; Stellato, Claudia; Biancardi, Rossella; Troisi, Jacopo; Di Spiezio Sardo, Attilio; Zullo, Fulvio; Weisz, Alessandro; Guida, Maurizio

    2015-01-01

    Small non-coding RNAs (sncRNAs) represent a heterogeneous group of <200nt-long transcripts comprising microRNAs, PIWI-interacting RNAs (piRNAs) and small-nucleolar-RNAs (snoRNAs) involved in physiological and pathological processes such as carcinogenesis and tumor progression. Aberrant sncRNA expression in cancer has been associated with specific clinical phenotypes, grading, staging, metastases development and resistance to therapy. Aim of the present work is to study the role of sncRNAs in endometrial carcinogenesis. Changes in sncRNA expression were identified by high-throughput genomic analysis of paired normal, hyperplastic and cancerous endometrial tissues obtained by endometrial biopsies (n = 10). Using smallRNA sequencing and microarrays we identified significant differences in sncRNA expression pattern between normal, hyperplastic and neoplastic endometrium. This led to the definition of a sncRNA signature (129 microRNAs, 2 of which not previously described, 10 piRNAs and 3 snoRNAs) of neoplastic transformation. Functional bioinformatics analysis identified as downstream targets multiple signaling pathways potentially involved in the hyperplastic and neoplastic tissue responses, including Wnt/β-catenin, and ERK/MAPK and TGF-β-Signaling. Considering the regulatory role of sncRNAs, this newly identified sncRNA signature is likely to reflect the events leading to endometrial cancer, which can be exploited to dissect the carcinogenic process including novel biomarkers for early and non-invasive diagnosis of these tumors. PMID:25686835

  13. An earlier rise in systemic progesterone and increased progesterone in the uterine vein during early pregnancy are associated with enhanced embryonic survival in the ewe.

    PubMed

    O'Connell, Anne R; Hurst, Peter R; Davis, George H; McNatty, Kenneth P; Taylor, Sarah L; Juengel, Jennifer L

    2013-08-01

    Improved livestock production efficiency through greater embryonic survival (ES) is of economic and animal welfare benefit. Physiological characterization of animals that are extreme outliers for ES provides a valuable opportunity to identify a naturally occurring mechanism by which this trait may be enhanced. The objective was to determine the likely cause for the lifetime history of enhanced or reduced ES in a line of ewes selected for high fecundity. To address this question, progesterone concentrations in peripheral plasma as well as ovarian and uterine venous plasma samples were compared between groups of ewes with a lifetime history of either enhanced or reduced ES. The ability of the uterus to synthesize progesterone de novo at Day 5 of gestation was also tested. Ewes with enhanced ES had an earlier rise in progesterone concentration after estrus, irrespective of pregnancy status. In addition, there were increased concentrations of progesterone in the uterine vein in enhanced ES compared with reduced ES ewes on Day 5 of gestation (8.3 ± 0.8 ng/mL and 3.9 ± 1.4 ng/mL, respectively, P < 0.05). However, there were no differences in ovarian venous plasma (enhanced ES, 1725 ± 166 ng/mL; reduced ES, 1665 ± 268 ng/mL) at Day 5 of gestation. Although the endometrial tissue of some ewes (3/8) at Day 5 of gestation expressed three of the key genes necessary for regulation of de novo synthesis of progesterone, expression was not present exclusively in either of the two ES groups and therefore was unlikely to explain differences in the uterine vein progesterone concentrations between the enhanced and reduced ES groups. Collectively, the earlier rise in progesterone concentrations in peripheral plasma during the first week of gestation in the enhanced ES animals was independent of the presence of an embryo. Moreover, increased progesterone concentrations were also observed in the uterine vein at Day 5 of gestation of the enhanced ES ewes. It is proposed that the

  14. Progesterone and Autoimmune Disease

    PubMed Central

    Hughes, Grant C.

    2011-01-01

    Sexual dimorphism in human immune systems is most apparent in the female predominance of certain autoimmune diseases (ADs) like systemic lupus erythematosus (SLE). Epidemiologic, observational and experimental evidence strongly suggest sex steroids are important modulators of genetic risk in human AD. In this regard, the roles of progesterone (Pg), an immunomodulatory female sex steroid, are poorly understood. Several lines of investigation indicate Pg and synthetic progestins impact risk of AD and immune-mediated injury in different ways depending on their concentrations and their engagement of various Pg receptors expressed in immune organs, immune cells or tissues targeted by immune attack. At low physiologic levels, Pg may enhance interferon-alpha (IFN-α) pathways important in SLE pathogenesis. Commonly used synthetic progestins may have the opposite effect. At pregnancy levels, Pg may suppress disease activity in rheumatoid arthritis (RA) and multiple sclerosis (MS) via inhibition of T helper type 1 (Th1) and Th17 pathways and induction of anti-inflammatory molecules. Importantly, Pg’s immunomodulatory effects differ from those of estrogens and androgens. An additional layer of complexity arises from apparent interdependence of sex hormone signaling pathways. Identifying mechanisms by which Pg and other sex steroids modulate risk of AD and immune-mediated injury will require clarification of their cellular and molecular targets in vivo. These future studies should be informed by recent genetic discoveries in human AD, particularly those revealing their sex-specific genetic associations. PMID:22193289

  15. The place of selective progesterone receptor modulators in myoma therapy.

    PubMed

    Donnez, Jacques; Donnez, Olivier; Courtoy, Guillaume E; Dolmans, Marie M

    2016-06-01

    Uterine fibroids are the most commonly encountered benign uterine tumors in women of reproductive age. As progesterone is known to play a key role in promoting myoma growth, the goal of the study was to analyze the efficacy of selective progesterone receptor modulators (SPRMs). From four studies, it was concluded that UPA (ulipristal acetate) treatment was able to control myoma-associated uterine bleeding in over 90% of cases and significantly reduce myoma volume in more than 80% of women. The results of long-term intermittent therapy (PEARL III and PEARL IV studies) (4 courses of 3 months) demonstrated that more than one course of UPA is able to maximize its potential benefits in terms of control of bleeding and fibroid volume reduction. The treatment was considered safe, even at the level of endometrial changes. With the advent of SPRMs, new algorithms should be discussed, as there is no doubt that there is a place for medical therapy with SPRMs in the current armamentarium of fibroid management. PMID:26930390

  16. Potential hazards to embryo implantation: A human endometrial in vitro model to identify unwanted antigestagenic actions of chemicals

    SciTech Connect

    Fischer, L.; Deppert, W.R.; Pfeifer, D.; Stanzel, S.; Weimer, M.; Hanjalic-Beck, A.; Stein, A.; Straßer, M.; Zahradnik, H.P.; Schaefer, W.R.

    2012-05-01

    Embryo implantation is a crucial step in human reproduction and depends on the timely development of a receptive endometrium. The human endometrium is unique among adult tissues due to its dynamic alterations during each menstrual cycle. It hosts the implantation process which is governed by progesterone, whereas 17β-estradiol regulates the preceding proliferation of the endometrium. The receptors for both steroids are targets for drugs and endocrine disrupting chemicals. Chemicals with unwanted antigestagenic actions are potentially hazardous to embryo implantation since many pharmaceutical antiprogestins adversely affect endometrial receptivity. This risk can be addressed by human tissue-specific in vitro assays. As working basis we compiled data on chemicals interacting with the PR. In our experimental work, we developed a flexible in vitro model based on human endometrial Ishikawa cells. Effects of antiprogestin compounds on pre-selected target genes were characterized by sigmoidal concentration–response curves obtained by RT-qPCR. The estrogen sulfotransferase (SULT1E1) was identified as the most responsive target gene by microarray analysis. The agonistic effect of progesterone on SULT1E1 mRNA was concentration-dependently antagonized by RU486 (mifepristone) and ZK137316 and, with lower potency, by 4-nonylphenol, bisphenol A and apigenin. The negative control methyl acetoacetate showed no effect. The effects of progesterone and RU486 were confirmed on the protein level by Western blotting. We demonstrated proof of principle that our Ishikawa model is suitable to study quantitatively effects of antiprogestin-like chemicals on endometrial target genes in comparison to pharmaceutical reference compounds. This test is useful for hazard identification and may contribute to reduce animal studies. -- Highlights: ► We compare progesterone receptor-mediated endometrial effects of chemicals and drugs. ► 4-Nonylphenol, bisphenol A and apigenin exert weak

  17. Perturbing the Cellular Levels of Steroid Receptor Coactivator-2 Impairs Murine Endometrial Function

    PubMed Central

    Szwarc, Maria M.; Kommagani, Ramakrishna; Jeong, Jae-Wook; Wu, San-Pin; Tsai, Sophia Y.; Tsai, Ming-Jer; O’Malley, Bert W.; DeMayo, Francesco J.; Lydon, John P.

    2014-01-01

    As pleiotropic coregulators, members of the p160/steroid receptor coactivator (SRC) family control a broad spectrum of transcriptional responses that underpin a diverse array of physiological and pathophysiological processes. Because of their potent coregulator properties, strict controls on SRC expression levels are required to maintain normal tissue functionality. Accordingly, an unwarranted increase in the cellular levels of SRC members has been causally linked to the initiation and/or progression of a number of clinical disorders. Although knockout mouse models have underscored the critical non-redundant roles for each SRC member in vivo, there are surprisingly few mouse models that have been engineered to overexpress SRCs. This deficiency is significant since SRC involvement in many of these disorders is based on unscheduled increases in the levels (rather than the absence) of SRC expression. To address this deficiency, we used recent mouse technology that allows for the targeted expression of human SRC-2 in cells which express the progesterone receptor. Through cre-loxP recombination driven by the endogenous progesterone receptor promoter, a marked elevation in expression levels of human SRC-2 was achieved in endometrial cells that are positive for the progesterone receptor. As a result of this increase in coregulator expression, female mice are severely subfertile due to a dysfunctional uterus, which exhibits a hypersensitivity to estrogen exposure. Our findings strongly support the proposal from clinical observations that increased levels of SRC-2 are causal for a number of endometrial disorders which compromise fertility. Future studies will use this mouse model to decipher the molecular mechanisms that underpin the endometrial defect. We believe such mechanistic insight may provide new molecular descriptors for diagnosis, prognosis, and/or therapy in the clinical management of female infertility. PMID:24905738

  18. Infiltrating Macrophages Induce ERα Expression through an IL17A-mediated Epigenetic Mechanism to Sensitize Endometrial Cancer Cells to Estrogen.

    PubMed

    Ning, Chengcheng; Xie, Bingying; Zhang, Lin; Li, Chunsheng; Shan, Weiwei; Yang, Bingyi; Luo, Xuezhen; Gu, Chao; He, Qizhi; Jin, Hongyan; Chen, Xiaojun; Zhang, Zhenbo; Feng, Youji

    2016-03-15

    Persistent unopposed estrogen stimulation is a central oncogenic mechanism driving the formation of type I endometrial cancer. Recent epidemiologic and clinical studies of endometrial cancer have also revealed a role for insulin resistance, clinically manifested by chronic inflammation. However, the role of inflammation in estrogen-driven endometrial cancer is not well characterized. In this study, we investigated the association between infiltrating macrophages and estrogen sensitivity in endometrial cancer. Evaluating tissue samples and serum from patients with precancerous lesions or endometrial cancer, we found that tissue macrophage infiltration, but not serum estradiol levels, correlated positively with endometrial cancer development. Furthermore, IL4/IL13-induced CD68(+)CD163(+) macrophages enhanced the proliferative effects of estradiol in endometrial cancer cells by upregulating estrogen receptor alpha (ERα), but not ERβ. Mechanistic investigations revealed that CD68(+)CD163(+) macrophages secreted cytokines, such as IL17A, that upregulated ERα expression through TET1-mediated epigenetic modulation of the ERα gene. Overall, our findings show how cytokines produced by infiltrating macrophages in the endometrial microenvironment can induce epigenetic upregulation of ERα expression, which in turn sensitizes endometrial cells to estrogen stimulation. The concept that inflammation-induced estrogen sensitivity in the endometrium acts as a driver of type I endometrial cancer has implications for infiltrating macrophages as a prognostic biomarker of progression in this disease setting. PMID:26744532

  19. Maternal placenta-like endometrial hyperplasia in a beagle dog (Canine deciduoma).

    PubMed

    Koguchi, A; Nomura, K; Fujiwara, T; Kawai, Y; Okaniwa, A

    1995-07-01

    Three thumb-sized segmental swellings were found in both uterine horns of a 15 month-old, non-pregnant and non-pseudopregnant female beagle dog. Histopathological examination of the uterus revealed a marked proliferation of the endometrium that was characterized by two distinct parts, an inner tightly-folded banded layer and an outer dilated spongy layer, quite similar to the maternal placenta except for the fetus and chorion in the lumen. Because the plasma level of progesterone was unusually high at autopsy, this hormonal disorder might be related to the pathogenesis of the endometrial hyperplasia in the present case.

  20. A case of advanced-stage endometrial stromal sarcoma of the ovary arising from endometriosis

    PubMed Central

    Back, Ju A; Choi, Myeong Gyune; Ju, U Chul; Kang, Woo Dae

    2016-01-01

    Endometrial stromal sarcoma (ESS) is a rare malignancy. Development of extrauterine ESS form endometriosis is particularly rare. The majority of extrauterine ESS occurs in areas with preexisting endometriosis. The most common site is the ovary. We experienced a case of ESS of the ovary that arose from endometriosis with multiple disseminated lesions. This disease was managed by total abdominal hysterectomy, bilateral salpingo-oophorectomy, both pelvic lymph nodes dissection, omentectomy, and appendectomy followed by postoperative high-dose progesterone therapy. Here, we report this case with literature review. PMID:27462602

  1. Regulation of progesterone signaling during pregnancy: implications for the use of progestins for the prevention of preterm birth.

    PubMed

    Byrns, Michael C

    2014-01-01

    Preterm birth is a major cause of neonatal morbidity and mortality. Progesterone plays a critical role in suppressing the inflammatory signals that would induce parturition prior to term. Progesterone signaling is regulated in a variety of ways during pregnancy. Endocrine production of high levels of progesterone by the placenta ensures the availability of high levels of progesterone throughout pregnancy. Paracrine regulation of progesterone metabolism in target tissues, particularly the myometrium and cervix, also determines the amount of progesterone ligand available. Progesterone metabolism can also lead to the formation of metabolites that contribute to its effects. In particular, 5β-dihydroprogesterone formation by aldo-keto reductase 1D1 appears to play an important role in maintaining uterine quiescence. Progesterone signaling can also be regulated at the receptor level through changes in the relative expression of the nuclear progesterone receptor isoforms, reduced expression of membrane receptors, and changes in the expression levels of coactivators and/or corepressors, including nuclear factor κB. Progesterone and 17α-hydroxyprogesterone caproate (17OH-PC) have recently been shown to reduce preterm births in women with previous preterm birth or shortened cervix. It is important to realize that these two progestins are likely to act in significantly different ways, which will likely influence their efficacy. The structural differences and resistance to metabolism exhibited by 17OH-PC means that it will be unable to activate some of the pathways that progesterone activates, but that it also will not be subject to paracrine inactivation. The fact that progesterone therapy works for maintaining pregnancy in some women, indicates that for those women insufficient levels of progesterone ligand in target tissues is a determining factor in early parturition, despite high levels of circulating progesterone. This article is part of a Special Issue entitled

  2. What's New in Endometrial Cancer Research and Treatment?

    MedlinePlus

    ... Next Topic Additional resources for endometrial cancer What`s new in endometrial cancer research and treatment? Molecular pathology ... that caused the endometrial cells to become cancerous. New treatments New drugs, combinations of drugs and targeted ...

  3. 6 Common Cancers - Gynecologic Cancers Cervical, Endometrial, and Ovarian

    MedlinePlus

    ... Bar Home Current Issue Past Issues 6 Common Cancers - Gynecologic Cancers Cervical, Endometrial, and Ovarian Past Issues / Spring 2007 ... of this page please turn Javascript on. Gynecologic Cancers Cervical, Endometrial, and Ovarian NCI estimates that endometrial, ...

  4. Adjuvant progestagens for endometrial cancer

    PubMed Central

    Martin-Hirsch, Pierre PL; Bryant, Andrew; Keep, Sarah L; Kitchener, Henry C; Lilford, Richard

    2014-01-01

    Background Endometrial cancer is the most common genital tract carcinoma among women in developed countries, with most women presenting with stage 1 disease. Adjuvant progestagen therapy has been advocated following primary surgery to reduce the risk of recurrence of disease. Objectives To evaluate the effectiveness and safety of adjuvant progestagen therapy for the treatment of endometrial cancer. Search methods We searched the Cochrane Gynaecological Cancer Group Trials Specilaised Register, Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2009. MEDLINE and EMBASE up to April 2009. Selection criteria Randomised controlled trials (RCTs) of progestagen therapy in women who have had surgery for endometrial cancer. Data collection and analysis Two review authors independently abstracted data and assessed risk of bias. Risk ratios (RRs) comparing survival in women who did and did not receive progestagen were pooled in random effects meta-analyses.. Main results Seven trials assessing 4556 women were identified. Three trials included women with stage one disease only, whereas four included women with more advanced disease. Meta-analysis of four trials showed that there was no significant difference in the risk of death at five years between adjuvant progestagen therapy and no further treatment (RR = 1.00, 95% CI 0.85 to 1.18). This conclusion is also robust to single trial analyses at 4 and 7 years and in one trial across all points in time using a hazard ratio (HR). There was also no significant difference between progestagen therapy and control in terms of the risk of death from endometrial cancer, cardiovascular disease and intercurrent disease. Relapse of disease appeared to be reduced by progestagen therapy in one trial (HR = 0.71, 95% CI 0.52 to 0.97 and 5 year RR = 0.74, 95% CI 0.58 to 0.96), but there was no evidence of a difference in disease recurrence in another trial at 7 years (RR = 1.34, 95% CI 0.79 to 2.27). Authors’ conclusions There

  5. Gene Tests May Improve Therapy for Endometrial Cancer

    MedlinePlus

    ... External link, please review our exit disclaimer . Subscribe Gene Tests May Improve Therapy for Endometrial Cancer By analyzing genes in hundreds of endometrial tumors, scientists identified details ...

  6. Progesterone vaginal ring for luteal support.

    PubMed

    Stadtmauer, Laurel; Waud, Kay

    2015-02-01

    Progesterone supplementation is universally used and has been shown to be beneficial in supplementation of the luteal phase in IVF. There are multiple options and the most commonly used include intramuscular and vaginal progesterone. A progesterone vaginal ring is a novel system for luteal support with advantages of controlled release with less frequent dosing. This review examines options for progesterone luteal support focusing on the rationale for a progesterone vaginal ring. Pub-med search of the literature. A weekly vaginal ring, although not yet FDA approved, is an effective and safe alternative for luteal supplementation in IVF. Large prospective clinical trials are needed to determine the best protocols for replacement cycles.

  7. Disturbances in production of progesterone and their implications in plant studies.

    PubMed

    Janeczko, Anna; Oklestkova, Jana; Novak, Ondrej; Śniegowska-Świerk, Katarzyna; Snaczke, Zuzanna; Pociecha, Ewa

    2015-04-01

    Progesterone is a mammalian hormone that has also been discovered in plants but its physiological function in plants is not explained. Experiments using inhibitors of progesterone synthesis and binding would be useful in studies on the significance of this compound in plants. Until now, trilostane and mifepristone have been used in medical sciences as progesterone biosynthesis and binding inhibitors, respectively. We tested these synthetic steroids for the first time in plants and found that they reduced the content of progesterone in wheat. The aim of further experiments was to answer whether the potential disturbances in the production/binding of progesterone, influence resistance to environmental stress (drought) and the development of wheat. Inhibitors and progesterone were applied to plants via roots in a concentration of 0.25-0.5mg/l water. Both inhibitors lowered the activity of CO2 binding enzyme (Rubisco) in wheat exposed to drought stress and trilostane additionally lowered the chlorophyll content. However, trilostane-treated plants were rescued by treatment with exogenous progesterone. The inhibitors also modulated the development of winter wheat, which indicated the significance of steroid regulators and their receptors in this process. In this study, in addition to progesterone and its inhibitors, brassinosteroid (24-epibrassinolide) and an inhibitor of biosynthesis of brassinosteroids were also applied. Mifepristone inhibited the generative development of wheat (like 24-epibrassinolide), while trilostane (like progesterone and an inhibitor of biosynthesis of brassinosteroids) stimulated the development. We propose a model of steroid-induced regulation of the development of winter wheat, where brassinosteroids act as inhibitors of generative development, while progesterone or other pregnane derivatives act as stimulators.

  8. Endogenous progesterone and its cellular binding sites in wheat exposed to drought stress.

    PubMed

    Janeczko, Anna; Oklešťková, Jana; Siwek, Agata; Dziurka, Michał; Pociecha, Ewa; Kocurek, Maciej; Novák, Ondřej

    2013-11-01

    Progesterone is a basic hormone that regulates the metabolism in mammals. The presence of this compound has also been found in certain plants. It is believed that progesterone can regulate growth processes and resistance to stress, however, its precise role in plants remains unknown. The research conducted in this study was aimed at analyzing the content of endogenous progesterone and its cellular binding sites in the leaves of spring wheat exposed to drought. Changes were studied in two cultivars of wheat - a cultivar sensitive to drought (Katoda) and tolerant cultivar (Monsun). Plants had undergone periodic droughts during the seedling stage or in the phase of heading. The occurrence of free progesterone as well as its conjugated forms was observed in wheat studied. The amount of progesterone ranged from 0.2 to 5.8pmolgFW(-1) and was dependent on the cultivar, age of the plants, stage of development and fluctuated as a result of the exposure to drought. Cv. Katoda responded to a water deficit by lowering the amount of progesterone and cv. Monsun by increasing its level. Progesterone in plants grown in limited water conditions occurred primarily in a free form. While in the optimal watering conditions, some of its pool was found in the form of conjugates. In the spring wheat the occurrence of binding sites for progesterone was detected in cell membranes, cytoplasm and nuclei in the range of 10-36fmol/mg of protein. The wheat cultivars tested, Monsun and Katoda, differ in their concentration of cellular binding sites for progesterone. This number varied in the individual fractions during different stages of plant development and due to the effect of drought stress. The number of binding sites for progesterone located in the membrane fraction of seedlings and flag leaves increased significantly under drought in the cv. Katoda (35-46%), but did not change in the cv. Monsun. Whereas the number of cytoplasmic progesterone binding sites increased during the drought in

  9. Endogenous progesterone and its cellular binding sites in wheat exposed to drought stress.

    PubMed

    Janeczko, Anna; Oklešťková, Jana; Siwek, Agata; Dziurka, Michał; Pociecha, Ewa; Kocurek, Maciej; Novák, Ondřej

    2013-11-01

    Progesterone is a basic hormone that regulates the metabolism in mammals. The presence of this compound has also been found in certain plants. It is believed that progesterone can regulate growth processes and resistance to stress, however, its precise role in plants remains unknown. The research conducted in this study was aimed at analyzing the content of endogenous progesterone and its cellular binding sites in the leaves of spring wheat exposed to drought. Changes were studied in two cultivars of wheat - a cultivar sensitive to drought (Katoda) and tolerant cultivar (Monsun). Plants had undergone periodic droughts during the seedling stage or in the phase of heading. The occurrence of free progesterone as well as its conjugated forms was observed in wheat studied. The amount of progesterone ranged from 0.2 to 5.8pmolgFW(-1) and was dependent on the cultivar, age of the plants, stage of development and fluctuated as a result of the exposure to drought. Cv. Katoda responded to a water deficit by lowering the amount of progesterone and cv. Monsun by increasing its level. Progesterone in plants grown in limited water conditions occurred primarily in a free form. While in the optimal watering conditions, some of its pool was found in the form of conjugates. In the spring wheat the occurrence of binding sites for progesterone was detected in cell membranes, cytoplasm and nuclei in the range of 10-36fmol/mg of protein. The wheat cultivars tested, Monsun and Katoda, differ in their concentration of cellular binding sites for progesterone. This number varied in the individual fractions during different stages of plant development and due to the effect of drought stress. The number of binding sites for progesterone located in the membrane fraction of seedlings and flag leaves increased significantly under drought in the cv. Katoda (35-46%), but did not change in the cv. Monsun. Whereas the number of cytoplasmic progesterone binding sites increased during the drought in

  10. Conceptus elongation in ruminants: roles of progesterone, prostaglandin, interferon tau and cortisol.

    PubMed

    Brooks, Kelsey; Burns, Greg; Spencer, Thomas E

    2014-01-01

    The majority of pregnancy loss in ruminants occurs during the first three weeks after conception, particularly during the period of conceptus elongation that occurs prior to pregnancy recognition and implantation. This review integrates established and new information on the biological role of ovarian progesterone (P4), prostaglandins (PGs), interferon tau (IFNT) and cortisol in endometrial function and conceptus elongation. Progesterone is secreted by the ovarian corpus luteum (CL) and is the unequivocal hormone of pregnancy. Prostaglandins (PGs) and cortisol are produced by both the epithelial cells of the endometrium and the trophectoderm of the elongating conceptus. In contrast, IFNT is produced solely by the conceptus trophectoderm and is the maternal recognition of pregnancy signal that inhibits production of luteolytic pulses of PGF2α by the endometrium to maintain the CL and thus production of P4. Available results in sheep support the idea that the individual, interactive, and coordinated actions of P4, PGs, IFNT and cortisol regulate conceptus elongation and implantation by controlling expression of genes in the endometrium and/or trophectoderm. An increased knowledge of conceptus-endometrial interactions during early pregnancy in ruminants is necessary to understand and elucidate the causes of infertility and recurrent early pregnancy loss and provide new strategies to improve fertility and thus reproductive efficiency.

  11. Hypoxia is not required for human endometrial breakdown or repair in a xenograft model of menstruation.

    PubMed

    Coudyzer, Pauline; Lemoine, Pascale; Jordan, Bénédicte F; Gallez, Bernard; Galant, Christine; Nisolle, Michelle; Courtoy, Pierre J; Henriet, Patrick; Marbaix, Etienne

    2013-09-01

    Menstrual endometrial breakdown induced by estradiol and progesterone withdrawal is regularly attributed to vasospasm of spiral arteries causing ischemia and hypoxia. We investigated whether hypoxia actually occurred in an in vivo model of menstruation. Three complementary approaches were used to look for signs of hypoxia in fragments of human functionalis xenografted to ovariectomized immunodeficient mice bearing pellets-releasing estradiol and progesterone, and then deprived of ovarian steroids. Hormone withdrawal 21 d after grafting induced menstrual breakdown and MMP expression within 4 d. Local partial oxygen pressure (pO2) was measured by electron paramagnetic resonance using implanted lithium phtalocyanine crystals. In mice with hormone maintenance until sacrifice, pO2 was low one week after grafting (14.8±3.4 mmHg) but increased twofold from the second week when tissue was largely revascularized. After 3 wk, pO2 was not modified by hormone withdrawal but was slightly increased on hormone reimpregnation 4 d after removal (34.7±6.1 mmHg) by comparison with hormone maintenance (27.1±8.6 mmHg). These results were confirmed using fluorescence quenching-based OxyLite measurements. In a further search for signs of hypoxia, we did not find significant HIF1-α immunostaining, nor pimonidazole adducts after hormone withdrawal. We conclude that hypoxia is not needed to trigger menstrual-like tissue breakdown or repair in human endometrial xenograft.

  12. The Impact of Serum Progesterone Levels on the Results of In Vitro Fertilization Treatments: A Literature Review.

    PubMed

    Castillo, Jaime Larach Del; Bousamra, Maroun; Fuente, Laura De La; Ruiz-Balda, Jose A; Palomo, Marissa

    2015-08-01

    The aim of this review is to analyze the relationship between preovulatory progesterone (P) rise and in vitro fertilization (IVF) pregnancy outcomes. It also investigates the sources and effects of rises in progesterone levels, including the underlying mechanisms and potential strategies in preventing its elevation during ovarian stimulation. Progesterone is produced in the early follicular phase in the adrenal gland, which shifts toward the ovaries prior to ovulation. Several factors contribute to the etiology of P level increase including the number of multiple follicles, the overdose of gonadotropins and poor ovarian response. Nowadays, the influence of the preovulatory P rise on IVF outcome remains controversial. Several authors have failed to demonstrate any negative impact, while others reported a detrimental effect associated with the rise of P. It seems that P rise (1.5 ng/ml or 4.77 nmol/l) may have deleterious effects on endometrial receptivity, namely, accelerating the endometrial maturation process that subsequently narrows the period for implantation and thus decreases pregnancy rates. Recent studies have proposed different cutoffs according to the ovarian response, which may be a little high in patients with high response in relation to those of normal response or low response. To prevent a P rise, it might be preferable to use milder stimulation protocols, earlier trigger of ovulation, cryopreservation of all embryos and transfer in the natural cycle.

  13. The Impact of Serum Progesterone Levels on the Results of In Vitro Fertilization Treatments: A Literature Review.

    PubMed

    Castillo, Jaime Larach Del; Bousamra, Maroun; Fuente, Laura De La; Ruiz-Balda, Jose A; Palomo, Marissa

    2015-01-01

    The aim of this review is to analyze the relationship between preovulatory progesterone (P) rise and in vitro fertilization (IVF) pregnancy outcomes. It also investigates the sources and effects of rises in progesterone levels, including the underlying mechanisms and potential strategies in preventing its elevation during ovarian stimulation. Progesterone is produced in the early follicular phase in the adrenal gland, which shifts toward the ovaries prior to ovulation. Several factors contribute to the etiology of P level increase including the number of multiple follicles, the overdose of gonadotropins and poor ovarian response. Nowadays, the influence of the preovulatory P rise on IVF outcome remains controversial. Several authors have failed to demonstrate any negative impact, while others reported a detrimental effect associated with the rise of P. It seems that P rise (1.5 ng/ml or 4.77 nmol/l) may have deleterious effects on endometrial receptivity, namely, accelerating the endometrial maturation process that subsequently narrows the period for implantation and thus decreases pregnancy rates. Recent studies have proposed different cutoffs according to the ovarian response, which may be a little high in patients with high response in relation to those of normal response or low response. To prevent a P rise, it might be preferable to use milder stimulation protocols, earlier trigger of ovulation, cryopreservation of all embryos and transfer in the natural cycle. PMID:27203093

  14. Cyclic remodeling of the nonhuman primate endometrium: a model for understanding endometrial receptivity.

    PubMed

    Slayden, Ov Daniel

    2014-09-01

    Old World monkeys display physiological responses to steroid hormones that are similar to those of women. In this review, we describe cyclic morphological changes that take place within the uterus of Old World primates during the menstrual cycle. In primates, estrogen stimulates endometrial growth in the follicular phase of the menstrual cycle. Progesterone secreted in the luteal phase acts to induce secretory differentiation, which is required for successful embryo implantation. During the differentiation process, endometrial estrogen receptor-1 (ESR-1) is suppressed, and reduced staining for ESR-1 is a definitive marker of the onset of uterine receptivity. Downregulation of ESR-1 is topographically limited to the functionalis (upper) zones of the endometrium, the zones in which embryo implantation occurs, indicating that zone-specific factors play a role in the differentiation process. Future genomic and proteomic studies are expected to reveal additional markers for diagnosing endometrial receptivity. Due to the distinct zonal response of the endometrium to ovarian steroids, accurate histological characterization will remain necessary to interpret novel targets in the assessment of fertility. PMID:24959820

  15. Novel genetic targets in endometrial cancer

    PubMed Central

    Bell, Daphne W.

    2014-01-01

    Worldwide, ~74,000 women die from endometrial cancer each year. Understanding the somatic genomic alterations that drive endometrial tumorigenesis may provide new opportunities to identify targeted therapies for specific subsets of patients. Since 2012, the use of next generation sequencing to decode the mutational landscape of endometrial tumors has not only confirmed prior knowledge of established genetic targets for serous and endometrioid endometrial carcinomas, but has also uncovered novel significantly mutated genes, referred to herein as novel genetic targets, which represent candidate cancer genes in these tumors. This editorial summarizes the novel genetic targets that have been identified in serous and endometrioid ECs, according to their unifying functional characteristics. An expert opinion section comments on remaining knowledge gaps that will undoubtedly be filled in future genomic studies of endometrial cancer. PMID:24750045

  16. Evaluation of endometrial cancer epidemiology in Romania.

    PubMed

    Bohîlțea, R E; Furtunescu, F; Dosius, M; Cîrstoiu, M; Radoi, V; Baroș, A; Bohîlțea, L C

    2015-01-01

    Endometrial cancer represents the most frequent gynecological malignant affection in the developed countries, in which the incidence of cervical cancer has significantly decreased due to the rigorous application of screening methods and prophylaxis. According to its frequency, endometrial cancer is situated on the fourth place in the category of women's genital-mammary malignant diseases, after breast, cervical and ovarian cancer in Romania. The incidence and mortality rates due to endometrial cancer have registered an increasing trend worldwide and also in Romania, a significant decrease of the age of appearance for the entire endometrial pathology sphere being noticed. At the national level, the maximum incidence is situated between 60 and 64 years old, the mortality rate of the women under 65 years old being high in Romania. The study evaluates endometrial cancer, from an epidemiologic point of view, at the national level compared to the international statistic data.

  17. Progesterone inhibits mast cell secretion.

    PubMed

    Vasiadi, M; Kempuraj, D; Boucher, W; Kalogeromitros, D; Theoharides, T C

    2006-01-01

    Mast cells are involved in allergic reactions, where they secrete numerous vasoactive, inflammatory and nociceptive mediators in response to immunoglobulin E (IgE) and antigen. However, they have also been implicated in inflammatory conditions, such as painful bladder syndrome/interstitial cystitis (PBS/IC), irritable bowel syndrome (IBS) and migraines, all of which occur more often in women and are exacerbated during ovulation, but are suppressed during pregnancy. Mast cells express high affinity estrogen receptors and estradiol augments their secretion, while tamoxifen inhibits it. Here we report that progesterone (100 nM), but not the structurally related cholesterol, inhibits histamine secretion from purified rat peritoneal mast cells stimulated immunologically or by substance P (SP), an effect also documented by electron microscopy. These results suggest that mast cell secretion may be regulated by progesterone and may explain the reduced symptoms of certain inflammatory conditions during pregnancy.

  18. Changes in Eutopic Endometrial Gene Expression During the Progression of Experimental Endometriosis in the Baboon, Papio Anubis1

    PubMed Central

    Afshar, Yalda; Hastings, Julie; Roqueiro, Damian; Jeong, Jae-Wook; Giudice, Linda C.; Fazleabas, Asgerally T.

    2013-01-01

    ABSTRACT Endometriosis is associated with aberrant gene expression in the eutopic endometrium of women with disease. To determine if the development of endometriotic lesions directly impacts eutopic endometrial gene expression, we sequentially analyzed the eutopic endometrium across the time course of disease progression in a baboon model of induced disease. Endometriosis was induced in baboons (n = 4) by intraperitoneal inoculation of autologous menstrual endometrium. Eutopic endometria were collected during the midsecretory phase (Days 9–11 postovulation) at 1, 3, 6–7, 10–12, and 15–16 mo after disease induction and compared with tissue from disease-free baboons. RNA was hybridized to Human Genome U133 Plus 2.0 Arrays, and data were extracted using Gene-Chip Operating Software. Subsequently, both Gene Set Enrichment Analysis and Ingenuity Pathways Analysis were used to find biological states that have a statistically significant enrichment concomitant with pairwise comparison of human endometriosis arrays. Within 1 mo of induction of the disease, 4331 genes were differentially expressed (P < 0.05). Hierarchical clustering revealed self-segregation into two groups—a) 1, 3, and 10–12 mo and b) 6–7 and 15–16 mo—together with controls. Clustering analysis at each stage of disease validated dysregulation of several signaling pathways, including Nodal-like receptor, EGF, ERK/MAPK, and PI3/AKT. Sequential analysis of the same animals during disease progression demonstrated an early disease insult and a transitory dominance of an estrogenic phenotype; however, as the disease progressed, a progesterone-resistant phenotype became evident. Furthermore, we demonstrate a 38.6% differential gene expression overlap with endometrial samples in the midsecretory phase from women with endometriosis, concomitant with similar dysregulation in human disease candidate genes Fos, Nodal, Suclg2, and Kras, among others. Molecular changes in the eutopic endometrium

  19. The utility of endometrial thickness measurement in asymptomatic postmenopausal women with endometrial fluid.

    PubMed

    Seckin, B; Ozgu-Erdinc, A S; Dogan, M; Turker, M; Cicek, M N

    2016-01-01

    The aim of this study was to assess the clinical usefulness of sonographic endometrium thickness measurement in asymptomatic postmenopausal women with endometrial fluid collection. Fifty-two asymptomatic postmenopausal women with endometrial fluid, who underwent endometrial sampling were evaluated. Histopathological findings revealed that 25 (48.1%) women had insufficient tissue, 20 (38.4%) had atrophic endometrium and 7 (13.5%) had endometrial polyps. No case of malignancy was found. There was no statistically significant difference between the various histopathological categories (insufficient tissue, atrophic endometrium and polyp) with regard to the mean single-layer endometrial thickness (1.54 ± 0.87, 2.04 ± 1.76 and 1.79 ± 0.69 mm, respectively, p = 0.436). Out of 44 patients with endometrial thickness of less than 3 mm, 38 (86.4%) had atrophic changes or insufficient tissue and 6 (13.6%) had endometrial polyps. In conclusion, if the endometrial thickness is 3 mm or less, endometrial sampling is not necessary in asymptomatic postmenopausal women with endometrial fluid.

  20. Immunohistochemical (Ki-67) study of endometrial maturation in mice after use of phosphodiesterase type 5 inhibitor

    PubMed Central

    Rashidi, Bahman; Rad, Jafar Soleimani; Rad, Leila Roshangar

    2015-01-01

    Background: Uterine receptivity for the implantation is a complicated process, that ovarian factors (hormonal), endometrium and embryo simultaneously are involved in this phenomenon. A successful implantation needs appropriate development of the endometrium. Furthermore, embryo must be capable of reacting with the endometrium and producing suitable adhesion molecules. This study aimed to examine one of endometrial maturation indices in mice before implantation, i.e., proliferation of stromal cells. Materials and Methods: A total of 40 adult female mice were divided into four groups: Control, gonadotropin, gonadotropin + progesterone, and gonadotropin + sildenafil citrate. The three experimental groups were first injected 7.5 IU of human chorionic gonadotropin (HCG) and then 7.5 IU of human menopausal gonadotropin (HMG). Then, every two female mice were placed in a cage with a male mouse for mating. Two groups were injected 1 mg of progesterone and 3 mg/kg of sildenafil citrate at intervals of 24, 48, and 72 h after injection of HMG. After 96 h, all the mice were killed, and their uterine samples subjected to tissue passage and prepared for analysis. Immunohistochemical method, Ki-67, and stromal mitotic cell count were used in this study. Results: Our observations in all groups showed changes in the luminal epithelium. ANOVA analysis Ki-67-positive stromal cells among all groups were not statistically significant. Conclusion: The results showed that administration of HMG and HCG following that of progesterone and sildenafil citrate could change the indices of endometrial maturation, and they were not involved in the phase immediately before implantation in stromal mitotic index. PMID:26380239

  1. Dietary insulin index and insulin load in relation to endometrial cancer risk in the Nurses’ Health Study

    PubMed Central

    Prescott, Jennifer; Bao, Ying; Viswanathan, Akila N.; Giovannucci, Edward L.; Hankinson, Susan E.; De Vivo, Immaculata

    2014-01-01

    Background While unopposed estrogen exposure is considered the main driver of endometrial carcinogenesis, factors associated with states of insulin resistance and hyperinsulinemia are independently associated with endometrial cancer risk. We used dietary insulin load and insulin index scores to represent the estimated insulin demand of overall diets and assessed their association with endometrial cancer risk in the prospective Nurses’ Health Study. Methods We estimated incidence rate ratios (RRs) and 95% confidence intervals (CI) for risk of invasive endometrial cancer using Cox proportional hazards models. Between the baseline dietary questionnaire (1980) and 2010, we identified a total of 798 incident invasive epithelial endometrial adenocarcinomas over 1,417,167 person-years of follow-up. Results Dietary insulin scores were not associated with overall risk of endometrial cancer. Comparing women in the highest to the lowest quintile, the multivariable-adjusted RRs of endometrial cancer were 1.07 (95% CI: 0.84, 1.35) for cumulative average dietary insulin load and 1.03 (95% CI: 0.82, 1.31) for cumulative average dietary insulin index. Findings did not vary substantially by alcohol consumption, total dietary fiber intake, or BMI and/or physical activity (Pheterogeneity ≥ 0.10). Conclusions Intake of a diet predicted to stimulate a high postprandial insulin response was not associated with endometrial cancer risk in this large prospective study. Considering the complex interplay of diet, lifestyle and genetic factors contributing to the hyperinsulinemic state, dietary measures alone may not sufficiently capture absolute long-term insulin exposure. Impact This study is the first to investigate dietary insulin scores in relation to endometrial cancer risk. PMID:24859872

  2. Endometrial responses to embryonic signals in the primate

    PubMed Central

    Banerjee, Prajna; Fazleabas, Asgerally T.

    2016-01-01

    The delicate interaction between an embryo and the uterus to initiate implantation and maintain pregnancy is one of the most elegant and fascinating interactions in human biology. Understanding the molecular events of embryo-maternal interaction is of interest to reproductive biologists, clinicians and couples affected by infertility. We have established the baboon as the non-human primate model for studying embryo implantation. Infusion of chorionic gonadotropin (CG), the major embryonic signal of primates, into the uterine cavity of normal cycling baboons during the window of receptivity induces a myriad of morphological, biochemical and molecular changes in the estrogen and progesterone primed endometrium. The luminal epithelium responds by forming plaques, the overall secretory function of the glandular epithelium increases and the stromal response is characterized by induction of α-smooth muscle actin (αSMA). Cross talk between ovarian and embryonic hormones is evidenced by the fact that these responses are inhibited upon treatment with a progesterone receptor antagonist. CG signals principally through the seven transmembrane LH/CG G-protein coupled receptor, and activates a mitogen activated protein kinase pathway in the endometrial epithelium that is unique and independent of all the classical signaling pathways. In the stromal compartment, CG both rescues stromal fibroblasts from their apoptotic demise and also differentiates them into the decidualized phenotype. We propose that stromal cell survival and differentiation is mediated by a critical modulator of cell fate, Notch-1. Thus, CG is an important embryonic signal which modulates communication between the embryo and the endometrium and induces changes that are critical to successful implantation. PMID:19876822

  3. Membrane progesterone receptors in reproduction and cancer.

    PubMed

    Valadez-Cosmes, Paulina; Vázquez-Martínez, Edgar Ricardo; Cerbón, Marco; Camacho-Arroyo, Ignacio

    2016-10-15

    Progesterone is a sexual steroid hormone that has a critical role in reproductive processes in males and females of several species, including humans. Furthermore, progesterone has been associated with pathological diseases such as breast, gynecological and brain cancer, regulating cell proliferation, apoptosis, and metastasis. In the past, progesterone actions were thought to be only mediated by its intracellular receptor (PR). However, recent evidence has demonstrated that membrane progesterone receptors (mPRs) mediate most of the non-classical progesterone actions. The role of the different mPRs subtypes in progesterone effects in reproduction and cancer is an emerging and exciting research area. Here we review studies to date regarding mPRs role in reproduction and cancer and discuss their functions and clinical relevance, suggesting mPRs as putative pharmacological targets and disease markers in cancer and diseases associated with reproduction. PMID:27368976

  4. [Biometric research in the cytomorphological diagnosis of endometrial lesions].

    PubMed

    Novik, V I; Agroskin, L S; Papaian, G V; Solov'eva, L V

    1990-01-01

    Morphometrical and optical density (including DNA content) parametres of nuclei of the endometrial epithelial cells in smears of endometrial aspirates obtained from 57 women without endometrial disorders with hyperplastic, precancer conditions and endometrial cancer have been measured by using television image analyzer IBAS-2. Biometrical data have demonstrated a good correlation with cytomorphological diagnostic criteria and in 85.7% they have facilitated discrimination of the normal and hyperplastic epithelium from precancer and high differentiated endometrial cancer. PMID:2318130

  5. Regulation of insulin-like growth factor signaling by metformin in endometrial cancer cells

    PubMed Central

    XIE, YA; WANG, JING-LU; JI, MEI; YUAN, ZHONG-FU; PENG, ZHENG; ZHANG, YI; WEN, JIAN-GUO; SHI, HUI-RONG

    2014-01-01

    Obesity, diabetes and insulin resistance are marked risk factors that promote the development of type I endometrial cancer. Previous studies have demonstrated that insulin-like growth factor 1 (IGF-1) and IGF-2 promote cell proliferation in endometrial cancer cells, while metformin reverses this effect and inhibits cell proliferation. However, the effects of metformin on the regulation of the IGF signaling pathway are unclear. The aim of this study was to investigate the regulation of IGF signaling by metformin in endometrial cancer cells, and to determine the effects of metformin combined with IGF-1 receptor (IGF-1R) inhibitor on cell proliferation and apoptosis. Cell proliferation was assessed following exposure of Ishikawa and HEC-1B endometrial cancer cell lines to metformin and/or the IGF-1R inhibitor, PPP. Apoptosis was assessed by TdT-mediated dUTP nick end labeling assay. Metformin was observed to downregulate IGF-1R and upregulate IGF binding protein-1 (IGFBP-1) mRNA and protein expression, while compound C, an adenosine monophosphate protein kinase inhibitor, reversed this effect. Metformin administered with PPP inhibited endometrial cancer cell proliferation to a greater degree than treatment with either agent alone. At high concentrations (1 or 2 mM), metformin induced apoptosis in endometrial cancer cells. Metformin combined with IGF-1R axis inhibitors may act synergistically to kill tumor cells, as metformin was shown to delay and prevent IGF-1R feedback. In conclusion, this study supported the results of animal studies and subclinical studies, demonstrating the feasibility of metformin combined with IGF-1R axis inhibitors in the treatment of endometrial cancer. PMID:25289085

  6. Recurrent hormone-binding domain truncated ESR1 amplifications in primary endometrial cancers suggest their implication in hormone independent growth.

    PubMed

    Holst, Frederik; Hoivik, Erling A; Gibson, William J; Taylor-Weiner, Amaro; Schumacher, Steven E; Asmann, Yan W; Grossmann, Patrick; Trovik, Jone; Necela, Brian M; Thompson, E Aubrey; Meyerson, Matthew; Beroukhim, Rameen; Salvesen, Helga B; Cherniack, Andrew D

    2016-01-01

    The estrogen receptor alpha (ERα) is highly expressed in both endometrial and breast cancers, and represents the most prevalent therapeutic target in breast cancer. However, anti-estrogen therapy has not been shown to be effective in endometrial cancer. Recently it has been shown that hormone-binding domain alterations of ERα in breast cancer contribute to acquired resistance to anti-estrogen therapy. In analyses of genomic data from The Cancer Genome Atlas (TCGA), we observe that endometrial carcinomas manifest recurrent ESR1 gene amplifications that truncate the hormone-binding domain encoding region of ESR1 and are associated with reduced mRNA expression of exons encoding the hormone-binding domain. These findings support a role for hormone-binding alterations of ERα in primary endometrial cancer, with potentially important therapeutic implications. PMID:27160768

  7. Recurrent hormone-binding domain truncated ESR1 amplifications in primary endometrial cancers suggest their implication in hormone independent growth

    PubMed Central

    Holst, Frederik; Hoivik, Erling A.; Gibson, William J.; Taylor-Weiner, Amaro; Schumacher, Steven E.; Asmann, Yan W.; Grossmann, Patrick; Trovik, Jone; Necela, Brian M.; Thompson, E. Aubrey; Meyerson, Matthew; Beroukhim, Rameen; Salvesen, Helga B.; Cherniack, Andrew D.

    2016-01-01

    The estrogen receptor alpha (ERα) is highly expressed in both endometrial and breast cancers, and represents the most prevalent therapeutic target in breast cancer. However, anti-estrogen therapy has not been shown to be effective in endometrial cancer. Recently it has been shown that hormone-binding domain alterations of ERα in breast cancer contribute to acquired resistance to anti-estrogen therapy. In analyses of genomic data from The Cancer Genome Atlas (TCGA), we observe that endometrial carcinomas manifest recurrent ESR1 gene amplifications that truncate the hormone-binding domain encoding region of ESR1 and are associated with reduced mRNA expression of exons encoding the hormone-binding domain. These findings support a role for hormone-binding alterations of ERα in primary endometrial cancer, with potentially important therapeutic implications. PMID:27160768

  8. Progesterone in normal and pathological pregnancy.

    PubMed

    Di Renzo, Gian Carlo; Giardina, Irene; Clerici, Graziano; Brillo, Eleonora; Gerli, Sandro

    2016-07-01

    Progesterone is an essential hormone in the process of reproduction. It is involved in the menstrual cycle, implantation and is essential for pregnancy maintenance. It has been proposed and extensively used in the treatment of different gynecological pathologies as well as in assisted reproductive technologies and in the maintenance of pregnancy. Called "the pregnancy hormone", natural progesterone is essential before pregnancy and has a crucial role in its maintenance based on different mechanisms such as: modulation of maternal immune response and suppression of inflammatory response (the presence of progesterone and its interaction with progesterone receptors at the decidua level appears to play a major role in the maternal defense strategy), reduction of uterine contractility (adequate progesterone concentrations in myometrium are able to counteract prostaglandin stimulatory activity as well as oxytocin), improvement of utero-placental circulation and luteal phase support (it has been demonstrated that progesterone may promote the invasion of extravillous trophoblasts to the decidua by inhibiting apoptosis of extravillous trophoblasts). Once the therapeutic need of progesterone is established, the key factor is the decision of the best route to administer the hormone and the optimal dosage determination. Progesterone can be administered by many different routes, but the most utilized are oral, the vaginal and intramuscular administration. The main uses of progesterone are represented by: threatened miscarriage, recurrent miscarriage and preterm birth (in the prevention strategy, as a tocolytic agent and also in the maintenance of uterine quiescence). PMID:27662646

  9. Endometrial receptivity array: Clinical application.

    PubMed

    Mahajan, Nalini

    2015-01-01

    Human implantation is a complex process requiring synchrony between a healthy embryo and a functionally competent or receptive endometrium. Diagnosis of endometrial receptivity (ER) has posed a challenge and so far most available tests have been subjective and lack accuracy and a predictive value. Microarray technology has allowed identification of the transcriptomic signature of the window of receptivity window of implantation (WOI). This technology has led to the development of a molecular diagnostic tool, the ER array (ERA) for diagnosis of ER. Use of this test in patients with recurrent implantation failure (RIF) has shown that the WOI is displaced in a quarter of these patients and use of a personalized embryo transfer (pET) on the day designated by ERA improves reproductive performance. Our results in the Indian population revealed an endometrial factor in 27.5% RIF patients, which was significantly greater than the non-RIF group 15% (P = 0.04). After pET, the overall ongoing pregnancy rate was 42.4% and implantation rate was 33%, which was at par with our in-vitro fertilization results over 1-year. We also performed ERA in patients with persistently thin endometrium, and it was reassuring to find that the endometrium in 75% of these patients was receptive despite being 6 mm or less. A pregnancy rate of 66.7% was achieved in this group. Though larger studies are required to validate these results ERA has become a useful tool in our diagnostic armamentarium for ER. PMID:26538853

  10. Preventing endometrial cancer risk in polycystic ovarian syndrome (PCOS) women: could metformin help?

    PubMed

    Shafiee, Mohamad Nasir; Khan, Gulafshana; Ariffin, Rina; Abu, Jafaru; Chapman, Caroline; Deen, Suha; Nunns, David; Barrett, David A; Seedhouse, Claire; Atiomo, William

    2014-01-01

    Current data indicate that there is a significant risk of endometrial cancer (EC) in women with polycystic ovarian syndrome (PCOS), although further research needed to clarify the exact molecular mechanisms. Endometrial hyperplasia is a premalignant condition that usually heralds EC and it shares identical risk factors with EC. Metabolic syndrome with a triad of obesity, hyperinsulinaemia and diabetes, which is commonly observed in PCOS appears to be a key mechanism in EC pathogenesis. Measures to improve insulin resistance could therefore play a role in reducing the risk of EC in women with PCOS. Metformin is an insulin sensitising agent which is safe, widely available and currently licensed for type-2 diabetes. It has been clearly shown in both animal and human studies that metformin is of value in reversing endometrial hyperplasia. Metformin may therefore prevent EC in PCOS. This article reviews the use of metformin in reducing EC risk in PCOS and makes a case for future research on this topic. PMID:24183733

  11. Breast cancer susceptibility polymorphisms and endometrial cancer risk: a Collaborative Endometrial Cancer Study

    PubMed Central

    Ahmed, Shahana; O’Mara, Tracy A.; Ferguson, Kaltin; Lambrechts, Diether; Garcia-Dios, Diego A.; Vergote, Ignace; Amant, Frederic; Howarth, Kimberley; Gorman, Maggie; Hodgson, Shirley; Tomlinson, Ian; Yang, Hannah P.; Lissowska, Jolanta; Brinton, Louise A.; Chanock, Stephen; Garcia-Closas, Montserrat; Hall, Per; Liu, Jianjun; Shah, Mitul; Pharoah, Paul D.P.; Thompson, Deborah J.; Rebbeck, Timothy R.; Strom, Brian L.; Dunning, Alison M.; Easton, Douglas F.; Spurdle, Amanda B.

    2011-01-01

    Recent large--scale association studies, both of genome-wide and candidate gene design, have revealed several single-nucleotide polymorphisms (SNPs) which are significantly associated with risk of developing breast cancer. As both breast and endometrial cancers are considered to be hormonally driven and share multiple risk factors, we investigated whether breast cancer risk alleles are also associated with endometrial cancer risk. We genotyped nine breast cancer risk SNPs in up to 4188 endometrial cases and 11 928 controls, from between three and seven Caucasian populations. None of the tested SNPs showed significant evidence of association with risk of endometrial cancer. PMID:21965274

  12. Cabozantinib-S-Malate in Treating Patients With Recurrent or Metastatic Endometrial Cancer

    ClinicalTrials.gov

    2016-10-10

    Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Serous Adenocarcinoma; Metastatic Endometrioid Adenocarcinoma; Recurrent Uterine Corpus Carcinoma; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer

  13. Endometrial transcriptional profiling of a bovine fertility model by Next-Generation Sequencing

    PubMed Central

    Mesquita, F.S.; Ramos, R.S.; Pugliesi, G.; Andrade, S.C.S.; Van Hoeck, V.; Langbeen, A.; Oliveira, M.L.; Gonella-Diaza, A.M.; Gasparin, G.; Fukumasu, H.; Pulz, L.H.; Membrive, C.M.; Coutinho, L.L.; Binelli, M.

    2015-01-01

    Studying the multitude of molecular networks and pathways that are potentially involved in a complex trait such as fertility requires an equally complex and broad strategy. Here, we used Next-Generation Sequencing for the characterization of the transcriptional signature of the bovine endometrial tissue. Periovulatory endocrine environments were manipulated to generate two distinctly different fertility phenotypes. Cycling, non-lactating, multiparous Nelore cows were manipulated to ovulate larger (> 13 mm; LF group; high fertility phenotype) or smaller (< 12 mm; SF group) follicles. As a result, greater proestrus estrogen concentrations, corpora lutea and early diestrus progesterone concentrations were also observed in LF group in comparison to SF group. Endometrial cell proliferation was estimated by the protein marker MKI67 on tissues collected 4 (D4) and 7 (D7) days after induction of ovulation. Total RNA extracts from D7 were sequenced and compared according to the transcriptional profile of each experimental group (LF versus SF). Functional enrichment analysis revealed that LF and SF endometria were asynchronous in regards to their phenotype manifestation. Major findings indicated an LF endometrium that was switching phenotypes earlier than the SF one. More specifically, a proliferating SF endometrium was observed on D7, whereas the LF tissue, which expressed a proliferative phenotype earlier at D4, seemed to have already shifted towards a biosynthetically and metabolically active endometrium on D7. Data on MKI67 support the transcriptomic results. RNA-Seq-derived transcriptional profile of the endometrial tissue indicated a temporal effect of the periovulatory endocrine environment, suggesting that the moment of the endometrial exposure to the ovarian steroids, E2 and P4, regulates the timing of phenotype manifestation. Gene expression profiling revealed molecules that may be targeted to elucidate ovarian steroid-dependent mechanisms that regulate

  14. 21 CFR 884.1185 - Endometrial washer.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... with negative pressure. This device is used to study endometrial cytology (cells). (b) Classification... a recent cesarean section, and (iii) Warning: Do not attach to a wall or any external suction,...

  15. 21 CFR 884.1185 - Endometrial washer.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... with negative pressure. This device is used to study endometrial cytology (cells). (b) Classification... a recent cesarean section, and (iii) Warning: Do not attach to a wall or any external suction,...

  16. 21 CFR 884.1185 - Endometrial washer.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... with negative pressure. This device is used to study endometrial cytology (cells). (b) Classification... a recent cesarean section, and (iii) Warning: Do not attach to a wall or any external suction,...

  17. 21 CFR 884.1185 - Endometrial washer.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... with negative pressure. This device is used to study endometrial cytology (cells). (b) Classification... a recent cesarean section, and (iii) Warning: Do not attach to a wall or any external suction,...

  18. 21 CFR 884.1185 - Endometrial washer.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... with negative pressure. This device is used to study endometrial cytology (cells). (b) Classification... for Standardization's ISO 10993 ‘Biological Evaluation of Medical Devices—Part I: Evaluation...

  19. Intraperitoneal Paclitaxel, Doxorubicin Hydrochloride, and Cisplatin in Treating Patients With Stage III-IV Endometrial Cancer

    ClinicalTrials.gov

    2016-10-26

    Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Squamous Cell Carcinoma; Endometrial Undifferentiated Carcinoma; Recurrent Uterine Corpus Carcinoma; Stage IIIA Uterine Corpus Cancer; Stage IIIC Uterine Corpus Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer

  20. Dasatinib, Paclitaxel, and Carboplatin in Treating Patients With Stage III-IV or Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2015-12-22

    Endometrial Adenocarcinoma; Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mucinous Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Undifferentiated Carcinoma; Endometrioid Adenocarcinoma; Recurrent Uterine Corpus Carcinoma; Stage IIIA Uterine Corpus Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIC Uterine Corpus Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer; Uterine Carcinosarcoma

  1. [Progesterone and nitric oxide systems].

    PubMed

    Wieser, F; Gruber, D M; Tschugguel, W; Huber, J C

    1997-01-01

    Sexual steroids play an established role in the mechanisms concerning reproduction, ovulation, menstruation and onset of labour. However, sexual steroids are also involved in extragenital mechanisms, which were described for both oestrogen, and progesterone. Progesterone and its mechanisms of signal transduction still remain to be fully understood. However, there is evidence, that nitric oxide (NO) seems to be an important mediator in these mechanisms. NO, the molecule, which was described to exist in acid rain, was elected the molecule of the year 1992 from the American Academy of Science. NO is a short-lived molecule, which is involved in many reactions as an modulating transmitter due to its high diffusibility and its polarity. NO regulates the immune response of mononuclear cells, contractility of smooth muscle cells and neuronal transmission of non-adrenergic and non-cholinergic nerves. Additionally it was found, that NO may be important in the regulation of menstruation, the maintenance of uterine quiescence as well as the initiation of labour and the maturation of the uterine cervix.

  2. [Peroxidase activity of catalase modified by progesterone].

    PubMed

    Artemchik, V D; Matveentsev, V D; Metelitsa, D I

    1986-08-01

    Catalase conjugates with 3, 7, 9 and 42 progesterone molecules were obtained by the reaction between the enzyme and N-oxy-succinimide ether of 3-0-carboxymethyloxime of progesterone. The enzyme modified by 42 progesterone molecules is effective in o-dianisidine oxidation by hydrogen peroxide and has a kcat/KM value of 512 M-1 s-1. The catalase conjugates with 3, 7 and 9 progesterone molecules exhibit a high activity during o-dianisidine oxidation by cumene hydroperoxide. The activity of conjugates is higher than that of the native non-modified enzyme in the same reaction. The maximum effectiveness was observed for catalase modified by 7 progesterone molecules. This conjugate is characterized by kcat/KM of 99,000 M-1 s-1 at 30 degrees C. The effect of the degree of enzyme modification on the kinetic parameters of o-dianisidine oxidation by H2O2 and cumene hydroperoxide is discussed. PMID:3021241

  3. Androgen receptors are acquired by healthy postmenopausal endometrial epithelium and their subsequent loss in endometrial cancer is associated with poor survival

    PubMed Central

    Kamal, A M; Bulmer, J N; DeCruze, S B; Stringfellow, H F; Martin-Hirsch, P; Hapangama, D K

    2016-01-01

    Background: Endometrial cancer (EC) is a hormone-driven disease, and androgen receptor (AR) expression in high-grade EC (HGEC) and metastatic EC has not yet been described. Methods: The expression pattern and prognostic value of AR in relation to oestrogen (ERα and ERβ) and progesterone (PR) receptors, and the proliferation marker Ki67 in all EC subtypes (n=85) were compared with that of healthy and hyperplastic endometrium, using immunohistochemisty and qPCR. Results: Compared with proliferative endometrium, postmenopausal endometrtial epithelium showed significantly higher expression of AR (P<0.001) and ERα (P=0.035), which persisted in hyperplastic epithelium and in low-grade EC (LGEC). High-grade EC showed a significant loss of AR (P<0.0001), PR (P<0.0001) and ERβ (P<0.035) compared with LGEC, whilst maintaining weak to moderate ERα. Unlike PR, AR expression in metastatic lesions was significantly (P=0.039) higher than that in primary tumours. Androgen receptor expression correlated with favourable clinicopathological features and a lower proliferation index. Loss of AR, with/without the loss of PR was associated with a significantly lower disease-free survival (P<0.0001, P<0.0001, respectively). Conclusions: Postmenopausal endometrial epithelium acquires AR whilst preserving other steroid hormone receptors. Loss of AR, PR with retention of ERα and ERβ may promote the unrestrained growth of HGEC. Androgen receptor may therefore be a clinically relevant prognostic indicator and a potential therapeutic target in EC. PMID:26930451

  4. Progesterone

    MedlinePlus

    ... not had a hysterectomy (surgery to remove the uterus). Hormone replacement therapy usually includes estrogen, which is ... cause abnormal thickening of the lining of the uterus and increase the risk of developing uterine cancer. ...

  5. From endometrial receptivity to infertility.

    PubMed

    Tabibzadeh, S; Shea, W; Lessey, B A; Broome, J

    1999-01-01

    Implantation of the blastocyst in endometrium requires establishment of a coordinated molecular dialogue between the embryo and the endometrium. Factors instrumental in the preparation of a receptive endometrium are derived from the hypothalamic-pituitary-gonadal axis. These factors modulate the expression of genes that drive the endometrium throughout the characteristic menstrual cycles. During each menstrual cycle, a series of coordinated, architectural, morphological, cytochemical, and molecular changes ultimately lead to the preparation of a receptive endometrium during the putative "receptive period" or "implantation window." It is during this critical period that a proper dialogue can be established between an intrusive blastocyst and a receptive endometrium. If, for any reason, this dialogue is not established or is perturbed, the embryo is aborted. The natural fate of the receptive endometrium, in the absence of implantation, is development of a second set of changes that ultimately lead to menstruation. The identity of the molecular repertoire that makes endometrium receptive to implantation and/or lead to menstruation is being revealed and broadly includes cytokines, heat shock factors, adhesion molecules and matrix metalloproteases. We identified a novel gene of the transforming growth factor-beta, superfamily of molecules, the so-called endometrial bleeding--associated factor or ebaf, whose expression is confined to the late secretory and menstrual phases. Various forms of female infertility were associated with dysregulated expression of ebaf during the implantation window. The findings show an occult molecular defect of endometrial receptivity that seems to be due to dysregulated and premature expression of a member of the premenstrual molecular repertoire. The dysregulated expression of ebaf may assist in the identification, prognostication, and monitoring of treatment of infertile women.

  6. Effect of luteal-phase support on endometrial microRNA expression following controlled ovarian stimulation

    PubMed Central

    2012-01-01

    Background Studies suggested that microRNAs influence cellular activities in the uterus including cell differentiation and embryo implantation. In assisted reproduction cycles, luteal phase support, given to improve endometrial characteristics and to facilitate the implantation process, has been a standard practice. The effect of different types of luteal phase support using steroid hormones in relation to endometrial miRNA profiles during the peri-implantation period has not seen described. This study was designed to evaluate the expression of miRNAs during the luteal phase following controlled ovarian stimulation for IVF and the influence of different luteal phase support protocols on miRNA profiles. Methods The study was approved by the Johns Hopkins Hospital Institutional Review Board. Endometrial biopsies were obtained on the day of oocyte retrieval from 9 oocyte donors (group I). An additional endometrial biopsy was obtained 3–5 days later (Group II) after the donors were randomized into three groups. Group IIa had no luteal-phase support, group IIb had luteal support with micronized progesterone (P), and Group IIc had luteal support with progesterone plus 17-beta-estradiol (P + E). Total RNA was isolated and microarray analysis was performed using an Illumina miRNA expression panel. Results A total of 526 miRNAs were identified. Out of those, 216 miRNAs were differentially regulated (p < 0.05) between the comparison groups. As compared to the day of retrieval, 19, 11 and 6 miRNAs were differentially regulated more than 2 fold in the groups of no support, in the P support only, and in the P + E support respectively, 3–5 days after retrieval. During the peri-implantation period (3–5 days after retrieval) the expression of 33 and 6 miRNAs increased, while the expression of 3 and 0 miRNAs decreased, in the P alone and in the P + E group respectively as compared to the no steroid supplementation group. Conclusion Luteal support

  7. Effect of folic acid plus glycine supplement on uterine prostaglandin and endometrial granulocyte-macrophage colony-stimulating factor expression during early pregnancy in pigs.

    PubMed

    Guay, Frédéric; Matte, J Jacques; Girard, Christiane L; Palin, Marie-France; Giguère, Alain; Laforest, Jean-Paul

    2004-01-15

    The objective was to determine the effects of folic acid+glycine supplement on uterine metabolism of prostaglandin and mRNA expression of endometrial granulocyte-macrophage colony-stimulating factor (GM-CSF) in nulliparous (NYL) and multiparous Yorkshire-Landrace (YL) sows, and in multiparous Meishan-Landrace sows (ML). In each of these three groups, sows were randomly assigned to two treatments: 15 ppm folic acid+0.6% glycine or no supplement. The dietary supplement was given from the estrus before mating to slaughter on Day 25 of pregnancy. At slaughter, endometrial tissue was collected to determine endometrial expression levels of GM-CSF mRNA, cyclooxygenase-1 (COX1) and -2 (COX2) and to evaluate in vitro endometrial secretion of prostaglandin E2 (PGE2) secretion. Allantoic fluid samples were also collected to determine the concentration of PGE2, prostaglandin F2alpha (PGF2alpha), estradiol-17beta (E2), progesterone (P4), and transforming-growth factor-beta2 (TGF-beta2). The allantoic contents of PGF2alpha, E2 and P4, and endometrial in vitro secretion of PGE2 were not significantly influenced by the folic acid+glycine supplement. The folic acid+glycine supplement tended (P<0.07) to increase allantoic content of PGE2 and TGF-beta2 in all sows and increased (P<0.05) endometrial expression of COX2, especially in NYL sows. The endometrial expression of COX1 was decreased (P<0.05) by folic acid+glycine supplement, especially in multiparous YL sows. The allantoic contents of PGE2 and PGF2alpha were not significantly affected by sow type. However, NYL sows had higher (P<0.05) endometrial in vitro secretion of PGE2 and allantoic content of P4 than multiparous YL and ML sows. The allantoic content of E2 was also higher (P<0.05) in NYL sows than in multiparous ML sows only. The allantoic content of TGF-beta2 was lower (P<0.05) in multiparous ML than in multiparous YL only sows. Finally, in YL and NYL sows, folic acid+glycine supplement decreased (P<0.05) the endometrial

  8. Endometrial cytology and computerized morphometric analysis of epithelial nuclei: a useful tool for reproductive diagnosis in the bitch.

    PubMed

    Groppetti, D; Pecile, A; Arrighi, S; Di Giancamillo, A; Cremonesi, F

    2010-04-15

    New diagnostic approaches are required to recognize early canine hypofertility or infertility. We suggest that the identification of different cytologic types, cellular aspects, and nuclear features of the endometrial epithelial cells may be suitable for this purpose. This study was performed on the bitch (Canis familiaris) during the physiologic reproductive cycle and in uterine diseases. We also applied computerized cytomorphometry to evaluate nuclear area, perimeter, diameter, density, aspect, and roundness of endometrial epithelial cells in healthy dogs (N=35) at different stages of the reproductive cycle (before puberty, during proestrus, estrus, diestrus, and anestrus) and in bitches affected by uterine disorders (N=10). The stage of the estrous cycle was determined by vaginal cytology and progesterone evaluation and also confirmed by clinical and histologic observations. Samples for endometrial cytology were collected in vivo by uterine flushing with transcervical uterine cannulation. After uterine sampling, each dog underwent OHE or uterine stump revision. Cytologic analyses were compared with histologic examinations to verify the uterine condition. The uterine cellular population was represented by endometrial epithelial cells, erythrocytes, neutrophils, lymphocytes, eosinophils, macrophages, plasma cells, and cervical or incidental vaginal cells. Bacteria and amorphous material were observed. The proportion of different cells and nuclear features in the cytologic samples varied throughout the stages of the reproductive cycle and between normal and pathologic uterine conditions. The computer-assisted nuclear morphometry, performed in cytologic specimens by means of the six nuclear parameters chosen to evaluate the endometrial epithelial cell population, proved to be useful for determining the stage of the reproductive cycle. Furthermore, this system was demonstrated to be a valid support to diagnose and distinguish uterine disorders. PMID:20116837

  9. Prostate Androgen-Regulated Mucin-Like protein 1: A Novel Regulator of Progesterone Metabolism

    PubMed Central

    Park, Ji Yeon; Jang, Hyein; Curry, Thomas E.; Sakamoto, Aiko

    2013-01-01

    The LH surge reprograms preovulatory follicular cells to become terminally differentiated luteal cells which produce high levels of progesterone and become resistant to apoptosis. PARM1 (prostate androgen regulated mucin-like protein 1) has been implicated in cell differentiation and cell survival in nonovarian cells, but little is known about PARM1 in the ovary. This study demonstrated that the LH surge induced a dramatic increase in Parm1 expression in periovulatory follicles and newly forming CL in both cycling and immature rat models. We further demonstrated that hCG increases Parm1 expression in granulosa cell cultures. The in vitro up-regulation of Parm1 expression was mediated by hCG-activated multiple signaling pathways and transcriptional activation of this gene. Parm1 knockdown increased the viability of cultured granulosa cells but resulted in a decrease in progesterone levels. The inhibitory effect of Parm1 silencing on progesterone was reversed by adenoviral mediated add-back expression of Parm1. Parm1 silencing had little effect on the expression of genes involved in progesterone biosynthesis and metabolism such as Scarb1, Ldlr, Vldlr, Scp2, Star, Cyp11a1, Hsd3b, and Srd5a1, while decreasing the expression of Akr1c3. Analyses of culture media steroid levels revealed that Parm1 knockdown had no effect on pregnenolone levels, while resulting in time-dependent decreases in progesterone and 20α-dihydroprogesterone and accelerated accumulation of 5α-pregnanediol. This study revealed that the up-regulation of Parm1 expression promotes progesterone and 20α-dihydroprogesterone accumulation in luteinizing granulosa cells by inhibiting progesterone catabolism to 5α-pregnanediol. PARM1 contributes to ovulation and/or luteal function by acting as a novel regulator of progesterone metabolism. PMID:24085821

  10. Progesterone Receptors: Form and Function in Brain

    PubMed Central

    Brinton, Roberta Diaz; Thompson, Richard F.; Foy, Michael R.; Baudry, Michel; Wang, JunMing; Finch, Caleb E; Morgan, Todd E.; Stanczyk, Frank Z.; Pike, Christian J.; Nilsen, Jon

    2008-01-01

    Emerging data indicate that progesterone has multiple non-reproductive functions in the central nervous system to regulate cognition, mood, inflammation, mitochondrial function, neurogenesis and regeneration, myelination and recovery from traumatic brain injury. Progesterone-regulated neural responses are mediated by an array of progesterone receptors (PR) that include the classic nuclear PRA and PRB receptors and splice variants of each, the seven transmembrane domain 7TMPRβ and the membrane-associated 25-Dx PR (PGRMC1). These PRs induce classic regulation of gene expression while also transducing signaling cascades that originate at the cell membrane and ultimately activate transcription factors. Remarkably, PRs are broadly expressed throughout the brain and can be detected in every neural cell type. The distribution of PRs beyond hypothalamic borders, suggests a much broader role of progesterone in regulating neural function. Despite the large body of evidence regarding progesterone regulation of reproductive behaviors and estrogen-inducible responses as well as effects of progesterone metabolite neurosteroids, much remains to be discovered regarding the functional outcomes resulting from activation of the complex array of PRs in brain by gonadally and / or glial derived progesterone. Moreover, the impact of clinically used progestogens and developing selective PR modulators for targeted outcomes in brain is a critical avenue of investigation as the non-reproductive functions of PRs have far-reaching implications for hormone therapy to maintain neurological health and function throughout menopausal aging. PMID:18374402

  11. Study establishes basis for genomic classification of endometrial cancers

    Cancer.gov

    A comprehensive genomic analysis of nearly 400 endometrial tumors suggests that certain molecular characteristics – such as the frequency of mutations – could complement current pathology methods and help distinguish between principal types of endometrial

  12. Progesterone in Peri- and Postmenopause: A Review

    PubMed Central

    Regidor, P.-A.

    2014-01-01

    Around 14.5 million peri- and postmenopausal women currently live in Germany. Moreover, approximately 450 000 women, each with a life expectancy of around 85 years, reach menopause every year in Germany. The challenge is therefore to find a therapy with few side effects which could improve the quality of life of women with menopausal symptoms. The aim of hormone therapy (HT) is to remedy hormone deficiencies using substances that offer the best trade-off between benefits and risks. This is where progesterone has a new and important role to play. Progesterone is one of the most important gestagens. Biologically effective progesterone formulations created with micronization techniques have been used in clinical practice since 1996. Nevertheless, up until 2003 preference was given to synthetic gestagens rather than progesterone. The increased breast cancer hazard ratio of 1.23 reported in the WHI study and of 2 given in the Million Women Study has been associated with the use of synthetic gestagens. In a comparison between synthetic gestagens and progesterone, the E3N Study showed that the transdermal administration of estrogen and progesterone did not lead to an increase in breast cancer rates (RR: 1.08). The administration of progesterone does not change the HDL/LDL cholesterol ratio. Because of its anti-mineralocorticoid effect, progesterone has no impact on carbohydrate metabolism, hemostasis, blood pressure, thrombogenicity and body weight. The administration of 200 mg/day progesterone over 12 days of a menstrual cycle or a daily administration of 100 mg combined with an estrogen are a safe and well-tolerated option to treat menopausal symptoms, with a better benefit risk profile compared to synthetic gestagens. PMID:25484373

  13. Progesterone in Peri- and Postmenopause: A Review.

    PubMed

    Regidor, P-A

    2014-11-01

    Around 14.5 million peri- and postmenopausal women currently live in Germany. Moreover, approximately 450 000 women, each with a life expectancy of around 85 years, reach menopause every year in Germany. The challenge is therefore to find a therapy with few side effects which could improve the quality of life of women with menopausal symptoms. The aim of hormone therapy (HT) is to remedy hormone deficiencies using substances that offer the best trade-off between benefits and risks. This is where progesterone has a new and important role to play. Progesterone is one of the most important gestagens. Biologically effective progesterone formulations created with micronization techniques have been used in clinical practice since 1996. Nevertheless, up until 2003 preference was given to synthetic gestagens rather than progesterone. The increased breast cancer hazard ratio of 1.23 reported in the WHI study and of 2 given in the Million Women Study has been associated with the use of synthetic gestagens. In a comparison between synthetic gestagens and progesterone, the E3N Study showed that the transdermal administration of estrogen and progesterone did not lead to an increase in breast cancer rates (RR: 1.08). The administration of progesterone does not change the HDL/LDL cholesterol ratio. Because of its anti-mineralocorticoid effect, progesterone has no impact on carbohydrate metabolism, hemostasis, blood pressure, thrombogenicity and body weight. The administration of 200 mg/day progesterone over 12 days of a menstrual cycle or a daily administration of 100 mg combined with an estrogen are a safe and well-tolerated option to treat menopausal symptoms, with a better benefit risk profile compared to synthetic gestagens. PMID:25484373

  14. Determining the Optimal Duration of Progesterone Supplementation prior to Transfer of Cryopreserved Embryos and Its Impact on Implantation and Pregnancy Rates: A Pilot Study

    PubMed Central

    Majumdar, Abha

    2016-01-01

    Objective. To determine the optimal duration of progesterone supplementation prior to transfer of cryopreserved embryos and its impact on implantation and pregnancy rates. Study Design. Prospective randomised study. Materials and Methods. In an IVF unit of a tertiary centre, sixty-six patients undergoing cryopreserved embryo transfer cycles were included. Endometrial preparation was done with estradiol valerate. Once it reached a minimum of 7 mm, patients were allocated randomly into group I (n = 39) and group II (n = 27). Injectable progesterone 100 mg daily was then started for 3 and 4 days, respectively. This was followed by transfer of at least one thawed cleavage stage day 2 embryo of good quality. Groups I and II were compared in terms of clinical pregnancy and implantation rates. Results. In group I (3-day progesterone) and group II (4-day progesterone) the pregnancy rates were 41.02% (16/39) and 18.51% (5/27), respectively. On the other hand, the implantation rates were 16.82% (18/107) and 7.69% (6/78), respectively. The difference was statistically significant (p values 0.0172 and 0.0386, resp.). Conclusion. Progesterone supplementation for three days before the transfer of cleavage stage (day 2) cryopreserved embryos has significantly higher pregnancy and implantation rates, as compared to four-day supplementation. PMID:27752538

  15. Overview of progesterone profiles in dairy cows.

    PubMed

    Blavy, P; Derks, M; Martin, O; Höglund, J K; Friggens, N C

    2016-09-01

    The aim of this study was to gain a better understanding of the variability in shape and features of all progesterone profiles during estrus cycles in cows and to create templates for cycle shapes and features as a base for further research. Milk progesterone data from 1418 estrus cycles, coming from 1009 lactations, was obtained from the Danish Cattle Research Centre in Foulum, Denmark. Milk samples were analyzed daily using a Ridgeway ELISA-kit. Estrus cycles with less than 10 data points or shorter than 4 days were discarded, after which 1006 cycles remained in the analysis. A median kernel of three data points was used to smooth the progesterone time series. The time between start of progesterone rise and end of progesterone decline was identified by fitting a simple model consisting of base length and a quadratic curve to progesterone data, and this luteal-like phase (LLP) was used for further analysis. The data set of 1006 LLP's was divided into five quantiles based on length. Within quantiles, a cluster analysis was performed on the basis of shape distance. Height, upward and downward slope, and progesterone level on Day 5 were compared between quantiles. Also, the ratio of typical versus atypical shapes was described, using a reference curve on the basis of data in Q1-Q4. The main results of this article were that (1) most of the progesterone profiles showed a typical profile, including the ones that exceeded the optimum cycle length of 24 days; (2) cycles in Q2 and Q3 had steeper slopes and higher peak progesterone levels than cycles in Q1 and Q4 but, when normalized, had a similar shape. Results were used to define differences between quantiles that can be used as templates. Compared to Q1, LLP's in Q2 had a shape that is 1.068 times steeper and 1.048 times higher. Luteal-like phases in Q3 were 1.053 times steeper and 1.018 times higher. Luteal-like phases in Q4 were 0.977 times steeper and 0.973 times higher than LLP's in Q1. This article adds to our

  16. [Progesterone transport across the wall of the rumen of sheep].

    PubMed

    Borisenkov, M F; Vaĭkishnoraĭte, M A; Kaneva, A M

    2003-09-01

    Data on content of fiber, lignin and progesterone in reticulo-ruminal chyme and progesterone in blood serum and saliva of sheep throughout the reproductive cycle and at intramuscular injection of progesterone, are presented. A direct correlation between concentration of progesterone in blood and chyme was revealed. 1.5% of progesterone entered the reticulo-rumen with saliva. Transport of hormone through the wall of forestomach is the main way of progesterone entering the reticulo-rumen. The transport is carried out against the gradient of hormone concentration. Possible participation of progesterone adsorption on lignin in explanation of this transport, is discussed.

  17. High-grade endometrial carcinoma: serous and grade 3 endometrioid carcinomas have different immunophenotypes and outcomes.

    PubMed

    Alkushi, Abdulmohsen; Köbel, Martin; Kalloger, Steve E; Gilks, C Blake

    2010-07-01

    High-grade endometrial carcinomas are a heterogeneous group of tumors and include grade 3 endometrioid (EC-3), serous (SC), and clear cell carcinomas (CCC). There are conflicting data about the prognosis of these subtypes of high-grade endometrial carcinoma; this may be a result of lack of reproducibility in classifying tumor cell type. The purpose of this study was to examine differences in immunophenotype and outcome in a series of high-grade endometrial carcinomas, focusing on the comparison of EC-3 versus SC. We selected 180 endometrial carcinomas of SC, EC, or CCC type. No mixed carcinomas were included in the study. We chose the following immunohistochemical markers, estrogen receptor (ER), insulin-like growth factor 2 mRNA-binding protein 3 (IMP3), p16, p53, progesterone receptor (PR), and phosphatase and tensin homolog (PTEN) as being significantly differentially expressed in endometrial carcinoma subtypes. The tumors were stratified into 4 groups on the basis of their cell type and grade: EC grade 1 or 2, EC-3, SC, and CCC. Univariate survival analysis revealed significant differences in outcome between the 4 groups (P<0.0001), with significantly longer disease-specific survival for grade 1 or 2 EC versus EC-3 (P=0.0001), and EC-3 versus SC (P=0.0003). p16, PTEN, and IMP3 expression was observed more frequently in SC compared with EC-3 (P<0.0001, P=0.021, and P=0.031, respectively). These 3 markers showed the highest sensitivity and specificity in distinguishing between EC-3 and SC, with receiver operating characteristics area under the curve of 0.85, 0.69, and 0.71, respectively. ER and p53 approached but did not reach significance for differential expression in EC-3 versus SC (P=0.055 and P=0.068, respectively). A combination of p16 and PTEN predicts EC-3 versus SC with a sensitivity of 90.0% and specificity of 96.8%. p16 and PTEN can aid in distinguishing between EC-3 and SC of the endometrium, and are superior to ER, PR, and p53 for this purpose. EC-3

  18. [Pten gene expression in the endometrial mucosa].

    PubMed

    Bakiewicz, Anna; Goździk, Jarosław; Sporny, Stanisław

    2006-04-01

    The opinions about the causes of the endometrial carcinoma have changed since 1995, due to molecular biology progress. The findings concerning the recently discovered suppressor PTEN gene localized on the chromosome 10 -10q23.3, the product of which is a specific phosphatase are especially valuable. The loss of the gene function is directly linked with the genesis and progression of endometrial carcinoma, as well as cancers of other tissues and organs, including thyroid, breast, ovary, prostate or skin. Immunohistochemical studies with the use of the 6H2.1 antibody directed against the protein coded by the PTEN gene indicate that the protein cannot be found in more than half of the patients with endometrial carcinoma and its precursor--EIN. Mutations of the PTEN gene have also been detected in many young women with normal microscopic structure of the endometrial mucosa. Thus, a test for the absence of the PTEN gene product in the endometrial cells may be used for precise identification of early stages of carcinogenesis.

  19. Immunohistological study of the endometrial stromal fibroblasts in the opossum, Monodelphis domestica: evidence for homology with eutherian stromal fibroblasts.

    PubMed

    Kin, Koryu; Maziarz, Jamie; Wagner, Günter P

    2014-05-01

    Molecular phylogenetic studies suggest that the hemochorial placentation and decidualization are ancestral traits of eutherian mammals. While the origin of the placental tissue is well understood, the origin of the decidual cells is unclear. Here we address the origin of decidual cells by examining the expression patterns of six transcription factors (TFs) as well as four structural proteins in the endometrium of a marsupial, Monodelphis domestica, and compared them with the patterns known from eutherian species. We found a mesenchymal cell population in the subepithelial compartment of the opossum endometrium. These cells express a set of TFs, such as homeobox A11 (HOXA11), CCAAT/enhancer-binding protein beta (CEBPB), and progesterone receptor (PGR), that are important for eutherian endometrial stromal cells. On the other hand, we did not find the expression of a decidual cell marker desmin (DES) or of TFs that are important for decidual cell differentiation, such as forkhead box O1 (FOXO1), in those cells. Based on these results, we propose that opossum has cells homologous to eutherian endometrial fibroblasts but no decidual cells. In addition, we describe cellular changes associated with the progression of pregnancy: nuclear localization of CEBPB in luminal epithelial cells as early as 8 days postcoitum, expansion of endometrial glands, nuclear localization of FOXO1 in glandular epithelial cells, and expression of smooth muscle actin in luminal epithelial cells. These data show that the luminal and glandular epithelium react to the presence of the preplacentation conceptus and suggest a limited form of pregnancy recognition.

  20. Progesterone exerts neuroprotective effects after brain injury.

    PubMed

    Stein, Donald G

    2008-03-01

    Progesterone, although still widely considered primarily a sex hormone, is an important agent affecting many central nervous system functions. This review assesses recent, primarily in vivo, evidence that progesterone can play an important role in promoting and enhancing repair after traumatic brain injury and stroke. Although many of its specific actions on neuroplasticity remain to be discovered, there is growing evidence that this hormone may be a safe and effective treatment for traumatic brain injury and other neural disorders in humans.

  1. Treatment Options by Stage (Endometrial Cancer)

    MedlinePlus

    ... mellitus . Taking tamoxifen for breast cancer or taking estrogen alone (without progesterone) can increase the risk of ... menstrual bleeding) as soon as possible. Women taking estrogen (a hormone that can affect the growth of ...

  2. Uterine endometrial polyp with severe hemorrhage and cystic endometrial hyperplasia-pyometra complex in a dog.

    PubMed

    Gumber, Sanjeev; Springer, Nora; Wakamatsu, Nobuko

    2010-05-01

    The current report describes an unusual presentation of uterine endometrial polyp with severe hemorrhage and cystic endometrial hyperplasia-pyometra complex in a 9.5-year-old female Doberman Pinscher. The dog presented with a 2-day history of bloody discharge from the vulva and an enlarged abdomen. The postmortem examination revealed a markedly distended right uterine horn with a large pedunculated mass (17 cm x 9 cm x 4 cm) and blood. Based on the histological findings, the diagnosis of uterine endometrial polyp was made. PMID:20453227

  3. Endometrial Stromal Nodule: Report of a Case

    PubMed Central

    Fdili Alaoui, F. Z.; Chaara, H.; Bouguern, H.; Melhouf, M. A.; Fatemi, H.; Belmlih, A.; Amarti, A.

    2011-01-01

    Endometrial stromal nodule (ESN) is the least common of the endometrial stromal tumors. They are rare neoplasms which are diagnosed in most instances by light microscopy. Although such nodules are benign, hysterectomy has been considered the treatment of choice to determine the margins of the tumor required for diagnosis and to differentiate it from invasive stromal sarcoma Whose prognosis is totally different. We report a case of a 45 years old woman, with presurgical diagnosis of adnexal mass or uterine tumor. She underwent a total abdominal hysterectomy. Pathologic examination revealed an endometrial stromal nodule. Through this observation, we insist on the fact that the ESNs are rare and benign entities which must be differentiated from the other invasive malignant stromal tumors; this can change the final prognosis. PMID:21423543

  4. Endometrial stromal nodule: report of a case.

    PubMed

    Fdili Alaoui, F Z; Chaara, H; Bouguern, H; Melhouf, M A; Fatemi, H; Belmlih, A; Amarti, A

    2011-01-01

    Endometrial stromal nodule (ESN) is the least common of the endometrial stromal tumors. They are rare neoplasms which are diagnosed in most instances by light microscopy. Although such nodules are benign, hysterectomy has been considered the treatment of choice to determine the margins of the tumor required for diagnosis and to differentiate it from invasive stromal sarcoma Whose prognosis is totally different. We report a case of a 45 years old woman, with presurgical diagnosis of adnexal mass or uterine tumor. She underwent a total abdominal hysterectomy. Pathologic examination revealed an endometrial stromal nodule. Through this observation, we insist on the fact that the ESNs are rare and benign entities which must be differentiated from the other invasive malignant stromal tumors; this can change the final prognosis. PMID:21423543

  5. Morphometric evaluation of endometrial blood vessels.

    PubMed

    Makhija, Divya; Mathai, Alka Mary; Naik, Ramadas; Kumar, Suneet; Rai, Sharada; Pai, Muktha R; Baliga, Poornima

    2008-01-01

    Five hundred endometrial specimens were studied to document the changes in blood vessels in various phases of menstrual cycle, menstrual disturbances and in unexplained infertility. Sixty-three cases were taken as control and 437 cases as study group which included cases of dysfunctional uterine bleeding (DUB), endometrial polyps, fibroids, adenomyosis, infertility and atrophic endometrium. Using light microscopy, the vascular morphology was studied. The blood vessels were concentrated more in basal layer in the proliferative phase and in functional layer in the secretory phase. Cases of complex hyperplasia and pill endometrium had significantly higher vessel concentration. Congestion and dilatation of blood vessels were significantly higher in cases of DUB. The present study showed a positive correlation between endometrial angiogenesis and menstrual disorders. The alteration in blood vessel morphology has significant role in prognosis and in various anti-angiogenic therapies.

  6. Low levels of cathepsin D are associated with a poor prognosis in endometrial cancer

    PubMed Central

    Falcón, O; Chirino, R; León, L; López-Bonilla, A; Torres, S; Fernández, L; García-Hernández, J A; Valerón, P F; Díaz-Chico, J C

    1999-01-01

    Total cytosolic cathepsin D (Cat D) levels were estimated by an immunoradiometric assay in a series of 156 consecutive patients with surgical stages I–III primary endometrial adenocarcinoma. Simultaneously, the tissue content of both oestrogen (ER) and progesterone (PR) receptors, and p185HER-2/neu, DNA content (ploidy), and the fraction of S-phase cells (S-phase) were also estimated. Tumoral Cat D content ranged from 0 to 243 pmol mg−1 protein (median 44 pmol mg−1 protein) and was not associated with any of the established clinicopathological and biological prognostic variables, with the exception of a weak positive correlation with the tumoral p185HER-2/neu levels. Univariable analysis performed on a subset of 97 patients, followed for a minimum of 2 years or until death, showed that patient age at diagnosis, high histological grade, advanced surgical stage, vascular invasion, positive peritoneal cytology, low levels of Cat D, negative ER and PR status, aneuploidy, and high S-phase were predictive of the presence of persistent or recurrent disease. However, multivariable analysis revealed that only histological grade, surgical stage, Cat D and PR were significantly associated with the patient's outcome. From these findings, we conclude that Cat D is an independent prognostic factor in endometrial adenocarcinoma, its low levels being associated with a worse clinical outcome. © 1999 Cancer Research Campaign PMID:10027332

  7. Risk of complex and atypical endometrial hyperplasia in relation to anthropometric measures and reproductive history.

    PubMed

    Epplein, Meira; Reed, Susan D; Voigt, Lynda F; Newton, Katherine M; Holt, Victoria L; Weiss, Noel S

    2008-09-15

    The authors sought to test the hypothesis that characteristics and exposures which influence the balance of estrogen and progesterone bear on the incidence of endometrial hyperplasia (EH), a noninvasive proliferation of the lining of the uterus. Cases included all female members of Group Health (Washington State) who were diagnosed with complex EH or EH with atypia during the period 1985-2003 and whose diagnoses were confirmed in a pathology review (n = 446). Controls were selected randomly from Group Health membership files and were matched to the cases by age and enrollment status at the reference date. An increased risk of EH was associated with increasing body mass index and nulliparity. There was a suggestion of a decreased risk of EH with atypia among current smokers. No association with diabetes or hypertension was found. The risk factors observed to be associated with EH in this study are similar to those associated with endometrial cancer. Whether these risk factors predispose women to cancer simply by increasing EH incidence or continue to augment cancer risk even after EH is present is currently unknown.

  8. Androgen responsiveness of the new human endometrial cancer cell line MFE-296.

    PubMed

    Hackenberg, R; Beck, S; Filmer, A; Hushmand Nia, A; Kunzmann, R; Koch, M; Slater, E P; Schulz, K D

    1994-04-01

    MFE-296 endometrial cancer cells express androgen receptors in vitro. These cells, which are tumorigenic in nude mice, are derived from a moderately differentiated human endometrial adenocarcinoma. They express vimentin and the cytokeratins 7, 8, 18, and 19. Karyotyping revealed near-tetraploidy for most of the cells. No marker chromosomes were observed. DNA analyses confirmed the genetic identity of the cell line and the patient from whom the cell line was derived. Proliferation of MFE-296 cells was inhibited by the progestin R5020 and the androgen dihydrotestosterone (DHT). The inhibition of proliferation by DHT was antagonized by the antiandrogen Casodex, demonstrating the involvement of the androgen receptor. Androgen binding was determined at 22,000 binding sites per cell using a whole-cell assay (KD = 0.05 nM) and 30 fmol/mg protein with the dextran charcoal method; 7 fmol/mg protein of progesterone receptors were found, whereas estrogen receptors were below 5 fmol/mg protein. The androgen receptor was functionally intact, as demonstrated by transfection experiments with a reporter-gene construct, containing an androgen-responsive element. In MFE-296 cells the content of the androgen receptor was up-regulated by its own ligand.

  9. Metformin for endometrial hyperplasia: a Cochrane protocol

    PubMed Central

    Clement, Naomi S; Oliver, Thomas R W; Shiwani, Hunain; Saner, Juliane R F; Mulvaney, Caroline A; Atiomo, William

    2016-01-01

    Introduction Endometrial hyperplasia is a precancerous lesion of the endometrium, commonly presenting with uterine bleeding. If managed expectantly, it frequently progresses to endometrial carcinoma, rates of which are increasing dramatically worldwide. However, the established treatment for endometrial hyperplasia (progestogens) involves multiple side effects and leaves the risk of recurrence. Metformin is the most commonly used oral hypoglycaemic agent in type 2 diabetes mellitus. It has also been linked to the reversal of endometrial hyperplasia and may therefore contribute to decreasing the prevalence of endometrial carcinoma without the fertility and side effect consequences of current therapies. However, the efficacy and safety of metformin being used for this therapeutic target is unclear and, therefore, this systematic review will aim to determine this. Methods and analysis We will search the following trials and databases with no language restrictions: Cochrane Gynaecology and Fertility Specialised Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; EBSCO Cumulative Index to Nursing and Allied Health Literature; PubMed; Google Scholar; ClinicalTrials.gov; the WHO International Trials Registry Platform portal; OpenGrey and the Latin American and Caribbean Health Sciences Literature (LILACS). We will include randomised controlled trials (RCTs) of use of metformin compared with a placebo or no treatment, conventional medical treatment (eg, progestogens) or any other active intervention. Two review authors will independently assess the trial eligibility, risk of bias and extract appropriate data points. Trial authors will be contacted for additional data. The primary review outcome is the regression of endometrial hyperplasia histology towards normal histology. Secondary outcomes include hysterectomy rate; abnormal uterine bleeding; quality of life scores and adverse reactions to treatments. Ethics and dissemination

  10. Osteopontin and Integrin αvβ3 Expression during the Implantation Window in IVF Patients with Elevated Serum Progesterone and Oestradiol Level

    PubMed Central

    He, Z.; Ma, Y.; Li, L.; Liu, J.; Yang, H.; Chen, C.; Lin, N.; Bai, Y.; Ma, R.; Li, R.; Wu, Z.; Qiao, J.

    2016-01-01

    Background: To explore whether endometrial receptivity is determined by osteopontin (OPN) and integrin αvβ3 expression in women with elevated serum progesterone (P) and/or oestradiol (E2) who are undergoing in vitro fertilisation (IVF). Methods: According to serum hormone levels on the day of HCG administration, 33 infertile women were divided into 3 groups: the high E2, high P, and high E2 and P groups. The control group included 11 fertile, healthy women. Endometrial biopsy was performed on ovulation day + 7 to + 8 for all study participants, and the mRNA and protein expression levels of OPN and integrin αvβ3 were analyzed. Result: No statistically significant differences regarding OPN and integrin αvβ3 expression were found between infertile patients in the high P, high E2, high E2 and P and control groups. There was no significant correlation between OPN and integrin αvβ3 staining intensity during the implantation window biopsy in any of the groups studied. Conclusion: Endometrial OPN and integrant αvβ3 expression/co-expression is not impaired during the window of implantation in patients with high P, high E2, or high E2 and P levels. The clinical value of assessing endometrial receptivity with OPN and integrin αvβ3 seems to be uncertain. PMID:27365542

  11. Both slowly developing embryos and a variable pace of luteal endometrial progression may conspire to prevent normal birth in spite of a capable embryo.

    PubMed

    Franasiak, Jason M; Ruiz-Alonso, Maria; Scott, Richard T; Simón, Carlos

    2016-04-01

    Embryonic implantation requires synchrony between the endometrium and the embryo. When analyzed in isolation, competent embryos may be unsuccessful when placed on a nonreceptive endometrium or vice versa, contributing to the "black box" of implantation failure. It is when the two are assessed together that dyssynchrony becomes evident, due to premature progesterone stimulus on the endometrium, physiologic displacement of the window of implantation or late blastulation of the embryo, or all combined. From the embryonic component, detailed assessment of the timing of blastulation is essential. The molecular diagnosis of endometrial receptivity based on its transcriptomic signature could be superior to other techniques used in the past for defining the endometrial window of implantation. PMID:26940791

  12. Reversing the reduced level of endometrial GLUT4 expression in polycystic ovary syndrome: a mechanistic study of metformin action

    PubMed Central

    Li, Xin; Cui, Peng; Jiang, Hong-Yuan; Guo, Yan-Rong; Pishdari, Bano; Hu, Min; Feng, Yi; Billig, Håkan; Shao, Ruijin

    2015-01-01

    Conflicting results have been reported regarding whether or not insulin-regulated glucose transporter 4 (GLUT4) is expressed in human and rodent endometria. There is an inverse relationship between androgen levels and insulin-dependent glucose metabolism in women. Hyperandrogenemia, hyperinsulinemia, and insulin resistance are believed to contribute to endometrial abnormalities in women with polycystic ovary syndrome (PCOS). However, it has been unclear in previous studies if endometrial GLUT4 expression is regulated by androgen-dependent androgen receptors (ARs) and/or the insulin receptor/Akt/mTOR signaling network. In this study, we demonstrate that GLUT4 is expressed in normal endometrial cells (mainly in the epithelial cells) and is down-regulated under conditions of hyperandrogenemia in tissues from PCOS patients and in a 5α-dihydrotestosterone-induced PCOS-like rat model. Western blot analysis revealed reduced endometrial GLUT4 expression and increased AR expression in PCOS patients. However, the reduced GLUT4 level was not always associated with an increase in AR in PCOS patients when comparing non-hyperplasia with hyperplasia. Using a human tissue culture system, we investigated the molecular basis by which GLUT4 regulation in endometrial hyperplasia tissues is affected by metformin in PCOS patients. We show that specific endogenous organic cation transporter isoforms are regulated by metformin, and this suggests a direct effect of metformin on endometrial hyperplasia. Moreover, we demonstrate that metformin induces GLUT4 expression and inhibits AR expression and blocks insulin receptor/PI3K/Akt/mTOR signaling in the same hyperplasia human tissues. These findings indicate that changes in endometrial GLUT4 expression in PCOS patients involve the androgen-dependent alteration of AR expression and changes in the insulin receptor/PI3K/Akt/mTOR signaling network. PMID:26045896

  13. Reversing the reduced level of endometrial GLUT4 expression in polycystic ovary syndrome: a mechanistic study of metformin action.

    PubMed

    Li, Xin; Cui, Peng; Jiang, Hong-Yuan; Guo, Yan-Rong; Pishdari, Bano; Hu, Min; Feng, Yi; Billig, Håkan; Shao, Ruijin

    2015-01-01

    Conflicting results have been reported regarding whether or not insulin-regulated glucose transporter 4 (GLUT4) is expressed in human and rodent endometria. There is an inverse relationship between androgen levels and insulin-dependent glucose metabolism in women. Hyperandrogenemia, hyperinsulinemia, and insulin resistance are believed to contribute to endometrial abnormalities in women with polycystic ovary syndrome (PCOS). However, it has been unclear in previous studies if endometrial GLUT4 expression is regulated by androgen-dependent androgen receptors (ARs) and/or the insulin receptor/Akt/mTOR signaling network. In this study, we demonstrate that GLUT4 is expressed in normal endometrial cells (mainly in the epithelial cells) and is down-regulated under conditions of hyperandrogenemia in tissues from PCOS patients and in a 5α-dihydrotestosterone-induced PCOS-like rat model. Western blot analysis revealed reduced endometrial GLUT4 expression and increased AR expression in PCOS patients. However, the reduced GLUT4 level was not always associated with an increase in AR in PCOS patients when comparing non-hyperplasia with hyperplasia. Using a human tissue culture system, we investigated the molecular basis by which GLUT4 regulation in endometrial hyperplasia tissues is affected by metformin in PCOS patients. We show that specific endogenous organic cation transporter isoforms are regulated by metformin, and this suggests a direct effect of metformin on endometrial hyperplasia. Moreover, we demonstrate that metformin induces GLUT4 expression and inhibits AR expression and blocks insulin receptor/PI3K/Akt/mTOR signaling in the same hyperplasia human tissues. These findings indicate that changes in endometrial GLUT4 expression in PCOS patients involve the androgen-dependent alteration of AR expression and changes in the insulin receptor/PI3K/Akt/mTOR signaling network. PMID:26045896

  14. Progesterone modulates the LPS-induced nitric oxide production by a progesterone-receptor independent mechanism.

    PubMed

    Wolfson, Manuel Luis; Schander, Julieta Aylen; Bariani, María Victoria; Correa, Fernando; Franchi, Ana María

    2015-12-15

    Genital tract infections caused by Gram-negative bacteria induce miscarriage and are one of the most common complications of human pregnancy. LPS administration to 7-day pregnant mice induces embryo resorption after 24h, with nitric oxide playing a fundamental role in this process. We have previously shown that progesterone exerts protective effects on the embryo by modulating the inflammatory reaction triggered by LPS. Here we sought to investigate whether the in vivo administration of progesterone modulated the LPS-induced nitric oxide production from peripheral blood mononuclear cells from pregnant and non-pregnant mice. We found that progesterone downregulated LPS-induced nitric oxide production by a progesterone receptor-independent mechanism. Moreover, our results suggest a possible participation of glucocorticoid receptors in at least some of the anti-inflammatory effects of progesterone.

  15. CDC2 mediates progestin initiated endometrial stromal cell proliferation: a PR signaling to gene expression independently of its binding to chromatin.

    PubMed

    Vallejo, Griselda; La Greca, Alejandro D; Tarifa-Reischle, Inti C; Mestre-Citrinovitz, Ana C; Ballaré, Cecilia; Beato, Miguel; Saragüeta, Patricia

    2014-01-01

    Although non-genomic steroid receptor pathways have been studied over the past decade, little is known about the direct gene expression changes that take place as a consequence of their activation. Progesterone controls proliferation of rat endometrial stromal cells during the peri-implantation phase of pregnancy. We showed that picomolar concentration of progestin R5020 mimics this control in UIII endometrial stromal cells via ERK1-2 and AKT activation mediated by interaction of Progesterone Receptor (PR) with Estrogen Receptor beta (ERb) and without transcriptional activity of endogenous PR and ER. Here we identify early downstream targets of cytoplasmic PR signaling and their possible role in endometrial stromal cell proliferation. Microarray analysis of global gene expression changes in UIII cells treated for 45 min with progestin identified 97 up- and 341 down-regulated genes. The most over-represented molecular functions were transcription factors and regulatory factors associated with cell proliferation and cell cycle, a large fraction of which were repressors down-regulated by hormone. Further analysis verified that progestins regulate Ccnd1, JunD, Usf1, Gfi1, Cyr61, and Cdkn1b through PR-mediated activation of ligand-free ER, ERK1-2 or AKT, in the absence of genomic PR binding. ChIP experiments show that progestin promoted the interaction of USF1 with the proximal promoter of the Cdc2 gene. Usf1 knockdown abolished Cdc2 progestin-dependent transcriptional regulation and cell proliferation, which also blocked Cdc2 knockdown. We conclude that progestin-induced proliferation of endometrial stromal cells is mediated by ERK1-2 and AKT dependent early regulation of USF1, which directly induces Cdc2. To our knowledge, this is the first description of early target genes of progestin-activated classical PR via crosstalk with protein kinases and independently of hormone receptor binding to the genomic targets. PMID:24859236

  16. p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans

    PubMed Central

    Wild, Peter J; Ikenberg, Kristian; Fuchs, Thomas J; Rechsteiner, Markus; Georgiev, Strahil; Fankhauser, Niklaus; Noske, Aurelia; Roessle, Matthias; Caduff, Rosmarie; Dellas, Athanassios; Fink, Daniel; Moch, Holger; Krek, Wilhelm; Frew, Ian J

    2012-01-01

    Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II subtypes. The mTORC1 signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, analyses of 521 human endometrial carcinomas identified frequent mTORC1 pathway activation in type I as well as type II endometrial carcinoma subtypes. mTORC1 pathway activation and p53 expression or mutation status each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the mTORC1 pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and mTORC1 pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours. PMID:22678923

  17. ZEB1 Expression in Endometrial Biopsy Predicts Lymph Node Metastases in Patient with Endometrial Cancer

    PubMed Central

    Feng, Gang; Wang, Xiangming; Cao, Xiaozhi; Shen, Lijuan; Zhu, Jiansheng

    2014-01-01

    Purpose. The purpose of this study was to analyze the expression of zinc-finger E-box-binding homeobox 1 (ZEB1) in endometrial biopsy and its correlation with preoperative characteristics, including lymph node metastases in patient with endometrial cancer. Methods. Using quantitative RT-PCR, ZEB1 expressions in endometrial biopsy from 452 patients were measured. The relationship between ZEB1 expression and preoperative characteristics was analyzed. Results. ZEB1 expressions were significantly associated with subtype, grade, myometrial invasion, and lymph node metastases. Lymph node metastases could be identified with a sensitivity of 57.8% at specificity of 74.1% by ZEB1 expression in endometrial biopsy. Based on combination of preoperative characteristics and ZEB1 expression, lymph node metastases could be identified with a sensitivity of 62.1% at specificity of 96.2% prior to hysterectomy. Conclusion. ZEB1 expression in endometrial biopsy could help physicians to better predict the lymph node metastasis in patients with endometrial cancer prior to hysterectomy. PMID:25544793

  18. Laparoscopic surgery for endometrial cancer: a review.

    PubMed

    Hauspy, Jan; Jiménez, Waldo; Rosen, Barry; Gotlieb, Walter H; Fung-Kee-Fung, Michael; Plante, Marie

    2010-06-01

    Uterine cancer is the fourth most common cancer in Canadian women, with an estimated 4200 new cases and 790 disease-related deaths in 2008. We investigated the domains that are important for further implementation of minimally invasive surgery for the management of endometrial cancer by performing a literature review to assess the available data on overall and disease-free survival in laparoscopic versus open surgery. We also investigated the influence of patient- related factors, surgical factors, quality of life, and cost implications. Among the 23 articles reviewed, five were randomized controlled trials (RCTs), four were prospective reviews, and 14 were retrospective reviews. The RCTs showed no difference in overall and disease-free survival for patients with endometrial cancer who had undergone laparoscopic hysterectomy compared with open surgery. Morbid obesity is a limiting factor for the feasibility of complete laparoscopic staging. Laparoscopy seems to decrease complications and decrease blood loss. It also shortens hospital stay, with improved short-term quality of life and cosmesis, while yielding similar lymph node counts. Overall, laparoscopy is cost-effective, because the increased operation cost of laparoscopy is offset by the shorter hospital stay and faster return to work. On the basis of currently available data, patients with endometrial cancer should be offered minimally invasive surgery as part of their treatment for endometrial cancer whenever possible.

  19. Therapeutic effects of progesterone in animal models of neurological disorders.

    PubMed

    De Nicola, Alejandro F; Coronel, Florencia; Garay, Laura I; Gargiulo-Monachelli, Gisella; Gonzalez Deniselle, Maria Claudia; Gonzalez, Susana L; Labombarda, Florencia; Meyer, Maria; Guennoun, Rachida; Schumacher, Michael

    2013-12-01

    Substantial evidence supports that progesterone exerts many functions in the central and peripheral nervous system unrelated to its classical role in reproduction. In this review we first discussed progesterone effects following binding to the classical intracellular progesterone receptors A and B and several forms of membrane progesterone receptors, the modulation of intracellular signalling cascades and the interaction of progesterone reduced metabolites with neurotransmitter receptors. We next described our results involving animal models of human neuropathologies to elucidate the protective roles of progesterone. We described: (a) the protective and promyelinating effects of progesterone in experimental spinal cord injury; (b) the progesterone protective effects exerted upon motoneurons in the degenerating spinal cord of Wobbler mouse model of amyotropic lateral sclerosis; (c) the protective and anti-inflammatory effects of progesterone in the murine experimental autoimmune encephalomyelitis model of multiple sclerosis and after lysolecithin demyelination; (d) the progesterone prevention of nociception and neuropathic pain which follow spinal cord injury; and (e) the protective effect of progesterone in experimental ischemic stroke. Whenever available, the molecular mechanisms involved in these progesterone effects were examined. The multiplicity of progesterone beneficial effects has opened new venues of research for neurological disorders. In this way, results obtained in animal models could provide the basis for novel therapeutic strategies and pre-clinical studies.

  20. Endometrial study in patients with postmenopausal metrorrhagia

    PubMed Central

    de Merlo, Gaspar González; Mirasol, Esteban González; García, María Teresa Gómez; Parra, Carmen Ángel; Goy, Enrique Iglesias

    2016-01-01

    Introduction The aim of the study was to devise a strategy to diagnose malign endometrial pathologies (adenocarcinoma or atypical hyperplasia) that minimizes the number of invasive tests done (hysteroscopy, aspiration biopsy or curettage) with no loss of its detection efficiency. Material and methods We retrospectively studied the clinical histories of 779 postmenopausal women at the University Hospital Complex of Albacete, for whom an endometrial study had been done (hysteroscopy, aspiration biopsy or curettage) with a 1-year follow-up between 1 March 2006 and 31 March 2008. Results There were 77 cases of a malignant pathology (66 adenocarcinomas and 11 hyperplasias with atypia); 96.1% had metrorrhagia, and there were only 3 cases of asymptomatic patients (all 3 presented endometrial thickness of > 5 mm: 10, 12 and 15 mm). The sensitivity and specificity of the transvaginal ultrasound, with a 5 mm cut-off point to diagnose a malignant pathology, were 98.4% and 30.1%, respectively; 89.1% and 99.6%, respectively, for aspiration biopsy; 83.9% and 99.1%, respectively, for hysteroscopy without biopsy; and both were 100% for biopsy. Statistical significance was considered at p < 0.05 and confidence intervals were calculated at 95%. Conclusions In postmenopausal women with metrorrhagia, the first action to take is to do a transvaginal ultrasound, followed by en endometrial study, but only if the endometrium is irregular or endometrial thickness is ≥ 5 mm; in asymptomatic women, the cut-off point should be set at 10 mm. The immediate method of choice is an ambulatory biopsy. PMID:27279854

  1. KSR1 Is Overexpressed in Endometrial Carcinoma and Regulates Proliferation and TRAIL-Induced Apoptosis by Modulating FLIP Levels

    PubMed Central

    Llobet, David; Eritja, Nuria; Domingo, Monica; Bergada, Laura; Mirantes, Cristina; Santacana, Maria; Pallares, Judit; Macià, Anna; Yeramian, Andree; Encinas, Mario; Moreno-Bueno, Gema; Palacios, Jose; Lewis, Robert E.; Matias-Guiu, Xavier; Dolcet, Xavi

    2011-01-01

    The Raf/MEK/extracellular signal-regulated kinase (ERK) pathway participates in many processes altered in development and progression of cancer in human beings such as proliferation, transformation, differentiation, and apoptosis. Kinase suppressor of Ras 1 (KSR1) can interact with various kinases of the Raf/MEK/extracellular signal-regulated kinase pathway to enhance its activation. The role of KSR1 in endometrial carcinogenesis was investigated. cDNA and tissue microarrays demonstrated that expression of KSR1 was up-regulated in endometrial carcinoma. Furthermore, inhibition of KSR1 expression by specific small hairpin RNA resulted in reduction of both proliferation and anchorage-independent cell growth properties of endometrial cancer cells. Because inhibition of apoptosis has a pivotal role in endometrial carcinogenesis, the effects of KSR1 in regulation of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–induced apoptosis were investigated. KSR1 knock-down sensitized resistant endometrial cell lines to both TRAIL- and Fas-induced apoptosis. Sensitization to TRAIL and agonistic anti-Fas antibody was caused by down-regulation of FLIP (FLICE-inhibitory protein). Also investigated was the molecular mechanism by which KSR1 regulates FLIP protein levels. It was demonstrated that KSR1 small hairpin RNA did not affect FLIP transcription or degradation. Rather, FLIP down-regulation was caused by Fas-associated death domain protein–dependent inhibition of FLIP translation triggered after TRAIL stimulation in KSR1-silenced cells. Re-expression of heterologous KSR1 in cells with down-regulated endogenous KSR1 restored FLIP protein levels and TRAIL resistance. In conclusion, KSR1 regulates endometrial sensitivity to TRAIL by regulating FLIP levels. PMID:21435442

  2. Lack of cyclical fluctuations of endometrial GLUT4 expression in women with polycystic ovary syndrome: Evidence for direct regulation of GLUT4 by steroid hormones.

    PubMed

    Cui, Peng; Li, Xin; Wang, Xiaoqin; Feng, Yi; Lin, Jin-Fang; Billig, Håkan; Shao, Ruijin

    2015-12-01

    Background Determination of the role of steroid hormones in expression and regulation of endometrial glucose transport 4 (GLUT4) in humans is important for understanding endometrial disorders such as polycystic ovary syndrome (PCOS), a common hormone-imbalance disease. Methods Endometrial biopsy samples were collected from non-PCOS patients with regular menstrual cycles or with hyperplasia and from PCOS patients with or without hyperplasia. In addition, endometrial tissues from postmenopausal women were incubated with human chorionic gonadotropin (hCG, 10 IU/ml), 17β-estradiol (E2, 10 nM), progesterone (P4, 100 nM), or a combination of E2 and P4 for 24 h. The expression of GLUT4 was measured at the mRNA level using quantitative real-time polymerase chain reaction (qRT-PCR) and at the protein level using Western blot analysis and immunohistochemistry. Results A cyclical change in GLUT4 expression pattern was observed in non-PCOS patients, and a high level of GLUT4 expression was seen in the proliferative phase compared to the secretory phase. Low levels of GLUT4 expression were found in PCOS patients compared to menstrual cycle phase-matched non-PCOS patients, and there was no significant change in GLUT4 expression in PCOS patients during the menstrual cycle. GLUT4 was localized in both epithelial and stromal cells, with notable changes in epithelial cells. We postulate that decreased GLUT4 expression might be regulated by steroid hormones. In support of this, we showed that in cultured endometrial tissues hCG and E2 alone had no effect on GLUT4 expression. However, P4 alone and P4 in combination with E2 decreased GLUT4 expression. Compared with non-PCOS controls, PCOS patients with endometrial hyperplasia exhibited decreased GLUT4 expression in particular in the epithelial cells. Conclusion We conclude that P4 can induce changes in endometrial GLUT4 expression during the menstrual cycle and that abnormal hormonal conditions such as PCOS disrupt normal patterns

  3. Lack of cyclical fluctuations of endometrial GLUT4 expression in women with polycystic ovary syndrome: Evidence for direct regulation of GLUT4 by steroid hormones

    PubMed Central

    Cui, Peng; Li, Xin; Wang, Xiaoqin; Feng, Yi; Lin, Jin-Fang; Billig, Håkan; Shao, Ruijin

    2015-01-01

    Background Determination of the role of steroid hormones in expression and regulation of endometrial glucose transport 4 (GLUT4) in humans is important for understanding endometrial disorders such as polycystic ovary syndrome (PCOS), a common hormone-imbalance disease. Methods Endometrial biopsy samples were collected from non-PCOS patients with regular menstrual cycles or with hyperplasia and from PCOS patients with or without hyperplasia. In addition, endometrial tissues from postmenopausal women were incubated with human chorionic gonadotropin (hCG, 10 IU/ml), 17β-estradiol (E2, 10 nM), progesterone (P4, 100 nM), or a combination of E2 and P4 for 24 h. The expression of GLUT4 was measured at the mRNA level using quantitative real-time polymerase chain reaction (qRT-PCR) and at the protein level using Western blot analysis and immunohistochemistry. Results A cyclical change in GLUT4 expression pattern was observed in non-PCOS patients, and a high level of GLUT4 expression was seen in the proliferative phase compared to the secretory phase. Low levels of GLUT4 expression were found in PCOS patients compared to menstrual cycle phase-matched non-PCOS patients, and there was no significant change in GLUT4 expression in PCOS patients during the menstrual cycle. GLUT4 was localized in both epithelial and stromal cells, with notable changes in epithelial cells. We postulate that decreased GLUT4 expression might be regulated by steroid hormones. In support of this, we showed that in cultured endometrial tissues hCG and E2 alone had no effect on GLUT4 expression. However, P4 alone and P4 in combination with E2 decreased GLUT4 expression. Compared with non-PCOS controls, PCOS patients with endometrial hyperplasia exhibited decreased GLUT4 expression in particular in the epithelial cells. Conclusion We conclude that P4 can induce changes in endometrial GLUT4 expression during the menstrual cycle and that abnormal hormonal conditions such as PCOS disrupt normal patterns

  4. Binding of ATP to the progesterone receptor.

    PubMed Central

    Moudgil, V K; Toft, D O

    1975-01-01

    The possible interaction of progesterone--receptor complexes with nucleotides was tested by affinity chromatography. The cytosol progesterone receptor from hen oviduct was partially purified by ammonium sulfate precipitation before use. When progesterone was bound to the receptor, the resulting complex could be selectively adsorbed onto columns of ATP-Sepharose. This interaction was reversible and of an ionic nature since it could be disrupted by high-salt conditions. A competitive binding assay was used to test the specificity of receptor binding to several other nucleotides, including ADP, AMP, and cAMP. A clear specificity for binding ATP was evident from these studies. When ATP was added to receptor preparations, the nucleotide did not affect the sedimentation properties or hormone binding characteristics of the receptor. Although the function of ATP remains unknown, these studies indicate a role of this nucleotide in some aspect of hormone receptor activity. PMID:165493

  5. Endometrial and ovarian carcinomas with undifferentiated components: clinically aggressive and frequently underrecognized neoplasms.

    PubMed

    Tafe, Laura J; Garg, Karuna; Chew, Ivy; Tornos, Carmen; Soslow, Robert A

    2010-06-01

    Carcinomas of the endometrium and ovary with undifferentiated components are uncommon neoplasms that are likely underdiagnosed. They are important to recognize as they have been shown to be clinically aggressive. We identified 32 carcinomas with undifferentiated components as defined by Silva and co-workers, 26 endometrial and 6 of ovarian origin. The patient age ranged from 21 to 76 years (median 55); 40% of patients were endometrial and 83% of ovarian carcinomas with undifferentiated components) presented at advanced stages (FIGO III-IV). Pelvic and para-aortic lymph nodes were the most frequent sites of metastases. Twenty tumors, entirely undifferentiated, consisted of sheets of dyshesive, ovoid cells with uniform, large vesicular nuclei, whereas 12 tumors contained combinations of differentiated endometrioid adenocarcinoma with undifferentiated components. Although most undifferentiated tumors had a monotonous cytologic appearance without prominent stroma, six showed focal nuclear pleomorphism and eight cases had variably sized zones of rhabdoid cells in a background of myxoid stroma. The tumors were frequently misdiagnosed; they received a wide range of diagnoses, including FIGO grade 2 or 3 endometrioid carcinoma, carcinosarcoma, high-grade sarcoma including endometrial stromal sarcoma, neuroendocrine carcinoma, lymphoma, granulosa cell tumor and epithelioid sarcoma. Up to 86% of the cases showed focal, but strong keratin and/or epithelial membrane antigen staining, with CK18 being the most frequently positive keratin stain. They were predominantly negative for neuroendocrine markers, smooth muscle markers and estrogen receptor/progesterone receptor. Mismatch repair protein expression by immunohistochemistry was evaluated in 17 cases, and 8 (47%) were abnormal (7 with loss of MLH1/PMS2 and 1 with MSH6 loss). Follow-up was available for 27 patients, although it was very short in many cases, ranging from 0.5 to 89

  6. 17β-Estradiol and natural progesterone for menopausal hormone therapy: REPLENISH phase 3 study design of a combination capsule and evidence review.

    PubMed

    Mirkin, Sebastian; Amadio, Julia M; Bernick, Brian A; Pickar, James H; Archer, David F

    2015-05-01

    Several formulations combining estrogens and progestins for hormone therapy (HT) have been approved worldwide for the treatment of menopausal symptoms, yet recent data indicate a decline in their use and an increase in compounded bioidentical HT. Up to now, no single product combining natural 17β-estradiol and progesterone has been approved by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA). A phase 3 trial (REPLENISH) is underway to study a novel oral formulation of solubilized 17β-estradiol and natural progesterone combined in a single gelatin capsule (TX-001HR; TherapeuticsMD, Inc, Boca Raton, FL) for treating vasomotor symptoms (VMS) in postmenopausal women. The REPLENISH trial evaluates the efficacy and safety of TX-001HR (4 doses) versus placebo for the reduction of moderate to severe VMS frequency and severity at 4 and 12 weeks and evaluates the endometrial safety of the combinations at 1 year. TX-001HR contains hormones that are molecularly identical to endogenous estradiol and progesterone and is intended as an option for women who prefer bioidentical hormones; further, it does not contain peanut oil, a common allergen. The constituents of TX-001HR, in a pharmacokinetic report, showed similar bioavailability and safety compared with reference estradiol tablets and micronized progesterone capsules administered together. Published data suggest a safer profile of estradiol and natural progesterone compared with HT containing conjugated equine estrogens and progestins. This report summarizes the methodology of the REPLENISH trial and reviews the evidence suggesting clinical differences between HT containing progesterone or progestins, and estradiol or conjugated equine estrogens.

  7. Endometrial adenocarcinoma in a 13-year-old girl.

    PubMed

    Kim, Sung Mee; Shin, So Jin; Bae, Jin Gon; Kwon, Kun Young; Rhee, Jeong Ho

    2016-03-01

    Endometrial cancer is the third most common gynecologic cancer in the Korea and occurs mainly in menopausal women. Although it can develop in young premenopausal women cancer as well, an attack in the adolescent girl is very rare. A 13-year-old girl visited gynecology department with the complaint of abnormal uterine bleeding. An endometrial biopsy revealed FIGO (International Federation of Gynecology and Obstetrics) grade II endometrial adenocarcinoma. In the treatment of endometrial cancer, conservative management should be considered if the patient is nulliparous or wants the fertility preservation. Therefore, we decided to perform a hormonal therapy and a follow-up endometrial biopsy after progestin administration for eight months revealed no residual tumor. We report a case of endometrial cancer occurred in a 13-year-old girl with a brief review of the literature.

  8. Endometrial adenocarcinoma in a 13-year-old girl

    PubMed Central

    Kim, Sung Mee; Shin, So Jin; Bae, Jin Gon; Kwon, Kun Young

    2016-01-01

    Endometrial cancer is the third most common gynecologic cancer in the Korea and occurs mainly in menopausal women. Although it can develop in young premenopausal women cancer as well, an attack in the adolescent girl is very rare. A 13-year-old girl visited gynecology department with the complaint of abnormal uterine bleeding. An endometrial biopsy revealed FIGO (International Federation of Gynecology and Obstetrics) grade II endometrial adenocarcinoma. In the treatment of endometrial cancer, conservative management should be considered if the patient is nulliparous or wants the fertility preservation. Therefore, we decided to perform a hormonal therapy and a follow-up endometrial biopsy after progestin administration for eight months revealed no residual tumor. We report a case of endometrial cancer occurred in a 13-year-old girl with a brief review of the literature. PMID:27004208

  9. Detection of endometrial lesions by degree of linear polarization maps

    NASA Astrophysics Data System (ADS)

    Kim, Jihoon; Fazleabas, Asgerally; Walsh, Joseph T.

    2010-02-01

    Endometriosis is one of the most common causes of chronic pelvic pain and infertility and is characterized by the presence of endometrial glands and stroma outside of the uterine cavity. A novel laparoscopic polarization imaging system was designed to detect endometriosis by imaging endometrial lesions. Linearly polarized light with varying incident polarization angles illuminated endometrial lesions. Degree of linear polarization image maps of endometrial lesions were constructed by using remitted polarized light. The image maps were compared with regular laparoscopy image. The degree of linear polarization map contributed to the detection of endometriosis by revealing structures inside the lesion. The utilization of rotating incident polarization angle (IPA) for the linearly polarized light provides extended understanding of endometrial lesions. The developed polarization system with varying IPA and the collected image maps could provide improved characterization of endometrial lesions via higher visibility of the structure of the lesions and thereby improve diagnosis of endometriosis.

  10. Endometrial adenocarcinoma in a 13-year-old girl.

    PubMed

    Kim, Sung Mee; Shin, So Jin; Bae, Jin Gon; Kwon, Kun Young; Rhee, Jeong Ho

    2016-03-01

    Endometrial cancer is the third most common gynecologic cancer in the Korea and occurs mainly in menopausal women. Although it can develop in young premenopausal women cancer as well, an attack in the adolescent girl is very rare. A 13-year-old girl visited gynecology department with the complaint of abnormal uterine bleeding. An endometrial biopsy revealed FIGO (International Federation of Gynecology and Obstetrics) grade II endometrial adenocarcinoma. In the treatment of endometrial cancer, conservative management should be considered if the patient is nulliparous or wants the fertility preservation. Therefore, we decided to perform a hormonal therapy and a follow-up endometrial biopsy after progestin administration for eight months revealed no residual tumor. We report a case of endometrial cancer occurred in a 13-year-old girl with a brief review of the literature. PMID:27004208

  11. Progesterone for Symptomatic Perimenopause Treatment - Progesterone politics, physiology and potential for perimenopause.

    PubMed

    Prior, J C

    2011-01-01

    Perimenopause, women's normal midlife reproductive transition, is highly symptomatic for about 20% of women who are currently inaccurately counseled and inappropriately treated with oral contraceptives, menopausal hormone therapy or hysterectomy. About 80% of perimenopausal women experience vasomotor symptoms (VMS), 25% have menorrhagia, and about 10% experience mastalgia. The majority of women describe varying intensities of sleep, -coping or mood difficulties. Women are more symptomatic because common knowledge inaccurately says that estradiol (E2) levels are dropping/deficient. Evidence shows that with disturbed brain-ovary feedbacks, E2 levels average 26% higher and soar erratically - some women describe feeling pregnant! Also, ovulation and progesterone (P4) levels become insufficient or absent. The most symptomatic women have higher E2 and lower P4 levels. Because P4 and E2 complement/counterbalance each other's tissue effects, oral micronized P4 (OMP4 300 mg at -bedtime) is a physiological therapy for treatment-seeking, symptomatic perimenopausal women. Given cyclically (cycle d 14-27, or 14 on/off) in menstruating midlife women, OMP4 decreases cyclic VMS, improves sleep and premenstrual mastalgia. Menorrhagia is treated with ibuprofen 200mg/6h plus OMP4 cycle d 4-28. For insulin resistance, metformin plus cyclic or daily OMP4 decreases insulin resistance and weight gain. Non-responsive migraines need daily OMP4 plus usual therapies. VMS and insomnia in late perimenopause respond to daily OMP4. In summary, OMP4 is a physiology-based therapy that improves sleep, treats VMS, does not increase breast proliferation or cancer risk, increases bone formation and has beneficial cardiovascular effects. A controlled trial is testing OMP4 for perimenopausal VMS - more evidence-based data are needed. PMID:24753856

  12. Progesterone for Symptomatic Perimenopause Treatment – Progesterone politics, physiology and potential for perimenopause

    PubMed Central

    Prior, J.C.

    2011-01-01

    Perimenopause, women’s normal midlife reproductive transition, is highly symptomatic for about 20% of women who are currently inaccurately counseled and inappropriately treated with oral contraceptives, menopausal hormone therapy or hysterectomy. About 80% of perimenopausal women experience vasomotor symptoms (VMS), 25% have menorrhagia, and about 10% experience mastalgia. The majority of women describe varying intensities of sleep, coping or mood difficulties. Women are more symptomatic because common knowledge inaccurately says that estradiol (E2) levels are dropping/deficient. Evidence shows that with disturbed brain-ovary feedbacks, E2 levels average 26% higher and soar erratically – some women describe feeling pregnant! Also, ovulation and progesterone (P4) levels become insufficient or absent. The most symptomatic women have higher E2 and lower P4 levels. Because P4 and E2 complement/counterbalance each other’s tissue effects, oral micronized P4 (OMP4 300 mg at bedtime) is a physiological therapy for treatment-seeking, symptomatic perimenopausal women. Given cyclically (cycle d 14-27, or 14 on/off) in menstruating midlife women, OMP4 decreases cyclic VMS, improves sleep and premenstrual mastalgia. Menorrhagia is treated with ibuprofen 200mg/6h plus OMP4 cycle d 4-28. For insulin resistance, metformin plus cyclic or daily OMP4 decreases insulin resistance and weight gain. Non-responsive migraines need daily OMP4 plus usual therapies. VMS and insomnia in late perimenopause respond to daily OMP4. In summary, OMP4 is a physiology-based therapy that improves sleep, treats VMS, does not increase breast proliferation or cancer risk, increases bone formation and has beneficial cardiovascular effects. A controlled trial is testing OMP4 for perimenopausal VMS – more evidence-based data are needed. PMID:24753856

  13. Progesterone receptor expression declines in the guinea pig uterus during functional progesterone withdrawal and in response to prostaglandins.

    PubMed

    Welsh, Toni N; Hirst, Jonathan J; Palliser, Hannah; Zakar, Tamas

    2014-01-01

    Progesterone withdrawal is essential for parturition, but the mechanism of this pivotal hormonal change is unclear in women and other mammals that give birth without a pre-labor drop in maternal progesterone levels. One possibility suggested by uterine tissue analyses and cell culture models is that progesterone receptor levels change at term decreasing the progesterone responsiveness of the myometrium, which causes progesterone withdrawal at the functional level and results in estrogen dominance enhancing uterine contractility. In this investigation we have explored whether receptor mediated functional progesterone withdrawal occurs during late pregnancy and labor in vivo. We have also determined whether prostaglandins that induce labor cause functional progesterone withdrawal by altering myometrial progesterone receptor expression. Pregnant guinea pigs were used, since this animal loses progesterone responsiveness at term and gives birth in the presence of high maternal progesterone level similarly to primates. We found that progesterone receptor mRNA and protein A and B expression decreased in the guinea pig uterus during the last third of gestation and in labor. Prostaglandin administration reduced while prostaglandin synthesis inhibitor treatment increased progesterone receptor A protein abundance. Estrogen receptor-1 protein levels remained unchanged during late gestation, in labor and after prostaglandin or prostaglandin synthesis inhibitor administration. Steroid receptor levels were higher in the non-pregnant than in the pregnant uterine horns. We conclude that the decreasing expression of both progesterone receptors A and B is a physiological mechanism of functional progesterone withdrawal in the guinea pig during late pregnancy and in labor. Further, prostaglandins administered exogenously or produced endogenously stimulate labor in part by suppressing uterine progesterone receptor A expression, which may cause functional progesterone withdrawal, promote

  14. Estradiol progesterone ratio on ovulation induction day: a determinant of successful pregnancy outcome after intra cytoplasmic sperm injection

    PubMed Central

    Rehman, Rehana; Khan, Rakhshaan; Baig, Mukhtiar; Hussain, Mehwish; Fatima, Syeda Sadia

    2014-01-01

    Background: Intracytoplasmic sperm injection (ICSI) is an advanced technique employed in assisted reproductive clinics for treatment of infertile couples. The reproductive endocrinologists try their level best to identify factors that enhance success rate after ICSI. Objective: To compare estradiol progesterone ratio on ovulation induction day amongst pregnancy outcome groups following ICSI. Materials and Methods: A cross sectional study was conducted on 323 couples of Assisted Reproductive Clinic in Islamabad from June 2010 till August 2011. Down regulation of females aged 18-40 years with gonadotrophin releasing hormone agonist was followed by calculated stimulation with gonadotrophin injections (COS). Oocytes pickup was done 36 hours after ovulation induction by 16G adapter and double lumen oocyte aspiration needle under general anesthesia. Oocytes were fertilized in vitro, graded and only blastocysts were transferred seven days after ovulation induction. Serum estradiol and progesterone were measured by enzyme linked immuno sorbent assay on ovulation induction day, ratio was compared in three groups of females; no conception with βhCG 5-25 mIU/ml, preclinical abortion with βhCG >25 mIU/ml and no cardiac activity on transvaginal scan and clinical pregnancy with βhCG >25mIU/ml and cardiac activity on transvaginal scan. Results: Females having high estradiol/ progesterone ratio were able to achieve clinical pregnancy shown by a positive βhCG and cardiac activity on transvaginal scan. These females also had significantly high number of oocytes, endometrial thickness and implantation rate. Conclusion: A high estradiol/progesterone ratio on the day of ovulation induction predicts the success of intra cytoplasmic sperm injection. PMID:25469136

  15. My approach to the interpretation of endometrial biopsies and curettings

    PubMed Central

    McCluggage, W G

    2006-01-01

    A major proportion of the workload in many histopathology laboratories is accounted for by endometrial biopsies, either curettage specimens or outpatient biopsy specimens. The increasing use of pipelle and other methods of biopsy not necessitating general anaesthesia has resulted in greater numbers of specimens with scant tissue, resulting in problems in assessing adequacy and in interpreting artefactual changes, some of which appear more common with outpatient biopsies. In this review, the criteria for adequacy and common artefacts in endometrial biopsies, as well as the interpretation of endometrial biopsies in general, are discussed, concentrating on areas that cause problems for pathologists. An adequate clinical history, including knowledge of the age, menstrual history and menopausal status, and information on the use of exogenous hormones and tamoxifen, is necessary for the pathologist to critically evaluate endometrial biopsies. Topics such as endometritis, endometrial polyps, changes that are induced by hormones and tamoxifen within the endometrium, endometrial metaplasias and hyperplasias, atypical polypoid adenomyoma, adenofibroma, adenosarcoma, histological types of endometrial carcinoma and grading of endometrial carcinomas are discussed with regard to endometrial biopsy specimens rather than hysterectomy specimens. The value of ancillary techniques, especially immunohistochemistry, is discussed where appropriate. PMID:16873562

  16. Progesterone to prevent spontaneous preterm birth

    PubMed Central

    Romero, Roberto; Yeo, Lami; Chaemsaithong, Piya; Chaiworapongsa, Tinnakorn; Hassan, Sonia

    2014-01-01

    Summary Preterm birth is the leading cause of perinatal morbidity and mortality worldwide, and its prevention is an important healthcare priority. Preterm parturition is one of the ‘great obstetrical syndromes’ and is caused by multiple etiologies. One of the mechanisms of disease is the untimely decline in progesterone action, which can be manifested by a sonographic short cervix in the midtrimester. The detection of a short cervix in the midtrimester is a powerful risk factor for preterm delivery. Vaginal progesterone can reduce the rate of preterm delivery by 45%, and the rate of neonatal morbidity (admission to neonatal intensive care unit, respiratory distress syndrome, need for mechanical ventilation, etc.). To prevent one case of spontaneous preterm birth <33 weeks of gestation, 12 patients with a short cervix would need to be treated. Vaginal progesterone reduces the rate of spontaneous preterm birth in women with a short cervix both with and without a prior history of preterm birth. In patients with a prior history of preterm birth, vaginal progesterone is as effective as cervical cerclage to prevent preterm delivery. 17α-Hydroxyprogesterone caproate has not been shown to be effective in reducing the rate of spontaneous preterm birth in women with a short cervix. PMID:24315687

  17. [Molecular based targets and endometrial cancer].

    PubMed

    Stoyanov, St; Ananiev, J; Ivanova, K; Velev, V; Todorova, M; Gulubova, M

    2015-01-01

    In recent years, increasing attention has been paid to the rate of spread of endometrial carcinoma, especially in the postmenopausal period. Along with routine diagnostic methods, giving information on the location and progression of the disease, there are some morphological methods determining very accurately the correlations in the development of this type of cancer and his prognosis. Moreover--in recent years, the accumulated information about the molecular profile of this type of cancer made it possible to implement a number of new drugs against the so-called molecular therapy -'targets' in the neoplastic process. Significant proportion of cases show response rates, it is more hope in the development of more successful formulas and target -based therapy. In this review, we present and discuss the role of certain molecular markers as potential indicators of prognosis and development, as well as determining the target treatment of endometrial carcinoma.

  18. microRNAs and Endometrial Pathophysiology.

    PubMed

    Chill, Henry H; Dior, Uri P; Kogan, Liron; Revel, Ariel

    2015-01-01

    Embryo implantation requires a reciprocal interaction between the blastocyst and endometrium and is associated with complex regulatory mechanisms. Since their discovery, microRNAs became prominent candidates providing missing links for many biological pathways. In recent years, microRNAs were implicated as one of the important players in regulation of various biological and physiological endometrial related processes. This chapter aims to present recent knowledge pertaining to the diverse aspects of microRNAs in the embryo-endometrial relationship. We will focus on the role of microRNAs in decidualization and their part in natural and stimulated cycles. Next, we will present recent studies deliberating the role of microRNAs in recurrent pregnancy loss and in the important phenomenon of recurrent implantation failure. Lastly, demonstrating an important aspect of embryo implantation and invasion, we will outline few microRNA related shared pathways of implantation and carcinogenesis. PMID:26662990

  19. [Molecular based targets and endometrial cancer].

    PubMed

    Stoyanov, St; Ananiev, J; Ivanova, K; Velev, V; Todorova, M; Gulubova, M

    2015-01-01

    In recent years, increasing attention has been paid to the rate of spread of endometrial carcinoma, especially in the postmenopausal period. Along with routine diagnostic methods, giving information on the location and progression of the disease, there are some morphological methods determining very accurately the correlations in the development of this type of cancer and his prognosis. Moreover--in recent years, the accumulated information about the molecular profile of this type of cancer made it possible to implement a number of new drugs against the so-called molecular therapy -'targets' in the neoplastic process. Significant proportion of cases show response rates, it is more hope in the development of more successful formulas and target -based therapy. In this review, we present and discuss the role of certain molecular markers as potential indicators of prognosis and development, as well as determining the target treatment of endometrial carcinoma. PMID:25909140

  20. Endometrial cancer: Not your grandmother's cancer.

    PubMed

    McAlpine, Jessica N; Temkin, Sarah M; Mackay, Helen J

    2016-09-15

    Worldwide, the incidence of endometrial carcinoma (EC) is rapidly increasing, and the highest disease burden is reported in North America and Western Europe. Although the prognosis remains good for patients with are diagnosed with early stage EC, for those with recurrent or metastatic disease, the options are few, and the median overall survival is short. It is imperative to gain a greater understanding of all aspects of EC, limit its effect on scarce health care resources and, more importantly, prevent this cancer from significantly impacting future generations of women. An exciting new era of endometrial cancer research and clinical management has begun that incorporates biologically and clinically relevant genomic and clinicopathologic parameters. Continued collaborative research efforts and funding are essential if we are to advance our understanding of this disease and improve clinical outcomes. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2787-2798. © 2016 American Cancer Society. PMID:27308732

  1. Inhibition of progesterone metabolism mimics the effect of progesterone withdrawal on forced swim test immobility.

    PubMed

    Beckley, Ethan H; Finn, Deborah A

    2007-10-01

    Withdrawal from high levels of progesterone in rodents has been proposed as a model for premenstrual syndrome or postpartum depression. Forced swim test (FST) immobility, used to model depression, was assessed in intact female DBA/2J mice following progesterone withdrawal (PWD) or treatment with the 5alpha-reductase inhibitor finasteride. Following 5 daily progesterone injections (5 mg/kg IP) FST immobility increased only in mice withdrawn for 3 days (p<.05). In another experiment, 3 days of PWD significantly decreased levels of progesterone compared to 0 days of withdrawal, but progesterone levels at 3 days of PWD did not differ from vehicle-treated controls. In a final study, mice received daily injections of progesterone (5 mg/kg IP) for 8 days, with 0 mg/kg, 50 mg/kg, or 100 mg/kg finasteride co-administered for the last three days. Mice that received 100 mg/kg finasteride, but not 50 mg/kg finasteride, displayed increased FST immobility. PWD and finasteride treatment, both of which reduce allopregnanolone levels, were associated with increased FST immobility in female DBA/2J mice. These findings suggest that decreased levels of the GABAergic neurosteroid allopregnanolone contribute to symptoms of PWD. Future studies of PWD may provide information about human conditions that are associated with hormone changes such as premenstrual syndrome or postpartum depression.

  2. Endometrial cancer: rising incidence, detection and treatment.

    PubMed

    Kistner, R W; Krantz, K E; Lebherz, T B; Lewis, G L; Reagan, J W; Smith, J; Tobin, J J; Wied, G L

    1973-02-01

    This editorial consists of summaries of the discussions on incidence, pathogenesis, prognosis and patient follow-up, and transcripts of the discussions on detection and treatment of endometrial carcinoma, from a symposium held in Carefree, Arizona. 75% of the cancers occur in postmenopausal women; average age is 52 years, but is decreasing. Endometrial carcinoma rose from 20.3 to 46.3% of all uterine cancers in Cleveland University Hospitals from 1941-1970. Older patients are often diabetic, overweight, nulliparous, with anovulatory or familial history; young women frequently resemble mild Stein-Levinthal syndrome. Clinically, 20% of patients are assymptomatic, others may have softer or larger uterus, larger ovaries, irregular postmenopausal bleeding, or lengthy onset of menopause. The Gravlee jet wash is indicated for high risk patients and those about to take estrogen. Endometrial carcinoma first affects epithelium, then endometrial stroma, then upper myometrium, lower myometrium, then other organs, perhaps via lymphatics, vagina, tubes, but ascites is uncommon. Generally, U.S. physicians use intrauterine radium followed by surgery, British use surgery first, and Swedish use radiation only. Cases must be treated individually, e.g. surgery only for minimal cancer, radium and surgery for more serious cases, and preoperative external radiation also for advanced disease. Although radiation lessens chance of implantation during surgical trauma, insertion of intrauterine radium enhances spread of tumor cells. Injectable progestins sometimes control metastatic disease, although they require 8 weeks to act. Progestins may help those with late recurrence, squamous metaplasia, or who are under 50 years of age. Estrogens are rarely effective. Prognois for terminal patients often includes subjective improvement, bowel obstruction, lung complications, hemorrhage. Radiation side effects and menopausal symptoms are often problems for cured patients. In young cured patients the

  3. The epidemiology of endometrial and ovarian cancer.

    PubMed

    Cramer, Daniel W

    2012-02-01

    This review highlights similarities in the epidemiology of endometrial and ovarian cancer, including highly correlated incidence rates and similar risk factor profiles. Factors that decrease risk for both cancers include a late menarche, early age at first birth, giving birth and breastfeeding, and use of oral contraceptives. Short or irregular cycles and late menopause are associated with increased risk for both. Other risk factors that appear to operate in a similar direction include decreased risk associated with IUD use or a tubal ligation, and increased risk associated with obesity, lack of exercise, and use of talc powders in genital hygiene. Estrogen excess is proposed as the underlying mechanism for most endometrial cancers, whereas incessant ovulation has been suggested as the explanation for ovarian cancer. However, an increased number of estimated ovulatory cycles correlates directly with risk for both endometrial and ovarian cancer, suggesting that reproductive tissue turnover with an accumulation of PTEN or p53 mutations represents a possible common mechanism. An immune-based explanation involving mucin proteins represents another common mechanism that could explain additional risk factors. Maintenance of ideal weight, breastfeeding children, use of oral contraceptives, and avoidance of talc powders in genital hygiene are measures that could lower the risk for both types of cancer. Careful selection of patients for prophylactic oophorectomy for those women who are coming to hysterectomy for benign disease is an additional measure to consider for ovarian cancer.

  4. Altrenogest and progesterone therapy during pregnancy in bottlenose dolphins (Tursiops truncatus) with progesterone insufficiency.

    PubMed

    Robeck, Todd R; Gill, Claudia; Doescher, Bethany M; Sweeney, Jay; De Laender, Piet; Van Elk, Cornelis E; O'Brien, Justine K

    2012-06-01

    Progesterone production is essential for growth and development of the conceptus during pregnancy. Abnormal development of the corpus luteum (CL) after conception can result in early embryonic loss or fetal abortion. Routine monitoring of bottlenose dolphin (Tursiops truncatus) pregnancy after artificial insemination or natural conception with ultrasonography and serum progesterone determination has allowed for the establishment of expected fetal growth rates and hormone concentrations. Using these monitoring techniques, we revealed four pregnant dolphins (12-24 yr old) with abnormally low progesterone production indicative of luteal insufficiency. Once diagnosed, animals were placed on altrenogest (0.044-0.088 mg/kg once daily) alone or with oral progesterone (50-200 mg twice daily). Doses of hormone were increased or decreased in each animal based on how fetal skull biparietal and thoracic growth rates compared with published normal values. Hormones were withdrawn starting from day 358 of gestation in animals 1 and 2, with labor occurring 6 and 7 days after withdrawal and at 376 and 373 days of gestation, respectively. Both deliveries were dystocic, with each calf requiring manual extraction and fetotomy for calf 1. The fetuses in animals 3 and 4 died at 348 and 390 days of gestation, respectively. Induction of labor was attempted in both animals, after fetal death, by using a combination of rapid progesterone withdrawal and steroid and prostaglandin F2alpha administration. The calf of animal 4 had to be removed with manual cervical dilation and fetotomy All adult females survived the procedures. These data provide the first in vivo evidence that the CL is the primary source of progesterone throughout pregnancy in the bottlenose dolphin. Until further characterization of hormones required during pregnancy and at parturition has been accomplished, the exogenous progestagen supplementation protocol described here cannot be recommended for treatment of progesterone

  5. Endometrial Adenocarcinoma Presenting in a Premenopausal Patient with Tuberous Sclerosis

    ERIC Educational Resources Information Center

    Jaffe, J. S.; Chambers, J. T.

    2005-01-01

    Background: Endometrial adenocarcinoma is very uncommon in women under 40 years of age. Case: A 39-year-old woman with tuberous sclerosis and severe intellectual disability presented with irregular bleeding unresponsive to oral contraceptive therapy. She was subsequently found to have a deeply invasive endometrial adenocarcinoma. Conclusion:…

  6. Uterine progesterone receptor expression, conceptus development, and ovarian function in pigs treated with RU 486 during early pregnancy.

    PubMed

    Mathew, Daniel J; Sellner, Erin M; Green, Jacob C; Okamura, Carol S; Anderson, Lloyd L; Lucy, Matthew C; Geisert, Rodney D

    2011-01-01

    Establishment of pregnancy in the pig depends on down-regulation of progesterone receptor (PGR) in the uterine luminal and glandular epithelium during the first week after breeding. The present study evaluated the regulation of endometrial PGR by progesterone and the possible role of endometrial tumor necrosis factor (ligand) superfamily member 11 (TNFSF11) and nuclear factor-kappa B (NFKB) activation in PGR expression. Mature, cycling gilts were inseminated (Day 0) and assigned to either untreated control (n = 9) or one of two treatments that employed RU 486 to block progesterone action either before (treatment 1 [T1]) or after (treatment 2 [T2]) the initiation of PGR down-regulation. The T1 gilts were treated with RU 486 (400 mg/day) on Days 3-5 of pregnancy (n = 9), and T2 gilts were treated with RU 486 on Days 6 and 7 of pregnancy (n = 9). Uteri and ovaries were collected on Day 8 or 12 of gestation. The diameter of the conceptuses in T1 gilts was approximately half that in controls by Day 8, and normal conceptuses were not collected from any T1 gilts on Day 12. Endometrial PGR mRNA was more abundant in T1 and T2 gilts compared with control gilts. The PGR-B protein decreased from Day 8 to Day 12 in the luminal epithelium and, to some extent, in superficial glandular epithelium in control and T2 gilts. In T1 gilts, the PGR-B protein remained elevated (i.e., failed to undergo down-regulation) on Day 12. Blocking PGR action early in the cycle (i.e., on or before Day 5), therefore, prevented normal conceptus development, caused elevated PGR mRNA, and prevented the decrease in PGR protein that typically occurs in pigs. We could not confirm a role for NFKB activation in PGR down-regulation, because pigs with extreme differences in PGR and TNFSF11 expression (T1 and controls) had similar NFKB activation on Day 8. Activated NFKB within the luminal epithelium and glandular epithelium (both superficial and deep) was observed in T2 and control pigs on Day 12 when

  7. Effects of tibolone and its metabolites on prolactin and insulin-like growth factor binding protein-1 expression in human endometrial stromal cells.

    PubMed

    Guzel, Elif; Buchwalder, Lynn; Basar, Murat; Kayisli, Umit; Ocak, Nehir; Bozkurt, Idil; Lockwood, Charles J; Schatz, Frederick

    2015-05-01

    The effects of the postmenopausal replacement steroid tibolone and its 3α-, 3β-OH and Δ-4 tibolone metabolites were evaluated on progesterone receptor-mediated classic decidualization markers insulin-like growth factor binding protein-1 (IGFBP-1) and prolactin expression in human endometrial stromal cells (HESCs). Supernatants of conditioned medium or erxtracted RNA from experimental cell incubations of confluent HESCs were subjected to ELISAs, Western blot analysis and RT/PCR, and results were statisically assesed. Over 21 days, specific ELISAs observed linear increases in secreted IGFBP-1 and prolactin levels elicited by tibolone and its metabolites. Cultured HESCs were refractory to E2 and dexamethasone, whereas tibolone and each metabolite exceeded medroxyprogesterone acetate in significantly elevating IGFBP-1 and prolactin output. Anti-progestins eliminated IGFBP-1 and prolactin induction by tibolone and its metabolites. Immunoblotting and RT/PCR confirmed ELISA results. These observations of IGFBP-1 and prolactin expression: (a) indicate the relevance of cultured HESCs in evaluating the chronic effects of tibolone administration to women; (b) are consistent with PR-mediated endometrial atrophy and protection against endometrial bleeding despite the persistence of circulating ER-binding, but not PR-binding metabolites following tibolone administration to women.

  8. Systemic therapy for endometrial stromal sarcomas: current treatment options.

    PubMed

    Serkies, Krystyna; Pawłowska, Ewa; Jassem, Jacek

    2016-01-01

    Uterine endometrial stromal sarcomas including true low-grade endometrial stromal sarcoma (LG-ESS) and high-grade (HG-ESS) or undifferentiated endometrial sarcoma (UES) constitute a group of rare, aggressive malignancies. Most LG-ESSs express steroid receptors. Surgery is the principal primary therapy for endometrial stromal sarcomas and should be considered in all cases. These malignancies are relatively radio- and chemoresistant. Chemotherapy is used in recurrent and advanced HG-ESS and UES. Currently, the combination of gemcitabine and docetaxel is considered the most effective regimen, but at the expense of substantial toxicity. In steroid receptor positive advanced LG-ESS hormonal therapy, mainly with progestins, allows in some patients for a long-term survival. Aromatase inhibitors seem to be equally effective as first- and subsequent-line of treatment, and are well tolerated. The role of molecular-targeted therapies in endometrial stromal sarcomas remains to be established. PMID:27629136

  9. Effect of normal endometrial stroma on growth and differentiation in Ishikawa endometrial adenocarcinoma cells.

    PubMed

    Arnold, Julia T; Lessey, Bruce A; Seppälä, Markku; Kaufman, David G

    2002-01-01

    Endometrial cancer is characterized by alterations in the stromal cells and the supporting extracellular matrix in addition to the intrinsic alterations of the malignant epithelial cells. We have developed a cell culture model that demonstrates the role of stromal cells in the regulation of proliferation, hormone responsiveness, and differentiation of an endometrial adenocarcinoma cell line (Ishikawa). Conditioned medium (CM) was collected from normal primary human endometrial stromal cells grown on plastic or within the basement membrane extract, Matrigel. The CM produced by stromal cells cultured in contact with Matrigel markedly inhibited Ishikawa cell proliferation compared with CM from stromal cells cultured on plastic. Ishikawa cell proliferation varied with steroid hormone treatment in the presence of CM from stromal cells embedded in Matrigel. When the Ishikawa cells were placed in coculture in contact with stromal cells in Matrigel, production of a differentiated epithelial secretory product, glycodelin, was induced. Gene expression of stromal cell hormone receptors, growth factors, and integrins was analyzed by reverse transcription-PCR in the presence of Matrigel to determine the potential factors involved in stromal regulatory function. These combined studies imply that the phenotype of the Ishikawa cells can be induced to differentiate to more closely resemble normal endometrial epithelium by reintroduction of stromal factors and appropriate extracellular matrix. Additionally, the study shows that basement membrane proteins influence the regulatory function of stromal cells as they mediate epithelial cell growth.

  10. Clear cell adenocarcinoma present exclusively within endometrial polyp: report of two cases.

    PubMed

    Ishida, Mitsuaki; Iwai, Muneo; Yoshida, Keiko; Kagotani, Akiko; Okabe, Hidetoshi

    2014-01-01

    Endometrial polyp is a common benign lesion that protrudes into the endometrial surface. The incidence of carcinoma within endometrial polyp is thought to be low, however, postmenopausal women with endometrial polyps are at an increased risk. Endometrial clear cell adenocarcinoma is a distinct and relatively rare subtype of endometrial carcinoma, and recent studies have proposed putative precursor lesions of clear cell adenocarcinoma, namely clear cell endometrial glandular dysplasia (EmGD) and clear cell endometrial intraepithelial carcinoma (EIC). Herein, we describe two cases of clear cell adenocarcinoma present exclusively within endometrial polyp and discuss the association of its precursor. Two postmenopausal Japanese females, 66-year-old (Case 1) and 54-year-old (Case 2) presented with abnormal genital bleeding. Cytological examination of both cases revealed adenocarcinoma, thus, hysterectomy was performed. Histopathological studies demonstrated clear cell adenocarcinoma within exclusively endometrial polyp in both cases. The peculiar finding in Case 1 was presence of atypical glandular cells with large round to oval nuclei and clear cytoplasm within the atrophic endometrial glands in the surrounding endometrial tissue, which corresponded to clear cell EIC. A recent study showed that 33% of uteri had at least one focus of clear cell EmGD in endometrial polyps. Accordingly, clear cell adenocarcinoma and clear cell EmGD can occur in association with endometrial polyps more frequently than previously thought. Therefore, detailed histopathological examination is important in diagnosis of endometrial polyps, especially in the postmenopausal women, moreover cytological examination is a useful tool in the postmenopausal women with endometrial polyps.

  11. Milk progesterone for pregnancy diagnosis in dairy goats.

    PubMed

    Pennington, J A; Hoffman, W F; Schultz, L H; Spahr, S L; Lodge, J R

    1982-10-01

    Factors affecting progesterone concentration in milk of lactating dairy goats and use of this milk for pregnancy diagnosis were studied. Radioimmunoassay was used to assay progesterone in milk. Mean milk progesterone (ng/ml) +/- standard errors of 6 pregnant does for first, composite, and last milk were 9.9 +/- 2.0, 18.2 +/- 3.5, and 21.7 +/- 4.1. Correlation between milk fat and progesterone in composite milk was low (.11). Composite milk samples from 4 nonpregnant does were obtained daily throughout the estrous cycle. Milk progesterone (ng/ml) was 1 to 2 at estrus, rose to 5 to 12 within 2 to 5 days, reached a plateau at 15 to 25 in the middle of the estrous cycle, and then dropped to low concentrations again at 3 to 5 days before the next estrus. Milk progesterone also was used to diagnose pregnancy in 72 does. Forty-two does were diagnosed pregnant by high progesterone; 36 of these does later produced kids, and 5 other does aborted in various stages of pregnancy. Of 21 does diagnosed not pregnant with low progesterone, 19 does were not pregnant by either return to estrus or lack of parturition in the spring. All three incorrectly diagnosed does were problem breeders. Nine does with intermediate milk progesterone were classified questionable. Milk progesterone can be used to provide an early indication of the pregnancy status of does. PMID:7174966

  12. High levels of Nrf2 determine chemoresistance in type II endometrial cancer

    PubMed Central

    Jiang, Tao; Chen, Ning; Zhao, Fei; Wang, Xiao-Jun; Kong, Beihua; Zheng, Wenxin; Zhang, Donna D.

    2010-01-01

    Type II endometrial cancer, which mainly presents as serous and clear cell types, has proved to be the most malignant and recurrent carcinoma among various female genital malignancies. The transcription factor, Nrf2, was first described as having chemopreventive activity. Activation of the Nrf2-mediated cellular defense response protects cells against the toxic and carcinogenic effects of environmental insults by upregulating an array of genes that detoxify reactive oxygen species (ROS) and restore cellular redox homeostasis. However, the cancer-promoting role of Nrf2 has recently been revealed. Nrf2 is constitutively upregulated in several types of human cancer tissues and cancer cell lines. Furthermore, inhibition of Nrf2 expression sensitizes cancer cells to chemotherapeutic drugs. In this study, the constitutive level of Nrf2 was compared in different types of human endometrial tumors. It was found that Nrf2 was highly expressed in endometrial serous carcinoma (ESC), whereas complex hyperplasia (CH) and endometrial endometrioid carcinoma (EEC) had no or marginal expression of Nrf2. Likewise, the ESC derived SPEC-2 cell line had a higher level of Nrf2 expression and was more resistant to the toxic effects of cisplatin and paclitaxel than that of the Ishikawa cell line, which was generated from EEC. Silencing of Nrf2 rendered SPEC-2 cells more susceptible to chemotherapeutic drugs while it had a limited effect on Ishikawa cells. Inhibition of Nrf2 expression by overexpressing Keap1 sensitized SPEC-2 cells or SPEC-2-derived xenografts to chemotherapeutic treatments using both cell culture and SCID mouse models. Collectively, we provide a molecular basis for the use of Nrf2 inhibitors to increase the efficacy of chemotherapeutic drugs and to combat chemoresistance, the biggest obstacle in chemotherapy. PMID:20530669

  13. Sophoricoside fails the embryo implantation by compromising the uterine endometrial receptivity at implantation "window" of pregnant mice.

    PubMed

    Zhou, Jianhong; Qu, Chengquan; Sun, Qi; Wu, Lisha; Liu, Yanglu; Yang, Zhirong; Zhang, Jie

    2014-08-01

    Sophoricoside (SOPH) is an isoflavone glycoside isolated from the fruits of Sophora japonica. Since its first isolation in 1961, there are rare findings about the effects of SOPH on reproductive system. In the present study, the pregnant mice administrated by different doses of SOPH were used to explore the effect of SOPH on embryo implantation, especially on the endometrial receptivity. The statistical results showed that the number of implanted embryos was gradually declining along the increasing dose of SOPH. When the administrated dose of SOPH was 600 mg/kg per day, great changes were observed in the exposed uterine morphology and up-regulated progesterone receptor (PR) and down-regulated estrogen receptor α (ERα), E-cadherin, matrix metalloproteinase-2 (MMP-2) and integrin β3 were also found in SOPH-exposed uterine. These findings demonstrated that SOPH exposure reduced the number of implanted embryos in a dose-dependent manner and failed the embryo implantation through altering the morphology of uterine and compromising the endometrial receptivity. PMID:24877640

  14. NAC1, a potential stem cell pluripotency factor expression in normal endometrium, endometrial hyperplasia and endometrial carcinoma.

    PubMed

    Ishikawa, Masako; Nakayama, Kentaro; Yeasmin, Shamima; Katagiri, Atsuko; Iida, Kouji; Nakayama, Naomi; Miyazaki, Kohji

    2010-05-01

    The purpose of this study was to investigate the role of NAC1 in the development of endometrial cancer. NAC1 expression and localization were assessed with immunohistochemistry in the normal cyclic human endometrium, hyperplastic endometrium, and endometrial cancer. Expression of NAC1 in the glandular cells was significantly higher in the early and mid proliferative phases than in the other menstrual phases, endometrial hyperplasia, and endometrial carcinoma. NAC1 expression was down-regulated during endometrial carcinogenesis. There were significant correlations between positive NAC1 expression and pathological grade (P=0.037). No significant associations were found between NAC1 expression and the other clinicopathological characteristics including patient age, FIGO staging, depth of myometrial invasion, pelvic lymph node metastasis, lymphovascular space invasion, menopause, or body mass index. NAC1 gene knockdown inhibited cell growth and induced apoptosis in Ishikawa, HHUA, and JHEM2 cell lines, all of which overexpressed NAC1. Ectopic overexpression of the NAC1 gene stimulated cell proliferation in the HEC1B, and JHEM1 endometrial cancer cell lines, which have lower endogenous NAC1 expression. Endometrial carcinomas with NAC1 overexpression are clinically aggressive, high-grade carcinomas. Therefore, detection of NAC1 overexpression in endometrial cancers may identify patients who will benefit from NAC1 targeted therapy.

  15. Structure of the human progesterone receptor gene.

    PubMed

    Misrahi, M; Venencie, P Y; Saugier-Veber, P; Sar, S; Dessen, P; Milgrom, E

    1993-11-16

    The complete organization of the human progesterone receptor (hPR) gene has been determined. It spans over 90 kbp and contains eight exons. The first exon encodes the N-terminal part of the receptor. The DNA binding domain is encoded by two exons, each exon corresponding to one zinc finger. The steroid binding domain is encoded by five exons. The nucleotide sequence of 1144 bp of the 5' flanking region has been determined. PMID:8241270

  16. Expression of retinoic acid receptors in human endometrial carcinoma.

    PubMed

    Tanabe, Kojiro; Utsunomiya, Hiroki; Tamura, Mitsutoshi; Niikura, Hitoshi; Takano, Tadao; Yoshinaga, Kohsuke; Nagase, Satoru; Suzuki, Takashi; Ito, Kiyoshi; Matsumoto, Mitsuyo; Hayashi, Shin-ichi; Yaegashi, Nobuo

    2008-02-01

    The retinoids (vitamin A and its biologically active derivatives) are essential for the health and survival of the individual. Several studies have reported a strong rationale for the use of retinoids in cancer treatment and chemoprevention. It has been discovered that expression of retinoic acid receptor (RAR) beta is frequently silenced in epithelial carcinogenesis, which has led to the hypothesis that RAR beta could act as a tumor suppressor. However, the status of RAR beta in human endometrial carcinoma has not been examined. In the present study, we initially studied the effects of retinoic acid on cell proliferation and the expression of RAR alpha, RAR beta, and RAR gamma using AM580 (a RAR-specific agonist) in the Ishikawa endometrial cancer cell line. We also examined the expression of RAR in human eutopic endometrium (30 cases), endometrial hyperplasia (28 cases), and endometrial carcinoma (103 cases) using immunohistochemistry. Finally, we correlated these findings with the clinicopathological parameters. In vitro, cell growth was inhibited and RAR beta and RAR gamma mRNA was significantly induced by AM580, compared with vehicle controls, whereas RAR alpha mRNA was significantly attenuated by AM580, compared with vehicle. RAR beta was detected predominantly in endometrial hyperplasia, compared with endometrial carcinoma. No statistically significant correlation was obtained between the expression of any other RAR subtypes and clinicopathological parameters in human endometrial carcinoma. The results of our study demonstrate that AM580 inhibits cell growth and induces RAR beta mRNA expression in the Ishikawa cell line, and the expression level of RAR beta in endometrial carcinoma is significantly lower than that in endometrial hyperplasia. AM580 might therefore be considered as a potential treatment for endometrial carcinoma.

  17. The PRB-dependent FOXO1/IGFBP-1 axis is essential for progestin to inhibit endometrial epithelial growth.

    PubMed

    Nakamura, Mitsuhiro; Takakura, Masahiro; Fujii, Reina; Maida, Yoshiko; Bono, Yukiko; Mizumoto, Yasunari; Zhang, Xian; Kiyono, Tohru; Kyo, Satoru

    2013-08-01

    Progestin inhibits the growth of normal and cancerous endometria via the progesterone receptor (PR), but the distinct functions and signalings of PR subtypes have not been fully understood. The aim of the present study was to dissect the key pathways of progestin to inhibit endometrial epithelial growth. Immortalized endometrial epithelial cells (EM-E6/E7/TERT) with stable PRA or PRB expression were established and used for the experiments. In vitro growth inhibition by progestin was mainly observed in EM-E6/E7/TERT cells with PRB rather than those with PRA. RT-PCR assay confirmed that FOXO1, a key gene for progestin action, was up-regulated by progestin in a PRB-dependent manner. cDNA microarray analysis identified IGFBP-1, which contains FOXO1 binding sites on its promoter, to be induced by medroxyprogesterone acetate (MPA) in EM-E6/E7/TERT cells with PRB but not with PRA. siRNA knockdown of FOXO1 disturbed the induction of IGFBP-1 by MPA, while IGFBP-1 knockdown showed no effect on MPA-induced FOXO1 expression, indicating that FOXO1 is an upstream regulator of IGFBP-1. Luciferase reporter assays showed that MPA activated the IGFBP-1 promoter, which was cancelled by FOXO1 knockdown. Chromatin immunoprecipitation assay confirmed the in vivo binding of FOXO1 to the core promoter of IGFBP-1. IGFBP-1 knockdown significantly attenuated the growth inhibitory effects of MPA. The FOXO1/IGFBP-1 axis is essential for PRB-dependent growth inhibition of endometrial epithelial cells, offering a potential therapeutic clue to enhance the progestin effect.

  18. MicroRNA-200a Locally Attenuates Progesterone Signaling in the Cervix, Preventing Embryo Implantation

    PubMed Central

    Haraguchi, Hirofumi; Saito-Fujita, Tomoko; Egashira, Mahiro; Matsumoto, Leona; Matsuo, Mitsunori; Hiraoka, Takehiro; Koga, Kaori; Yamauchi, Naoko; Fukayama, Masashi; Bartos, Amanda; Cha, Jeeyeon; Dey, Sudhansu K.; Fujii, Tomoyuki; Osuga, Yutaka

    2014-01-01

    Although cervical pregnancy and placenta previa, in which the embryo and placenta embed in or adjacent to the cervix, are life-threatening complications that result in massive bleeding and poor pregnancy outcomes in women, the incidence of these aberrant conditions is uncommon. We hypothesized that a local molecular mechanism is normally in place to prevent embryo implantation in the cervix. The ovarian hormones progesterone (P4) and estrogen differentially direct differentiation and proliferation of endometrial cells, which confers the receptive state for implantation: P4 dominance causes differentiation of the luminal epithelium but increases stromal cell proliferation in preparation of the uterus for implantation. In search for the cause of cervical nonresponsiveness to implantation, we found that the statuses of cell proliferation and differentiation between the uterus and cervix during early pregnancy are remarkably disparate under identical endocrine milieu in both mice and humans. We also found that cervical levels of progesterone receptor (PR) protein are low compared with uterine levels during this period, and the low PR protein levels are attributed to elevated levels of microRNA(miR)-200a in the cervix. These changes were associated with up-regulation of the P4-metabolizing enzyme 20α-hydroxysteroid dehydrogenase (200α-HSD) and down-regulation of its transcriptional repressor signal transducer and activator of transcription 5 in the cervix. The results provide evidence that elevated levels of miR-200a lead to down-regulation of P4-PR signaling and up-regulation of (200α-HSD) in the cervix, rendering it nonresponsive to implantation. These findings may point toward not only the physiological but also the pathological basis of the cervical milieu in embryo implantation. PMID:24850415

  19. Molecular Expression Profile Reveals Potential Biomarkers and Therapeutic Targets in Canine Endometrial Lesions

    PubMed Central

    Voorwald, Fabiana Azevedo; Marchi, Fabio Albuquerque; Villacis, Rolando Andre Rios; Alves, Carlos Eduardo Fonseca; Toniollo, Gilson Hélio; Amorim, Renee Laufer

    2015-01-01

    Cystic endometrial hyperplasia (CEH), mucometra, and pyometra are common uterine diseases in intact dogs, with pyometra being a life threatening disease. This study aimed to determine the gene expression profile of these lesions and potential biomarkers for closed-cervix pyometra, the most severe condition. Total RNA was extracted from 69 fresh endometrium samples collected from 21 healthy female dogs during diestrus, 16 CEH, 15 mucometra and 17 pyometra (eight open and nine closed-cervixes). Global gene expression was detected using the Affymetrix Canine Gene 1.0 ST Array. Unsupervised analysis revealed two clusters, one mainly composed of diestrus and CEH samples and the other by 12/15 mucometra and all pyometra samples. When comparing pyometra with other groups, 189 differentially expressed genes were detected. SLPI, PTGS2/COX2, MMP1, S100A8, S100A9 and IL8 were among the top up-regulated genes detected in pyometra, further confirmed by external expression data. Notably, a particular molecular profile in pyometra from animals previously treated with exogenous progesterone compounds was observed in comparison with pyometra from untreated dogs as well as with other groups irrespective of exogenous hormone treatment status. In addition to S100A8 and S100A9 genes, overexpression of the inflammatory cytokines IL1B, TNF and IL6 as well as LTF were detected in the pyometra from treated animals. Interestingly, closed pyometra was more frequently detected in treated dogs (64% versus 33%), with IL1B, TNF, LBP and CXCL10 among the most relevant overexpressed genes. This molecular signature associated with potential biomarkers and therapeutic targets, such as CXCL10 and COX2, should guide future clinical studies. Based on the gene expression profile we suggested that pyometra from progesterone treated dogs is a distinct molecular entity. PMID:26222498

  20. Molecular Expression Profile Reveals Potential Biomarkers and Therapeutic Targets in Canine Endometrial Lesions.

    PubMed

    Voorwald, Fabiana Azevedo; Marchi, Fabio Albuquerque; Villacis, Rolando Andre Rios; Alves, Carlos Eduardo Fonseca; Toniollo, Gilson Hélio; Amorim, Renee Laufer; Drigo, Sandra Aparecida; Rogatto, Silvia Regina

    2015-01-01

    Cystic endometrial hyperplasia (CEH), mucometra, and pyometra are common uterine diseases in intact dogs, with pyometra being a life threatening disease. This study aimed to determine the gene expression profile of these lesions and potential biomarkers for closed-cervix pyometra, the most severe condition. Total RNA was extracted from 69 fresh endometrium samples collected from 21 healthy female dogs during diestrus, 16 CEH, 15 mucometra and 17 pyometra (eight open and nine closed-cervixes). Global gene expression was detected using the Affymetrix Canine Gene 1.0 ST Array. Unsupervised analysis revealed two clusters, one mainly composed of diestrus and CEH samples and the other by 12/15 mucometra and all pyometra samples. When comparing pyometra with other groups, 189 differentially expressed genes were detected. SLPI, PTGS2/COX2, MMP1, S100A8, S100A9 and IL8 were among the top up-regulated genes detected in pyometra, further confirmed by external expression data. Notably, a particular molecular profile in pyometra from animals previously treated with exogenous progesterone compounds was observed in comparison with pyometra from untreated dogs as well as with other groups irrespective of exogenous hormone treatment status. In addition to S100A8 and S100A9 genes, overexpression of the inflammatory cytokines IL1B, TNF and IL6 as well as LTF were detected in the pyometra from treated animals. Interestingly, closed pyometra was more frequently detected in treated dogs (64% versus 33%), with IL1B, TNF, LBP and CXCL10 among the most relevant overexpressed genes. This molecular signature associated with potential biomarkers and therapeutic targets, such as CXCL10 and COX2, should guide future clinical studies. Based on the gene expression profile we suggested that pyometra from progesterone treated dogs is a distinct molecular entity. PMID:26222498

  1. Isolated humeral recurrence in endometrial carcinoma

    PubMed Central

    Devdas, Santosh Kumar; Digumarti, Leela; Digumarti, Raghunadharao; Patro, Kunha Charan; Nutakki, Ramakoteswararao

    2016-01-01

    Isolated skeletal metastasis in endometrial carcinoma at recurrence is very rare. We report a 52-year-old woman diagnosed to have FIGO Stage 1b, Grade 1 endometrioid adenocarcinoma, presenting with isolated distal humerus metastasis, 2 years after surgery and adjuvant radiotherapy for primary disease. Imaging, bone scintigraphy, and cytology confirmed the diagnosis of poorly differentiated metastatic adenocarcinoma. She was treated with local radiotherapy followed by six cycles of paclitaxel and carboplatin chemotherapy along with zoledronic acid, monthly. She is symptom-free after the treatment and at a first follow-up visit after 3 months.

  2. Endometrial carcinoma in a young dog.

    PubMed

    Payne-Johnson, C E; Kelly, D F; Davies, P T

    1986-07-01

    A 2-years-old nulliparous cross-bred bitch had persistent vulval discharge following treatments that included a combined ethinyloestradiol/methyltestosterone preparation and megoestrol acetate. The uterus, removed at ovarohysterectomy, contained a large polypoid intraluminal mass with the histological features of endometrial carcinoma. The bitch has remained well for thirty-one months after surgery. The possibility is considered that the lesion is drug-related but no firm conclusion can be drawn about the precise nature and pathogenesis of this unusual lesion.

  3. Isolated humeral recurrence in endometrial carcinoma.

    PubMed

    Devdas, Santosh Kumar; Digumarti, Leela; Digumarti, Raghunadharao; Patro, Kunha Charan; Nutakki, Ramakoteswararao

    2016-01-01

    Isolated skeletal metastasis in endometrial carcinoma at recurrence is very rare. We report a 52-year-old woman diagnosed to have FIGO Stage 1b, Grade 1 endometrioid adenocarcinoma, presenting with isolated distal humerus metastasis, 2 years after surgery and adjuvant radiotherapy for primary disease. Imaging, bone scintigraphy, and cytology confirmed the diagnosis of poorly differentiated metastatic adenocarcinoma. She was treated with local radiotherapy followed by six cycles of paclitaxel and carboplatin chemotherapy along with zoledronic acid, monthly. She is symptom-free after the treatment and at a first follow-up visit after 3 months. PMID:27688615

  4. Isolated humeral recurrence in endometrial carcinoma

    PubMed Central

    Devdas, Santosh Kumar; Digumarti, Leela; Digumarti, Raghunadharao; Patro, Kunha Charan; Nutakki, Ramakoteswararao

    2016-01-01

    Isolated skeletal metastasis in endometrial carcinoma at recurrence is very rare. We report a 52-year-old woman diagnosed to have FIGO Stage 1b, Grade 1 endometrioid adenocarcinoma, presenting with isolated distal humerus metastasis, 2 years after surgery and adjuvant radiotherapy for primary disease. Imaging, bone scintigraphy, and cytology confirmed the diagnosis of poorly differentiated metastatic adenocarcinoma. She was treated with local radiotherapy followed by six cycles of paclitaxel and carboplatin chemotherapy along with zoledronic acid, monthly. She is symptom-free after the treatment and at a first follow-up visit after 3 months. PMID:27688615

  5. [Reproductive physiology of the European mink: progesterone profile during pregnancy].

    PubMed

    Amstislavskiĭ, S Ia; Zav'ialov, E L; Ternovskaia, Iu G; Gerlinskaia, L A

    2010-04-01

    Reproductive physiology of the European mink, an endangered mustelid species, has been so far scarcely investigated. This study confirms that in European mink embryo implantation occurs on the day 12 of pregnancy. Progesterone profile during pregnancy has been compared in European mink and domestic ferret. In both species, progesterone increases at peri-implantation period, i. e. on day 8 and day 12 after mating. However, toward the end of pregnancy, on day 40 after mating, progesterone concentration in faeces of the ferrets decreases and does not differ from the initial level. In contrast, increase of progesterone during first 12 days of pregnancy in European mink is not as rapid as in ferrets, but in this species, there is no visible decrease of progesterone at the end of pregnancy. Peak levels of progesterone in faeces (day 8, 12) are lower in European mink than in ferret.

  6. Progesterone for Neuroprotection in Pediatric Traumatic Brain Injury

    PubMed Central

    Robertson, Courtney L.; Fidan, Emin; Stanley, Rachel M.; MHSA; Noje, Corina; Bayir, Hülya

    2016-01-01

    Objective To provide an overview of the preclinical literature on progesterone for neuroprotection after traumatic brain injury (TBI), and to describe unique features of developmental brain injury that should be considered when evaluating the therapeutic potential for progesterone treatment after pediatric TBI. Data Sources National Library of Medicine PubMed literature review. Data Selection The mechanisms of neuroprotection by progesterone are reviewed, and the preclinical literature using progesterone treatment in adult animal models of TBI are summarized. Unique features of the developing brain that could either enhance or limit the efficacy of neuroprotection by progesterone are discussed, and the limited preclinical literature using progesterone after acute injury to the developing brain is described. Finally, the current status of clinical trials of progesterone for adult TBI is reviewed. Data Extraction and Synthesis Progesterone is a pleotropic agent with beneficial effects on secondary injury cascades that occur after TBI, including cerebral edema, neuroinflammation, oxidative stress, and excitotoxicity. More than 40 studies have used progesterone for treatment after TBI in adult animal models, with results summarized in tabular form. However, very few studies have evaluated progesterone in pediatric animal models of brain injury. To date, two human Phase II trials of progesterone for adult TBI have been published, and two multi-center Phase III trials are underway. Conclusions The unique features of the developing brain from that of a mature adult brain make it necessary to independently study progesterone in clinically relevant, immature animal models of TBI. Additional preclinical studies could lead to the development of a novel neuroprotective therapy that could reduce the long-term disability in head-injured children, and could potentially provide benefit in other forms of pediatric brain injury (global ischemia, stroke, statue epilepticus). PMID

  7. Endometrial cancer and antidepressants: A nationwide population-based study.

    PubMed

    Lin, Chiao-Fan; Chan, Hsiang-Lin; Hsieh, Yi-Hsuan; Liang, Hsin-Yi; Chiu, Wei-Che; Huang, Kuo-You; Lee, Yena; McIntyre, Roger S; Chen, Vincent Chin-Hung

    2016-07-01

    To our knowledge, the association between antidepressant exposure and endometrial cancer has not been previously explored. Herein, we aim to investigate the association between antidepressant prescription, including novel antidepressants, and the risk for endometrial cancer in a population-based study.Data for the analysis were derived from National Health Insurance Research Database. We identified 8392 cases with a diagnosis of endometrial cancer and 82,432 matched controls. A conditional logistic regression model was used, with adjusting for potentially confounding variables (e.g., comorbid psychiatric diseases, comorbid physical diseases, and other medications). Risk for endometrial cancer in the population-based study sample was categorized by, and assessed as a function of, antidepressant prescription and cumulative dosage.We report no association between endometrial cancer incidence and antidepressant prescription, including those prescribed either selective serotonin reuptake inhibitors (adjusted odds ratio [OR] = 0.98; 95% confidence interval [CI], 0.84-1.15) or serotonin norepinephrine reuptake inhibitors (adjusted OR = 1.14; 95% CI, 0.76-1.71). We also did not identify an association between higher cumulative doses of antidepressant prescription and endometrial cancer.There was no association between antidepressant prescription and endometrial cancer. PMID:27442640

  8. Regression of latent endometrial precancers by progestin infiltrated intrauterine device.

    PubMed

    Ørbo, Anne; Rise, Cecil E; Mutter, George L

    2006-06-01

    PTEN tumor suppressor inactivation is the earliest step in endometrial carcinogenesis, occurring in morphologically unremarkable endometrial glands in half of normal women. We test the hypothesis that sex hormones positively or negatively select for these "latent precancers" by examining their emergence, persistence, and regression rates under differing hormonal conditions. Perimenopausal and postmenopausal women had an intake endometrial biopsy and underwent hormonal therapy with progestin-impregnated intrauterine device (IUD; n = 21), cyclic oral progestins (n = 28), or surveillance only (n = 22) with follow-up biopsies. For comparison, premenopausal naturally cycling endometrial biopsies were studied as single time points in 87 patients and multiple surveillance time points in 34 patients. Biopsies in which any PTEN protein-null glands were found by immunohistochemistry were scored as containing a latent endometrial precancer. All groups had a similar proportion of latent precancers at intake but differed after therapy. Emergence rates were highest (21%) for the naturally cycling premenopausal group compared with just 9% for untreated perimenopausal women. The IUD group had the highest rate of regression, with a 62% pretherapy and 5% post-therapy rate of latent precancers. This contrasted to nonsignificant changes for the oral progestin and untreated control groups. Delivery of high doses of progestins locally to the endometrium by IUD leads to ablation of preexisting PTEN-inactivated endometrial latent precancers and is a possible mechanism for reduction of long-term endometrial cancer risk known to occur in response to this hormone.

  9. Regression of latent endometrial precancers by progestin infiltrated intrauterine device

    PubMed Central

    Ørbo, Anne; Rise, Cecil E.; Mutter, George L.

    2008-01-01

    PTEN tumor suppressor inactivation is the earliest step in endometrial carcinogenesis, occurring in morphologically unremarkable endometrial glands in half of normal women. We test the hypothesis that sex hormones positively or negatively select for these “latent precancers” by examining their emergence, persistence, and regression rates under differing hormonal conditions. Peri and postmenopausal women had an intake endometrial biopsy and underwent hormonal therapy with progestin-impregnated intrauterine device (“IUD”, n=21), cyclic oral progestins (n=28), or surveillance only (n=22), with followup biopsies. For comparison, premenopausal naturally cycling endometrial biopsies were studied as single timepoints in 87 patients, and multiple surveillance timepoints in 34. Biopsies in which any PTEN protein null glands were found by immunohistochemistry were scored as containing a latent endometrial precancer. All groups had a similar proportion of latent precancers at intake, but differed after therapy. Emergence rates were highest (21%) for the naturally cycling premenopausal group, in comparison to just 9% for untreated perimenopausal women. The IUD group had the highest rate of regression, with a 62% pre and 5% post therapy rate of latent precancers. This contrasted to non-significant changes for the oral progestin and untreated control groups. Delivery of high doses of progestins locally to the endometrium by IUD leads to ablation of pre-existing PTEN-inactivated endometrial latent precancers, and is a possible mechanism for reduction of long term endometrial cancer risk known to occur in response to this hormone. PMID:16740697

  10. [Environmental and genetic risk factors for endometrial carcinoma].

    PubMed

    Sénéchal, Claire; Cottereau, Edouard; de Pauw, Antoine; Elan, Camille; Dagousset, Isabelle; Fourchotte, Virginie; Gauthier-Villars, Marion; Lae, Marick; Stoppa-Lyonnet, Dominique; Buecher, Bruno

    2015-03-01

    In France, endometrial cancer is at the first rank of gynecological cancers for cancer incidence, before ovarian and cervical cancers. In fact, the number of incident cases has been estimated to 7275 for the year 2012; the number of death due to endometrial cancer to 2025. This cancer is hormone-dependent and endogenous (reproductive factors) or exogenous (oral combined contraceptives, hormone replacement therapy) causes of exposition to estrogens are the major environmental risk factors for both types of endometrial cancers: type I or well-differentiated endometrioid adenocarcinomas; and type II including all other histological types: papillary serous adenocarcinomas, clear cell adenocarcinomas and carcinosarcomas, also known as malignant mixed Mullerian tumor, MMMT. Obesity, diabetes mellitus and adjuvant treatment of breast cancer with tamoxifen are also associated with an increased risk of endometrial cancer. Genetic factors may also be implicated in the pathogenesis of endometrial cancer either as "minor genetic factors" (susceptibility factors), which remain largely unknown and are responsible for the increased observed risk in relatives of women affected with endometrial cancer; or as major genetic factors responsible for hereditary forms and namely for Lynch syndrome whose genetic transmission is of autosomic dominant type. The appropriate recognition of Lynch syndrome is of critical importance because affected patients and their relatives should benefit from specific care. The aims of this review is to describe major environmental and genetic risk factors for endometrial cancer with specific attention to most recent advances in this field and to describe recommendations for care of at-risk women.

  11. Identification of Displaced Endometrial Glands and Embryonic Duct Remnants in Female Fetal Reproductive Tract: Possible Pathogenetic Role in Endometriotic and Pelvic Neoplastic Processes

    PubMed Central

    Bouquet de Jolinière, Jean; Ayoubi, Jean Marc; Lesec, Guy; Validire, Pierre; Goguin, Alexandre; Gianaroli, Luca; Dubuisson, Jean Bernard; Feki, Anis; Gogusev, Jean

    2012-01-01

    Background: Recent findings strongly promoted the hypothesis that common pelvic gynecological diseases including endometriosis and ovarian neoplasia may develop de novo from ectopic endometrial-like glands and/or embryonic epithelial remnants. To verify the frequency, the anatomical localization and the phenotype of misplaced endometrial tissue along the fetal female reproductive tract, histological and immunohistochemical analyses of uteri, fallopian tubes, and uterosacral ligaments were performed. Methods: Reproductive organs were collected from seven female fetuses at autopsy, five of them from gestational ages between 18 and 26 weeks and two fetuses with gestational ages of 33 and 36 weeks deceased of placental anomalies. Serial sections from areas containing ectopic glands and embryonic duct residues were analyzed by histological and immunohistochemical procedures. Results: Numerous ectopic endometrial glands and stroma were detected in the myometrium in two fetuses with low levels of expression of estrogen receptor-alpha (ER-α) and progesterone receptors (PR). The embryonic ducts were localized in the uterine broad and ovarian ligaments and under the fallopian tube serosa in six fetuses. Low levels of steroid receptors expression were found in the embryonic residues, whereas the carcino-embryonic antigen (CEA) and the tumor marker Ca 125 were not detected. The embryonic residues stromal component strongly expressed the CD 10 and vimentin proteins. Conclusion: The anatomical and the immunohistochemical features of the ectopic organoid structures identified in fetal female reproductive tract suggest that endometriotic as well as neoplastic disease in adult women may develop on the basis of misplaced endometrial glands and/or embryonic cell remnants. PMID:23227010

  12. Ethanol labeling: detection of early fluid absorption in endometrial resection.

    PubMed

    Duffy, S; Cruise, M; Reilly, C; Reid, P C; Sharp, F

    1992-02-01

    A study is presented of ethanol labeling of irrigation fluid in endometrial resection. The introduction of ethanol labeling and intraoperative breath ethanol analysis provided an inexpensive and potentially useful means of detecting early fluid absorption during uterine surgery. The breath ethanol analyzer used was a hand-held meter; the irrigant solution was 5% dextrose with 1% ethanol. Simultaneous breath and venous samples were taken from women undergoing endometrial resection. An increase in breath ethanol was positively correlated with fluid absorption, blood ethanol, and serum glucose. This technique may prove valuable in preventing fluid overload during endometrial resection.

  13. Aurora kinase A has a significant role as a therapeutic target and clinical biomarker in endometrial cancer

    PubMed Central

    UMENE, KIYOKO; YANOKURA, MEGUMI; BANNO, KOUJI; IRIE, HARUKO; ADACHI, MASATAKA; IIDA, MIHO; NAKAMURA, KANAKO; NOGAMI, YUYA; MASUDA, KENTA; KOBAYASHI, YUSUKE; TOMINAGA, EIICHIRO; AOKI, DAISUKE

    2015-01-01

    Aurora kinase A (AURKA) regulates the cell cycle checkpoint and maintains genomic integrity. AURKA is overexpressed in various malignant tumors and its upregulation induces chromosomal instability, which leads to aneuploidy and cell transformation. To investigate the role of AURKA in endometrial cancer, we evaluated the association of immunohistochemical expression of AURKA with clinicopathological factors. Furthermore, we examined the effects of AURKA inhibition by transfected siRNA in HEC-1B cells on colony-forming ability, invasion and migration capacity, and chemosensitivity. Immunohistochemical staining showed that overexpression of AURKA was significantly associated with tumor grade (P<0.05) and poor histologic differentiation (P<0.05). The recurrence rate also tended to be high in cases with overexpression of AURKA (P<0.1) and these cases also had a tendency for shorter disease-free survival (DFS) (P<0.1). AURKA inhibition in endometrial cancer cell lines significantly decreased cell growth, invasion and migration (P<0.05), and increased chemosensitivity to paclitaxel. We also evaluated the efficacy of a combination of AURKA siRNA and paclitaxel against subcutaneous tumors formed in a nude mouse. After treatment, the tumor volume shrank significantly compared to treatment with paclitaxel only (P<0.05). To our knowledge, this is the first study in endometrial carcinoma to show a correlation between overexpression of AURKA and tumor grade, histological type and sensitivity to paclitaxel. AURKA is a promising therapeutic target in endometrial cancer and the combination therapy with AURKA inhibitors and paclitaxel could be effective for endometrial cancer that is resistant to conventional treatment and has a poor prognosis. PMID:25625960

  14. Endometrial stem/progenitor cells: the first 10 years

    PubMed Central

    Gargett, Caroline E.; Schwab, Kjiana E.; Deane, James A.

    2016-01-01

    BACKGROUND The existence of stem/progenitor cells in the endometrium was postulated many years ago, but the first functional evidence was only published in 2004. The identification of rare epithelial and stromal populations of clonogenic cells in human endometrium has opened an active area of research on endometrial stem/progenitor cells in the subsequent 10 years. METHODS The published literature was searched using the PubMed database with the search terms ‘endometrial stem cells and menstrual blood stem cells' until December 2014. RESULTS Endometrial epithelial stem/progenitor cells have been identified as clonogenic cells in human and as label-retaining or CD44+ cells in mouse endometrium, but their characterization has been modest. In contrast, endometrial mesenchymal stem/stromal cells (MSCs) have been well characterized and show similar properties to bone marrow MSCs. Specific markers for their enrichment have been identified, CD146+PDGFRβ+ (platelet-derived growth factor receptor beta) and SUSD2+ (sushi domain containing-2), which detected their perivascular location and likely pericyte identity in endometrial basalis and functionalis vessels. Transcriptomics and secretomics of SUSD2+ cells confirm their perivascular phenotype. Stromal fibroblasts cultured from endometrial tissue or menstrual blood also have some MSC characteristics and demonstrate broad multilineage differentiation potential for mesodermal, endodermal and ectodermal lineages, indicating their plasticity. Side population (SP) cells are a mixed population, although predominantly vascular cells, which exhibit adult stem cell properties, including tissue reconstitution. There is some evidence that bone marrow cells contribute a small population of endometrial epithelial and stromal cells. The discovery of specific markers for endometrial stem/progenitor cells has enabled the examination of their role in endometrial proliferative disorders, including endometriosis, adenomyosis and Asherman

  15. The Role of Progesterone in Maternal Recognition of Pregnancy in Domestic Ruminants.

    PubMed

    Lonergan, Pat; Forde, Niamh

    2015-01-01

    Progesterone (P4) secretion by the corpus luteum is critical for the establishment and maintenance of pregnancy and plays a major role in regulating endometrial secretions essential for stimulating and mediating changes in conceptus growth and differentiation throughout early pregnancy. Numerous studies have demonstrated an association between elevated P4 and acceleration in conceptus elongation. Given that larger conceptuses produce more interferon tau, the pregnancy recognition signal in ruminants, it would be reasonable to hypothesize that treatments aimed at increasing peripheral concentrations of P4 should improve pregnancy rate. However, data on the impact of post-insemination supplementation of P4 on pregnancy rates are conflicting and, at best, indicate a modest positive response. Whether a P4-induced increase in conceptus size can improve fertility continues to be an active area of investigation. The aim of this chapter is to review recent data on the role of P4 in conceptus development in ruminants, particularly cattle, and to summarize results from attempts at manipulating endogenous P4 with the aim of improving conceptus survival and pregnancy rate.

  16. Expression of steroid and xenobiotic receptor in uterine carcinosarcoma, leiomyosarcoma and endometrial stromal sarcoma

    PubMed Central

    YUE, XIAONI; UTSUNOMIYA, HIROKI; AKAHIRA, JUN-ICHI; SUZUKI, FUMIHIKO; ITO, KIYOSHI; NAGASE, SATORU; SASANO, HIRONOBU; YAEGASHI, NOBUO

    2013-01-01

    We analyzed the expression of the steroid and xenobiotic receptor (SXR) in human uterine sarcomas and evaluated its clinical significance. Forty-seven cases with archival specimens were examined for SXR expression using immunohistochemistry. All cases were scored using a semi-quantitative histological scoring (HSCORE) method. Specimens with a HSCORE >40 were regarded as SXR-positive. Various clinicopathological variables, including the expression status of estrogen receptor (ER)-α, progesterone receptor (PR) and Ki67 (MIB-1) were examined. The mean SXR HSCOREs of carcinosarcoma (CS) and leiomyosarcoma (LMS) were 9.13 and 23.6, respectively, and SXR-positive rates were 3 out of 24 (12.5%) and 4 out of 17 (23.5%), respectively. SXR was not detected in endometrial stromal sarcoma (ESS). In CS cases, significant differences were detected between the expression of SXR and age and disease stages. There was no significant correlation between SXR-positive status and either disease-free survival or overall survival. Our results support an association between SXR and malignant behavior. Our results show that overexpression of SXR may represent a useful marker to identify patients with advanced-stage CS. In addition, our results showed that SXR may aid in the diagnosis of uterine sarcomas. PMID:23443531

  17. Expression of steroid and xenobiotic receptor in uterine carcinosarcoma, leiomyosarcoma and endometrial stromal sarcoma.

    PubMed

    Yue, Xiaoni; Utsunomiya, Hiroki; Akahira, Jun-Ichi; Suzuki, Fumihiko; Ito, Kiyoshi; Nagase, Satoru; Sasano, Hironobu; Yaegashi, Nobuo

    2013-03-01

    We analyzed the expression of the steroid and xenobiotic receptor (SXR) in human uterine sarcomas and evaluated its clinical significance. Forty-seven cases with archival specimens were examined for SXR expression using immunohistochemistry. All cases were scored using a semi-quantitative histological scoring (HSCORE) method. Specimens with a HSCORE >40 were regarded as SXR-positive. Various clinicopathological variables, including the expression status of estrogen receptor (ER)-α, progesterone receptor (PR) and Ki67 (MIB-1) were examined. The mean SXR HSCOREs of carcinosarcoma (CS) and leiomyosarcoma (LMS) were 9.13 and 23.6, respectively, and SXR-positive rates were 3 out of 24 (12.5%) and 4 out of 17 (23.5%), respectively. SXR was not detected in endometrial stromal sarcoma (ESS). In CS cases, significant differences were detected between the expression of SXR and age and disease stages. There was no significant correlation between SXR-positive status and either disease-free survival or overall survival. Our results support an association between SXR and malignant behavior. Our results show that overexpression of SXR may represent a useful marker to identify patients with advanced-stage CS. In addition, our results showed that SXR may aid in the diagnosis of uterine sarcomas. PMID:23443531

  18. Adenovirus mediated homozygous endometrial epithelial Pten deletion results in aggressive endometrial carcinoma

    SciTech Connect

    Joshi, Ayesha; Ellenson, Lora Hedrick

    2011-07-01

    Pten is the most frequently mutated gene in uterine endometriod carcinoma (UEC) and its precursor complex atypical hyperplasia (CAH). Because the mutation frequency is similar in CAH and UEC, Pten mutations are thought to occur relatively early in endometrial tumorigenesis. Previous work from our laboratory using the Pten{sup +/-} mouse model has demonstrated somatic inactivation of the wild type allele of Pten in both CAH and UEC. In the present study, we injected adenoviruses expressing Cre into the uterine lumen of adult Pten floxed mice in an attempt to somatically delete both alleles of Pten specifically in the endometrium. Our results demonstrate that biallelic inactivation of Pten results in an increased incidence of carcinoma as compared to the Pten{sup +/-} mouse model. In addition, the carcinomas were more aggressive with extension beyond the uterus into adjacent tissues and were associated with decreased expression of nuclear ER{alpha} as compared to associated CAH. Primary cultures of epithelial and stromal cells were prepared from uteri of Pten floxed mice and Pten was deleted in vitro using Cre expressing adenovirus. Pten deletion was evident in both the epithelial and stromal cells and the treatment of the primary cultures with estrogen had different effects on Akt activation as well as Cyclin D3 expression in the two purified components. This study demonstrates that somatic biallelic inactivation of Pten in endometrial epithelium in vivo results in an increased incidence and aggressiveness of endometrial carcinoma compared to mice carrying a germline deletion of one allele and provides an important in vivo and in vitro model system for understanding the genetic underpinnings of endometrial carcinoma.

  19. Endometrial and acute myeloid leukemia cancer genomes characterized

    Cancer.gov

    Two studies from The Cancer Genome Atlas (TCGA) program reveal details about the genomic landscapes of acute myeloid leukemia (AML) and endometrial cancer. Both provide new insights into the molecular underpinnings of these cancers with the potential to i

  20. Monitoring of human endometrial function by radiommunoassay of PEP

    SciTech Connect

    Joshi, Sh. G.

    1984-12-18

    The present invention relates to a novel method for the quantitative determination of PEP (progestagen-associated endometrial protein) in a body fluid by radioimmunoassay. The technique is useful in monitoring the function of the human endometrium.

  1. Epidemiology of Endometrial Cancer Consortium (E2C2)

    Cancer.gov

    The Epidemiology of Endometrial Cancer Consortium studies the etiology of this common cancer and build on resources from existing studies by combining data across studies in order to advance the understanding of the etiology of this disease.

  2. Control of parturition in the sow using progesterone and prostaglandin.

    PubMed

    Gooneratne, A; Hartmann, P E; McCauley, I; Martin, C E

    1979-12-01

    The effect of progesterone and prostaglandin administration on the timing of farrowing was studied in three groups of 25 sows each. Progesterone treatment (100 mg/day) on days 112, 113 and 114 of gestation (group I) significantly prolonged the gestation length to 116.4 +/- 0.4 (mean +/- s.e.) days compared to the control sows (group III; 115.5 +/- 0.2; P less than 0.05). Administration of prostaglandin (200 micrograms Cloprostanol intramuscularly) on day 115 of gestation following progesterone treatment (group II) resulted in a gestation length of 116.0 +/- 0.1 days, with the sows farrowing 25.4 +/- 1.0 h after the prostaglandin injection. 80% of the sows farrowed between 0800 and 1700 h of day 116 of gestation. Plasma progesterone levels were maintained by the exogenous progesterone during treatment. At farrowing, higher levels of progesterone were observed in groups I and II compared to controls. Prostaglandin treatment did not significantly alter withdrawal of progesterone in progesterone treated sows, suggesting that the actions of exogenous prostaglandin is primarily on the myometrium and the cervix. Hormonal treatment in late pregnancy did not have any adverse effects on piglet viability and growth rate, or subsequent reproductive performances of sows. Lactation was initiated normally, and the concentrations of lactose, protein, fat, IgG, Na+, Ca2+ and K+ in colostrum and milk were similar in all groups during the first 5 days of lactation.

  3. Ventilatory response of rabbits and goats to chronic progesterone administration.

    PubMed

    Smith, C A; Kellogg, R H

    1980-03-01

    We assessed the ventilatory response to chronic progesterone administration of 37 male rabbits and 4 castrated male goats. Rabbits, in response to 2.72 mg.kg-1.day-1 of progesterone, did not chronically hyperventilate as measured by changes in CSF [HCO-3]. Two goats given 10 mg/kg/day of progesterone by intramuscular injection, alone or in combination with estradiol or testosterone, manifested no convincing ventilatory changes. Two goats were given progesterone in the form of progesterone-containing Silastic implants. Serum progesterone levels of 8-27 ng/ml were maintained over the course of 45 days. The hyperventilation in these goats, unlike that of man, was slow to develop (8-15 days), slow to decay (10-30 days), and relatively small (resting PETCO2 fell 3-5 mm Hg relative to control); and there was no change in slope of the CO2 response curves. We conclude that goats and rabbits do not respond to progesterone like man, and therefore are not good models with which to study the mechanism(s) by which progesterone produces hyperventilation in man. PMID:7384660

  4. RNF43 is frequently mutated in colorectal and endometrial cancers

    PubMed Central

    Giannakis, Marios; Hodis, Eran; Mu, Xinmeng Jasmine; Yamauchi, Mai; Rosenbluh, Joseph; Cibulskis, Kristian; Saksena, Gordon; Lawrence, Michael S.; Qian, ZhiRong; Nishihara, Reiko; Van Allen, Eliezer M.; Hahn, William C.; Gabriel, Stacey B.; Lander, Eric S.; Getz, Gad; Ogino, Shuji; Fuchs, Charles S.; Garraway, Levi A.

    2014-01-01

    We report somatic mutations of RNF43 in over 18% of colorectal adenocarcinomas and endometrial carcinomas. RNF43 encodes an E3 ubiquitin ligase that negatively regulates Wnt signaling. Truncating mutations of RNF43 are more prevalent in microsatellite-unstable tumors and show mutual exclusivity with inactivating APC mutations in colorectal adenocarcinomas. These results indicate that RNF43 is one of the most commonly mutated genes in colorectal and endometrial cancers. PMID:25344691

  5. Protective Effect of Progesterone during Pregnancy against Ovarian Cancer

    PubMed Central

    Han, Kyung Hee; Kim, Mi-Kyung; Kim, Hee Seung; Chung, Hyun Hoon; Song, Yong Sang

    2013-01-01

    There have been several epidemiologic studies supporting the protective role of pregnancy, although the mechanism is not clear. High level of progesterone, which is crucial in maintaining pregnancy, has been supposed to be one of the causative factors. Progesterone is produced at the corpus luteum in the early pregnancy and the placenta in the late pregnancy period. In several experimental studies, progesterone was reported to induce apoptosis of ovarian cancer cells through intrinsic and extrinsic pathways. In addition, progesterone has been shown to exert its anticancer effect through genomic and non-genomic action. The objective of this review is to discuss the protective mechanism of pregnancy against ovarian cancer focusing on the steroid hormone, progesterone. PMID:25337537

  6. Effects of an antiprogesterone (RU486) on the hypothalamic-hypophyseal-ovarian-endometrial axis during the luteal phase of the menstrual cycle.

    PubMed

    Garzo, V G; Liu, J; Ulmann, A; Baulieu, E; Yen, S S

    1988-03-01

    The impact of the antiprogesterone RU486 [17 beta-hydroxy-11 beta-(4-dimethylaminophenyl) 17 alpha-(1-propynyl)estra- 4,9-dien-3-one] on the hypothalamic-pituitary-ovarian-endometrial axis was examined in normal cycling women during the mid (MLP)- and late (LLP) luteal phases. During the MLP, 10 women received 3 mg/kg RU486 for 3 days. During the LLP, a single dose of 600 mg RU486 was administered to 4 women, and in another 4 women a single dose of 3 mg/kg was given during corpus luteum rescue by hCG. Longitudinal studies with daily and frequent blood samples (every 10 min for 10 h) were conducted during 3 consecutive cycles (control-treatment-recovery). During the MLP, RU486-induced uterine bleeding occurred in all 10 women 36-72 h after the first dose. No histological evidence of endometrial breakdown was found in endometrial biopsies taken 12-24 h before the onset of bleeding. Significant decreases in LH secretion (P less than 0.001) and LH pulse amplitude (P less than 0.006) and blunted pituitary responses to GnRH (P less than 0.01) were evident by the last treatment day, but LH pulse frequency did not change. Complete luteolysis occurred in 2 of the 10 women. Incomplete luteolysis occurred in 8 women and was associated with an initial decline of serum estradiol (P less than 0.001), but not progesterone levels, followed by rebound increases (P less than 0.001) in LH, estradiol, and progesterone levels 3 days later, which may have reversed the luteolytic processes and prolonged corpus luteum function. Spontaneous luteolysis ensued 3-5 days later with the onset of second episodes of uterine bleeding. For serum FSH, an early rise occurred during the luteal phase in advance of the onset of the second episodes of uterine bleeding. This rise may have resulted in early follicle recruitment and accounted for the shorter duration of the follicular phase during recovery cycles. During the LLP, the single RU486 dose resulted in significant decreases in LH pulse amplitude

  7. Persistent genital hyperinnervation following progesterone administration to adolescent female rats.

    PubMed

    Liao, Zhaohui; Smith, Peter G

    2014-12-01

    Provoked vestibulodynia, a female pelvic pain syndrome affecting substantial numbers of women, is characterized by genital hypersensitivity and sensory hyperinnervation. Previous studies have shown that the risk of developing provoked vestibulodynia is markedly elevated following adolescent use of oral contraceptives with high progesterone content. We hypothesized that progesterone, a steroid hormone with known neurotropic properties, may alter genital innervation through direct or indirect actions. Female Sprague Dawley rats received progesterone (20 mg/kg subcutaneously) from Days 20-27; tissue was removed for analysis in some rats on Day 28, while others were ovariectomized on Day 43 and infused for 7 days with vehicle or 17beta estradiol. Progesterone resulted in overall increases in vaginal innervation at both Day 28 and 50 due to proliferation of peptidergic sensory and sympathetic (but not parasympathetic) axons. Estradiol reduced innervation in progesterone-treated and untreated groups. To assess the mechanisms of sensory hyperinnervation, we cultured dissociated dorsal root ganglion neurons and found that progesterone increases neurite outgrowth by small unmyelinated (but not myelinated) sensory neurons, it was receptor mediated, and it was nonadditive with NGF. Pretreatment of ganglion with progesterone also increased neurite outgrowth in response to vaginal target explants. However, pretreatment of vaginal target with progesterone did not improve outgrowth. We conclude that adolescent progesterone exposure may contribute to provoked vestibulodynia by eliciting persistent genital hyperinnervation via a direct effect on unmyelinated sensory nociceptor neurons and that estradiol, a well-documented therapeutic, may alleviate symptoms in part by reducing progesterone-induced sensory hyperinnervation. PMID:25359899

  8. Progesterone neuroprotection in traumatic CNS injury and motoneuron degeneration.

    PubMed

    De Nicola, Alejandro F; Labombarda, Florencia; Gonzalez Deniselle, Maria Claudia; Gonzalez, Susana L; Garay, Laura; Meyer, Maria; Gargiulo, Gisella; Guennoun, Rachida; Schumacher, Michael

    2009-07-01

    Studies on the neuroprotective and promyelinating effects of progesterone in the nervous system are of great interest due to their potential clinical connotations. In peripheral neuropathies, progesterone and reduced derivatives promote remyelination, axonal regeneration and the recovery of function. In traumatic brain injury (TBI), progesterone has the ability to reduce edema and inflammatory cytokines, prevent neuronal loss and improve functional outcomes. Clinical trials have shown that short-and long-term progesterone treatment induces a significant improvement in the level of disability among patients with brain injury. In experimental spinal cord injury (SCI), molecular markers of functional motoneurons become impaired, including brain-derived neurotrophic factor (BDNF) mRNA, Na,K-ATPase mRNA, microtubule-associated protein 2 and choline acetyltransferase (ChAT). SCI also produces motoneuron chromatolysis. Progesterone treatment restores the expression of these molecules while chromatolysis subsided. SCI also causes oligodendrocyte loss and demyelination. In this case, a short progesterone treatment enhances proliferation and differentiation of oligodendrocyte progenitors into mature myelin-producing cells, whereas prolonged treatment increases a transcription factor (Olig1) needed to repair injury-induced demyelination. Progesterone neuroprotection has also been shown in motoneuron neurodegeneration. In Wobbler mice spinal cord, progesterone reverses the impaired expression of BDNF, ChAT and Na,K-ATPase, prevents vacuolar motoneuron degeneration and the development of mitochondrial abnormalities, while functionally increases muscle strength and the survival of Wobbler mice. Multiple mechanisms contribute to these progesterone effects, and the role played by classical nuclear receptors, extra nuclear receptors, membrane receptors, and the reduced metabolites of progesterone in neuroprotection and myelin formation remain an exciting field worth of exploration

  9. YAP/TAZ regulates the insulin signaling via IRS1/2 in endometrial cancer

    PubMed Central

    Wang, Chao; Jeong, Kangjin; Jiang, Hongyuan; Guo, Wei; Gu, Chao; Lu, Yiling; Liang, Jiyong

    2016-01-01

    Insulin resistance (IR) is an important mechanism of pathogenesis of endometrial cancer (EC) and explains the pathogenic mechanism of high risk factors including Obesity BMI (body mass index), Type 2 Diabetes Mellitus, PCOS and so on. Relieving IR or inhibiting the function of insulin could be one of the potential therapeutic strategies for EC, which is a PI3K-driven disease. PI3K/Akt are the central mediators for insulin/IGF1 signaling, however, the involvement of HIPPO pathway co-activators, YAP and TAZ, in insulin resistance remains to be elucidated. In the present study, we analyzed the clinical and biological data of EC patients from TCGA and observed a correlation between insulin resistance and EC. By comparing the expression level of IRS1/2 in obese vs non-obese patients, we found that the most important insulin resistance relative (IRR) genes are the contributing factors to IR. Interestingly, IRS1/2 was correlated positively with YAP/TAZ in EC patients. Knockdown of YAP/TAZ by specific siRNA inhibited the phosphorylation of IRS1 while increased the phosphorylation of IGFR1, the inhibitor of insulin signaling. Treating EC with siYAP/TAZ, YAP inhibitor Verteporfin or metformin alone only partially inhibited the function of insulin and IGF1. However, combination of siYAP/TAZ with metformin could completely inhibit the effects of insulin. Thus, our study demonstrated a novel function of YAP and TAZ in the insulin resistance via IRS1/2 in endometrial cancer. Our study also provided the rationale for the potential therapeutic treatment of EC with the combination of inhibiting YAP/TAZ and metformin. PMID:27293994

  10. Progesterone action in breast, uterine, and ovarian cancers

    PubMed Central

    Diep, Caroline H.; Daniel, Andrea R.; Mauro, Laura J.; Knutson, Todd P.; Lange, Carol A.

    2015-01-01

    Progesterone and progesterone receptors (PR) are essential for the development and cyclical regulation of hormone-responsive tissues including the breast and reproductive tract. Altered functions of PR isoforms contribute to the pathogenesis of tumors that arise in these tissues. In the breast, progesterone acts in concert with estrogen to promote proliferative and pro-survival gene programs. In sharp contrast, progesterone inhibits estrogen-driven growth in the uterus and protects the ovary from neoplastic transformation. Progesterone-dependent actions and associated biology in diverse tissues and tumors are mediated by two progesterone receptor isoforms, PR-A and PR-B. These isoforms are subject to altered transcriptional activity or expression levels, differential cross-talk with growth factor signaling pathways, and distinct post-translational modifications and cofactor binding partners. Herein, we summarize and discuss the recent literature focused on progesterone and PR isoform-specific actions in breast, uterine, and ovarian cancers. Understanding the complexity of context-dependent PR actions in these tissues is critical to developing new models that will allow us to advance our knowledge base with the goal of revealing novel and efficacious therapeutic regimens for these hormone-responsive diseases. PMID:25587053

  11. Progesterone and mental rotation task: is there any effect?

    PubMed

    Noreika, Donatas; Griškova-Bulanova, Inga; Alaburda, Aidas; Baranauskas, Mindaugas; Grikšienė, Ramunė

    2014-01-01

    Mental rotation task (MRT) incorporates elements of spatial abilities, important in many professions, with people of both genders involved. Importantly, these are the areas where spatial tasks might be performed for long time periods; thus adverse effects of mental fatigue are highly unwanted. Substantial variation of MRT performance in relation to estrogen levels has been observed in many studies, whereas the role of progesterone remains elusive. Here we aimed to elucidate the effect of progesterone level on the long-duration (1.5 hours) performance of MRT. We included three groups of subjects: a group of males as a control, a group of females in their follicular phase (low progesterone) and a group of females in their luteal phase (high progesterone), MRT accuracy and response time, subjective fatigue ratings and cardiovascular measures together with 17 β -estradiol and progesterone concentrations were analyzed. We found that subjective ratings of fatigue increased, performance accuracy increased, and mean response times decreased during the task in all groups. Females in luteal phase were significantly slower not only than men, but also than females in their follicular phase. An increase in subjective fatigue ratings was positively related to progesterone level-at higher progesterone levels, females felt more tired. PMID:24818150

  12. [Intracellular traffic of the progesterone receptor].

    PubMed

    Guiochon-Mantel, A; Lescop, P; Christin-Maitre, S; Perrot-Applanat, M; Milgrom, E

    1992-01-01

    The nuclear localization of the progesterone receptor is mediated by two signal sequences: one is constitutive and lies in the hinge region (between the DNA and steroid binding domains), the other is hormone-dependent and is localized in the second zinc finger of the DNA binding domain. The use of various inhibitors of energy synthesis in cells expressing permanently or transiently the wild-type receptor or a receptor mutated within the nuclear localization signals, demonstrated that the nuclear residency of the receptor reflects a dynamic situation: the receptor diffusing into the cytoplasm and being constantly and actively transported back into the nucleus. The existence of this nucleo-cytoplasmic shuttle mechanism was confirmed by receptor transfer from one nucleus to the other in heterokaryons. Preliminary evidence was obtained, using oestrogen receptor, that this phenomenon may be of general significance for steroid receptors. PMID:1492716

  13. Efficacy of microwave ablation for the treatment of endometrial carcinoma: A report of 3 cases

    PubMed Central

    NAKAMURA, KOHEI; NAKAYAMA, KENTARO; ISHIKAWA, MASAKO; KATAGIRI, HIROSHI; ISHIBASHI, TOMOKA; SATO, EMI; AMANO, CHIKA; KYO, SATORU

    2016-01-01

    Microwave endometrial ablation (MEA) is effective for the emergency control of uterine hemorrhage. However, to the best of our knowledge, there has been only a single report of life-threatening hemorrhage induced by endometrial carcinoma that was treated with MEA. The present report evaluates the efficacy of MEA as an emergency therapeutic option for the control of bleeding due to advanced endometrial carcinoma and minimally-invasive, early-stage endometrial carcinoma in 3 patients. MEA was able to effectively control massive uterine bleeding due to endometrial carcinoma in 2 patients with advanced disease and was curative in a patient with minimally-invasive endometrial carcinoma. Given its safety, simplicity and effectiveness, MEA may be utilized for the emergency treatment of uterine bleeding in advanced endometrial carcinoma, and may be used as a curative treatment in early-stage endometrial carcinoma. PMID:27123057

  14. What Should You Ask Your Health Care Team About Endometrial Cancer?

    MedlinePlus

    ... endometrial cancer survivor What should you ask your health care team about endometrial cancer? As you cope with ... only ones who can give you information. Other health care professionals, such as nurses and social workers, can ...

  15. Progesterone promotes propagation and viability of mouse embryonic stem cells.

    PubMed

    Shen, Shan-Wei; Song, Hou-Yan

    2009-10-25

    It has been known that estrogen-17beta stimulates proliferation of mouse embryonic stem (mES) cells. To explore the function of another steroid hormone progesterone, we used MTT method and BrdU incorporation assay to obtain growth curves, clone forming assay to detect the propagation and viability of individual mES cells, Western blot to test the expression of ES cell marker gene Oct-4, fluorescence activated cell sorter (FACS) to test cell cycle, and real-time PCR to detect the expressions of cyclins, cyclin-dependent kinases and proto-oncogenes. The results showed that progesterone promoted proliferation of mES cells. The number of clones was more in progesterone-treated group than that in the control group. The expression of pluripotency-associated transcriptional factor Oct-4 changed little after progesterone treatment as shown by Western blot, indicating that most of mES cells were in undifferentiated state. The results of FACS proved that progesterone promoted DNA synthesis in mES cells. The proportion of mES cells in S+G(2)/M phase was higher in progesterone-treated group than that in the control group. Cyclins and cyclin-dependent kinases, as well as proto-oncogenes (c-myc, c-fos) were up-regulated when cells were treated with progesterone. The results obtained indicate that progesterone promotes propagation and viability of mES cells. The up-regulation of cell cycle-related factors might contribute to the function of progesterone.

  16. Expression of androgen and progesterone receptors in primary human meningiomas.

    PubMed

    Maxwell, M; Galanopoulos, T; Neville-Golden, J; Antoniades, H N

    1993-03-01

    Meningiomas are common brain tumors that show a predilection for females and become more aggressive during pregnancy and menses. The existence of gender-specific hormone receptors in meningiomas has long been a matter of controversy; the recent cloning of androgen, estrogen, and progesterone receptors has facilitated their direct evaluation. The authors have demonstrated the expression of androgen and progesterone receptor messenger ribonucleic acid and protein product in nine primary human meningiomas by Northern blot analysis. Cellular localization was achieved by in situ hybridization analysis. Estrogen receptor expression was not detected. Normal adult meninges were shown to express very low levels of both androgen and progesterone receptors.

  17. Advances in uterine leiomyoma research: the progesterone hypothesis.

    PubMed

    Rein, M S

    2000-10-01

    Uterine leiomyomas are monoclonal tumors. However, the factors involved in their initiation and growth remain poorly understood. The neoplastic transformation of myometrium to leiomyoma likely involves somatic mutations of normal myometrium and the complex interactions of sex steroids and local growth factors. Traditionally, estrogen has been considered the major promoter of myoma growth. The purpose of this review is to highlight the biochemical, histologic, and clinical evidence that supports an equally important role for progesterone in the growth of uterine myomas. Biochemical studies suggest that progesterone, progestins, and the progesterone receptor modulate myoma mitotic activity. A hypothesis to explain the pathogenesis of myomas is presented.

  18. Immunoreactive oestrogens and progesterone in amniotic fluid in twin pregnancies.

    PubMed

    Norman, R J; Joubert, S M

    1985-03-01

    Amniotic fluid concentrations of immunoreactive oestrogens and progesterone were measured at the time of caesarean section in 32 twin pregnancies; 25 women had an elective section and seven were in labour at the time of operation. No significant differences between concentrations in the amniotic fluid of the first and second twin were found in respect of conjugated and unconjugated oestrone, oestradiol, oestriol, oestetrol and unconjugated progesterone either before or during labour. It is unlikely that changes in oestrogens or progesterone in the amniotic fluid are responsible for the selective changes seen in prostaglandins and fetal adrenal steroid during labour in the first twin. PMID:3978052

  19. Endometrial beta3 Integrin profile reflects endometrial receptivity defects in women with unexplained recurrent pregnancy loss

    PubMed Central

    2014-01-01

    Background The pathophysiology of recurrent pregnancy loss (RPL) is still unknown in 50% of the cases. Herein we measure the expression of beta3 integrin subunit, a well-known implantation marker, in women with or without RPL and correlate it with the histological dating of the endometrial tissue. Methods LH-timed endometrial biopsies were obtained from cases (RPL; n = 21, age 33.9+/-4.7) and healthy controls (n = 29; age 29.8+/-4.1) during the mid-secretory phase (post ovulatory day: 8 to 10). Endometrial samples were timed histologically according to Noyes’ criteria and underwent immunohistochemical staining for beta3 integrin expression. For statistical analysis the semi-quantitative HSCORE was assessed. Type I (beta3 negative in an out-of-phase endometrium) and Type II defect (beta3 negative in an in-phase endometrium) were also analysed. Statistical analysis was done with Student t-test, Mann Whitney U test, ANCOVA and chi square for trend. Significance was set as P < 0.05. Results The mean (SD) age in controls was lower compared to cases [(29.8 (4.1) vs. 33.9 (4.7) – P = 0.001; Student t-test)]. The median (range) expression of beta3 integrin in controls and cases was 1.94 (0 to 3.5) vs. 0.82 (0 to 3.6), respectively (P = 0.001; Mann Whitney U test). Significance was still significant after adjusting for age (P = 0.03;ANCOVA). The normal positive staining > =0.7 of beta3 integrin subunit and in-phase endometrium was seen in 24 out of 29 (82.8%) controls, but in only 6 out of 21 (28.6%) of cases with RPL; Type I and II defects were seen in 10.3 and 6.9% of controls, while present in 52.4 and 19.1% of cases, respectively (P = 0.0005; chi-square). Conclusions Women with unexplained RPL had significantly reduced integrin expression compared to controls. Our findings underline the need for further molecular analysis of endometrial tissue in affected women. PMID:24950982

  20. [Participation of progesterone receptors in plus-maze behavior in female mice].

    PubMed

    Galeeva, A Iu; Pivina, S G; Tuohimaa, P; Ordian, N E

    2006-07-01

    The current study tested delayed effect pf progesterone on the anxiety level of female mice. The elevated plus maze (EPM) behavior was assessed in ovariectomized mice injected for 7 days with estradiol benzoate and progesterone or progesterone alone after 6 hrs of the last treatment. One group of ovariectomized mice was injected with progesterone receptor blocker Mifepristone before 2 hrs of the last treatment. The immunocytochemistry method was used to visualize cells in different brain areas having immunoreactivity (ir) for progesterone receptors. In the EPM, progesterone administration significantly increased the anxiety levels of ovariectomized mice as compared with estradiol benzoate and progesterone administration. The participation of nuclear progesterone receptors in anxiety levels regulation is confirmed by high correlation of the change of progesterone receptor-ir cell number in some brain areas and anxiety levels. Mifepristone decreased anxiety levels and progesterone receptor-ir cell number in both groups of mice that suggests involvement of genomic mechanisms in anxiety regulation in female mice.

  1. Influence of genetic dissimilarity of mother and fetus on progesterone concentrations in pregnant mice and adaptive features of offspring.

    PubMed

    Gerlinskaya, L A; Evsikov, V I

    2001-03-01

    Concentrations of progesterone in blood plasma and tissue were studied in pregnant mice of strains BALB/cLac and C57BL/6J. Both intra- and interstrain mating and embryo transplantations were used as models of homo- and heterotopic pregnancy. On day 4 of heterotopic pregnancy, plasma progesterone concentrations of females of both strains were higher than those in females of both strains undergoing homotopic pregnancy. In addition, tissue progesterone content of hybrid embryos was higher than that of purebred embryos. Adrenocortical responses to social conflict as indicators of stress resistance were studied in progeny aged 2-3 months. There was a minimal increase in plasma glucocorticoid concentrations in heterotopic transplantants after 15 min pair-matching tests and 30 min crowding compared with those of other progeny, including purebred male mice of BALB/cLac and C57BL/6J strains, homotransplantants and reciprocal hybrids. Thus, genetic dissimilarity of mother and fetuses plays an important role in progesterone provision during pregnancy and also modifies development of progeny. PMID:11226067

  2. Body Mass Index Genetic Risk Score and Endometrial Cancer Risk

    PubMed Central

    Prescott, Jennifer; Setiawan, Veronica W.; Wentzensen, Nicolas; Schumacher, Fredrick; Yu, Herbert; Delahanty, Ryan; Bernstein, Leslie; Chanock, Stephen J.; Chen, Chu; Cook, Linda S.; Friedenreich, Christine; Garcia-Closas, Monserrat; Haiman, Christopher A.; Le Marchand, Loic; Liang, Xiaolin; Lissowska, Jolanta; Lu, Lingeng; Magliocco, Anthony M.; Olson, Sara H.; Risch, Harvey A.; Shu, Xiao-Ou; Ursin, Giske; Yang, Hannah P.; Kraft, Peter; De Vivo, Immaculata

    2015-01-01

    Genome-wide association studies (GWAS) have identified common variants that predispose individuals to a higher body mass index (BMI), an independent risk factor for endometrial cancer. Composite genotype risk scores (GRS) based on the joint effect of published BMI risk loci were used to explore whether endometrial cancer shares a genetic background with obesity. Genotype and risk factor data were available on 3,376 endometrial cancer case and 3,867 control participants of European ancestry from the Epidemiology of Endometrial Cancer Consortium GWAS. A BMI GRS was calculated by summing the number of BMI risk alleles at 97 independent loci. For exploratory analyses, additional GRSs were based on subsets of risk loci within putative etiologic BMI pathways. The BMI GRS was statistically significantly associated with endometrial cancer risk (P = 0.002). For every 10 BMI risk alleles a woman had a 13% increased endometrial cancer risk (95% CI: 4%, 22%). However, after adjusting for BMI, the BMI GRS was no longer associated with risk (per 10 BMI risk alleles OR = 0.99, 95% CI: 0.91, 1.07; P = 0.78). Heterogeneity by BMI did not reach statistical significance (P = 0.06), and no effect modification was noted by age, GWAS Stage, study design or between studies (P≥0.58). In exploratory analyses, the GRS defined by variants at loci containing monogenic obesity syndrome genes was associated with reduced endometrial cancer risk independent of BMI (per BMI risk allele OR = 0.92, 95% CI: 0.88, 0.96; P = 2.1 x 10−5). Possessing a large number of BMI risk alleles does not increase endometrial cancer risk above that conferred by excess body weight among women of European descent. Thus, the GRS based on all current established BMI loci does not provide added value independent of BMI. Future studies are required to validate the unexpected observed relation between monogenic obesity syndrome genetic variants and endometrial cancer risk. PMID:26606540

  3. A Risk-Scoring Model for the Prediction of Endometrial Cancer among Symptomatic Postmenopausal Women with Endometrial Thickness > 4 mm

    PubMed Central

    Mfuta, Kabala; Setti, Tiziano; Cerami, Lillo Bruno; Bergamini, Ezio; Boselli, Fausto

    2014-01-01

    Objective. To develop and test a risk-scoring model for the prediction of endometrial cancer among symptomatic postmenopausal women at risk of intrauterine malignancy. Methods. We prospectively studied 624 postmenopausal women with vaginal bleeding and endometrial thickness > 4 mm undergoing diagnostic hysteroscopy. Patient characteristics and endometrial assessment of women with or without endometrial cancer were compared. Then, a risk-scoring model, including the best predictors of endometrial cancer, was tested. Univariate, multivariate, and ROC curve analysis were performed. Finally, a split-sampling internal validation was also performed. Results. The best predictors of endometrial cancer were recurrent vaginal bleeding (odds ratio (OR) = 2.96), the presence of hypertension (OR = 2.01) endometrial thickness > 8 mm (OR = 1.31), and age > 65 years (OR = 1.11). These variables were used to create a risk-scoring model (RHEA risk-model) for the prediction of intrauterine malignancy, with an area under the curve of 0.878 (95% CI 0.842 to 0.908; P < 0.0001). At the best cut-off value (score ≥ 4), sensitivity and specificity were 87.5% and 80.1%, respectively. Conclusion. Among symptomatic postmenopausal women with endometrial thickness > 4 mm, a risk-scoring model including patient characteristics and endometrial thickness showed a moderate diagnostic accuracy in discriminating women with or without endometrial cancer. Based on this model, a decision algorithm was developed for the management of such a population. PMID:24991535

  4. Oral Bisphosphonate Use and Risk of Postmenopausal Endometrial Cancer

    PubMed Central

    Newcomb, Polly A.; Passarelli, Michael N.; Phipps, Amanda I.; Anderson, Garnet L.; Wactawski-Wende, Jean; Ho, Gloria Y.F.; O'Sullivan, Mary Jo; Chlebowski, Rowan T.

    2015-01-01

    Purpose Bisphosphonates are common medications used for the treatment of osteoporosis and are also used to reduce metastases to bone in patients with cancer. Several studies, including the Women's Health Initiative (WHI), have found that use of bisphosphonates is associated with reduced risk of developing breast cancer, but less is known about associations with other common malignancies. This study was aimed at examining the effects of bisphosphonates on the risk of endometrial cancer. Methods We evaluated the relationship between use of oral bisphosphonates and endometrial cancer risk in a cohort of 89,918 postmenopausal women participating in the WHI. A detailed health interview was conducted at baseline, and bisphosphonate use was ascertained from an inventory of regularly used medications at baseline and over follow-up. All women had an intact uterus at the time of study entry. Results During a median follow-up of 12.5 years, 1,123 women were diagnosed with incident invasive endometrial cancer. Ever use of bisphosphonates was associated with reduced endometrial cancer risk (adjusted hazard ratio, 0.80; 95% CI, 0.64 to 1.00; P = .05), with no interactions observed with age, body mass index, or indication for use. Conclusion In this large prospective cohort of postmenopausal women, bisphosphonate use was associated with a statistically significant reduction in endometrial cancer risk. PMID:25713431

  5. Estrogen- and progesterone-induced uterine motility of anestrous goats.

    PubMed

    Verma, O P; Singh, L P

    1976-02-01

    Uterine motility was studied in the anestrous goats after a series of estradiol injections was given and after estradiol-plus-progesterone treatment was administered. Estradiol (0.1 mg/kg) given alone by intramuscular route every 6 hours for 4 continuous days produced only a moderate increase in the uterine contractions during treatment, but significantly higher amplitude and frequency of contractions occurred at 2 days after treatment was stopped. The same doses of estradiol administered for a 24-hour period and followed by 4 injections of progesterone (1.0 mg/kg) given intramuscularly once a day produced a moderate response during treatment, but depressed the amplitude and the frequency of contractions after the treatment was stopped. The results indicate that the tissues primed with estrogen produced a stimulatory effect after their estrogen contents diminished. Progesterone, likewise, produced inhibition after a decrease in the progesterone contents of the uterine tissue. PMID:944003

  6. 21 CFR 522.1940 - Progesterone and estradiol benzoate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... in calves to be processed for veal. (2) Steers—(i) Amount—(A) 200 mg progesterone and 20 mg estradiol... calves. Do not use in calves to be processed for veal. (3) Steers fed in confinement for...

  7. 21 CFR 522.1940 - Progesterone and estradiol benzoate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... in calves to be processed for veal. (2) Steers—(i) Amount—(A) 200 mg progesterone and 20 mg estradiol... calves. Do not use in calves to be processed for veal. (3) Steers fed in confinement for...

  8. 21 CFR 522.1940 - Progesterone and estradiol benzoate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... in calves to be processed for veal. (2) Steers—(i) Amount—(A) 200 mg progesterone and 20 mg estradiol... calves. Do not use in calves to be processed for veal. (3) Steers fed in confinement for...

  9. Endoplasmic Reticulum Stress in Endometrial Cancer

    PubMed Central

    Ulianich, Luca; Insabato, Luigi

    2014-01-01

    Endometrial cancer (EC) is a common gynecologic malignancy often diagnosed at early stage. In spite of a huge advance in our understanding of EC biology, therapeutic modalities do not have significantly changed over the past 40 years. A restricted number of genes have been reported to be mutated in EC, mediating cell proliferation and invasiveness. However, besides these alterations, few other groups and ourselves recently identified the activation of the unfolded protein response (UPR) and GRP78 increase following endoplasmic reticulum (ER) stress as mechanisms favoring growth and invasion of EC cells. Here, a concise update on currently available data in the field is presented, analyzing the crosstalk between the UPR and the main signaling pathways regulating EC cell proliferation and survival. It is evident that this is a rapidly expanding and promising issue. However, more data are very likely to yield a better understanding on the mechanisms through which EC cells can survive the low oxygen and glucose tumor microenvironment. In this perspective, the UPR and, particularly, GRP78 might constitute a novel target for the treatment of EC in combination with traditional adjuvant therapy. PMID:25593927

  10. The molecular charge and size of heparins determine their impact on the decidualization of human endometrial stromal cells.

    PubMed

    Fluhr, Herbert; Spratte, Julia; Heidrich, Stephanie; Ehrhardt, Jens; Greinacher, Andreas; Zygmunt, Marek

    2011-06-01

    Heparin modulates the decidualization of human endometrial stromal cells (ESCs), but the molecular mechanisms behind these effects are still unknown. In the present study, we further specified this biological effect of heparin in human ESCs in vitro. ESCs were isolated from hysterectomy specimens, decidualized over 12 days using progesterone and 17β-estradiol and incubated with thrombin, factor Xa (FXa), unfractionated heparin, dextran sulfate, danaparoid or different low-molecular-weight heparins (LMWHs). Production of insulin-like growth factor (IGF)-I, prolactin (PRL) and IGF-binding protein (IGFBP)-1 by ESCs was measured using ELISAs. Like heparin, thrombin and FXa cause an increase in IGF-I in ESCs, suggesting an action of heparin independent from its anticoagulatory effects. This was supported by demonstrating the induction of the same effects on IGF-I, PRL and IGFBP-1 as heparin by dextran sulfate, a polysaccharide of similar size and charge as heparin, but without anticoagulatory properties. LMWHs with the same anti-FXa activity as heparin showed less pronounced effects on ESCs than heparin, whereas the very short pentasaccharide fondaparinux (17 kDa) had barely any effect, further supporting the primary role of molecular size and charge mediating these biological effects of heparin on ESCs. In conclusion, the effects of heparin on the decidualization of human ESCs seem to be independent of its anticoagulatory function, but rather depend on the charge and the size of this polysulfated glycosaminoglycan. Therefore, highly sulfated polysaccharides with a molecular weight >17 kDa might be an interesting pharmacological approach for the therapy of endometrial pathologies, e.g. the treatment of women suffering from recurrent miscarriage or repeated implantation failure. PMID:21220249

  11. Uterine activty and plasma progesterone levels in pregnant goats.

    PubMed

    Jones, D E; Kinfton, A

    1977-01-01

    Uterine activity was recorded during the last few weeks of pregnacy in goats, and related to changes in plasma progesterone concentration. In six of the 14 pregnancies, there was little activity until immediately pre-partum, but the remainder showed a progressive increase in uterine motility, particularly during the last seven days of pregnancy. There was a significant correlation between increased uterine activity and decline of peripheral plasma progesterone levels. PMID:841203

  12. Uterine activty and plasma progesterone levels in pregnant goats.

    PubMed

    Jones, D E; Kinfton, A

    1977-01-01

    Uterine activity was recorded during the last few weeks of pregnacy in goats, and related to changes in plasma progesterone concentration. In six of the 14 pregnancies, there was little activity until immediately pre-partum, but the remainder showed a progressive increase in uterine motility, particularly during the last seven days of pregnancy. There was a significant correlation between increased uterine activity and decline of peripheral plasma progesterone levels.

  13. Use of serum progesterone levels to detect pregnancy in elk

    SciTech Connect

    Weber, B.J.; Wolfe, M.L.; White, G.C.

    1982-01-01

    The objective of this investigation was to determine the realibility of serum progesterone assays as a means for detecting pregnancy in elk (Cervus elaphus). The elk were trapped during February through April in the Jemez Mountains of New Mexico. Blood samples were set to Bio-Science Laboratories for projesterone analysis by radioimmunoassay. Levels of progesteron were highly variable within the pregnant and nonpregnant elk. (RJC)

  14. Progesterone Improves Neurobehavioral Outcome in Models of Intracerebral Hemorrhage.

    PubMed

    Lei, Beilei; Wang, Haichen; Jeong, Seongtae; Hsieh, Justin T; Majeed, Mohammed; Dawson, Hana; Sheng, Huaxin; Warner, David S; James, Michael L

    2016-01-01

    In models of acute brain injury, progesterone improves recovery through several mechanisms including modulation of neuroinflammation. Secondary injury from neuroinflammation is a potential therapeutic target after intracerebral hemorrhage (ICH). For potential translation of progesterone as a clinical acute ICH therapeutic, the present study sought to define efficacy of exogenous progesterone administration in ICH-relevant experimental paradigms. Young and aged C57BL/6 male, female, and ovariectomized (OVX) mice underwent left intrastriatal collagenase (0.05-0.075 U) or autologous whole blood (35 μl) injection. Progesterone at varying doses (4-16 mg/kg) was administered at 2, 5, 24, 48, and 72 h after injury. Rotarod and Morris water maze latencies were measured on days 1-7 and days 28-31 after injury, respectively. Hematoma volume, brain water content (cerebral edema), complementary immunohistochemistry, multiplex cytokine arrays, and inflammatory proteins were assessed at prespecified time points after injury. Progesterone (4 mg/kg) administration improved rotarod and water maze latencies (p < 0.01), and decreased cerebral edema (p < 0.05), microglial proliferation, and neuronal loss (p < 0.01) in young and aged male, young OVX, and aged female mice. Brain concentration of proinflammatory cytokines and Toll-like receptor-associated proteins were also decreased after progesterone (4 mg/kg) treatment (p < 0.01). Progesterone-treated young female mice showed no detectable effects. Exogenous progesterone improved short- and long-term neurobehavioral recovery and modulated neuroinflammation in male and OVX mice after ICH. Future studies should validate these findings, and address timing and length of administration before translation to clinical trial.

  15. Estetrol and utero-placental flow after progesterone load.

    PubMed

    Benassi, L; Alfieri, L; Debiasi, D; Trentadue, R; Salvadori, B

    1982-01-01

    On the basis of recent demonstration in animals of the effect of some hormones on uteroplacental flow, the Authors examined the response of plasmatic Estetrol (15 alpha-hydroxy-estriol) after the administration of progesterone to pregnant women with low Estrogen values. The increase of this compound was related to an improvement of placental function, probably dependent on an increase of available O2, and therefore on uterine blood flow. This can justify a progesterone treatment in such pregnancies. PMID:7168897

  16. Paclitaxel and Carboplatin With or Without Metformin Hydrochloride in Treating Patients With Stage III, IV, or Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2016-02-09

    Endometrial Adenocarcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Undifferentiated Carcinoma; Recurrent Uterine Corpus Carcinoma; Stage IIIA Uterine Corpus Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIC Uterine Corpus Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer

  17. Age at Last Birth in Relation to Risk of Endometrial Cancer: Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium

    PubMed Central

    Setiawan, Veronica Wendy; Pike, Malcolm C.; Karageorgi, Stalo; Deming, Sandra L.; Anderson, Kristin; Bernstein, Leslie; Brinton, Louise A.; Cai, Hui; Cerhan, James R.; Cozen, Wendy; Chen, Chu; Doherty, Jennifer; Freudenheim, Jo L.; Goodman, Marc T.; Hankinson, Susan E.; Lacey, James V.; Liang, Xiaolin; Lissowska, Jolanta; Lu, Lingeng; Lurie, Galina; Mack, Thomas; Matsuno, Rayna K.; McCann, Susan; Moysich, Kirsten B.; Olson, Sara H.; Rastogi, Radhai; Rebbeck, Timothy R.; Risch, Harvey; Robien, Kim; Schairer, Catherine; Shu, Xiao-Ou; Spurdle, Amanda B.; Strom, Brian L.; Thompson, Pamela J.; Ursin, Giske; Webb, Penelope M.; Weiss, Noel S.; Wentzensen, Nicolas; Xiang, Yong-Bing; Yang, Hannah P.; Yu, Herbert; Horn-Ross, Pamela L.; De Vivo, Immaculata

    2012-01-01

    Childbearing at an older age has been associated with a lower risk of endometrial cancer, but whether the association is independent of the number of births or other factors remains unclear. Individual-level data from 4 cohort and 13 case-control studies in the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 8,671 cases of endometrial cancer and 16,562 controls were included in the analysis. After adjustment for known risk factors, endometrial cancer risk declined with increasing age at last birth (Ptrend < 0.0001). The pooled odds ratio per 5-year increase in age at last birth was 0.87 (95% confidence interval: 0.85, 0.90). Women who last gave birth at 40 years of age or older had a 44% decreased risk compared with women who had their last birth under the age of 25 years (95% confidence interval: 47, 66). The protective association was similar across the different age-at-diagnosis groups and for the 2 major tumor histologic subtypes (type I and type II). No effect modification was observed by body mass index, parity, or exogenous hormone use. In this large pooled analysis, late age at last birth was independently associated with a reduced risk of endometrial cancer, and the reduced risk persisted for many years. PMID:22831825

  18. Progesterone Upregulates Gene Expression in Normal Human Thyroid Follicular Cells.

    PubMed

    Bertoni, Ana Paula Santin; Brum, Ilma Simoni; Hillebrand, Ana Caroline; Furlanetto, Tania Weber

    2015-01-01

    Thyroid cancer and thyroid nodules are more prevalent in women than men, so female sex hormones may have an etiological role in these conditions. There are no data about direct effects of progesterone on thyroid cells, so the aim of the present study was to evaluate progesterone effects in the sodium-iodide symporter NIS, thyroglobulin TG, thyroperoxidase TPO, and KI-67 genes expression, in normal thyroid follicular cells, derived from human tissue. NIS, TG, TPO, and KI-67 mRNA expression increased significantly after TSH 20 μUI/mL, respectively: 2.08 times, P < 0.0001; 2.39 times, P = 0.01; 1.58 times, P = 0.0003; and 1.87 times, P < 0.0001. In thyroid cells treated with 20 μUI/mL TSH plus 10 nM progesterone, RNA expression of NIS, TG, and KI-67 genes increased, respectively: 1.78 times, P < 0.0001; 1.75 times, P = 0.037; and 1.95 times, P < 0.0001, and TPO mRNA expression also increased, though not significantly (1.77 times, P = 0.069). These effects were abolished by mifepristone, an antagonist of progesterone receptor, suggesting that genes involved in thyroid cell function and proliferation are upregulated by progesterone. This work provides evidence that progesterone has a direct effect on thyroid cells, upregulating genes involved in thyroid function and growth. PMID:26089899

  19. Milk fat progesterone concentrations in goats and early pregnancy diagnosis.

    PubMed

    de Montigny, G; Millerioux, P; Jeanguyot, N; Humblot, P; Thibier, M

    1982-04-01

    Blood and milk samples from foremilk during afternoon milking, were simultaneously collected from 285 dairy goats. In experiment 1, fiva cyclic goats were sampled daily for 21 days. In experiment 2, 280 females from 9 flocks were submitted to sampling 21 days after insemination. In addition, some milk samples were divided in two parts, after which one was frozen and the other kept at +4 degrees C until assay. Progesterone concentrations were measured in blood, whole milk and milk fat by radioimmunoassay. No difference in whole milk or fat progesterone levels was found between frozen and refrigerated milk samples. Milk butterfat progesterone concentrations paralleled those in plasma or whole milk throughout the estrous cycle and ranged from about 20 ng/ml at estrus to about 400 ng/ml in mid-luteal phase. The ratio of mid-luteal phase progesterone levels to those seen in the estrous period was over 20 in fat and in blood. This ratio was very much lower in whole milk. Consequently the determination of pregnant and non-pregnant goats from the samples collected 21 days after service was very much easier and accuracy was better when the progesterone content was assayed from milk fat than from whole milk. It was concluded that early pregnancy diagnosis in goats can be done routinely by determination of progesterone levels in milk fat. PMID:16725705

  20. Progesterone Upregulates Gene Expression in Normal Human Thyroid Follicular Cells

    PubMed Central

    Bertoni, Ana Paula Santin; Brum, Ilma Simoni; Hillebrand, Ana Caroline; Furlanetto, Tania Weber

    2015-01-01

    Thyroid cancer and thyroid nodules are more prevalent in women than men, so female sex hormones may have an etiological role in these conditions. There are no data about direct effects of progesterone on thyroid cells, so the aim of the present study was to evaluate progesterone effects in the sodium-iodide symporter NIS, thyroglobulin TG, thyroperoxidase TPO, and KI-67 genes expression, in normal thyroid follicular cells, derived from human tissue. NIS, TG, TPO, and KI-67 mRNA expression increased significantly after TSH 20 μUI/mL, respectively: 2.08 times, P < 0.0001; 2.39 times, P = 0.01; 1.58 times, P = 0.0003; and 1.87 times, P < 0.0001. In thyroid cells treated with 20 μUI/mL TSH plus 10 nM progesterone, RNA expression of NIS, TG, and KI-67 genes increased, respectively: 1.78 times, P < 0.0001; 1.75 times, P = 0.037; and 1.95 times, P < 0.0001, and TPO mRNA expression also increased, though not significantly (1.77 times, P = 0.069). These effects were abolished by mifepristone, an antagonist of progesterone receptor, suggesting that genes involved in thyroid cell function and proliferation are upregulated by progesterone. This work provides evidence that progesterone has a direct effect on thyroid cells, upregulating genes involved in thyroid function and growth. PMID:26089899

  1. Pathophysiology and management of endometrial hyperplasia and carcinoma.

    PubMed Central

    Fu, Y. S.; Gambone, J. C.; Berek, J. S.

    1990-01-01

    Endometrial cancer is currently the commonest pelvic malignancy affecting American women, most of whom share the same pathophysiologic basis, that is, unopposed estrogenic stimulation. The initial result of hyperestrogenism is the development of endometrial hyperplasia, which is reversible in most cases by appropriate hormonal therapy. Persistent stimulation eventually leads to atypical hyperplasia with nuclear atypia and invasive carcinoma. Because there is no cost-effective screening method for the detection of endometrial hyperplasia and carcinoma, it is essential to survey the high-risk population with appropriate diagnostic techniques. After diagnosis, therapy should be individualized based on pathologic findings (cell type and histologic grade) and extent of disease (International Federation of Gynaecologists and Obstetricians stage, depth of myometrial invasion, and pelvic and para-aortic lymph node status). Recent studies suggest that sex hormone receptors and nuclear DNA ploidy patterns provide useful prognostic information independent of histologic grade. Images PMID:2202159

  2. ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer

    PubMed Central

    Colombo, Nicoletta; Creutzberg, Carien; Amant, Frederic; Bosse, Tjalling; González-Martín, Antonio; Ledermann, Jonathan; Marth, Christian; Nout, Remi; Querleu, Denis; Mirza, Mansoor Raza; Sessa, Cristiana

    2016-01-01

    Abstract The first joint European Society for Medical Oncology (ESMO), European SocieTy for Radiotherapy & Oncology (ESTRO) and European Society of Gynaecological Oncology (ESGO) consensus conference on endometrial cancer was held on 11–13 December 2014 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of endometrial cancer. Before the conference, the expert panel prepared three clinically-relevant questions about endometrial cancer relating to the following four areas: prevention and screening, surgery, adjuvant treatment and advanced and recurrent disease. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. Results of this consensus conference, together with a summary of evidence supporting each recommendation, are detailed in this article. All participants have approved this final article. PMID:26645990

  3. The Equine Endometrial Cup Reaction: A Fetomaternal Signal of Significance

    PubMed Central

    Antczak, D. F.; de Mestre, Amanda M.; Wilsher, Sandra; Allen, W. R.

    2015-01-01

    A remarkable feature of equine pregnancy is the development of the invasive trophoblast of the chorionic girdle and its formation of the gonadotrophin-secreting endometrial cup cells in early gestation. The details of this process have been revealed only slowly over the past century, since the first description of the endometrial cups in 1912. This centennial presents an opportunity to review the characteristics of the cells and molecules involved in this early, critical phase of placentation in the mare. The invasiveness of the chorionic girdle trophoblast appears to represent an atavistic attribute more commonly associated with the hemochorial placentae of primates and rodents but not with the more recently derived epitheliochorial placentae of the odd-toed ungulates. The nature of and raison d’etre for the strong fetal signals transmitted to the mare by the endometrial cup reaction, and her responses to these messages, are the subject of the present review. PMID:25387026

  4. Endometrial abnormality in women with polycystic ovary syndrome.

    PubMed

    Shang, Kewei; Jia, Xiao; Qiao, Jie; Kang, Jihong; Guan, Youfei

    2012-07-01

    Polycystic ovary syndrome (PCOS) is the most common endocrinopathy associated with infertility and metabolic disorder in women of reproductive age. Although the clinical and biochemical features are heterogeneous with individuals, the most widely accepted clinical characteristics of PCOS are oligo- or anovulation combined with hyperandrogenism. With the higher rate of implantation failure after induction of ovulation or higher risk of spontaneous miscarriage after pregnancy, the reduced fertility is apparently attributed not only to anovulation but also to endometrial dysfunction in patients with PCOS. Here we review the features of the endometrial abnormalities in women with PCOS. The ability to improve the endometrial functions is of potential therapeutic targets to increase reproductive outcome of women with PCOS.

  5. New endometrial ablation techniques for treatment of menorrhagia.

    PubMed

    Bradley, Linda D

    2004-01-01

    Endometrial ablation is an excellent alternative to hysterectomy in women with menorrhagia and small intramural fibroids. Preoperative evaluation, which includes office hysteroscopy or saline infusion sonography, is critical to patient management and choice of procedure. A vast array of endometrial ablation technology is available currently that includes balloon therapy, cryosurgery hot circulating saline, bipolar impedance technology, and microwave: (1) ThermaChoice UTB System (Gynecare, Inc., Somerville, NJ, USA), (2) Uterine Balloon Therapy (UBT) System, HerOption Uterine Cryoblation Therapy System (American Medical Systems, Inc., Minnetonka, MN, USA), (3) Hydro ThermAblator HTA System (BEI Medical/Boston Scientific, Natick, MA), (4) NovaSure System (Novacept, Palo Alto, CA, USA), and (5) Microsulis Microwave Endometrial Ablation (MEA) System (Microsulis Medical Ltd., Pompano Beach, FL, USA). Each method is described herein, and Summary of Safety and Effectiveness Data (SSED) data for each product are reviewed.

  6. Endometrial polyp in an African wild dog (Lycaon pictus).

    PubMed

    Cho, H S; Park, N Y

    2006-11-01

    An 8-year-old female African wild dog (Lycaon pictus) from a zoo in Gyeonggi province, Republic of Korea presented with a 3.0 x 2.0 x 2.5 cm in size, smooth-surfaced, solitary pedunculated mass protruding into the uterine lumen. Microscopically, the mass was covered with epithelium, contained endometrial gland tissue, and was dilated in the vascularised stroma. Within the mass, there was extensive diffuse haemorrhage with several blood vessels apparently plugged with fibrin. At the base of the mass, the spaces lined with epithelium near the attachment of the stalk were interpreted to be glandular structures. There were segments of cuboidal epithelium found on the surface of the mass, which was similar to the lining the uterus. A diagnosis of an endometrial polyp was made based on the gross and histology findings. This is the first case report of a spontaneous endometrial polyp in an African wild dog.

  7. A Comparison of the Effects of Transdermal Estradiol and Estradiol Valerate on Endometrial Receptivity in Frozen-thawed Embryo Transfer Cycles: A Randomized Clinical Trial

    PubMed Central

    Davar, Robab; Janati, Sima; Mohseni, Fereshteh; Khabazkhoob, Mehdi; Asgari, Soheila

    2016-01-01

    Background: The purpose of this study was to determine the optimal endometrial preparation protocol by comparing the clinical outcome of two methods of endometrial preparation in frozen-thawed embryo transfer (FET) cycles, including that is, oral estradiol and 17ß-estradiol transdermal patch. Methods: In this randomized controlled trial, women underwent either conventional IVF or intracytoplasmic sperm injection (ICSI) who had at least two top-quality embryos appropriate for cryopreservation and frozen embryos from previous cycles. In the study group (n=45), 17-B estradiol transdermal patches 100 μg were applied from the second day of the cycle and continued every other day. Then, each patch was removed after four days. In the control group (n=45), oral estradiol valerate 6 mg was started at the same time and continued daily. Results: There was a significant difference in estradiol level on the day of progesterone administration and the day of embryo transfer between the two groups (p= 0.001 in both), but no significant difference was observed between them in biochemical and clinical pregnancy rates (32.6% vs. 33.3%, p=1.000 and 30.2% vs. 33.3%, p=0.810, respectively). Conclusion: It is suggested that estradiol transdermal patches be used instead of oral estradiol in FET cycles. Due to the reduced costs, drug dose, and emotional stress as well as the simplicity of the protocol for patients. PMID:27141464

  8. Aptamer-based label-free impedimetric biosensor for detection of progesterone.

    PubMed

    Contreras Jiménez, Gastón; Eissa, Shimaa; Ng, Andy; Alhadrami, Hani; Zourob, Mohammed; Siaj, Mohamed

    2015-01-20

    Rising progesterone (P4) levels in humans due to its overconsumption through hormonal therapy, food products, or drinking water can lead to many negative health effects. Thus, the simple and accurate assessment of P4 in both environmental and clinical samples is highly important to protect public health. In this work, we present the selection, identification, and characterization of ssDNA aptamers with high binding affinity to P4. The aptamers were selected in vitro from a single-stranded DNA library of 1.8 × 10(15) oligonucleotides showing dissociation constants (KD) in the low nanomolar range. The dissociation constant of the best aptamer, designated as P4G13, was estimated to be 17 nM by electrochemical impedance spectroscopy (EIS) as well as fluorometric assay. Moreover, the aptamer P4G13 did not show cross-reactivity to analogues similar to progesterone such as 17β-estradiol (E2) and norethisterone (NET). An impedimetric aptasensor for progesterone was then fabricated based on the conformational change of P4G13 aptamer, immobilized on the gold electrode by self-assembly, upon binding to P4, which results in an increase in electron transfer resistance. Aptamer-complementary DNA (cDNA) oligonucleotides were tested to maximize the signal gain of the aptasensor after binding with progesterone. Significant signal enhancement was observed when the aptamer hybridized with a short complementary sequence at specific site was used instead of pure aptamer. This signal gain is likely due to the more significant conformational change of the aptamer-cDNA than the pure aptamer upon binding with P4, as confirmed by circular dichroism (CD) spectroscopy. The developed aptasensor exhibited a linear range for concentrations of P4 from 10 to 60 ng/mL with a detection limit of 0.90 ng/mL. Moreover, the aptasensor was applied in spiked tap water samples and showed good recovery percentages. The new selected progesterone aptamers can be exploited in further biosensing applications

  9. Studies Using an in Vitro Model Show Evidence of Involvement of Epithelial-Mesenchymal Transition of Human Endometrial Epithelial Cells in Human Embryo Implantation*

    PubMed Central

    Uchida, Hiroshi; Maruyama, Tetsuo; Nishikawa-Uchida, Sayaka; Oda, Hideyuki; Miyazaki, Kaoru; Yamasaki, Akiko; Yoshimura, Yasunori

    2012-01-01

    Human embryo implantation is a critical multistep process consisting of embryo apposition/adhesion, followed by penetration and invasion. Through embryo penetration, the endometrial epithelial cell barrier is disrupted and remodeled by an unknown mechanism. We have previously developed an in vitro model for human embryo implantation employing the human choriocarcinoma cell line JAR and the human endometrial adenocarcinoma cell line Ishikawa. Using this model we have shown that stimulation with ovarian steroid hormones (17β-estradiol and progesterone, E2P4) and suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, enhances the attachment and adhesion of JAR spheroids to Ishikawa. In the present study we showed that the attachment and adhesion of JAR spheroids and treatment with E2P4 or SAHA individually induce the epithelial-mesenchymal transition (EMT) in Ishikawa cells. This was evident by up-regulation of N-cadherin and vimentin, a mesenchymal cell marker, and concomitant down-regulation of E-cadherin in Ishikawa cells. Stimulation with E2P4 or SAHA accelerated Ishikawa cell motility, increased JAR spheroid outgrowth, and enhanced the unique redistribution of N-cadherin, which was most prominent in proximity to the adhered spheroids. Moreover, an N-cadherin functional blocking antibody attenuated all events but not JAR spheroid adhesion. These results collectively provide evidence suggesting that E2P4- and implanting embryo-induced EMT of endometrial epithelial cells may play a pivotal role in the subsequent processes of human embryo implantation with functional control of N-cadherin. PMID:22174415

  10. Predicting Lymph Node Metastasis in Endometrial Cancer Using Serum CA125 Combined with Immunohistochemical Markers PR and Ki67, and a Comparison with Other Prediction Models

    PubMed Central

    Xue, Xiaohong; Wang, Huaying; Shan, Weiwei; Ning, Chengcheng; Zhou, Qiongjie; Chen, Xiaojun; Luo, Xuezhen

    2016-01-01

    We aimed to evaluate the value of immunohistochemical markers and serum CA125 in predicting the risk of lymph node metastasis (LNM) in women with endometrial cancer and to identify a low-risk group of LNM. The medical records of 370 patients with endometrial endometrioid adenocarcinoma who underwent surgical staging in the Obstetrics & Gynecology Hospital of Fudan University were collected and retrospectively reviewed. Immunohistochemical markers were screened. A model using serum cancer antigen 125 (CA125) level, the immunohistochemical markers progesterone receptor (PR) and Ki67 was created for prediction of LNM. A predicted probability of 4% among these patients was defined as low risk. The developed model was externally validated in 200 patients from Shanghai Cancer Center. The efficiency of the model was compared with three other reported prediction models. Patients with serum CA125 < 30.0 IU/mL, either or both of positive PR staining > 50% and Ki67 < 40% in cancer lesion were defined as low risk for LNM. The model showed good discrimination with an area under the receiver operating characteristic curve of 0.82. The model classified 61.9% (229/370) of patients as being at low risk for LNM. Among these 229 patients, 6 patients (2.6%) had LNM and the negative predictive value was 97.4% (223/229). The sensitivity and specificity of the model were 84.6% and 67.4% respectively. In the validation cohort, the model classified 59.5% (119/200) of patients as low-risk, 3 out of these 119 patients (2.5%) has LNM. Our model showed a predictive power similar to those of two previously reported prediction models. The prediction model using serum CA125 and the immunohistochemical markers PR and Ki67 is useful to predict patients with a low risk of LNM and has the potential to provide valuable guidance to clinicians in the treatment of patients with endometrioid endometrial cancer. PMID:27163153

  11. Cyclooxygenase-2 and p53 expressions in endometrial cancer.

    PubMed

    Jeon, Yong-Tark; Kang, Sokbom; Kang, Dae-Hee; Yoo, Keun-Young; Park, In-Ae; Bang, Yung-Jue; Kim, Jae Weon; Park, Noh-Hyun; Kang, Soon-Beom; Lee, Hyo-Pyo; Song, Yong-Sang

    2004-09-01

    Cyclooxygenase-2 (COX-2) has been known to be related with various types of carcinoma, but we have insufficient knowledge about the association between COX-2 and endometrial cancer. Many have reported a close relationship between p53 expression and a poor prognosis in endometrial cancer, but it is unclear whether p53 is an independent prognostic factor. To clarify these uncertainties, we examined the expressions of COX-2 and p53 in endometrial cancer tissues. The study was carried on 152 endometrial cancer patients who had operation at Seoul National University Hospital. Paraffin-embedded tissue blocks were sectioned and immunostained using monoclonal anti-COX-2 and anti-p53 antibodies. Twenty-seven (17.8%) specimens stained as COX-2 positive. COX-2 positivity was more frequently observed in postmenopausal patients than in premenopausal patients (8.8% versus 25.0%; P = 0.009). However, COX-2 positivity did not show a statistically significant association with any other clinicopathologic characteristic (parity, body mass index, histotype, International Federation of Gynecology and Obstetrics stage, grade, lymph node metastasis, deep myometrial invasion, or p53 overexpression). Thirty-one (20.4%) specimens showed p53 overexpression and this was significantly correlated with an advanced stage (P = 0.001), poor differentiation (P < 0.001), lymph node metastasis (P = 0.012), and deep myometrial invasion (P < 0.001). Multivariate Cox regression analysis showed that advanced stage was an independent prognostic factor of survival, but p53 overexpression was not. COX-2 may be associated with endometrial cancer carcinogenesis during the postmenopausal period but not with tumor aggressiveness and p53 overexpression. The p53 overexpression was found to be strongly associated with endometrial cancer aggressiveness.

  12. Progesterone, as well as 17β-estradiol, is important for regulating AHR battery homoeostasis in the rat uterus.

    PubMed

    Rataj, Felicitas; Möller, Frank Josef; Jähne, Maria; Hönscheid, Pia; Zierau, Oliver; Vollmer, Günter; Kretzschmar, Georg

    2015-03-01

    Several studies indicate that the aryl hydrocarbon receptor (AHR), which plays an important role in mediating the toxicity of many industrial chemicals, plays an important role in the physiology of female reproductive tract organs. This makes it likely that the AHR and additional components of the AHR signalling pathway are under the control of female sex steroids. In a previous study, we could already demonstrate the regulation of many members of the AHR battery by 17β-estradiol (E2) in the uterus of rats. In this study, we addressed the potential role of progesterone (P4) in this context. In a comparative approach using ovariectomized rats which were treated for 3 days with either vehicle control, E2, progesterone (P4) or the combination of both hormones in addition to sham-operated animals, we could demonstrate that in addition to E2, P4 is also an important factor in regulating AHR signalling in the rat uterus. P4 has effects similar to E2 on uterine Ahr, Arnt and Arnt2 mRNA levels, resulting in a downregulation of these genes, while the E2-mediated downregulation of key AHR response genes Cyp1a1, Gsta2 and Ugt1 is completely antagonized by P4. As with E2, P4 leads to an increase in uterine AHR levels, especially in the endometrial epithelium despite the decrease in corresponding mRNA levels. This indicates a complex gene-specific regulatory network involving E2, P4 and possibly AHR itself to maintain all components of the AHR signalling cascade at the required levels during all stages of the oestrous cycle and pregnancy.

  13. Paraneoplastic cerebellar degeneration as a marker of endometrial cancer recurrence.

    PubMed

    Lie, Geoffrey; Morley, Thomas; Chowdhury, Muhammad

    2016-01-01

    An 84-year-old woman developed a cerebellar syndrome having undergone a total abdominal hysterectomy and bilateral salpingo-oophorectomy for endometrial cancer 1 year previously. She was found to be anti-Yo antibody positive and was diagnosed with paraneoplastic cerebellar degeneration (PCD). A subsequent positron emission tomography scan and lymph node biopsy identified recurrence of her endometrial cancer. This case illustrates how PCD can be an indicator of cancer recurrence, underlines the significance of PCD as a prompt to search for underlying malignancy, and highlights the difficulties PCD poses to the clinician in terms of diagnosis and management.

  14. [Endometrial ossification: a report of four cases and literature review].

    PubMed

    Nevarez Bernal, Roberto; Vilchis Nava, Pablo; Kably Ambe, Alberto

    2007-03-01

    Endometrial ossification is a rare endometrial pathology. Its predisposing factors include history of uterine curettage to metabolic abnormalities. It usually presents in patients with secondary infertility and history of first trimester pregnancy loss, accompanied by severe dysmenorrhea and dyspareunia. The diagnosis is suspected by OB-GYN history and USG findings, therapeutic strategies range from D&C to hysterectomy, we propose diagnosis and management by hysteroscopy in order to preserve future fertility and minimize uterine damage. A review of four cases during 1985-2004 from a large assisted reproduction center in Mexico City is presented.

  15. Progesterone improves porcine in vitro fertilisation system.

    PubMed

    Malo, Clara; Gil, Lydia; Cano, Rafael; Martinez, Felisa; Gonzalez, Noelia

    2014-03-01

    In an effort to improve the quality of in vitro produced porcine embryos, the effect of progestagens - progesterone analogues - on the in vitro developmental competence of porcine oocytes was studied. A total of 1421 in vitro matured oocytes, from 4 replicates, were inseminated with frozen-thawed spermatozoa. Progestagens were added to late maturation and embryo cultures (10 IU/ml). Fertilisation success (pre-maturation, penetration, monospermy and efficiency) and nuclear maturation were evaluated. There were no differences among prematuration rates between groups (P = 0.221). Penetration rates were higher (P < 0.001) in the presence of progestagens (75.0%) as compared to the control (51.7%). However, no differences were observed in monospermy percentages (P = 0.246). The results indicated that supplementation with progestagens increased the efficiency of the in vitro fertilisation system (P < 0.001). An additional beneficial effect was observed in nuclear maturation with progestagens (P = 0.035). In summary, progestagen supplementation is an important factor to improve the in vitro fertilisation procedure.

  16. Evaluation of Metachronous Breast and Endometrial Cancers

    PubMed Central

    Grzankowski, Kassondra S.; Szender, J. Brian; Spring-Robinson, Chandra L.; Lele, Shashikant B.; Odunsi, Kunle O.; Frederick, Peter J.

    2016-01-01

    Background The time interval between diagnoses of breast cancer (BC) and endometrial cancer (EC) is not well established in women with metachronous primary tumors. We sought to examine this interval and identify associations with treatment-related and clinicopathologic factors. Methods We identified 141 patients who developed both cancers during 1966 to 2013. Patients were divided into 2 groups: group 1, BC first, and group 2, EC first. Subanalysis performed of group 1 (59 patients) stratified around adjuvant tamoxifen use: pre-1990 BC diagnosis and post. Results Fifty-nine and 82 patients were in groups 1 and 2, respectively. The mean time interval was comparable (76 vs 74 months, P = 0.861). Subanalysis divided group 1 into pre- (n = 27) and post- (n = 32) 1990 and resulted in different mean time intervals between diagnosis of metachronous cancers (106 vs 50 months, respectively [P = 0.042]). Median progression-free survival (PFS) and overall survival (OS) for EC were longer in the pre group (PFS, 51 vs 26 months [P = 0.169]; OS, 59 vs 27 months [P = 0.190]). Median PFS and OS for BC were also longer in this group (PFS, 147 vs 109 months [P = 0.005]; OS, 166 vs 114 months [P < 0.001]). Conclusions Our data indicate the mean time interval between the diagnosis of EC and BC was approximately 6 years. Disease-specific EC survival was worse for patients with a previous diagnosis of BC. Stratification around implementation of tamoxifen use shows comparable grade and stage but different time interval and survival, suggesting resulting effects from adjuvant therapy for BC. These results are useful in counseling women at risk. PMID:27648713

  17. Metformin Use and Endometrial Cancer Survival

    PubMed Central

    Nevadunsky, Nicole S.; Van Arsdale, Anne; Strickler, Howard D.; Moadel, Alyson; Kaur, Gurpreet; Frimer, Marina; Conroy, Erin; Goldberg, Gary L.; Einstein, Mark H.

    2013-01-01

    Objective Impaired glucose tolerance and diabetes are risk factors for the development of uterine cancer. Although greater progression free survival among diabetic patients with ovarian and breast cancer using metformin have been reported, no studies have assessed the association of metformin use with survival in women with endometrial cancer (EC). Methods We conducted a single-institution retrospective cohort study of all patients treated for uterine cancer from January 1999 through December 2009. Demographic, medical, social, and survival data were abstracted from medical records and the national death registry. Overall survival (OS) was estimated using Kaplan-Meier methods. Cox models were utilized for multivariate analysis. All statistical tests were two-sided. Results Of 985 patients, 114 (12%) had diabetes and were treated with metformin, 136 (14%) were diabetic but did not use metformin, and 735 (74%) had not been diagnosed with diabetes. Greater OS was observed in diabetics with non-endometrioid EC who used metformin than in diabetic cases not using metformin and non-endometrioid EC cases without diabetes (log rank test (p=0.02)). This association remained significant (hazard ratio = 0.54, 95% CI: 0.30–0.97, p<0.04) after adjusting for age, clinical stage, grade, chemotherapy treatment, radiation treatment and presence of hyperlipidemia in multivariate analysis. No association between metformin use and OS in diabetics with endometrioid histology was observed. Conclusion Diabetic EC patients with non-endometrioid tumors who used metformin had lower risk of death than women with EC who did not use metformin. These data suggest that metformin might be useful as adjuvant therapy for non-endometrioid EC. PMID:24189334

  18. Embryo-endometrial interactions during early development after embryonic diapause in the marsupial tammar wallaby.

    PubMed

    Renfree, Marilyn B; Shaw, Geoff

    2014-01-01

    The marsupial tammar wallaby has the longest period of embryonic diapause of any mammal. Reproduction in the tammar is seasonal, regulated by photoperiod and also lactation. Reactivation is triggered by falling daylength after the austral summer solstice in December. Young are born late January and commence a 9-10-month lactation. Females mate immediately after birth. The resulting conceptus develops over 6- 7 days to form a unilaminar blastocyst of 80-100 cells and enters lactationally, and later seasonally, controlled diapause. The proximate endocrine signal for reactivation is an increase in progesterone which alters uterine secretions. Since the diapausing blastocyst is surrounded by the zona and 2 other acellular coats, the mucoid layer and shell coat, the uterine signals that maintain or terminate diapause must involve soluble factors in the secretions rather than any direct cellular interaction between uterus and embryo. Our studies suggest involvement of a number of cytokines in the regulation of diapause in tammars. The endometrium secretes platelet activating factor (PAF) and leukaemia inhibitory factor, which increase after reactivation. Receptors for PAF are low on the blastocyst during diapause but are upregulated at reactivation. Conversely, there is endometrial expression of the muscle segment homeobox gene MSX2 throughout diapause, but it is rapidly downregulated at reactivation. These patterns are consistent with those observed in diapausing mice and mink after reactivation, despite the very different patterns of endocrine control of diapause in these 3 divergent species. These common patterns suggest a similar underlying mechanism for diapause, perhaps common to all mammals, but which is activated in only a few. PMID:25023683

  19. Effects of estrogen and phytoestrogens on endometrial leakage in ovariectomized rats and the related mechanisms.

    PubMed

    Li, Hong-Fang; Duan, Ying; Wang, Long-De; Tian, Zhi-Feng; Qiu, Xiao-Qing; Zhang, Ying-Fu; Zhang, Hua; Yang, Li-Na

    2013-02-25

    Phytoestrogens, a group of plant-derived non-steroidal compounds that can behave as estrogens by binding to estrogen receptors, have drawn great attention for their potentially beneficial effects on human health. However, there are few studies investigating the potential side effects of phytoestrogens on the reproductive system. The present study was to elucidate the effects of 17β-estradiol (E2), progesterone (P4), and phytoestrogens genistein (Gen), resveratrol (Res), and phloretin (Phl) on eosinophilic infiltration of the ovariectomized rat uterus and endometrial vascular permeability, and to analyze the underlying mechanisms. The ovariectomized rats received daily subcutaneous injections of E2, E2+P4, P4, Gen, Res, Phl, or an equivalent volume of vehicle for 21 days, and sham-operated animals (Sham rats) were used as the controls. Hematoxylin-eosin staining revealed a marked increase in uterine eosinophilic infiltrations in ovariectomized rats treated with E2, E2+P4 or P4, which was associated with increased expression of vascular endothelial growth factor (VEGF), nuclear factor-κB (NF-κB), and tumor necrosis factor-α (TNF-α) proteins as determined by immunohistochemical and Western blot analysis. However, all three phytoestrogens had no markedly effect on the uterine eosinophilic infiltration and the expressions of VEGF, NF-κB, and TNF-α in the uterus of ovariectomized rats. Our data demonstrate that E2 alone or in combination with P4 increases uterine eosinophilic infiltration which is related with vascular hyperpermeability caused by VEGF, NF-κB and TNF-α, whereas phytoestrogens Gen, Res, and Phl, have no such an effect.

  20. Endometrial pathology in postmenopausal tamoxifen treatment: comparison between gynaecologically symptomatic and asymptomatic breast cancer patients.

    PubMed Central

    Cohen, I; Perel, E; Flex, D; Tepper, R; Altaras, M M; Cordoba, M; Beyth, Y

    1999-01-01

    AIMS: To evaluate whether endometrial pathology is more likely to be diagnosed in gynaecologically symptomatic rather than in gynaecologically asymptomatic postmenopausal breast cancer patients with tamoxifen treatment; and to evaluate the possible influence of various clinical factors on the incidence of endometrial pathology. METHODS: Endometrial histological findings, transvaginal ultrasonographic endometrial thickness, demographic characteristics, health habits, and risk factors for endometrial cancer were compared between 14 gynaecologically symptomatic (group I) and 224 gynaecologically asymptomatic (group II) postmenopausal breast cancer patients with tamoxifen treatment. RESULTS: Overall, 28.6% of the study population had endometrial pathology. The incidence of overall positive endometrial histological findings was significantly higher in group I than in group II (92.9% v 24.6%, p < 0.0001). Atrophic endometrium was more common in group II than in group I (75.3% v 7.1%, p < 0.0001). Most other endometrial pathology was significantly more common in group I than in group II (endometrial hyperplasia, 35.7% v 5.6%, p < 0.0001; endometrial polyps, 35.7% v 13.4%, p < 0.0111; endometrial carcinoma, 21.5% v 0.9%, p < 0.0001). Endometrial pathology appeared considerably later in the gynaecologically asymptomatic patients than in gynaecologically symptomatic patients (p = 0.0002). Vaginal bleeding or spotting occurred exclusively in group I. The incidence of endometrial pathology in the entire study population was consistent with that reported elsewhere, and higher than that reported for healthy postmenopausal women. CONCLUSIONS: Endometrial pathology is more likely to be diagnosed in gynaecologically symptomatic postmenopausal breast cancer patients with tamoxifen treatment, and after a shorter duration of time, than in gynaecologically asymptomatic patients. PMID:10474520

  1. Determination of estriol, estradiol, estrone, and progesterone in cosmetic products.

    PubMed

    Hubinger, Jean C

    2015-01-01

    This report describes the development and validation of a reverse phase high-performance liquid chromatography (HPLC) method with UV detection for the determination of the hormones estriol, estradiol, estrone, and progesterone in topically applied products. The developed method was then used to conduct a postmarket survey of consumer products for these hormones. Each product was first mixed with Celite and then extracted with methanol. Extracts were cleaned on a Waters Oasis HLB solid phase extraction cartridge, and then analyzed using reversed phase HPLC. The analytes were separated using an Agilent Zorbax Eclipse XDB C8 (5 μm, 250 mm by 4.6 mm) analytical column and detected by their absorbance at 230 nm. Chromatographic separation was achieved by a 1.0-ml/min linear gradient from 30% acetonitrile and 70% water to 80% acetonitrile and 20% water over 30 min. A final 5 min hold time and a re-equilibration time of 10 min were used to prepare the column for subsequent analysis. Recovery from two different brand lotions spiked with three different levels of estriol, estradiol, estrone, and progesterone ranged from 81.8% to 101%. In this study, a total of 70 cosmetic products were surveyed. Twenty two (63%) of the 35 products were labeled as containing an estrogen and/ or progesterone and also provided quantitative label information about the hormone ingredient. The most frequently labeled hormones were progesterone (66%), estriol (46%), estradiol (11%), and estrone (6%). Six products labeled as containing estriol were found to contain estradiol. An estrogen and/or progesterone were found in 34 products at concentrations ranging from 86.0 to 26,800 μg/g. Progesterone was not found in one product labeled as containing this hormone. An additional 35 products, which did not list hormones on their labels, were analyzed and estrogen or progesterone was not detected in these products. PMID:26454975

  2. Uterine Leiomyoma Stem Cells: Linking Progesterone to Growth.

    PubMed

    Bulun, Serdar E; Moravek, Molly B; Yin, Ping; Ono, Masanori; Coon, John S; Dyson, Matthew T; Navarro, Antonia; Marsh, Erica E; Zhao, Hong; Maruyama, Tetsuo; Chakravarti, Debabrata; Kim, J Julie; Wei, Jian-Jun

    2015-09-01

    Uterine leiomyomas (fibroids) represent the most common class of benign tumors in women. Multiple leiomyomas usually arise from the uterus of a symptomatic woman. These tumors cause a variety of symptoms, including abnormal uterine bleeding, pelvic pain, bladder or bowel dysfunction, and recurrent pregnancy loss, and are responsible for more than 200,000 hysterectomies in the United States annually. Each leiomyoma seems to arise from the clonal expansion of a single myometrial smooth muscle cell transformed by a mutation. Tumor expansion is sustained by cell proliferation together with the production of large amounts of extracellular matrix. Estrogen and progesterone stimulate the growth of leiomyomas. Estrogen, together with its receptor ERα, enables progesterone action via induction of progesterone receptor (PR) expression. Progesterone induces the growth of leiomyoma by regulation of a set of key genes that control proliferation and apoptosis. A distinct cell population with stem-progenitor properties is indispensable for progesterone-dependent growth of leiomyomas. This stem-progenitor cell population is deficient in ERα and PR and dependent on the much higher levels of these steroid receptors in surrounding mature leiomyoma or myometrial cells. Progesterone sends paracrine signals from these mature cells to stem cells. The WNT/β-catenin pathway comprises a key component of this paracrine signaling system. The majority of medical treatments currently available for leiomyoma works by inhibiting estrogen or progesterone production or action, but tumors tend to regrow once treatment is stopped. Targeting stem cells and their paracrine interactions with more differentiated cell populations within leiomyoma may lead to the development of more effective therapeutics.

  3. Intrauterine devices and endometrial cancer risk: a pooled analysis of the Epidemiology of Endometrial Cancer Consortium

    PubMed Central

    Felix, Ashley S.; Gaudet, Mia M.; La Vecchia, Carlo; Nagle, Christina M.; Ou Shu, Xiao; Weiderpass, Elisabete; Olov Adami, Hans; Beresford, Shirley; Bernstein, Leslie; Chen, Chu; Cook, Linda S.; De Vivo, Immaculata; Doherty, Jennifer A.; Friedenreich, Christine M.; Gapstur, Susan M.; Hill, Dierdre; Horn-Ross, Pamela L.; Lacey, James V.; Levi, Fabio; Liang, Xiaolin; Lu, Lingeng; Magliocco, Anthony; McCann, Susan E.; Negri, Eva; Olson, Sara H.; Palmer, Julie R.; Patel, Alpa V.; Petruzella, Stacey; Prescott, Jennifer; Risch, Harvey A.; Rosenberg, Lynn; Sherman, Mark E.; Spurdle, Amanda B.; Webb, Penelope M.; Wise, Lauren A.; Xiang, Yong-Bing; Xu, Wanghong; Yang, Hannah P.; Yu, Herbert; Zeleniuch-Jacquotte, Anne; Brinton, Louise A.

    2014-01-01

    Intrauterine devices (IUDs), long-acting and reversible contraceptives, induce a number of immunological and biochemical changes in the uterine environment that could affect endometrial cancer (EC) risk. We addressed this relationship through a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We combined individual-level data from 4 cohort and 14 case-control studies, in total 8,801 EC cases and 15,357 controls. Using multivariable logistic regression, we estimated pooled odds ratios (pooled-ORs) and 95% confidence intervals (CIs) for EC risk associated with ever use, type of device, ages at first and last use, duration of use, and time since last use, stratified by study and adjusted for confounders. Ever use of IUDs was inversely related to EC risk (pooled-OR=0.81, 95% CI=0.74–0.90). Compared with never use, reduced risk of EC was observed for inert IUDs (pooled-OR=0.69, 95% CI=0.58–0.82), older age at first use (≥35 years pooled-OR=0.53, 95% CI=0.43–0.67), older age at last use (≥45 years pooled-OR=0.60, 95% CI=0.50–0.72), longer duration of use (≥10 years pooled-OR=0.61, 95% CI=0.52–0.71), and recent use (within 1 year of study entry pooled-OR=0.39, 95% CI=0.30–0.49). Future studies are needed to assess the respective roles of detection biases and biologic effects related to foreign body responses in the endometrium, heavier bleeding (and increased clearance of carcinogenic cells), and localized hormonal changes. PMID:25242594

  4. Ethmoid metastasis of endometrial carcinoma causing mucocoele of maxillary antrum.

    PubMed

    Scott, A; Raine, M; Stansbie, J M

    1998-03-01

    We report a case of an antral mucocoele secondary to the obstruction of its ostium by metastatic endometrial carcinoma. This is the first report of such a cause for a mucocoele, and for a metastasis from such a tumour in the head and neck.

  5. Predictors of limph node metastasis in endometrial cancer

    PubMed Central

    IGNAT, FLORIN LAURENTIU; IRIMIE, ALEXANDRU; COSTIN, NICOLAE; ACHIMAS-CADARIU, PATRICIU; LISENCU, IOAN COSMIN

    2013-01-01

    Introduction Endometrial cancer is the most common gynecologic malignancy in developed countries. The adequate surgical staging proposed by FIGO (International Federation for Gynaecology and Obstetrics) advocates lymphadenectomy; however, it does not establish the indications, the type and the extent of lymphadenectomy, thus generating multiple controversies. Methods Retrospective, analytical study of patients treated surgically for endometrial adenocarcinoma in the Oncological Institute ”Prof. Dr. Ion Chiricuţă” Cluj-Napoca (IOCN) between January 2008 and December 2012 – 709 cases eligible for the study. Results 206 pelvic and/or paraaortic lymphadenectomies were performed, the average number of excised lymph nodes being 15.6. Overall in 4.4% of patients the lymph nodes were affected by metastases. The presence of each risk factor analysed was statistically significantly associated with lymph node metastasis (p<0.05). Age above 55 years was statistically significantly associated (p<0.05) with the presence of negative prognostic factors in the study. Conclusions The analysed histopathological and clinical prognostic factors were statistically significantly associated with lymphatic dissemination in endometrial cancer. We recommend treating endometrial cancer in tertiary centres by surgeons or gynaecologists-oncologists with experience in extensive peritoneal and retroperitoneal surgery. PMID:26527979

  6. JAZF1/SUZ12 gene fusion in endometrial stromal sarcomas.

    PubMed

    Hrzenjak, Andelko

    2016-01-01

    Endometrial stromal sarcomas (ESSs) belong to the rarest uterine malignancies (prevalence category <1-9/1,000,000). According to the new 2014 World Health Organisation (WHO) classification, they are separated into four categories; benign endometrial stromal nodules (ESNs), low grade endometrial stromal sarcomas (LG-ESSs), high-grade endometrial stromal sarcomas (HG-ESSs) and undifferentiated uterine sarcomas (UUSs). Due to heterogeneous histopathologic appearance these tumors still represent diagnostic challenge, even for experienced pathologists. ESSs are genetically very heterogeneous and several chromosomal translocations and gene fusions have so far been identified in these malignancies. To date the JAZF1/SUZ12 gene fusion is by far the most frequent and seems to be the cytogenetic hallmark of ESN and LG-ESS. Based on present literature data this gene fusion is present in approximately 75% of ESN, 50% of LG-ESS and 15% of HG-ESS cases. The frequency of JAZF1/SUZ12 appearance varies between classic ESS and different morphologic variants. This gene fusion is suggested to become a specific diagnostic tool, especially in difficult borderline cases. In combination with the recently described YWHAE/FAM22 gene fusion the JAZF1/SUZ12 fusion could be used to differentiate between LG-ESS and HG-ESS. The purpose of this review is to summarize literature data published in last two and a half decades about this gene fusion, as a contribution to our understanding of ESS genetics and pathogenesis. PMID:26879382

  7. Primary pulmonary carcinoid tumor with metastasis to endometrial polyp

    PubMed Central

    Momeni, Mazdak; Kolev, Valentin; Costin, Dan; Mizrachi, Howard H.; Chuang, Linus; Warner, Richard R.P.; Gretz, Herbert F.

    2012-01-01

    INTRODUCTION A carcinoid tumor occurring in the endometrium has been documented in the literature, but there is no report in regard to carcinoid tumor metastasis to endometrium. PRESENTATION OF CASE We report a case of a malignant carcinoid metastasis to an endometrial polyp. Patient underwent hysteroscopy, and polypectomy. The pathology demonstrated an endometrial polyp containing a 4 mm x 5 mm nodule of metastatic carcinoid tumor, consistent with metastasis from patient's known pulmonary carcinoid. The tumor was morphologically similar to the tumors of the right lung, with similar immune-profile. DISCUSSION This patient presented with a suspicious pelvic ultrasound. Due to her age, the first priority was to exclude uterine cancer. The endometrial polyp, which was found, had a small focus of metastatic carcinoid tumor. To the best of our knowledge, this finding has not been previously recorded in the literature. Our patient also had a history of metastatic carcinoid tumor to breast. This finding is also very uncommon. CONCLUSION This is the first case in the literature described a malignant carcinoid metastasis to an endometrial polyp. PMID:23127865

  8. Shadow cell differentiation from squamoid morule in endometrial adenoacanthoma.

    PubMed

    Nakamura, Toshitsugu

    2015-01-01

    Shadow cell differentiation (SCD), commonly found in cutaneous pilomatricoma (PMX), has been said to be extremely rare in extracutaneous tumors and its morphogenesis has not been clarified yet. In the present study, 25 cases of endometrial adenoacanthoma were examined with special reference to SCD and with immunohistochemistry for beta-catenin and CD10. Shadow cell nests (SCNs) were observed in 2 out of 5 cases of adenocarcinoma with squamoid morules and all of 4 cases of adenocarcinoma with squamous differentiation and morules, but not in any cases of adenocarcinoma with squamous differentiation. SCNs were just adjacent to morules with or without a mutual transition. Immunohistochemical examination revealed nuclear accumulation of beta-catenin and expression of CD10 in the squamoid morules around SCNs. These results indicate that SCNs are derived from squamoid morules in endometrial adenoacanthoma, and established a link between matrical basaloid cells in PMX and squamoid morules in endometrial adenoacanthoma, as common original tissues, showing nuclear accumulation of beta-catenin and expression of CD10, of SCNs. It seems that SCD is not so uncommon as previously estimated in endometrial adenoacanthoma.

  9. Synchronous Endometrial and Ovarian Carcinomas: Evidence of Clonality.

    PubMed

    Anglesio, Michael S; Wang, Yi Kan; Maassen, Madlen; Horlings, Hugo M; Bashashati, Ali; Senz, Janine; Mackenzie, Robertson; Grewal, Diljot S; Li-Chang, Hector; Karnezis, Anthony N; Sheffield, Brandon S; McConechy, Melissa K; Kommoss, Friedrich; Taran, Florin A; Staebler, Annette; Shah, Sohrab P; Wallwiener, Diethelm; Brucker, Sara; Gilks, C Blake; Kommoss, Stefan; Huntsman, David G

    2016-06-01

    Many women with ovarian endometrioid carcinoma present with concurrent endometrial carcinoma. Organ-confined and low-grade synchronous endometrial and ovarian tumors (SEOs) clinically behave as independent primary tumors rather than a single advanced-stage carcinoma. We used 18 SEOs to investigate the ancestral relationship between the endometrial and ovarian components. Based on both targeted and exome sequencing, 17 of 18 patient cases of simultaneous cancer of the endometrium and ovary from our series showed evidence of a clonal relationship, ie, primary tumor and metastasis. Eleven patient cases fulfilled clinicopathological criteria that would lead to classification as independent endometrial and ovarian primary carcinomas, including being of FIGO stage T1a/1A, with organ-restricted growth and without surface involvement; 10 of 11 of these cases showed evidence of clonality. Our observations suggest that the disseminating cells amongst SEOs are restricted to physically accessible and microenvironment-compatible sites yet remain indolent, without the capacity for further dissemination. PMID:26832771

  10. Common mitochondrial polymorphisms as risk factor for endometrial cancer

    PubMed Central

    Czarnecka, Anna M; Klemba, Aleksandra; Semczuk, Andrzej; Plak, Katarzyna; Marzec, Barbara; Krawczyk, Tomasz; Kofler, Barbara; Golik, Pawel; Bartnik, Ewa

    2009-01-01

    Endometrial carcinoma is the most commonly diagnosed gynaecological cancer in developed countries. Although the molecular genetics of this disease has been in the focus of many research laboratories for the last 20 years, relevant prognostic and diagnostic markers are still missing. At the same time mitochondrial DNA mutations have been reported in many types of cancer during the last two decades. It is therefore very likely that the mitochondrial genotype is one of the cancer susceptibility factors. To investigate the presence of mtDNA somatic mutations and distribution of inherited polymorphisms in endometrial adenocarcinoma patients we analyzed the D-loop sequence of cancer samples and their corresponding normal tissues and moreover performed mitochondrial haplogroup analysis. We detected 2 somatic mutation and increased incidence of mtDNA polymorphisms, in particular 16223C (80% patients, p = 0.005), 16126C (23%, p = 0.025) and 207A (19%, p = 0.027). Subsequent statistical analysis revealed that endometrial carcinoma population haplogroup distribution differs from the Polish population and that haplogroup H (with its defining polymorphism - C7028T) is strongly underrepresented (p = 0.003), therefore might be a cancer-protective factor. Our report supports the notion that mtDNA polymorphisms establish a specific genetic background for endometrial adenocarcinoma development and that mtDNA analysis may result in the development of new molecular tool for cancer detection. PMID:19863780

  11. Exposure of mice to benzo(a)pyrene impairs endometrial receptivity and reduces the number of implantation sites during early pregnancy.

    PubMed

    Zhao, Yi; Chen, Xuemei; Liu, Xueqing; Ding, Yubin; Gao, Rufei; Qiu, Yiwen; Wang, Yingxiong; He, Junlin

    2014-07-01

    Benzo(a)pyrene (BaP) is a ubiquitous environmental pollutant. Studies have demonstrated it to be an endocrine-disrupting chemical that can cause adverse effects on the female reproductive system. However, the effect of BaP on early pregnancy has not been reported. We investigated the effect of BaP on endometrial receptivity and embryo implantation. Pregnant mice were dosed with BaP at 0.2, 2 and 20 mg/kg/day from day 1 (D1) to day 5 (D5) of gestation. Exposure to BaP impaired the morphology of the endometrium and decreased the number of implantation sites (p0.2=0.006, p2=0.167, p20=0.003). Levels of estrodiol (p<0.001, for three treatment group compare with control group) and progesterone-4 in plasma were elevated in BaP-treatment groups (p0.2<0.001, p2<0.001, p20=0.032). Expression of estrogen receptor-α was up-regulated (p0.2=0.002, p2=0.131, p20=0.024) whereas expression of the progesterone receptor was down-regulated (p0.2<0.001, p2=0.064, p20=0.021). Levels of receptivity-related genes HoxA10 (p0.2<0.001, p2=0.135, p20<0.001) and E-cadherin (p0.2=0.002, p2=0.624, p20=0.137) were changed by BaP. These results revealed that BaP can disrupt the balance of estrogen and progesterone, influence expression of their receptors and downstream related genes, lead to changes in endometrium receptivity, and reduce of the number of implantation sites.

  12. Selective suppression of endothelial cytokine production by progesterone receptor.

    PubMed

    Goddard, Lauren M; Ton, Amy N; Org, Tõnis; Mikkola, Hanna K A; Iruela-Arispe, M Luisa

    2013-01-01

    Steroid hormones are well-recognized suppressors of the inflammatory response, however, their cell- and tissue-specific effects in the regulation of inflammation are far less understood, particularly for the sex-related steroids. To determine the contribution of progesterone in the endothelium, we have characterized and validated an in vitro culture system in which human umbilical vein endothelial cells constitutively express human progesterone receptor (PR). Using next generation RNA-sequencing, we identified a selective group of cytokines that are suppressed by progesterone both under physiological conditions and during pathological activation by lipopolysaccharide. In particular, IL-6, IL-8, CXCL2/3, and CXCL1 were found to be direct targets of PR, as determined by ChIP-sequencing. Regulation of these cytokines by progesterone was also confirmed by bead-based multiplex cytokine assays and quantitative PCR. These findings provide a novel role for PR in the direct regulation of cytokine levels secreted by the endothelium. They also suggest that progesterone-PR signaling in the endothelium directly impacts leukocyte trafficking in PR-expressing tissues. PMID:23747964

  13. Expression of E-Cadherin, Leukemia Inhibitory Factor and Progesterone Receptor in Mouse Blastocysts after Ovarian Stimulation

    PubMed Central

    Movaghar, Bahar; Askarian, Saeedeh

    2012-01-01

    Objective: The appropriate interaction between a blastocyst and the endometrium is essential for successful implantation. Numerous factors, including hormone receptors (progesterone receptor), cytokines [leukemia inhibitory factors (LIF)], and adherence molecules such as E-cadherin are involved in the cross-talk that occurs between the embryo and endometrium. Studies show that a lack of these genes impact endometrial receptivity. In this study, we compare the expression levels of E-cadherin, LIF, and progesterone receptor (PgR) genes in blastocysts that have been obtained from superovulated mice to those obtained from natural cycles. Materials and Methods: In this experimental study, for the experimental group, a total of 17 virgin female NMRI mice (6- 8 weeks old) were injected with 7.5 IU pregnant mare serum gonadotropin (PMSG). Their blastocysts (approximately n= 120) were flushed out after 3.5 days, following administration of human chorionic gonadotropin (hCG). The control group consisted of blastocysts from 62 female mice that were mated with male mice. The natural cycle blastocysts were flushed out from the female mice uteri 3.5 days after mating. The expression levels of E-cadherin, LIF, t PgR genes were examined by quantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR). Data were analyzed by the student’s t-test (one sample t-test). Results: Expression levels of all studied genes were significantly lower in the hormone-treated group compared to the natural cycle blastocysts (p<0.05). Conclusion: Although ovarian stimulation is utilized to obtain more oocytes in ART cycles, it seems that this could disadvantageous to implantation because of the decrease in expression levels of certain genes. Because of the important roles of E-cadherin, LIF, and progesterone receptor in the implantation process, we have shown lower expression levels of these genes in mouse blastocysts obtained from ovarian-stimulated mice than those derived from

  14. Estradiol and Progesterone have Opposing Roles in the Regulation of Fear Extinction in Female Rats.

    PubMed

    Graham, Bronwyn M; Daher, Melissa

    2016-02-01

    Fear extinction, the laboratory basis of exposure therapy for anxiety disorders, fluctuates across the female rat estrous cycle, where extinction is enhanced during proestrus (high estradiol and progesterone), and impaired during metestrus (low estradiol and progesterone). During the estrous cycle increasing levels of estradiol precede and then overlap with increased levels of progesterone. We sought to isolate the impact of these hormonal changes on fear extinction by systematically treating ovariectomized female rats with estradiol alone, or in combination with progesterone. We found that estradiol alone facilitated extinction recall, whereas the effects of progesterone on estradiol-treated rats were biphasic and dependent on the time interval between progesterone administration and extinction training. Progesterone potentiated estradiol's facilitation of extinction recall when extinction training occurred 6 h after progesterone administration. However, progesterone abolished estradiol's facilitation of extinction recall when extinction training occurred 24 h after progesterone administration. Furthermore, in naturally cycling rats, blocking progesterone receptor activation during proestrus (when progesterone levels peak) prevented the impairment in extinction recall in rats extinguished during metestrus. These results suggest that in naturally cycling females whereas cyclical increases in estradiol facilitate fear extinction, cyclical increases in progesterone may lead to fear extinction impairments. As extinction training took place after the hormonal treatments had been metabolized, we propose that genomic mechanisms may at least partly mediate the impact of cyclic fluctuations in sex hormones on fear extinction.

  15. Soy Intake Is Associated With Lower Endometrial Cancer Risk

    PubMed Central

    Zhang, Guo-Qiang; Chen, Jin-Liang; Liu, Qin; Zhang, Yong; Zeng, Huan; Zhao, Yong

    2015-01-01

    Abstract Epidemiologic studies reporting the effect of soy intake on endometrial cancer risk conveyed conflicting results. We systematically reviewed the literature to investigate whether there was an inverse relation between dietary soy intake and endometrial cancer risk. PubMed, EMBASE, the Cochrane Library, and 4 main Chinese literature databases were searched from their inception to August 25, 2015 for both case–control studies and cohort studies that assessed the effect of soy intake on endometrial cancer risk. Study-specific most-adjusted odds ratios (ORs) or relative risks (RRs) were combined by using fixed-effects or random-effects model to calculate pooled risk estimates (REs). A total of 10 epidemiologic studies were included in this meta-analysis, including 8 case–control studies and 2 prospective cohort studies. Dietary soy intake was inversely associated with endometrial cancer risk with an overall RE of 0.81 (95% CI: 0.72, 0.91). In subgroup analyses, a statistically significant protective effect of soy intake was found for unfermented soy food (RE: 0.81, 95% CI: 0.67, 0.97), postmenopausal women (RE: 0.76, 95% CI: 0.61, 0.95), and Asian (RE: 0.79, 95% CI: 0.66, 0.95) and non-Asian population (RE: 0.83, 95% CI: 0.71, 0.96). Current evidence indicates that soy food intake is associated with lower endometrial cancer risk. Further larger cohort studies are warranted to fully clarify such an association. PMID:26683956

  16. Effects of combined progesterone and 17β-estradiol treatment on the transcriptome of cultured human myometrial smooth muscle cells.

    PubMed

    Chandran, Sreenath; Cairns, Michael T; O'Brien, Margaret; O'Connell, Enda; Mashayekhi, Kaveh; Smith, Terry J

    2016-01-01

    A transcriptomic analysis of cultured human uterine smooth muscle cells (hUtSMCs) was performed to examine gene expression profiles in smooth muscle in an environment containing the two major steroid hormones that regulate the human myometrium in physiological states associated with estrous, pregnancy, labor, and pathophysiological states such as leiomyoma and endometrial cancer. hUtSMCs were treated with progesterone (P4) and 17β-estradiol (E2) individually and in combination, in the presence and absence of RU486 (mifepristone). Transcription of many genes was modulated in the presence of P4 or E2 alone, but almost six times more genes were transcriptionally modulated in the presence of the P4/E2 hormone combination. In total 796 annotated genes were significantly differentially expressed in the presence of both P4 and E2 relative to their expression in untreated cells. Functional withdrawal of P4 by addition of RU486 effectively reversed almost all transcriptional changes caused by P4/E2 treatment. Gene ontology analysis of differentially expressed genes revealed a strong association between P4/E2 treatment and downregulated expression of genes involved in cell communication, signal transduction, channel activity, inflammatory response, and differentiation. Upregulated processes included cell survival, gene transcription, steroid hormone biosynthesis, muscle development, insulin receptor signaling, and cell growth.

  17. Changes in uterine estrogen and progesterone receptors during delayed implantation and early implantation in the spotted skunk.

    PubMed

    Mead, R A; Eroschenko, V P

    1995-10-01

    Although the exact cause(s) of embryonic diapause in the western spotted skunk and other carnivores remains unknown, it has been hypothesized that it may be due to levels of ovarian hormone secretion that are insufficient to promote a uterine environment conducive to continuous embryonic development and implantation. Immunocytochemistry was used to determine whether changes in abundance or distribution of estrogen receptors (ER) and progesterone receptors (PR) may be associated with the cessation or renewal of embryonic development. Thirty pregnant skunks were killed during delayed implantation and periimplantation periods. ER and PR were detected in luminal and glandular epithelium, endometrial stroma, vasculature, and myometrium of the uterus during the period of delayed implantation. There was a significant reduction of both ER and PR receptors during the periimplantation period. The most pronounced change was the complete loss or reduction in staining intensity for PR and ER in the luminal epithelium during the first 2-3 days after implantation. These findings suggest that the failure of skunk blastocysts to undergo continuous development and implant without a prolonged period of diapause is not the result of an insufficient number of ER or PR in the uterus. The data also indicate that renewed embryonic development and implantation is not associated with an increase in these uterine steroid receptors.

  18. Ultrasound in assisted reproduction: a call to fill the endometrial gap.

    PubMed

    Hershko-Klement, Anat; Tepper, Ronnie

    2016-06-01

    Ultrasound offers essential details and an overall view of the anatomic features of the reproductive organs, as well as physiologic assessment. There is still a great gap, however, in our understanding and interpretation of endometrial sonographic findings. Endometrial thickness, growth, and sonographic patterns have been repeatedly tested and compared with pregnancy rates in IVF cycles, yielding conflicting results. Generally, the data accrued so far suggest refraining from clinical decisions based solely on endometrial thickness. The three-layer ultrasound pattern reflects normal follicular/proliferative dynamics, and its presence in the pre-hCG period was reported to carry a better outcome: Significantly higher clinical pregnancy rates were found in patients with this pattern on the day of hCG administration among IVF cohorts. Subendometrial contractility (endometrial "waves") offers a tool that can be used in cases of repeated implantation failure in patients reporting cramps around the planned time of embryo transfer, or as a reassuring modality to assess uterine quiescence during preparations for embryo transfer. We support the creation of an integrated endometrial score incorporating conservative endometrial measurements, endometrial-myometrial junction studies, and endometrial contractility, as well as new concepts that remain to be tested, such as endometrial surface area. Such scores may enable us to improve the effectiveness of endometrial ultrasound imaging in the clinical setting. PMID:27140291

  19. Measuring the biological effect of presurgical metformin treatment in endometrial cancer

    PubMed Central

    Sivalingam, V N; Kitson, S; McVey, R; Roberts, C; Pemberton, P; Gilmour, K; Ali, S; Renehan, A G; Kitchener, H C; Crosbie, E J

    2016-01-01

    Background: Preclinical studies in endometrial cancer (EC) show that metformin reduces cellular proliferation by PI3K-AKT-mTOR inhibition. We tested the hypothesis that short-term presurgical metformin reduces cellular proliferation in atypical endometrial hyperplasia (AEH) and endometrioid EC, and assessed the feasibility of using phosphorylated PI3K-AKT-mTOR proteins as tissue end points. Methods: Women with AEH or EC received metformin 850 mg twice a day or no drug in the presurgical window between diagnosis and hysterectomy. Before and after the window, tissue samples were obtained; serum markers of insulin resistance (e.g. homeostasis model of assessment of insulin resistance index) were determined; and anthropometrics measured (e.g. BMI). Cell proliferation (Ki-67) and PI3K-AKT-mTOR phosphostatus were assessed by immunohistochemistry and scored blinded to treatment. Results: Twenty-eight metformin-treated and 12 untreated patients, well matched for age and BMI, completed the study. Metformin treatment (median 20 days, range 7–34) was associated with a 17.2% reduction in tumour Ki-67 (95% CI −27.4, −7.0, P=0.002), in a dose-dependent manner. Tumour PI3K-AKT-mTOR protein phosphostatus varied but the effects were not significant after adjusting for changes in controls. Conclusions: Short-term metformin was associated with reduced Ki-67 expression in EC. Changes in tumour PI3K-AKT-mTOR protein phosphostatus were seen in both groups. Future studies should address the variability attributed to different sampling techniques including devascularisation of the uterus at hysterectomy. PMID:26794276

  20. [Aspects of progesterone receptor (PR) activity regulation - impact on breast cancer progression].

    PubMed

    Piasecka, Dominika; Składanowski, Andrzej C; Kordek, Radzisław; Romańska, Hanna M; Sądej, Rafał

    2015-01-01

    Progesterone receptor (PR) and its specific ligand play a key role in development and physiology of mammary gland. The role of PR in initiation and progression of breast carcinoma (BCa) is unquestionable, although molecular mechanism of PR action is complex and not fully understood. It is known that increased risk of breast cancer is associated with progestin-based (synthetic ligands of progesterone) hormonal contraception or hormone replacement therapies. It is estimated that ER/PR-positive tumours represent approximately 50-70% of all BCa cases, and the loss of PR is associated with resistance to hormonal therapy and increased tumour invasiveness. In classical, genomic signalling pathway cytoplasmic PR, following ligand binding, translocates to the nucleus and regulates expression of genes with the PRE sequence. PR is also involved in a large number of alternative, non-genomic signalling cascades, e.g. PR is able to activate MAPK and PI3K/AKT pathways, which leads to regulation of gene expression. The cross-talk between PR and Growth Factors Receptors (GFR) results in progesterone-independent activation of PR as well as PR-regulated GFR expression and activation. Growth factors signalling promotes formation of a pool of hypersensitive PR responsive to even very low ligand concentration. Transcriptional activity of PR as well as its dynamic impact on processes such as cell migration and adhesion are crucial for BCa progression. Further studies of multifaceted mechanisms of PR action may contribute to new PR-targeting therapeutic strategies for breast cancer patients. PMID:26689013

  1. Identification of chimeric TSNAX-DISC1 resulting from intergenic splicing in endometrial carcinoma through high-throughput RNA sequencing.

    PubMed

    Li, Na; Zheng, Jian; Li, Hua; Deng, Jieqiong; Hu, Min; Wu, Hongchun; Li, Wei; Li, Fang; Lan, Xun; Lu, Jiachun; Zhou, Yifeng

    2014-12-01

    Gene fusion is among the primary processes that generate new genes and has been well characterized as potent pathway of oncogenesis. Here, by high-throughput RNA sequencing in nine paired human endometrial carcinoma (EC) and matched non-cancerous tissues, we obtained that chimeric translin-associated factor X-disrupted-in-schizophrenia 1 (TSNAX-DISC1) occurred significantly upregulated in multiple EC samples. Experimental investigation showed that TSNAX-DISC1 appears to be formed by splicing without chromosomal rearrangement. The chimera expression inversely correlated with the binding of CCCTC-binding factor (CTCF) to the insulators. Subsequent investigations indicate that long intergenic non-coding RNA lincRNA-NR_034037, separating TSNAX from DISC1, regulates TSNAX -DISC1 production and TSNAX/DISC1 expression levels by extricating CTCF from insulators. Dysregulation of TSNAX influences steroidogenic factor-1-stimulated transcription on the StAR promoter, altering progesterone actions, implying the association with cancer. Together, these results advance our understanding of the mechanism in which lincRNA-NR_034037 regulates TSNAX-DISC1 formation programs that tightly regulate EC development.

  2. Identification of chimeric TSNAX-DISC1 resulting from intergenic splicing in endometrial carcinoma through high-throughput RNA sequencing.

    PubMed

    Li, Na; Zheng, Jian; Li, Hua; Deng, Jieqiong; Hu, Min; Wu, Hongchun; Li, Wei; Li, Fang; Lan, Xun; Lu, Jiachun; Zhou, Yifeng

    2014-12-01

    Gene fusion is among the primary processes that generate new genes and has been well characterized as potent pathway of oncogenesis. Here, by high-throughput RNA sequencing in nine paired human endometrial carcinoma (EC) and matched non-cancerous tissues, we obtained that chimeric translin-associated factor X-disrupted-in-schizophrenia 1 (TSNAX-DISC1) occurred significantly upregulated in multiple EC samples. Experimental investigation showed that TSNAX-DISC1 appears to be formed by splicing without chromosomal rearrangement. The chimera expression inversely correlated with the binding of CCCTC-binding factor (CTCF) to the insulators. Subsequent investigations indicate that long intergenic non-coding RNA lincRNA-NR_034037, separating TSNAX from DISC1, regulates TSNAX -DISC1 production and TSNAX/DISC1 expression levels by extricating CTCF from insulators. Dysregulation of TSNAX influences steroidogenic factor-1-stimulated transcription on the StAR promoter, altering progesterone actions, implying the association with cancer. Together, these results advance our understanding of the mechanism in which lincRNA-NR_034037 regulates TSNAX-DISC1 formation programs that tightly regulate EC development. PMID:25239642

  3. Effect of Endometrial Injury on Secretion of Endometrial Cytokines and IVF Outcomes in Women with Unexplained Subfertility

    PubMed Central

    Liang, Yu; Han, Junyan; Jia, Chanwei; Ma, Yanmin; Lan, Yonglian; Li, Ying; Wang, Shuyu

    2015-01-01

    In order to determine the effect of endometrial injury (EI) on in vitro fertilization (IVF) outcomes in women with unexplained subfertility and explore the relationship between EI and endometrial inflammatory cytokines, 66 women with unexplained subfertility undergoing IVF treatment were recruited. 38 patients in the EI group underwent EI in the mid-luteal phase of the cycle and 28 patients in the non-EI (NEI) group. According to the pregnancy outcome, the NEI and EI groups were divided into NEI-nonpregnant (NEI-NP), NEI-pregnant (NEI-P), EI-NP, and EI-P. All patients underwent aspiration of endometrial secretions immediately before embryo transfer. The concentrations of ten mediators were measured using Milliplex Magnetic Bead assay. The clinical pregnancy was significantly higher in the EI than in the NEI group. The concentrations of interleukin- (IL-) 6, IL-8, IL-12 (p70), IL-13, interferon- (IFN-) γ, monocyte chemotactic protein- (MCP-) 1, and vascular endothelial growth factor (VEGF) were significantly higher in the EI than the NEI group. The expression of IFN-γ and VEGF in the EI-P was significantly increased compared to the EI-NP group. These findings suggest that, in women with unexplained subfertility, endometrial injury might be a potential method to improve clinical pregnancy rates by promoting the expression of IFN-γ and VEGF. PMID:26586929

  4. Effect of Endometrial Injury on Secretion of Endometrial Cytokines and IVF Outcomes in Women with Unexplained Subfertility.

    PubMed

    Liang, Yu; Han, Junyan; Jia, Chanwei; Ma, Yanmin; Lan, Yonglian; Li, Ying; Wang, Shuyu

    2015-01-01

    In order to determine the effect of endometrial injury (EI) on in vitro fertilization (IVF) outcomes in women with unexplained subfertility and explore the relationship between EI and endometrial inflammatory cytokines, 66 women with unexplained subfertility undergoing IVF treatment were recruited. 38 patients in the EI group underwent EI in the mid-luteal phase of the cycle and 28 patients in the non-EI (NEI) group. According to the pregnancy outcome, the NEI and EI groups were divided into NEI-nonpregnant (NEI-NP), NEI-pregnant (NEI-P), EI-NP, and EI-P. All patients underwent aspiration of endometrial secretions immediately before embryo transfer. The concentrations of ten mediators were measured using Milliplex Magnetic Bead assay. The clinical pregnancy was significantly higher in the EI than in the NEI group. The concentrations of interleukin- (IL-) 6, IL-8, IL-12 (p70), IL-13, interferon- (IFN-) γ, monocyte chemotactic protein- (MCP-) 1, and vascular endothelial growth factor (VEGF) were significantly higher in the EI than the NEI group. The expression of IFN-γ and VEGF in the EI-P was significantly increased compared to the EI-NP group. These findings suggest that, in women with unexplained subfertility, endometrial injury might be a potential method to improve clinical pregnancy rates by promoting the expression of IFN-γ and VEGF.

  5. The incidence rates of endometrial hyperplasia and endometrial cancer: a four-year population-based study

    PubMed Central

    2016-01-01

    Introduction The aim of this study was to determine the incidence rates of endometrial hyperplasia (EH) and endometrial cancer (EC) in the Republic of Korea using national insurance claim data generated from 2009 to 2012. Materials and Methods Data that were generated from 2009 to 2012 were sourced from the Korean Health Insurance Review and Assessment Service-National Inpatients Sample database. The data from women who were assigned diagnosis codes representing EH or EC within 1 month of being assigned codes that corresponded to procedures that included endometrial biopsies and several types of gynecologic surgeries to obtain endometrial pathology samples, were selected for analysis. Results Data from 2,477,424 women were entered into the database between 2009 and 2012, and the data from 1,868 women with EH and 868 women with EC were extracted for analysis. The mean ages of the patients were 44.1 ± 0.4 years for those with EH and 52.7 ± 0.6 years for those with EC. The EH and EC incidence rates were 37 per 100,000 woman-years and 8 per 100,000 woman-years, respectively. The EH and EC incidence rates peaked when the women were in their late forties and fifties, respectively. Conclusions The EH and EC incidence rates determined in this study were somewhat lower than those determined from previous studies. Further studies are required that adjust the data for race, menopausal hormone therapy, and obesity.

  6. The incidence rates of endometrial hyperplasia and endometrial cancer: a four-year population-based study

    PubMed Central

    2016-01-01

    Introduction The aim of this study was to determine the incidence rates of endometrial hyperplasia (EH) and endometrial cancer (EC) in the Republic of Korea using national insurance claim data generated from 2009 to 2012. Materials and Methods Data that were generated from 2009 to 2012 were sourced from the Korean Health Insurance Review and Assessment Service-National Inpatients Sample database. The data from women who were assigned diagnosis codes representing EH or EC within 1 month of being assigned codes that corresponded to procedures that included endometrial biopsies and several types of gynecologic surgeries to obtain endometrial pathology samples, were selected for analysis. Results Data from 2,477,424 women were entered into the database between 2009 and 2012, and the data from 1,868 women with EH and 868 women with EC were extracted for analysis. The mean ages of the patients were 44.1 ± 0.4 years for those with EH and 52.7 ± 0.6 years for those with EC. The EH and EC incidence rates were 37 per 100,000 woman-years and 8 per 100,000 woman-years, respectively. The EH and EC incidence rates peaked when the women were in their late forties and fifties, respectively. Conclusions The EH and EC incidence rates determined in this study were somewhat lower than those determined from previous studies. Further studies are required that adjust the data for race, menopausal hormone therapy, and obesity. PMID:27635340

  7. Effect of Endometrial Injury on Secretion of Endometrial Cytokines and IVF Outcomes in Women with Unexplained Subfertility.

    PubMed

    Liang, Yu; Han, Junyan; Jia, Chanwei; Ma, Yanmin; Lan, Yonglian; Li, Ying; Wang, Shuyu

    2015-01-01

    In order to determine the effect of endometrial injury (EI) on in vitro fertilization (IVF) outcomes in women with unexplained subfertility and explore the relationship between EI and endometrial inflammatory cytokines, 66 women with unexplained subfertility undergoing IVF treatment were recruited. 38 patients in the EI group underwent EI in the mid-luteal phase of the cycle and 28 patients in the non-EI (NEI) group. According to the pregnancy outcome, the NEI and EI groups were divided into NEI-nonpregnant (NEI-NP), NEI-pregnant (NEI-P), EI-NP, and EI-P. All patients underwent aspiration of endometrial secretions immediately before embryo transfer. The concentrations of ten mediators were measured using Milliplex Magnetic Bead assay. The clinical pregnancy was significantly higher in the EI than in the NEI group. The concentrations of interleukin- (IL-) 6, IL-8, IL-12 (p70), IL-13, interferon- (IFN-) γ, monocyte chemotactic protein- (MCP-) 1, and vascular endothelial growth factor (VEGF) were significantly higher in the EI than the NEI group. The expression of IFN-γ and VEGF in the EI-P was significantly increased compared to the EI-NP group. These findings suggest that, in women with unexplained subfertility, endometrial injury might be a potential method to improve clinical pregnancy rates by promoting the expression of IFN-γ and VEGF. PMID:26586929

  8. Progesterone generates cancer stem cells through membrane progesterone receptor-triggered signaling in basal-like human mammary cells.

    PubMed

    Vares, Guillaume; Sai, Sei; Wang, Bing; Fujimori, Akira; Nenoi, Mitsuru; Nakajima, Tetsuo

    2015-07-01

    Ionizing radiation and cumulative exposure to steroid hormones are known risk factors for breast cancer. There is increasing evidence that breast tumors are driven by a subpopulation of tumor-initiating cancer stem cells (CSCs). In MCF10A non-cancerous basal-like PR(-) cells, progesterone treatment and X-rays generated ALDH(+) and CD44(+)/CD24(-) CSCs. Here, we report that in irradiated MCF10A cells, progesterone activated the PI3K/Akt pathway via membrane progesterone receptor (mPR). Inhibition of the PI3K/Akt pathway counteracted the generation of CSCs by progesterone and irradiation. The stimulation of PI3K/Akt via mPR resulted in the inactivation of FOXO transcriptional activity, the upregulation of snail and slug expression and a downregulation of miR-29 expression, which led to increased levels of KLF4, a transcription factor required for breast CSC maintenance. Stabilization of miR-29 expression impeded the generation of CSCs, while its inhibition alone was sufficient to generate CSCs. This study provides a new mechanistic basis for progesterone and radiation-induced breast cancer risk in basal cells. In addition, the elucidation of new pathways and miRNA regulations involved in CSC generation and maintenance may open the door to potential novel anti-CSC strategies.

  9. Pharmaceutical and clinical development of a novel progesterone formulation.

    PubMed

    Cometti, Barbara

    2015-11-01

    Progesterone plays an essential role in reproductive events. Its use for luteal support in patients undergoing infertility treatment is an established practice. The different routes used to administer progesterone impact on its efficacy in luteal support: oral administration has been shown to be ineffective due to an extensive first-pass metabolism in the liver; vaginal application has a good efficacy but has drawbacks such as vaginal leakage, irritation, discomfort and uncertainty about the real dose adsorbed; finally, intramuscular administration ensures a precise dosage but can be extremely painful with, in some cases, formation of sterile abscesses. A new progesterone preparation is now available in several European and extra-European countries that combines the precise dosage of the injectable formulation with the comfort of a well-tolerated subcutaneous self-administration. The pharmacokinetic and pharmacodynamic properties of this new product are reviewed here, together with the clinical evidence obtained in two multicenter randomized clinical trials. PMID:26342177

  10. Properties of proteins binding plasma progesterone in pregnant Cape porcupines (Hystrix africaeaustralis).

    PubMed

    Louw, A I; van Wyk, V; van Aarde, R J

    1992-09-01

    The properties of progesterone-binding proteins in plasma of pregnant Cape porcupines were investigated using radiolabelled progesterone and either progesterone or cortisol as competing ligands as well as native plasma and heated (60 degrees C for 30 min) plasma. The results demonstrated that plasma from pregnant porcupines contains corticosteroid-binding globulin, but that it constitutes a significant portion of plasma progesterone-binding proteins only during the early stages of pregnancy. Corticosteroid-binding globulin of porcupines appears to be as heat labile as that of guinea-pigs. Concentrations of progesterone-binding proteins in plasma increased during pregnancy to reach concentrations at the eleventh week that were 25 times higher than those of progesterone; concentrations increased significantly (r2 = 0.88) with the increase in progesterone concentration. The results indicate that plasma progesterone-binding proteins in Cape porcupines (Old World hystricomorph) are similar in composition to those in guinea-pigs (New World hystricomorph).

  11. Progesterone directly and rapidly inhibits GnRH neuronal activity via progesterone receptor membrane component 1.

    PubMed

    Bashour, Nicholas Michael; Wray, Susan

    2012-09-01

    GnRH neurons are essential for reproduction, being an integral component of the hypothalamic-pituitary-gonadal axis. Progesterone (P4), a steroid hormone, modulates reproductive behavior and is associated with rapid changes in GnRH secretion. However, a direct action of P4 on GnRH neurons has not been previously described. Receptors in the progestin/adipoQ receptor family (PAQR), as well as progesterone receptor membrane component 1 (PgRMC1) and its partner serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1) mRNA binding protein 1 (SERBP1), have been shown to mediate rapid progestin actions in various tissues, including the brain. This study shows that PgRMC1 and SERBP1, but not PAQR, are expressed in prenatal GnRH neurons. Expression of PgRMC1 and SERBP1 was verified in adult mouse GnRH neurons. To investigate the effect of P4 on GnRH neuronal activity, calcium imaging was used on primary GnRH neurons maintained in explants. Application of P4 significantly decreased the activity of GnRH neurons, independent of secretion of gamma-aminobutyric acidergic and glutamatergic input, suggesting a direct action of P4 on GnRH neurons. Inhibition was not blocked by RU486, an antagonist of the classic nuclear P4 receptor. Inhibition was also maintained after uncoupling of the inhibitory regulative G protein (G(i/o)), the signal transduction pathway used by PAQR. However, AG-205, a PgRMC1 ligand and inhibitor, blocked the rapid P4-mediated inhibition, and inhibition of protein kinase G, thought to be activated downstream of PgRMC1, also blocked the inhibitory activity of P4. These data show for the first time that P4 can act directly on GnRH neurons through PgRMC1 to inhibit neuronal activity.

  12. Estimation of oestrogen and progesterone receptors in chronic rhinitis.

    PubMed

    Wilson, J A; Hawkins, R A; Sangster, K; von Haacke, N P; Tesdale, A; Leese, A M; Murray, J A; Maran, A G

    1986-08-01

    The turbinates of 38 patients with chronic rhinitis were examined biochemically for oestrogen and progesterone receptors. Low levels of oestrogen-receptor-like activity (1-20 fmol/mg protein) were found in 50% of patients of both sexes. Progesterone receptor activity was also weak (1-16 fmol/mg protein) but was present only in 5 female patients. Immunocytochemical assay failed to demonstrate focal areas of oestrogen receptor activity. One juvenile nasopharyngeal angiofibroma was negative for both oestrogen and androgen receptors. Other possible mechanisms of hormonal action are considered.

  13. The accuracy of endometrial sampling in women with postmenopausal bleeding: a systematic review and meta-analysis.

    PubMed

    van Hanegem, Nehalennia; Prins, Marileen M C; Bongers, Marlies Y; Opmeer, Brent C; Sahota, Daljit Singh; Mol, Ben Willem J; Timmermans, Anne

    2016-02-01

    Postmenopausal bleeding (PMB) can be the first sign of endometrial cancer. In case of thickened endometrium, endometrial sampling is often used in these women. In this systematic review, we studied the accuracy of endometrial sampling for the diagnoses of endometrial cancer, atypical hyperplasia and endometrial disease (endometrial pathology, including benign polyps). We systematically searched the literature for studies comparing the results of endometrial sampling in women with postmenopausal bleeding with two different reference standards: blind dilatation and curettage (D&C) and hysteroscopy with histology. We assessed the quality of the detected studies by the QUADAS-2 tool. For each included study, we calculated the fraction of women in whom endometrial sampling failed. Furthermore, we extracted numbers of cases of endometrial cancer, atypical hyperplasia and endometrial disease that were identified or missed by endometrial sampling. We detected 12 studies reporting on 1029 women with postmenopausal bleeding: five studies with dilatation and curettage (D&C) and seven studies with hysteroscopy as a reference test. The weighted sensitivity of endometrial sampling with D&C as a reference for the diagnosis of endometrial cancer was 100% (range 100-100%) and 92% (71-100) for the diagnosis of atypical hyperplasia. Only one study reported sensitivity for endometrial disease, which was 76%. When hysteroscopy was used as a reference, weighted sensitivities of endometrial sampling were 90% (range 50-100), 82% (range 56-94) and 39% (21-69) for the diagnosis of endometrial cancer, atypical hyperplasia and endometrial disease, respectively. For all diagnosis studied and the reference test used, specificity was 98-100%. The weighted failure rate of endometrial sampling was 11% (range 1-53%), while insufficient samples were found in 31% (range 7-76%). In these women with insufficient or failed samples, an endometrial (pre) cancer was found in 7% (range 0-18%). In women with

  14. Methylated DNA collected by tampons--a new tool to detect endometrial cancer.

    PubMed

    Fiegl, Heidi; Gattringer, Conny; Widschwendter, Andreas; Schneitter, Alois; Ramoni, Angela; Sarlay, Daniela; Gaugg, Inge; Goebel, Georg; Müller, Hannes M; Mueller-Holzner, Elisabeth; Marth, Christian; Widschwendter, Martin

    2004-05-01

    This proof of principle study aimed to define a new and simple strategy for detection of endometrial cancer using epigenetic markers. We investigated DNA isolated from vaginal secretion collected from tampon for aberrant methylation of five genes (CDH13, HSPA2, MLH1, RASSF1A, and SOCS2) using MethyLight in 15 patients with endometrial cancer and 109 patients without endometrial cancer. All endometrial cancer patients revealed three or more methylated genes, whereas 91% (99 of 109) of the patients without endometrial cancer had no or fewer than three genes methylated in their vaginal secretion. The methods developed in this study provide the basis for a prospective clinical trial to screen asymptomatic women who are at high risk for endometrial cancer.

  15. Surgical Management of Endometrial Polyps in Infertile Women: A Comprehensive Review

    PubMed Central

    Pereira, Nigel; Petrini, Allison C.; Lekovich, Jovana P.; Elias, Rony T.; Spandorfer, Steven D.

    2015-01-01

    Endometrial polyps are benign localized lesions of the endometrium, which are commonly seen in women of reproductive age. Observational studies have suggested a detrimental effect of endometrial polyps on fertility. The natural course of endometrial polyps remains unclear. Expectant management of small and asymptomatic polyps is reasonable in many cases. However, surgical resection of endometrial polyps is recommended in infertile patients prior to treatment in order to increase natural conception or assisted reproductive pregnancy rates. There is mixed evidence regarding the resection of newly diagnosed endometrial polyps during ovarian stimulation to improve the outcomes of fresh in vitro fertilization cycles. Hysteroscopy polypectomy remains the gold standard for surgical treatment. Evidence regarding the cost and efficacy of different methods for hysteroscopic resection of endometrial polyps in the office and outpatient surgical settings has begun to emerge. PMID:26301260

  16. The putative roles of nuclear and membrane-bound progesterone receptors in the female reproductive tract.

    PubMed

    Kowalik, Magdalena K; Rekawiecki, Robert; Kotwica, Jan

    2013-12-01

    Progesterone produced by the corpus luteum (CL) is a key regulator of normal cyclical reproductive functions in the females of mammalian species. The physiological effects of progesterone are mediated by the canonical genomic pathway after binding of progesterone to its specific nuclear progesterone receptor (PGR), which acts as a ligand-activated transcription factor and has two main isoforms, PGRA and PGRB. These PGR isoforms play different roles in the cell; PGRB acts as an activator of progesterone-responsive genes, while PGRA can inhibit the activity of PGRB. The ratio of these isoforms changes during the estrous cycle and pregnancy, and it corresponds to the different levels of progesterone signaling occurring in the reproductive tract. Progesterone exerts its effects on cells also by a non-genomic mechanism by the interaction with the progesterone-binding membrane proteins including the progesterone membrane component (PGRMC) 1 and 2, and the membrane progestin receptors (mPRs). These receptors rapidly activate the appropriate intracellular signal transduction pathways, and subsequently they can initiate specific cell responses or modulate genomic cell responses. The diversity of progesterone receptors and their cellular actions enhances the role of progesterone as a factor regulating the function of the reproductive system and other organs. This paper deals with the possible involvement of nuclear and membrane-bound progesterone receptors in the function of target cells within the female reproductive tract.

  17. Ovine maternal nutrient restriction from mid to late gestation decreases heptic progesterone inactivating enzyme activity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Previously we have shown increased concentrations of progesterone and decreased liver weight in mid to late pregnant ewes provided a nutrient restricted vs. adequate diet. This alteration in peripheral progesterone could be due to increased synthesis and/or decreased clearance of progesterone. There...

  18. A critical assessment on the role of sentinel node mapping in endometrial cancer

    PubMed Central

    Ditto, Antonino; Martinelli, Fabio; Signorelli, Mauro; Perotto, Stefania; Lorusso, Domenica; Raspagliesi, Francesco

    2015-01-01

    Endometrial cancer is the most common gynecologic malignancy in the developed countries. Although the high incidence of this occurrence no consensus, about the role of retroperitoneal staging, still exists. Growing evidence support the safety and efficacy of sentinel lymph node mapping. This technique is emerging as a new standard for endometrial cancer staging procedures. In the present paper, we discuss the role of sentinel lymph node mapping in endometrial cancer, highlighting the most controversies features. PMID:26508591

  19. Rat endometrial bioelectric activity in vivo and in vitro: effects of adrenaline.

    PubMed Central

    Levin, R J; Phillips, J C

    1983-01-01

    The transuterine potential difference (p.d.) generated by the endometrium was measured in vivo in anaesthetized, ovariectomized rats treated with 10 micrograms oestradiol-17 beta each day for 3 days. Intravenous injection of adrenaline induced transient hyperpolarization of the p.d.; sigmoid dose-dependency was observed over the range 2-40 micrograms/kg. Pre-treatment of the rats with syrosingopine shifted the dose-response curve to the left (enhancement) while combined propranolol (800 micrograms/kg) and phentolamine (800 micrograms/kg) shifted the dose-response curve to the right (depression). Isoprenaline gave similar quantitative changes in the p.d. in vivo which displayed a similar time course and sigmoid dose-dependency. Propranolol alone (800 micrograms/kg) shifted this dose-response curve significantly to the right. Addition of adrenaline or isoprenaline to the serosal solution bathing uteri incubated in vitro after removal from oestradiol-treated rats induced changes in endometrial bioelectric activity that exhibited sigmoid dose-response curves for the transuterine p.d. and short-circuit current (Isc). Propranolol significantly shifted the dose-response curves for adrenaline to the right. Only adrenaline caused small but significant decreases in the uterine resistance but these were not dose-dependent. Acetylcholine, 5-hydroxytryptamine, noradrenaline and phenylephrine had no effect on the transuterine p.d. in vivo or in vitro or on the Isc in vitro. No significant electrical changes could be induced by adrenaline or any of the other drugs across the uteri from untreated ovariectomized rats either in vivo or in vitro. The transluminal membrane p.d. of surface endometrial cells measured with micro-electrodes was depolarized by an addition of serosal adrenaline but only 41% of the cells successfully impaled responded in this way. The results indicate that endometrial cells under oestrogen stimulation possess electrogenic processes that can be modulated

  20. Dasatinib in Treating Patients With Recurrent or Persistent Ovarian, Fallopian Tube, Endometrial or Peritoneal Cancer

    ClinicalTrials.gov

    2016-11-02

    Endometrial Clear Cell Adenocarcinoma; Estrogen Receptor Negative; Ovarian Clear Cell Cystadenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma

  1. Evaluation of the anti-tumor effects of lactate dehydrogenase inhibitor galloflavin in endometrial cancer cells.

    PubMed

    Han, Xiaoyun; Sheng, Xiugui; Jones, Hannah M; Jackson, Amanda L; Kilgore, Joshua; Stine, Jessica E; Schointuch, Monica N; Zhou, Chunxiao; Bae-Jump, Victoria L

    2015-01-29

    High rates of aerobic glycolysis represent a key mechanism by which endometrial cancer cells consume glucose as its primary energy source. The up-regulated glycolytic pathway is a common therapeutic target whose inhibition has implications for anti-tumor activity in cancer cells. The present study was aimed at evaluating the potential of a novel lactate dehydrogenase (LDH) inhibitor, Galloflavin, as a therapeutic agent for endometrial cancer. Our results revealed that Galloflavin effectively inhibited cell growth in endometrial cancer cell lines and primary cultures of human endometrial cancer through its involvement in multiple signaling pathways that regulate metabolism, cell cycle, apoptosis, cell stress and metastasis.

  2. Progesterone and estrogens in the pregnant and nonpregnant dolphin, Tursiops truncatus, and the effects of induced ovulation.

    PubMed

    Sawyer-Steffan, J E; Kirby, V L; Gilmartin, W G

    1983-05-01

    Baseline serum levels of progesterone and total immunoreactive estrogens were determined for intact and ovariectomized captive female Atlantic bottlenose dolphins (Tursiops truncatus), as well as newly captured wild adult females. Stimulation of ovarian follicular growth and ovulation was attempted by intramuscular injection of pregnant mare's serum gonadotropin (PMSG). High doses of PMSG were required to increase serum estrogen levels. When PMSG was followed by an injection of human chorionic gonadotropin (hCG), ovulation was presumed to have occurred as indicated by subsequent high levels of serum progesterone. From these observations, it appears that 1) females with progesterone levels greater than 3000 pg/ml over an extended period are pregnant, 2) Tursiops truncatus is capable of spontaneous ovulation in captivity without gonadotropin therapy, 3) captive female dolphins, although relatively resistant to PMSG, can be induced to ovulate using a combination of high intramuscular-injected doses of PMSG followed by hCG, and 4) spontaneous ovulation is likely to follow an induced ovulation. PMID:6860744

  3. Glucocorticoid and progesterone receptors in yolk sac placenta.

    PubMed

    Carbone, J P; Baldridge, R C; Magen, A B; Andrew, C L; Koszalka, T R; Brent, R L

    1986-01-01

    The parietal yolk sac (PYS) of the rat fetus at the 14th day of gestation contains glucocorticoid as well as progesterone receptors; both are present in the trophoblast cell layer. Following heat activation the receptors are capable of binding to deoxyribonucleic acid- (DNA-)cellulose. Glucocorticoid receptors, but not progesterone receptors, are also present in the visceral yolk sac (VYS) at the 14th day of gestation. Greater amounts (some 250 femtomoles/mg cytosol protein) of a glucocorticoid receptor are present in the VYS on the 17th day of gestation. The Kd is approximately 4 X 10(-9) M; following activation it also binds to DNA-cellulose. The elution pattern of the activated VYS receptor from diethylaminoethyl-(DEAE-)Sephadex, however, is similar to that found with kidney and colon rather than that of liver (i.e., it resembles corticosteroid binder IB rather than binder II) indicating a possible role in transport. Although the receptors are separate entities, progesterone competes as effectively as corticosterone for binding to the glucocorticoid receptors in both the PYS and and VYS, thus raising the question of the possible effect of changes in progesterone concentrations on the functioning of glucocorticoids during development.

  4. Progesterone Regulation of Synaptic Transmission and Plasticity in Rodent Hippocampus

    ERIC Educational Resources Information Center

    Foy, Michael R.; Akopian, Garnik; Thompson, Richard F.

    2008-01-01

    Ovarian hormones influence memory formation by eliciting changes in neural activity. The effects of various concentrations of progesterone (P4) on synaptic transmission and plasticity associated with long-term potentiation (LTP) and long-term depression (LTD) were studied using in vitro hippocampal slices. Extracellular studies show that the…

  5. 21 CFR 522.1940 - Progesterone and estradiol benzoate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Progesterone and estradiol benzoate. 522.1940 Section 522.1940 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL...

  6. 21 CFR 529.1940 - Progesterone intravaginal inserts.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Progesterone intravaginal inserts. 529.1940 Section 529.1940 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS CERTAIN OTHER DOSAGE FORM NEW ANIMAL DRUGS §...

  7. Current Issues in the Diagnosis and Treatment of Endometrial Carcinoma

    PubMed Central

    Stubert, J.; Gerber, B.

    2016-01-01

    Endometrial carcinoma is the most common carcinoma of the female genital tract. Its most important clinical sign is postmenopausal bleeding. An endometrial biopsy is essential for diagnosis. Treatment decisions are governed by tumour risk assessment and patient comorbidity, which is often present. Pelvic and paraaortic lymph node dissection is unnecessary in low risk cases (definition: pT1 a, G1/2) and adjuvant radiotherapy and systemic treatments are usually avoidable. Treatment of high-risk patients (G3 and/or pT1b) and palliative cases is difficult and not well standardised. New molecular-based subtype classification may help treatment decision making in future. PMID:26941450

  8. Protective actions of progesterone in the cardiovascular system: potential role of membrane progesterone receptors (mPRs) in mediating rapid effects.

    PubMed

    Thomas, Peter; Pang, Yefei

    2013-06-01

    The protective functions of progesterone in the cardiovascular system have received little attention even though evidence has accumulated that progesterone lowers blood pressure, inhibits coronary hyperactivity and has powerful vasodilatory and natriuretic effects. One possible reason why potential beneficial actions of progesterone on cardiovascular functions have not been extensively studied is that divergent effects to those of progesterone have been observed in many clinical trials with synthetic progestins such as medroxyprogesterone acetate which are associated with increased risk of coronary disease. Evidence that progesterone exerts protective effects on cardiovascular functions is briefly reviewed. The finding that progesterone administration decreases blood vessel vasoconstriction in several animal models within a few minutes suggests that rapid, nongenomic progesterone mechanisms are of physiological importance in regulating vascular tone. Rapid activation of second messenger pathways by progesterone has been observed in vascular endothelial and smooth muscle cells, resulting in alterations in endothelial nitric oxide synthase (eNOS) activity and calcium influx, respectively. Both nuclear progesterone receptors (PRs) and novel membrane progesterone receptors (mPRs) are candidates for the intermediaries in these rapid, cell-surface initiated progesterone actions in endothelial and smooth muscle vascular cells. PRs have been detected in both cell types. New data are presented showing mPRα, mPRβ and mPRγ are also present in human endothelial and smooth muscle vascular cells. Preliminary evidence suggests mPRs mediate rapid progestin signaling in these endothelial cells, resulting in down-regulation of cAMP production and increased nitric oxide synthesis. The role of mPRs in progesterone regulation of cardiovascular functions warrants further investigation.

  9. Protective actions of progesterone in the cardiovascular system: potential role of membrane progesterone receptors (mPRs) in mediating rapid effects.

    PubMed

    Thomas, Peter; Pang, Yefei

    2013-06-01

    The protective functions of progesterone in the cardiovascular system have received little attention even though evidence has accumulated that progesterone lowers blood pressure, inhibits coronary hyperactivity and has powerful vasodilatory and natriuretic effects. One possible reason why potential beneficial actions of progesterone on cardiovascular functions have not been extensively studied is that divergent effects to those of progesterone have been observed in many clinical trials with synthetic progestins such as medroxyprogesterone acetate which are associated with increased risk of coronary disease. Evidence that progesterone exerts protective effects on cardiovascular functions is briefly reviewed. The finding that progesterone administration decreases blood vessel vasoconstriction in several animal models within a few minutes suggests that rapid, nongenomic progesterone mechanisms are of physiological importance in regulating vascular tone. Rapid activation of second messenger pathways by progesterone has been observed in vascular endothelial and smooth muscle cells, resulting in alterations in endothelial nitric oxide synthase (eNOS) activity and calcium influx, respectively. Both nuclear progesterone receptors (PRs) and novel membrane progesterone receptors (mPRs) are candidates for the intermediaries in these rapid, cell-surface initiated progesterone actions in endothelial and smooth muscle vascular cells. PRs have been detected in both cell types. New data are presented showing mPRα, mPRβ and mPRγ are also present in human endothelial and smooth muscle vascular cells. Preliminary evidence suggests mPRs mediate rapid progestin signaling in these endothelial cells, resulting in down-regulation of cAMP production and increased nitric oxide synthesis. The role of mPRs in progesterone regulation of cardiovascular functions warrants further investigation. PMID:23357432

  10. Ultrastructural aspects of endometrial surface in Kartagener's syndrome.

    PubMed

    Marchini, M; Losa, G A; Nava, S; Di Nola, G; Fedele, L

    1992-02-01

    The endometrium of an infertile patient with Kartagener's syndrome showed initial secretory phase characteristics at SEM, whereas TEM analysis demonstrated several alterations in the central and peripheral microtubular distribution in 87% of the cilia examined. Such aspects seemed appropriate for a normal implantation, but the ciliary immotility or dyskinesia could cause an altered flow of the endometrial secretions and compromise the upstream movement of the spermatozoa.

  11. Xanthogranulomatous Endometritis: An Unusual Pathological Entity Mimicking Endometrial Carcinoma

    PubMed Central

    Makkar, M; Gill, MK; Singh, DP

    2013-01-01

    Xanthogranulomatous endometritis is an unusual pathological entity mimicking endometrial carcinoma. This shows sheets of foamy histiocytes alongwith other inflammatory cells. We, hereby, report a case of 45 year multigravida female with irregular menstrual history, clinically diagnosed as carcinoma and histopathologically turned out as xanthogranulomatous endometritis. So, this condition should always be dealt with caution, and pathologists and clinicians should be aware of it. PMID:24349850

  12. Menstrual physiology: implications for endometrial pathology and beyond

    PubMed Central

    Maybin, Jacqueline A.; Critchley, Hilary O.D.

    2015-01-01

    BACKGROUND Each month the endometrium becomes inflamed, and the luminal portion is shed during menstruation. The subsequent repair is remarkable, allowing implantation to occur if fertilization takes place. Aberrations in menstrual physiology can lead to common gynaecological conditions, such as heavy or prolonged bleeding. Increased knowledge of the processes involved in menstrual physiology may also have translational benefits at other tissue sites. METHODS Pubmed and Cochrane databases were searched for all original and review articles published in English until April 2015. Search terms included ‘endometrium’, ‘menstruation’, ‘endometrial repair’, ‘endometrial regeneration’ ‘angiogenesis’, ‘inflammation’ and ‘heavy menstrual bleeding’ or ‘menorrhagia’. RESULTS Menstruation occurs naturally in very few species. Human menstruation is thought to occur as a consequence of preimplantation decidualization, conferring embryo selectivity and the ability to adapt to optimize function. We highlight how current and future study of endometrial inflammation, vascular changes and repair/regeneration will allow us to identify new therapeutic targets for common gynaecological disorders. In addition, we describe how increased knowledge of this endometrial physiology will have many translational applications at other tissue sites. We highlight the clinical applications of what we know, the key questions that remain and the scientific and medical possibilities for the future. CONCLUSIONS The study of menstruation, in both normal and abnormal scenarios, is essential for the production of novel, acceptable medical treatments for common gynaecological complaints. Furthermore, collaboration and communication with specialists in other fields could significantly advance the therapeutic potential of this dynamic tissue. PMID:26253932

  13. The Effects of Sugammadex on Progesterone Levels in Pregnant Rats

    PubMed Central

    Et, Tayfun; Topal, Ahmet; Erol, Atilla; Tavlan, Aybars; Kılıçaslan, Alper; Uzun, Sema Tuncer

    2015-01-01

    Background: Sugammadex has been shown to decrease the efficiency of progesterone-containing oral contraceptive drugs which possess a steroid structure. Aims: The aim of the present study was to evaluate the effects of sugammadex on progesterone levels in pregnant rats as well as on the physiological course of the pregnancy. Study Design: Animal experiment. Methods: This study was approved by the Selçuk University Ethical Committee for Experimental Animal Research. Pregnant Winster Albino rats (n=26) were divided into three groups and administered with various intravenous injections on the 7th day of pregnancy. The control group (Group K, n=6) received 1.5 mL serum physiologic, the sugammadex group (Group S, n=10) received 30 mg/kg sugammadex and the sugammadex + rocuronium group (Group SR, n=10) received 30 mg/kg sugammadex and 3.5 mg/kg rocuronium. Progesterone levels were measured and the offspring were monitored for morphologic status. Results: Mean progesterone levels were 94.16±15.54 ng/mL in Group K, 87.86±12.48 ng/mL in Group S, and 94.53±16.10 ng/mL in Group SR (p>0.05). No stillbirth or miscarriage was observed in the rats. The mean number of offspring was 6.8±1.47 in Group K, 6.5±1.35 in Group S, and 6.4±1.17 in Group SR. The offspring appeared macroscopically normal. Conclusion: Sugammadex does not appear to affect the progesterone levels in pregnant rats in the first trimester and the clinical course. Successful completion of pregnancy and the absence of stillbirth or miscarriage will guide future studies about the use of sugammadex, particularly in the first trimester of the pregnancy. PMID:26167346

  14. Xanthogranulomatous Endometritis: A Challenging Imitator of Endometrial Carcinoma

    PubMed Central

    Doğan-Ekici, A. Işın; Usubütün, Alp; Küçükali, Türkan; Ayhan, Ali

    2007-01-01

    Xanthogranulomatous inflammation is a distinguished histopathological entity affecting several organs, predominantly the kidney and gallbladder. So far, only a small number of cases of xanthogranulomatous inflammation occurring in female genital tract have been described, most frequently affecting the endometrium and histologically characterized by replacement of endometrium by xanthogranulomatous inflammation composed of abundant foamy histiocytes, siderophages, giant cells, fibrosis, calcification and accompanying polymorphonuclear leucocytes, plasma cells and lymphocytes of polyclonal origin. We present a case of a 69-year-old female complained of post menopausal bleeding and weight loss. Clinical preliminary diagnoses were endometrial carcinoma or hyperplasia and ultrasound was supposed to be endometrial malignancy, hyperplasia or pyometra by radiologist. Histopathological examination of uterus revealed xanthogranulomatous endometritis. Since xanthogranulomatous endometritis may mimic endometrial malignancy clinically and pathologically as a result of the replacement of the endometrium and occasionally invasion of the myometrium by friable yellowish tissue composed of histiocytes, knowledge of this unusual inflammatory disease is needed for both clinicians and pathologists. PMID:17710239

  15. Endometrial echotexture variables in postpartum cows with subclinical endometritis.

    PubMed

    Polat, B; Cengiz, M; Cannazik, O; Colak, A; Oruc, E; Altun, S; Salar, S; Bastan, A

    2015-04-01

    The aim of this study was to evaluate endometrial echotexture changes on ultrasonographic digital images during subclinical endometritis using a computer-assisted image analysis program. Endometrial samples were collected from 140 Brown Swiss cows (days in milk = 35 ± 3) using a cytobrush method and classified as having a non-inflamed uterus (n = 66) and uterus with acute (n = 42), subacute (n = 21), and chronic (n = 11) inflammations. The mean cellular infiltration density was 0%, 31 ± 5%, 37 ± 6%, and 16 ± 8% for cows with non-inflamed uterus and cows with acute, subacute, and chronic uterine inflammations (P < 0.0001). As the cell infiltration density increased, both cervical diameter and mean gray level did not change. There were a liner decrease in homogeneity and a linear increase in contrast in response to increased cellular infiltration density. The sensitivity and specificity were 79.73% and 46.97% for the homogeneity value and 59.46% and 69.70% for the contrast value, respectively. In conclusion, monitoring endometrial echotexture alterations, especially homogeneity and contrast, changed depending on the cellular density and inflammation status and may be potential diagnostic markers for subclinical endometritis in cows. PMID:25721562

  16. The enantiomer of progesterone (ent-progesterone) is a competitive inhibitor of human cytochromes P450c17 and P450c21.

    PubMed

    Auchus, Richard J; Sampath Kumar, A; Andrew Boswell, C; Gupta, Manisha K; Bruce, Kristen; Rath, Nigam P; Covey, Douglas F

    2003-01-01

    Human cytochrome P450c17 (17alpha-hydroxylase, 17,20-lyase) (CYP17) and cytochrome P450c21 (21-hydroxylase) (CYP21) differ by only 14 amino acids in length and share 29% amino acid identity. Both enzymes hydroxylate progesterone at carbon atoms that lie only 2.6A apart, but CYP17 also metabolizes other steroids and demonstrates additional catalytic activities. To probe the active site topologies of these related enzymes, we synthesized the enantiomer of progesterone and determined if ent-progesterone is a substrate or inhibitor of CYP17 and CYP21. Neither enzyme metabolizes ent-progesterone; however, ent-progesterone is a potent competitive inhibitor of CYP17 (K(I)=0.2 microM). The ent-progesterone forms a type I difference spectrum with CYP17, but molecular dynamics simulations suggest different binding orientations for progesterone and its enantiomer. The ent-progesterone also inhibits CYP21, with weaker affinity than for CYP17. We conclude that CYP17 accommodates the stereochemically unnatural ent-progesterone better than CYP21. Enantiomeric steroids can be used to probe steroid binding sites, and these compounds may be effective inhibitors of steroid biosynthesis.

  17. Steroidogenesis in plants--Biosynthesis and conversions of progesterone and other pregnane derivatives.

    PubMed

    Lindemann, Peter

    2015-11-01

    In plants androstanes, estranes, pregnanes and corticoids have been described. Sometimes 17β-estradiol, androsterone, testosterone or progesterone were summarized as sex hormones. These steroids influence plant development: cell divisions, root and shoot growth, embryo growth, flowering, pollen tube growth and callus proliferation. First reports on the effect of applicated substances and of their endogenous occurrence date from the early twenties of the last century. This caused later on doubts on the identity of the compounds. Best investigated is the effect of progesterone. Main steps of the progesterone biosynthetic pathway have been analyzed in Digitalis. Cholesterol-side-chain-cleavage, pregnenolone and progesterone formation as well as the stereospecific reduction of progesterone are described and the corresponding enzymes are presented. Biosynthesis of androstanes, estranes and corticoids is discussed. Possible progesterone receptors and physiological reactions on progesterone application are reviewed. PMID:26282543

  18. Steroidogenesis in plants--Biosynthesis and conversions of progesterone and other pregnane derivatives.

    PubMed

    Lindemann, Peter

    2015-11-01

    In plants androstanes, estranes, pregnanes and corticoids have been described. Sometimes 17β-estradiol, androsterone, testosterone or progesterone were summarized as sex hormones. These steroids influence plant development: cell divisions, root and shoot growth, embryo growth, flowering, pollen tube growth and callus proliferation. First reports on the effect of applicated substances and of their endogenous occurrence date from the early twenties of the last century. This caused later on doubts on the identity of the compounds. Best investigated is the effect of progesterone. Main steps of the progesterone biosynthetic pathway have been analyzed in Digitalis. Cholesterol-side-chain-cleavage, pregnenolone and progesterone formation as well as the stereospecific reduction of progesterone are described and the corresponding enzymes are presented. Biosynthesis of androstanes, estranes and corticoids is discussed. Possible progesterone receptors and physiological reactions on progesterone application are reviewed.

  19. Use of monoclonal antibodies for radioimmunoassay of water buffalo milk progesterone.

    PubMed

    Capparelli, R; Iannelli, D; Bordi, A

    1987-11-01

    In order to standardize a radioimmunoassay of milk progesterone as a routine method for confirmation of oestrus and diagnosis of pregnancy in water buffalo, monoclonal antibodies against progesterone were produced. Hybridomas were prepared by fusing spleen cells from a Balb/c mouse immunized with progesterone 11 alpha-hemisuccinate-bovine serum albumin conjugate with the mouse myeloma cell line NS-1. Thirty wells out of 94 secreted anti-progesterone antibodies. Of the ten independent hybridomas derived, one (AF65) was suitable for the quantification of milk progesterone by radioimmunoassay. The tracer used in the assay was progesterone-11 alpha-hemisuccinate [( 2-125I]iodohistamine). The sensitivity of the assay was 50 pg/tube. The mean progesterone concentration at oestrus was 0.8 +/- 0.2 ng/ml increasing to 8.5 +/- 0.8 ng/ml 24 d later in pregnant animals.

  20. Progesterone and threatened abortion: a randomized clinical trial on endocervical cytokine concentrations.

    PubMed

    Alimohamadi, Shohreh; Javadian, Pouya; Gharedaghi, Mohammad Hadi; Javadian, Nima; Alinia, Hossein; Khazardoust, Soghra; Borna, Sedigheh; Hantoushzadeh, Sedigheh

    2013-06-01

    The purpose of this study was to investigate the effect of vaginal progesterone on endocervical cytokine concentration in women at risk of threatened abortion. One hundred and sixty pregnant women with clinical symptoms of threatened abortion before the 20th week of pregnancy were randomly assigned to receive vaginal progesterone or placebo. Cervical fluids were collected and endocervical concentrations of different cytokines (IFNγ, TNFα, IL-8, IL-10 and IL-12) were analyzed before and one week after progesterone or placebo treatment. A significant decrease in IFNγ and increase in IL-10 in endocervical fluid was seen when the values were compared before and after progesterone treatment. However, there were no significant differences in pregnancy outcomes between the placebo and progesterone groups. We conclude that despite the failure of vaginal progesterone treatment to improve pregnancy outcomes, progesterone can induce a shift in the concentration of cytokines in endocervical secretions. PMID:23489467

  1. Short communication: Plasma progesterone concentration and ovarian dynamics of lactating Jersey cows treated with 1 or 2 intravaginal progesterone inserts.

    PubMed

    Moraes, João G N; Silva, Paula R B; Bortoletto, Nathália; Scanavez, Alexandre L A; Chebel, Ricardo C

    2016-03-01

    The objectives of the current experiment were to determine circulating progesterone concentrations and ovarian follicle development of lactating Jersey cows treated with 1 or 2 controlled internal drug release (CIDR) insert containing 1.38 g of progesterone during proestrus. Cows were enrolled in the experiment at 34 ± 3 d in milk and were paired by parity, body condition score, body weight, and milk yield. Estrous cycles were presynchronized with an injection of GnRH concurrent with a new CIDR insert (study d -7) and 2 injections of PGF2α given 5 and 6 d after the GnRH injection (study d -2 and -1, respectively). Cows assigned to the 1CIDR treatment (n=30) or 2CIDR treatment (n=30) received 1 and 2 CIDR inserts, respectively, from study d 0 through 7. Control cows (n=10) did not receive further treatment. On study d -2 and daily from study d 0 through 7, ovaries were examined by transrectal ultrasound and blood samples were collected for determination of progesterone. On study d 7, CIDR inserts were removed after ultrasound exam and blood sample collection. Progesterone concentration from study d 0 through 7 was greatest for 2CIDR cows (2.17 ± 0.09 ng/mL), followed by 1CIDR cows (1.37 ± 0.10 ng/mL) and control cows (0.62 ± 0.21 ng/mL). The interaction between treatment and study day affected progesterone concentration from study d 0 through 7. The average increase in progesterone concentration from study d 1 through 7 was 0.80 ng/mL for 1CIDR and 1.72 ng/mL for 2CIDR cows compared with control cows. The percentage of cows that ovulated between study d 0 and 7 was greatest for control cows (80%), but it did not differ between 1CIDR (12%) and 2CIDR (3.7%) cows. Growth of class III follicles (10-17 mm) identified on study d 0 was affected by treatment because 1CIDR cows had larger class III follicles than 2CIDR cows on study d 5, 6 and 7. A larger proportion of control cows developed a new follicular wave between study d 0 and 7 (control=60.0%, 1CIDR=12.0%, 2

  2. Does dilation and curettage versus expectant management for spontaneous abortion in patients undergoing in vitro fertilization affect subsequent endometrial development?

    PubMed

    Moon, Kimberly S; Richter, Kevin S; Levy, Michael J; Widra, Eric A

    2009-11-01

    In in vitro fertilization patients, treatment of spontaneous abortion with dilation and curettage (D&C) versus expectant management has no long-term effect on subsequent endometrial development, as measured by change in endometrial thickness. A transient reduction in endometrial thickness was found within the first 6 months after D&C, which is a novel finding, but it is likely to have little or no effect on pregnancy rates given the small absolute effect on endometrial thickness.

  3. Does dilation and curettage versus expectant management for spontaneous abortion in patients undergoing in vitro fertilization affect subsequent endometrial development?

    PubMed

    Moon, Kimberly S; Richter, Kevin S; Levy, Michael J; Widra, Eric A

    2009-11-01

    In in vitro fertilization patients, treatment of spontaneous abortion with dilation and curettage (D&C) versus expectant management has no long-term effect on subsequent endometrial development, as measured by change in endometrial thickness. A transient reduction in endometrial thickness was found within the first 6 months after D&C, which is a novel finding, but it is likely to have little or no effect on pregnancy rates given the small absolute effect on endometrial thickness. PMID:19560759

  4. Relationships between Serum Luteinizing Hormone Level, Endometrial Thickness and Body Mass Index in Polycystic Ovary Syndrome Patients with and without Endometrial Hyperplasia

    PubMed Central

    Ramezanali, Fariba; Khalili, Gholamreza; Arabipoor, Arezoo; Bagheri Lankarani, Narges; Moini, Ashraf

    2016-01-01

    Background The endometrial hyperplasia measured by ultrasound in polycystic ovary syndrome (PCOS) women is strongly related to pathologic endometrial thickness, but there is no consensus on the relation between serum luteinizing hormone (LH) and either of these factors: pathologic endometrial hyperplasia and body mass index (BMI). Materials and Methods In this observational cross-sectional study, three hundred fifty infertile PCOS women were involved in this research. An endometrial biopsy was taken by using a pipelle instrument, regardless of menstrual cycle’s day and all samples were reported by the same pathologist. Basal serum LH level was compared between two subgroups (hyperplasia and non-hyperplasia). The intended population was divided into three groups according to BMI and basal serum LH, later on the comparison was made in three groups. Chi-square test was applied to compare nominal variables between groups. Mann-Whitney U, and one way ANOVA tests were used to compare means on the basis of the result of normality test. Results The frequency of endometrial hyperplasia was 2.6%. Endometrial thickness in the patients with endometrial hyperplasia was significantly higher than that of a normal endometrium (10.78 ± 3.70 vs. 7.90 ± 2.86 respectively, P=0.020). There was no relation between endometrial hyperplasia and serum LH (P=0.600). The ANOVA test showed serum LH levels were not the same among three BMI groups (P=0.007). Post hoc test was also performed. It showed that the LH level in normal BMI group was significantly higher than those of other groups (P=0.005 and P=0.004), but there was no statistical difference between overweight and obese groups (P=0.8). We found no relationship between BMI and endometrial thickness in PCOS patients (P=0.6). Conclusion Sonographic endometrial stripe thickness is predictive for endometrial hyperplasia in PCOS women. We could not find out any relationship between serum LH level and BMI with endometrial thickness in

  5. Very Early Administration of Progesterone for Acute Traumatic Brain Injury

    PubMed Central

    Wright, David W.; Yeatts, Sharon D.; Silbergleit, Robert; Palesch, Yuko Y.; Hertzberg, Vicki S.; Frankel, Michael; Goldstein, Felicia C.; Caveney, Angela F.; Howlett-Smith, Harriet; Bengelink, Erin M.; Manley, Geoffrey T.; Merck, Lisa H.; Janis, L. Scott; Barsan, William G.

    2015-01-01

    BACKGROUND Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI. METHODS We conducted a double-blind, multicenter clinical trial in which patients with severe, moderate-to-severe, or moderate acute TBI (Glasgow Coma Scale score of 4 to 12, on a scale from 3 to 15, with lower scores indicating a lower level of consciousness) were randomly assigned to intravenous progesterone or placebo, with the study treatment initiated within 4 hours after injury and administered for a total of 96 hours. Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome, as determined with the use of the stratified dichotomy of the Extended Glasgow Outcome Scale score at 6 months after injury. Secondary outcomes included mortality and the Disability Rating Scale score. RESULTS A total of 882 of the planned sample of 1140 patients underwent randomization before the trial was stopped for futility with respect to the primary outcome. The study groups were similar with regard to baseline characteristics; the median age of the patients was 35 years, 73.7% were men, 15.2% were black, and the mean Injury Severity Score was 24.4 (on a scale from 0 to 75, with higher scores indicating greater severity). The most frequent mechanism of injury was a motor vehicle accident. There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P = 0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes. CONCLUSIONS This clinical trial did not show a

  6. Stromal deletion of the APC tumor suppressor in mice triggers development of endometrial cancer

    PubMed Central

    Tanwar, Pradeep S.; Zhang, LiHua; Roberts, Drucilla J.; Teixeira, Jose M.

    2011-01-01

    The contribution of the stromal microenvironment to the progression of endometrial cancer (EC) has not been well explored. We have conditionally expressed a mutant allele of adenomatous polyposis coli (APCcKO) in murine uterine stroma cells to study its effect on uterine development and function. In addition to metrorrhagia, the mice develop complex atypical endometrial gland hyperplasia that progresses to endometrial carcinoma in situ and endometrial adenocarcinoma as evidenced by myometrial invasion. Stromal cells subjacent to the carcinoma cells express αSMA with fewer cells expressing PDGFR-α compared to normal stromal cells suggesting that the mutant stromal cells have acquired a more myofibroblastic phenotype, which have been described as cancer-associated fibroblasts and have been shown to induce carcinogenesis in other organ systems. Analyses of human EC specimens showed substantial αSMA expression in the stroma compared with normal endometrial stroma cells. We also show that APCcKO mutant uteri and human EC have decreased stromal levels of TGFβ and BMP activities and that the mutant uteri failed to respond to exogenous estradiol stimulation. The mutant stroma cells also had higher levels of VEGF and SDF signaling components and diminished expression of ERα and PR which is common in advanced stages of human EC and is an indicator of poor prognosis. Our results indicate that de novo mutation or loss of heterozygosity in stromal APC is sufficient to induce endometrial hyperplasia and endometrial carcinogenesis by mechanisms that are consistent with unopposed estrogen signaling in the endometrial epithelium. PMID:21363919

  7. The value of hysteroscopic biopsy in the diagnosis of endometrial polyps.

    PubMed

    Spadoto-Dias, Daniel; Bueloni-Dias, Flávia Neves; Elias, Leonardo Vieira; Leite, Nilton José; Modotti, Waldir Pereira; Lasmar, Ricardo Bassil; Dias, Rogério

    2016-07-01

    Several studies have demonstrated that the combination of hysteroscopy with endometrial biopsy is more accurate in differentiating endometrial polyps from endometrial hyperplasia and cancer. However, blind biopsy not always confirms hysteroscopic findings due to high rates of inadequate or insufficient material. The objective of this clinical, prospective, and comparative study was to establish a correlation between the histological results of office-based endometrial biopsies (hysteroscopically guided and blind) with the surgical polypectomy specimens. We evaluated 82 patients with hysteroscopic diagnosis of endometrial polyp, who randomly underwent hysteroscopically guided biopsy or blind biopsy, referred for surgical resection. A total of 36 women (43.9%) underwent hysteroscopically guided biopsy and 46 women (56.1%) underwent blind biopsy. The sensitivity of hysteroscopically guided biopsy for the diagnosis of endometrial polyps ranged between 35.3 and 36.8%, when carried out at the apex and base of the lesion, compared with 29.2% for blind biopsy. Specificity was 33.3, 50, and 60%, respectively, for each biopsy. The positive predictive values were 75, 77.8, and 87.5%, and negative predictive values were 8.3, 14.3, and 8.1% respectively, compared with surgical polypectomy specimens. The office-based endometrial biopsies had low diagnostic accuracy for endometrial polyps compared with surgical polypectomy specimens. PMID:27638896

  8. Use of Outpatient Endometrial Biopsy in a Population with Intellectual Disability

    ERIC Educational Resources Information Center

    Jaffe, Joshua S.

    2008-01-01

    Background: To demonstrate the feasibility of outpatient endometrial sampling to evaluate abnormal uterine bleeding in a population of women with intellectual disability. Method: Retrospective chart review was completed of all endometrial biopsies performed on women attending a dedicated gynaecology clinic for women with intellectual disability…

  9. Diagnostic utility of hepatocyte nuclear factor 1-beta immunoreactivity in endometrial carcinomas: lack of specificity for endometrial clear cell carcinoma.

    PubMed

    Fadare, Oluwole; Liang, Sharon X

    2012-12-01

    Hepatocyte nuclear factor 1-beta (HNF1β) has recently emerged as a relatively sensitive and specific marker for ovarian clear cell carcinoma. The purpose of this study is to assess the diagnostic utility of this marker for endometrial clear cell carcinoma. Immunohistochemical analysis was performed on 75 endometrial tissues using a goat polyclonal antibody raised against a peptide mapping at the C-terminus of human HNF1β protein. The 75 cases included 15 clear cell carcinomas, 20 endometrioid carcinomas, 15 endometrial serous carcinomas/uterine papillary serous carcinomas, 20 cases of normal endometrium, 2 cases of clear cell metaplasia, and 3 cases of Arias Stella reaction. Staining interpretations were based on a semiquantitative scoring system, a 0 to 12+ continuous numerical scale that was derived by multiplying the extent of staining (0 to 4+ scale) by the intensity of staining (0 to 3+ scale) for each case. HNF1β expression was found to be present in a wide spectrum of tissues. Twenty-seven (54%) of the 50 carcinomas displayed at least focal nuclear HNF1β expression, including 11 (73%) of 15, 9 (60%) of 15, and 7 (35%) of 20 clear cell, serous, and endometrioid carcinomas, respectively. The average nuclear staining scores for clear cell carcinomas, endometrioid carcinomas, and serous carcinomas were 5.2, 1.4, and 4.1, respectively. Clear cell carcinomas and endometrioid carcinomas displayed statistically significant differences regarding their nuclear staining scores (P = 0.0027), but clear cell carcinomas and endometrial serous carcinomas did not (P = 0.45). The calculated sensitivity of any nuclear HNF1β expression in classifying a carcinoma as being of the clear cell histotype was 73%, whereas the specificity was 54%. Nineteen of 20 normal endometrium samples displayed at least focal nuclear expression of HNF1β, and this expression was often diffuse. The 5 cases of benign histologic mimics of clear cell carcinomas (Arias Stella reaction and clear

  10. Endocrine responsiveness: understanding how progesterone receptor can be used to select endocrine therapy.

    PubMed

    Osborne, C Kent; Schiff, Rachel; Arpino, Grazia; Lee, Adrian Susan; Hilsenbeck, V G

    2005-12-01

    The receptor for the female hormone progesterone (PR), like that for estrogen (ER), is an important predictive marker for response to endocrine therapy in patients with breast cancer. PR exists as two isoforms, A and B. PR is important in mammary gland development and excess production of PRB is associated with breast cancer risk. Overabundance of PRA is related to resistance to tamoxifen. Total loss of PR is linked to reduced benefit from tamoxifen in both the adjuvant and metastatic settings. The predictive significance of PR expression was originally explained on the basis that PR is an ER-regulated gene and its presence indicates a functioning ER pathway and, therefore, an endocrine-responsive tumor. More recent data, however, suggest an alternative explanation. While many studies show that loss of PR predicts relative resistance to the antiestrogen tamoxifen, a recent study suggests that PR loss may not indicate resistance to aromatase inhibition. The finding that PR loss may not correlate with resistance to aromatase inhibition may be related to crosstalk between ER and PR and growth factor receptor pathways such as HER2. PR loss in some tumors is due to excessive growth factor receptor signaling (overexpression of HER2), which downregulates expression of the PR gene. Neoadjuvant studies also show that HER2 signaling is associated with tamoxifen resistance, but not resistance to aromatase inhibitors. Therefore, high HER2 signaling could explain both PR loss and resistance to tamoxifen while the response to aromatase inhibitors is maintained. In this way, PR loss in some tumors may be a surrogate marker for increased signaling through the growth factor receptor tyrosine kinase pathway and it may help clinicians decide between initial use of an aromatase inhibitor or tamoxifen in the individual patient.

  11. Fecal and urinary lignans, intrafollicular estradiol, and endometrial receptors in lactating dairy cows fed diets supplemented with hydrogenated animal fat, flaxseed or sunflower seed.

    PubMed

    Thangavelu, Govindarajan; Colazo, Marcos Germán; Oba, Masahito; Dyck, Michael Kane; Okine, Erasmus Kojo; Ambrose, Divakar Justus

    2008-12-01

    We hypothesized that the inclusion of flaxseed in the diets of lactating dairy cows will increase urinary and fecal concentrations of the lignans, secoisolariciresinol diglycoside (SDG), enterolactone and enterodiol, reduce intrafollicular concentrations of IGF-I and estradiol, and subsequently reduce estradiol and oxytocin receptor expression in the endometrium. To test this hypothesis, 27 cycling, lactating Holstein cows were assigned to 1 of 3 diets supplemented with saturated fatty acids (SAT), flax (FLX), or sunflower (SUN) seed. Rations were formulated to provide 750 g supplemental fat/cow/d in all dietary groups. Ovulation (Day 0) was synchronized, and 5 d later, follicles>8 mm were ablated by an ultrasound-guided procedure in all cows. Samples of blood (Days 0 to 14), follicular fluid (Day 5 and 15), endometrium (Day 15), as well as urine and feces were collected in a subset of the animals. The fecal concentrations of SDG and enterodiol were higher (P<0.05) in cows fed FLX than in those fed SAT or SUN. Enterodiol increased (P<0.05) in urine samples of cows fed FLX, compared to those of cows fed SUN. However, follicular estradiol concentrations on Day 5 and 15 and endometrial concentrations of estradiol and oxytocin receptors on Day 15 did not differ among the dietary groups. Mean plasma progesterone concentrations were higher (P<0.05) in cows fed FLX and SUN than in those fed SAT. In summary, a diet supplemented with flaxseed increased the concentrations of SDG and enterodiol in feces, as hypothesized, but did not alter intrafollicular concentrations of IGF-I or estradiol, or endometrial populations of oxytocin or estrogen receptors in lactating dairy cows.

  12. The Role of Endometrial Selectins and Their Ligands on Bovine Conceptus Attachment to the Uterine Epithelium During Peri-Implantation Period.

    PubMed

    Bai, Rulan; Kusama, Kazuya; Sakurai, Toshihiro; Bai, Hanako; Wang, Changshou; Zhang, Jinfeng; Kuse, Mariko; Ideta, Atsushi; Aoyagi, Yoshito; Okuda, Kiyoshi; Imakawa, Kazuhiko

    2015-08-01

    A successful pregnancy depends on the blastocyst's implantation to the maternal endometrium; however, the initial interaction between blastocyst and uterine epithelium has not been well characterized. The objectives of this study were to determine if selectins and their ligands were expressed in the bovine conceptus and/or uterus during the periattachment period and to study whether selectins were associated with conceptus attachment to the uterine epithelium. Through the RNA-sequence analysis of bovine conceptuses on Days 17, 20, and 22 (Day 0 = day of estrus), only the SELL ligand, podocalyxin (PODXL), and P-selectin (SELP) ligand, SELPLG, were found. Quantitative PCR analysis confirmed the presence of PODXL and SELPLG in these conceptuses and revealed that SELL, mRNA and protein, detected in the uterine epithelium but not in conceptuses increased during the periattachment period. In the cultured endometrial epithelial cells (EECs), SELL transcript was up-regulated when uterine flushings from Day 20 pregnant animals were placed onto these cells. SELL was also up-regulated when cultured EECs were treated with progesterone, EGF, or bFGF, but not with IFNT. In the coculture system with EECs and bovine trophoblast CT-1 cells, SELL expression in EECs was effectively reduced by its small interfering RNA; however, IFNT, a marker for CT-1 cell attachment to EECs, was not reduced, nor was a transcription factor of IFNT, CDX2. These observations suggest that the conceptus could attach to the uterine epithelium through the use of endometrial SELL and embryonic selectin ligands, possibly initiating the conceptus attachment process in the bovine species. PMID:26134867

  13. Comparison of Risk Factors and survival of Type 1 and Type II Endometrial Cancers

    PubMed Central

    Malik, Tahira Y.; Chishti, Uzma; Aziz, Aliya B.; Sheikh, Irfan

    2016-01-01

    Objective: To compare risk factors and progression free survival of type 1 & 2 endometrial cancers. Methods: A retrospective analysis of 149 patients with early stage endometrial carcinoma treated between 1997 and 2012 in Aga Khan University Hospital, Karachi was performed. Results: A total of 149 patients were analyzed. Type I tumors accounted for 92% of cases in the study while 8% were type II tumors. The mean age, BMI, parity, co-morbidities (hypertension & Diabetes), family history and history of polycystic disease were comparable in both groups. Overall better survival (113 Vs 24 months) was observed for type I endometrial cancer. Conclusion: Both types of endometrial cancer may share common etiologic factors. Despite the limitation of small numbers in one group this study confirms better survival in type 1 endometrial cancer. PMID:27648033

  14. MMAC/PTEN gene expression in endometrial cancer: RT-PCR studies.

    PubMed

    Sobczuk, Anna; Smolarz, Beata; Romanowicz-Makowska, Hanna; Pertyński, Tomasz

    2006-01-01

    Mutations in the MMAC/PTEN (phosphatase and tensin homologue deleted on chromosome 10) gene are documented in cancers of the breast, prostate, ovary, colon, melanoma, glioblastoma, lymphoma and endometrium. In the present work MMAC/PTEN gene expression in women with endometrial adenocarcinoma (n=70) in RNA samples obtained from cancer tissue were investigated. Control DNA was obtained from 68 normal endometrial tissue. The MMAC/PTEN expression was determined by RT-PCR analysis. The expression of MMAC/PTEN gene in endometrial adenocarcinoma cases was significantly reduced compared to the expression in the normal samples (P < 0.05). Furthermore the significant difference (P < 0.05) was observed between the expression of MMAC/PTEN in stage III versus lower stages of endometrial cancer. The results support the hypothesis that the MMAC/PTEN gene expression may be associated with the incidence of endometrial cancer.

  15. Two methods for establishing primary human endometrial stromal cells from hysterectomy specimens.

    PubMed

    Jividen, Kasey; Movassagh, Mercedeh Javanbakht; Jazaeri, Amir; Li, Hui

    2014-01-01

    Many efforts have been devoted to establish in vitro cell culture systems. These systems are designed to model a vast number of in vivo processes. Cell culture systems arising from human endometrial samples are no exception. Applications range from normal cyclic physiological processes to endometrial pathologies such as gynecological cancers, infectious diseases, and reproductive deficiencies. Here, we provide two methods for establishing primary endometrial stromal cells from surgically resected endometrial hysterectomy specimens. The first method is referred to as "the scraping method" and incorporates mechanical scraping using surgical or razor blades whereas the second method is termed "the trypsin method." This latter method uses the enzymatic activity of trypsin to promote the separation of cells and primary cell outgrowth. We illustrate step-by-step methodology through digital images and microscopy. We also provide examples for validating endometrial stromal cell lines via quantitative real time polymerase chain reactions (qPCR) and immunofluorescence (IF). PMID:24894444

  16. Human Endometrial Side Population Cells Exhibit Genotypic, Phenotypic and Functional Features of Somatic Stem Cells

    PubMed Central

    Cervelló, Irene; Gil-Sanchis, Claudia; Mas, Aymara; Delgado-Rosas, Francisco; Martínez-Conejero, José Antonio; Galán, Amparo; Martínez-Romero, Alicia; Martínez, Sebastian; Navarro, Ismael; Ferro, Jaime; Horcajadas, José Antonio; Esteban, Francisco José; O'Connor, José Enrique; Pellicer, Antonio; Simón, Carlos

    2010-01-01

    During reproductive life, the human endometrium undergoes around 480 cycles of growth, breakdown and regeneration should pregnancy not be achieved. This outstanding regenerative capacity is the basis for women's cycling and its dysfunction may be involved in the etiology of pathological disorders. Therefore, the human endometrial tissue must rely on a remarkable endometrial somatic stem cells (SSC) population. Here we explore the hypothesis that human endometrial side population (SP) cells correspond to somatic stem cells. We isolated, identified and characterized the SP corresponding to the stromal and epithelial compartments using endometrial SP genes signature, immunophenotyping and characteristic telomerase pattern. We analyzed the clonogenic activity of SP cells under hypoxic conditions and the differentiation capacity in vitro to adipogenic and osteogenic lineages. Finally, we demonstrated the functional capability of endometrial SP to develop human endometrium after subcutaneous injection in NOD-SCID mice. Briefly, SP cells of human endometrium from epithelial and stromal compartments display genotypic, phenotypic and functional features of SSC. PMID:20585575

  17. Comparison of Risk Factors and survival of Type 1 and Type II Endometrial Cancers

    PubMed Central

    Malik, Tahira Y.; Chishti, Uzma; Aziz, Aliya B.; Sheikh, Irfan

    2016-01-01

    Objective: To compare risk factors and progression free survival of type 1 & 2 endometrial cancers. Methods: A retrospective analysis of 149 patients with early stage endometrial carcinoma treated between 1997 and 2012 in Aga Khan University Hospital, Karachi was performed. Results: A total of 149 patients were analyzed. Type I tumors accounted for 92% of cases in the study while 8% were type II tumors. The mean age, BMI, parity, co-morbidities (hypertension & Diabetes), family history and history of polycystic disease were comparable in both groups. Overall better survival (113 Vs 24 months) was observed for type I endometrial cancer. Conclusion: Both types of endometrial cancer may share common etiologic factors. Despite the limitation of small numbers in one group this study confirms better survival in type 1 endometrial cancer.

  18. Paclitaxel, Carboplatin, and Bevacizumab or Paclitaxel, Carboplatin, and Temsirolimus or Ixabepilone, Carboplatin, and Bevacizumab in Treating Patients With Stage III, Stage IV, or Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2016-10-27

    Endometrial Adenocarcinoma; Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Serous Adenocarcinoma; Recurrent Uterine Corpus Carcinoma; Stage IIIA Uterine Corpus Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIC Uterine Corpus Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer

  19. Stress-induced progesterone secretion and progesterone receptor immunoreactivity in the paraventricular nucleus are modulated by pubertal development in male rats.

    PubMed

    Romeo, Russell D; Bellani, Rudy; McEwen, Bruce S

    2005-12-01

    Male rats show a differential adrenocortical response to stress before and after pubertal development, such that prepubertal animals have a more prolonged stress-induced corticosterone response compared to adults. Whether pubertal maturation affects other adrenocortical responses to stress is currently unknown. To address this question, we assessed stress-induced progesterone secretion in both intact and gonadectomized prepubertal (28 days of age) and adult (77 days of age) male rats either before or after exposure to a 30 min session of restraint stress. We found that prepubertal males show a greater and more prolonged stress-induced progesterone response compared to adults. We also found a similar effect in castrated prepubertal and adult males, indicating the differential stress-induced progesterone response is not gonadal in origin. We also examined progesterone receptor (PR) levels by immunohistochemistry in the paraventricular nucleus (PVN) of the hypothalamus, a key regulatory nucleus of the hypothalamic-pituitary-adrenal (HPA) axis, and found lower PR protein expression in the PVN of prepubertal compared to adult males. These data indicate that in addition to corticosterone, stress-induced adrenocortical progesterone levels are differentially affected by pubertal maturation. Furthermore, these data raise the possibility of different progesterone sensitivity of the PVN before and after puberty. The significance of this differential response is presently unknown. However, given the pleiotropic effects of progesterone on male physiology and behaviour, it is likely that the disparate post-stress exposure to progesterone affects the prepubertal and adult male differently.

  20. Progesterone-Based Therapy Protects Against Influenza by Promoting Lung Repair and Recovery in Females.

    PubMed

    Hall, Olivia J; Limjunyawong, Nathachit; Vermillion, Meghan S; Robinson, Dionne P; Wohlgemuth, Nicholas; Pekosz, Andrew; Mitzner, Wayne; Klein, Sabra L

    2016-09-01

    Over 100 million women use progesterone therapies worldwide. Despite having immunomodulatory and repair properties, their effects on the outcome of viral diseases outside of the reproductive tract have not been evaluated. Administration of exogenous progesterone (at concentrations that mimic the luteal phase) to progesterone-depleted adult female mice conferred protection from both lethal and sublethal influenza A virus (IAV) infection. Progesterone treatment altered the inflammatory environment of the lungs, but had no effects on viral load. Progesterone treatment promoted faster recovery by increasing TGF-β, IL-6, IL-22, numbers of regulatory Th17 cells expressing CD39, and cellular proliferation, reducing protein leakage into the airway, improving pulmonary function, and upregulating the epidermal growth factor amphiregulin (AREG) in the lungs. Administration of rAREG to progesterone-depleted females promoted pulmonary repair and improved the outcome of IAV infection. Progesterone-treatment of AREG-deficient females could not restore protection, indicating that progesterone-mediated induction of AREG caused repair in the lungs and accelerated recovery from IAV infection. Repair and production of AREG by damaged respiratory epithelial cell cultures in vitro was increased by progesterone. Our results illustrate that progesterone is a critical host factor mediating production of AREG by epithelial cells and pulmonary tissue repair following infection, which has important implications for women's health. PMID:27631986

  1. Tightly bound nuclear progesterone receptor is not phosphorylated in primary chick oviduct cultures.

    PubMed Central

    Garcia, T; Jung-Testas, I; Baulieu, E E

    1986-01-01

    Oviduct cells from estradiol-treated chicks were grown in primary culture. After 3-5 days of culture in medium containing estradiol, 90% of the cellular progesterone binding sites were detected in the cytosol. After exposure to [3H]progesterone at 37 degrees C, 80% of the progesterone binding sites were found in nuclear fractions. Progesterone receptor phosphorylation was assessed after incubating the cells with [32P]orthophosphate. Receptor components were immunoprecipitated with a specific polyclonal antibody (IgG-G3) and analyzed by NaDodSO4/PAGE and autoradiography. In the cytosol, constant amounts of 32P-labeled 110-kDa subunit (the B subunit, one of the progesterone-binding components of the receptor) and of the non-steroid-binding heat shock protein hsp90 were found, whether cells had been exposed to progesterone or not. No 32P-labeled 79-kDa subunit (the A subunit, another progesterone-binding subunit) was detected. Various procedures were used to solubilize nuclear progesterone receptor (0.5 M KCl, micrococcal nuclease, NaDodSO4), and in no case was 32P-labeled B subunit detected in the extracts. However, nonradioactive B subunit was detected by immunoblot in a nuclear KCl extract of progesterone-treated cells. These results suggest that the fraction of the B subunit that becomes strongly attached to nuclear structures is not phosphorylated upon exposure of cells to progesterone. Images PMID:3463987

  2. Ovarian cycle approach by rectal temperature and fecal progesterone in a female killer whale, Orcinus orca.

    PubMed

    Kusuda, Satoshi; Kakizoe, Yuka; Kanda, Koji; Sengoku, Tomoko; Fukumoto, Yohei; Adachi, Itsuki; Watanabe, Yoko; Doi, Osamu

    2011-01-01

    This study aimed to validate the measurements of body temperature and fecal progesterone concentrations as minimally invasive techniques for assessing ovarian cycle in a single sexually mature female killer whale. Rectal temperature data, fecal and blood samples were collected in the dorsal position using routine husbandry training on a voluntary basis. The correlations between rectal temperature and plasma progesterone concentration and between fecal and plasma progesterone concentrations were investigated. Fecal progesterone metabolites were identified by a combination of high-performance liquid chromatography and enzyme immunoassay. Plasma progesterone concentrations (range: 0.2-18.6 ng/ml) and rectal temperature (range: 35.3-35.9°C) changed cyclically, and cycle lengths were an average (±SD) of 44.9±4.0 days (nine cycles) and 44.6±5.9 days (nine cycles), respectively. Rectal temperature positively correlated with the plasma progesterone concentrations (r=0.641, P<0.01). There was a visual trend for fecal progesterone profiles to be similar to circulating plasma progesterone profiles. Fecal immunoreactive progestagen analysis resulted in a marked immunoreactive peak of progesterone. The data from the single killer whale indicate that the measurement of rectal temperature is suitable for minimally invasive assessment of the estrous cycle and monitoring the fecal progesterone concentration is useful to assess ovarian luteal activity.

  3. Progesterone-Based Therapy Protects Against Influenza by Promoting Lung Repair and Recovery in Females

    PubMed Central

    Vermillion, Meghan S.; Robinson, Dionne P.; Pekosz, Andrew; Mitzner, Wayne

    2016-01-01

    Over 100 million women use progesterone therapies worldwide. Despite having immunomodulatory and repair properties, their effects on the outcome of viral diseases outside of the reproductive tract have not been evaluated. Administration of exogenous progesterone (at concentrations that mimic the luteal phase) to progesterone-depleted adult female mice conferred protection from both lethal and sublethal influenza A virus (IAV) infection. Progesterone treatment altered the inflammatory environment of the lungs, but had no effects on viral load. Progesterone treatment promoted faster recovery by increasing TGF-β, IL-6, IL-22, numbers of regulatory Th17 cells expressing CD39, and cellular proliferation, reducing protein leakage into the airway, improving pulmonary function, and upregulating the epidermal growth factor amphiregulin (AREG) in the lungs. Administration of rAREG to progesterone-depleted females promoted pulmonary repair and improved the outcome of IAV infection. Progesterone-treatment of AREG-deficient females could not restore protection, indicating that progesterone-mediated induction of AREG caused repair in the lungs and accelerated recovery from IAV infection. Repair and production of AREG by damaged respiratory epithelial cell cultures in vitro was increased by progesterone. Our results illustrate that progesterone is a critical host factor mediating production of AREG by epithelial cells and pulmonary tissue repair following infection, which has important implications for women’s health. PMID:27631986

  4. TReP-132 Is a Novel Progesterone Receptor Coactivator Required for the Inhibition of Breast Cancer Cell Growth and Enhancement of Differentiation by Progesterone

    PubMed Central

    Gizard, Florence; Robillard, Romain; Gross, Barbara; Barbier, Olivier; Révillion, Françoise; Peyrat, Jean-Philippe; Torpier, Gérard; Hum, Dean W.; Staels, Bart

    2006-01-01

    The sex steroid progesterone is essential for the proliferation and differentiation of the mammary gland epithelium during pregnancy. In relation to this, in vitro studies using breast carcinoma T47D cells have demonstrated a biphasic progesterone response, consisting of an initial proliferative burst followed by a sustained growth arrest. However, the transcriptional factors acting with the progesterone receptor (PR) to mediate the progesterone effects on mammary cell growth and differentiation remain to be determined. Recently, it has been demonstrated that the transcriptional regulating protein of 132 kDa (TReP-132), initially identified as a regulator of steroidogenesis, is also a cell growth suppressor. Similar to progesterone-bound PR, TReP-132 acts by inducing the gene expression of the G1 cyclin-dependent kinase inhibitors p21WAF1/Cip1 (p21) and p27Kip1 (p27). The putative interaction between TReP-132 and progesterone pathways in mammary cells was therefore analyzed in the present study. Our results show that TReP-132 interacts in vitro and in T47D cells with progesterone-activated PR. TReP-132 synergizes with progesterone-bound PR to trans activate the p21 and p27 gene promoters at proximal Sp1-binding sites. Moreover, TReP-132 overexpression and knockdown, respectively, increased or prevented the induction of p21 and p27 gene expression by progesterone. As a consequence, TReP-132 knockdown also resulted in the loss of the inhibitory effects of progesterone on pRB phosphorylation, G1/S cell cycle progression, and cell proliferation. Furthermore, the knockdown of TReP-132 expression also prevented the induction of both early and terminal markers of breast cell differentiation which had been previously identified as progesterone target genes. As well, the progesterone-induced accumulation of lipid vacuoles was inhibited in the TReP-132-depleted cells. Finally, TReP-132 gene expression levels increased following progesterone treatment, indicating the

  5. Body Mass Index Is Positively Associated with Endometrial Cancer in Chinese Women, Especially Prior to Menopause

    PubMed Central

    Gao, Yifei; Dai, Xujing; Chen, Limei; Lee, Arier C; Tong, Mancy; Wise, Michelle; Chen, Qi

    2016-01-01

    Objective: Obesity is a well-known risk factor for developing endometrial cancer. However, the incidence and survival rate of endometrial cancer are associated with ethnicity and geographical area. In addition, whether menopausal status is associated with developing endometrial cancer in obese women and whether obesity is associated with subtypes of endometrial cancer have not been fully investigated. Here, we investigated the effect of BMI on developing endometrial cancer in Chinese women taking into account menopausal status and cancer subtypes. Methods: Data on 1,127 women with endometrial cancer including body mass index (BMI), age at diagnosis, parity, menopausal status and cancer subtype were collected from the largest obstetrics & gynaecology hospital in China and analysed. Results: After adjusting for age and parity, the odds for developing endometrial cancer in overweight or obese perimenopausal women was significantly higher than that in women with normal weight (OR=2.6 with 95%CI:1.9-3.5, and OR=3.5 with 95%CI: 2.2-5.4, respectively). The odds of developing endometrial cancer in overweight postmenopausal women were significantly higher than that in women who were normal weight (OR=2.4 with 95%CI: 1.8-3.1), however this was not the case for obese postmenopausal women. We further found that BMI, menopausal status, age and parity were not associated with subtypes of endometrial cancer. Conclusion: Our data demonstrate that obesity is positively associated with the incidence of developing endometrial cancer in Chinese women, with more significant effects in perimenopausal women. PMID:27326261

  6. Progesterone and Overlooked Endocrine Pathways in Breast Cancer Pathogenesis

    PubMed Central

    Hess, Kathryn; Jeitziner, Rachel

    2015-01-01

    Worldwide, breast cancer incidence has been increasing for decades. Exposure to reproductive hormones, as occurs with recurrent menstrual cycles, affects breast cancer risk, and can promote disease progression. Exogenous hormones and endocrine disruptors have also been implicated in increasing breast cancer incidence. Numerous in vitro studies with hormone-receptor-positive cell lines have provided insights into the complexities of hormone receptor signaling at the molecular level; in vivo additional layers of complexity add on to this. The combined use of mouse genetics and tissue recombination techniques has made it possible to disentangle hormone action in vivo and revealed that estrogens, progesterone, and prolactin orchestrate distinct developmental stages of mammary gland development. The 2 ovarian steroids that fluctuate during menstrual cycles act on a subset of mammary epithelial cells, the hormone-receptor-positive sensor cells, which translate and amplify the incoming systemic signals into local, paracrine stimuli. Progesterone has emerged as a major regulator of cell proliferation and stem cell activation in the adult mammary gland. Two progesterone receptor targets, receptor activator of NfκB ligand and Wnt4, serve as downstream paracrine mediators of progesterone receptor-induced cell proliferation and stem cell activation, respectively. Some of the findings in the mouse have been validated in human ex vivo models and by next-generation whole-transcriptome sequencing on healthy donors staged for their menstrual cycles. The implications of these insights into the basic control mechanisms of mammary gland development for breast carcinogenesis and the possible role of endocrine disruptors, in particular bisphenol A in this context, will be discussed below. PMID:26241069

  7. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

    SciTech Connect

    Kallander, Lara S.; Washburn, David G.; Hoang, Tram H.; Frazee, James S.; Stoy, Patrick; Johnson, Latisha; Lu, Qing; Hammond, Marlys; Barton, Linda S.; Patterson, Jaclyn R.; Azzarano, Leonard M.; Nagilla, Rakesh; Madauss, Kevin P.; Williams, Shawn P.; Stewart, Eugene L.; Duraiswami, Chaya; Grygielko, Eugene T.; Xu, Xiaoping; Laping, Nicholas J.; Bray, Jeffrey D.; Thompson, Scott K.

    2010-09-17

    The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.

  8. Progesterone and Overlooked Endocrine Pathways in Breast Cancer Pathogenesis.

    PubMed

    Brisken, Cathrin; Hess, Kathryn; Jeitziner, Rachel

    2015-10-01

    Worldwide, breast cancer incidence has been increasing for decades. Exposure to reproductive hormones, as occurs with recurrent menstrual cycles, affects breast cancer risk, and can promote disease progression. Exogenous hormones and endocrine disruptors have also been implicated in increasing breast cancer incidence. Numerous in vitro studies with hormone-receptor-positive cell lines have provided insights into the complexities of hormone receptor signaling at the molecular level; in vivo additional layers of complexity add on to this. The combined use of mouse genetics and tissue recombination techniques has made it possible to disentangle hormone action in vivo and revealed that estrogens, progesterone, and prolactin orchestrate distinct developmental stages of mammary gland development. The 2 ovarian steroids that fluctuate during menstrual cycles act on a subset of mammary epithelial cells, the hormone-receptor-positive sensor cells, which translate and amplify the incoming systemic signals into local, paracrine stimuli. Progesterone has emerged as a major regulator of cell proliferation and stem cell activation in the adult mammary gland. Two progesterone receptor targets, receptor activator of NfκB ligand and Wnt4, serve as downstream paracrine mediators of progesterone receptor-induced cell proliferation and stem cell activation, respectively. Some of the findings in the mouse have been validated in human ex vivo models and by next-generation whole-transcriptome sequencing on healthy donors staged for their menstrual cycles. The implications of these insights into the basic control mechanisms of mammary gland development for breast carcinogenesis and the possible role of endocrine disruptors, in particular bisphenol A in this context, will be discussed below. PMID:26241069

  9. Non-canonical Progesterone Signaling in Granulosa Cell Function

    PubMed Central

    Peluso, John J.; Pru, James K.

    2014-01-01

    It has been known for over three decades that progesterone (P4) suppresses follicle growth. It has been assumed that P4 acts directly on granulosa cells of developing follicles to slow their development, since P4 inhibits both mitosis and apoptosis of cultured granulosa cells. However, granulosa cells of developing follicles of mice, rats, monkeys and humans do not express the A or B form of the classic nuclear receptor for progesterone (PGR). In contrast, these granulosa cells express other progesterone binding proteins, one of which is referred to as Progesterone Receptor Membrane Component 1 (PGRMC1). PGRMC1 specifically binds P4 with high affinity and mediates P4’s anti-mitotic and anti-apoptotic action as evidenced by the lack of these P4-dependent effects in PGRMC1-depleted cells. In addition, mice in which PGRMC1 is conditionally depleted in granulosa cells show diminished follicle development. While the mechanism through which P4 activation of PGRMC1 affects granulosa cell function is not well defined, it appears that PGRMC1 controls granulosa cell function in part by regulating gene expression in T cell specific transcription factor/lymphoid enhancer factor (Tcf/Lef)-dependent manner. Clinically, altered PGRMC1 expression has been correlated with premature ovarian failure/insufficiency, polycystic ovarian syndrome and infertility. These collective studies provide strong evidence that PGRMC1 functions as a receptor for P4 in granulosa cells and that altered expression results in compromised reproductive capacity. Ongoing studies seek to define the components of the signal transduction cascade through which P4-activation of PGRMC1 results in the regulation of granulosa cell function. PMID:24516175

  10. Transcriptional regulation of genes related to progesterone production.

    PubMed

    Mizutani, Tetsuya; Ishikane, Shin; Kawabe, Shinya; Umezawa, Akihiro; Miyamoto, Kaoru

    2015-01-01

    Steroid hormones are synthesized from cholesterol in various tissues, mainly in the adrenal glands and gonads. Because these lipid-soluble steroid hormones immediately diffuse through the cells in which they are produced, their secretion directly reflects the activity of the genes related to their production. Progesterone is important not only for luteinization and maintenance of pregnancy, but also as a substrate for most other steroids. Steroidogenic acute regulatory protein (STAR), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), and 3β-hydroxysteroid dehydrogenase/Δ(5)-Δ(4) isomerase (3β-HSD) are well-known proteins essential for progesterone production. In addition to them, glutathione S-transferase A1-1 and A3-3 are shown to exert Δ(5)-Δ(4) isomerization activity to produce progesterone in a cooperative fashion with 3β-HSD. 5-Aminolevulinic acid synthase 1, ferredoxin 1, and ferredoxin reductase also play a role in steroidogenesis as accessory factors. Members of the nuclear receptor 5A (NR5A) family (steroidogenic factor 1 and liver receptor homolog 1) play a crucial role in the transcriptional regulation of these genes. The NR5A family activates these genes by binding to NR5A responsive elements present within their promoter regions, as well as to the elements far from their promoters. In addition, various NR5A-interacting proteins including peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), nuclear receptor subfamily 0, group B, member 1 (DAX-1), and CCAAT/enhancer-binding proteins (C/EBP) are involved in the transcription of NR5A target genes and regulate the transcription either positively or negatively under both basal and tropic hormone-stimulated conditions. In this review, we describe the transcriptional regulation of genes related to progesterone production. PMID:26135521

  11. Interaction of progesterone receptor with immobilized adenosine triphosphate.

    PubMed

    Moudgil, V K; Toft, D O

    1977-02-22

    Affinity chromatography has been used to study the binding of ATP to cyto-plasmic progesterone receptors of hen oviduct. A resin which selectively binds the receptor protein was prepared by linking ATP covalently to Sepharose 4B through a 6-carbon bridge of adipic acid dihydrazide. Receptor bound to the affinity resin was recovered in a single peak upon gradient elution with KCl (0.2-1 M) or ATP (0-0.1 M). While affinity chromatography was normally accomplished using the [3H]progesterone receptor complex, the hormone was not necessary for ATP binding under the conditions employed. The chromatography of crude receptor preparations allowed up to 100-fold purification with greater than 80% recovery of the receptor. The semipurified receptor appeared intact when analysed by sucrose gradient centrifugation, polyacrylamide gel electrophoresis, and DEAE-cellulose chromatography. The latter procedure separated the receptor into two components, A and B, both of which were capable of binding ATP. Although a specific biochemical role of ATP in hormone receptor action has not been demonstrated, the present studies support this possibility and, in addition, offer a convenient and reliable step for the purification of progesterone receptors. PMID:836885

  12. Inhibition of human placental progesterone synthesis by danazol in vivo.

    PubMed

    Rabe, T; Kiesel, L; Franke, C; Runnebaum, B; Mösch, R; Nobakht, N

    1984-01-01

    In vivo, a single dose of 1000 mg danazol was given orally to pregnant volunteers (n = 8) prior to a therapeutic abortion (8th-12th week of gestation). Changes in serum progesterone and estradiol were evaluated both by analysis of percentage values related to initial concentrations or statistically by a Kruskal-Wallis test comparing absolute steroid concentrations. Following treatment (n = 8), a significant decrease in mean plasma progesterone of about 20% was observed within 2-4 hours; progesterone levels varied between 80-120% during 24 hours in controls (n = 10); individual serum estradiol decreased up to 30% of control values 2 hours after danazol application. Changes in estradiol in controls versus tests were not statistically significant (p less than 0.05) when absolute estradiol concentrations were compared. Only a slight (10-20%) decrease in mean serum DHAS was found between 2 to 6 hours following danazol treatment. This study demonstrates the inhibitory activity of danazol on the human maternal and fetal steroidogenesis in vivo. The possible sites of action of danazol are discussed.

  13. MOLECULAR MECHANISMS INVOLVED IN PROGESTERONE RECEPTOR REGULATION OF UTERINE FUNCTION

    PubMed Central

    Lee, K.; Jeong, J.; Tsai, M.-J.; Tsai, S.; Lydon, J. P.; DeMayo, F. J.

    2007-01-01

    The ovarian steroid hormone progesterone is a major regulator of uterine function. The actions of this hormone is mediated through its cognate receptor, the progesterone receptor, Pgr. Ablation of the Pgr has shown that this receptor is critical for all female reproductive functions including the ability of the uterus to support and maintain the development of the implanting mouse embryo. High density DNA microarray analysis has identified direct and indirect targets of Pgr action. One of the targets of Pgr action is a member of the Hedgehog morphogen Indian hedgehog, Ihh. Ihh and members of the Hh signaling cascade show a coordinate expression pattern in the mouse uterus during the preimplantation period of pregnancy. The expression of Ihh and its receptor Patched-1, Ptc1, as well as, down stream targets of Ihh-Ptch1 signaling, such as the orphan nuclear receptor COUP-TF II show that this morphogen pathway mediates communication between the uterine epithelial and stromal compartments. The members of the Ihh signaling axis may function to coordinate the proliferation, vascularization and differentiation of the uterine stroma during pregnancy. This analysis demonstrates that progesterone regulates uterine function in the mouse by coordinating the signals from the uterine epithelium to stroma in the preimplantation mouse uterus. PMID:17067792

  14. Methylation Analysis of DNA Mismatch Repair Genes Using DNA Derived from the Peripheral Blood of Patients with Endometrial Cancer: Epimutation in Endometrial Carcinogenesis.

    PubMed

    Takeda, Takashi; Banno, Kouji; Yanokura, Megumi; Adachi, Masataka; Iijima, Moito; Kunitomi, Haruko; Nakamura, Kanako; Iida, Miho; Nogami, Yuya; Umene, Kiyoko; Masuda, Kenta; Kobayashi, Yusuke; Yamagami, Wataru; Hirasawa, Akira; Tominaga, Eiichiro; Susumu, Nobuyuki; Aoki, Daisuke

    2016-10-14

    Germline mutation of DNA mismatch repair (MMR) genes is a cause of Lynch syndrome. Methylation of MutL homolog 1 (MLH1) and MutS homolog 2 (MSH2) has been detected in peripheral blood cells of patients with colorectal cancer. This methylation is referred to as epimutation. Methylation of these genes has not been studied in an unselected series of endometrial cancer cases. Therefore, we examined methylation of MLH1, MSH2, and MSH6 promoter regions of peripheral blood cells in 206 patients with endometrial cancer using a methylation-specific polymerase chain reaction (MSP). Germline mutation of MMR genes, microsatellite instability (MSI), and immunohistochemistry (IHC) were also analyzed in each case with epimutation. MLH1 epimutation was detected in a single patient out of a total of 206 (0.49%)-1 out of 58 (1.72%) with an onset age of less than 50 years. The patient with MLH1 epimutation showed high level MSI (MSI-H), loss of MLH1 expression and had developed endometrial cancer at 46 years old, complicated with colorectal cancer. No case had epimutation of MSH2 or MSH6. The MLH1 epimutation detected in a patient with endometrial cancer may be a cause of endometrial carcinogenesis. This result indicates that it is important to check epimutation in patients with endometrial cancer without a germline mutation of MMR genes.

  15. Methylation Analysis of DNA Mismatch Repair Genes Using DNA Derived from the Peripheral Blood of Patients with Endometrial Cancer: Epimutation in Endometrial Carcinogenesis

    PubMed Central

    Takeda, Takashi; Banno, Kouji; Yanokura, Megumi; Adachi, Masataka; Iijima, Moito; Kunitomi, Haruko; Nakamura, Kanako; Iida, Miho; Nogami, Yuya; Umene, Kiyoko; Masuda, Kenta; Kobayashi, Yusuke; Yamagami, Wataru; Hirasawa, Akira; Tominaga, Eiichiro; Susumu, Nobuyuki; Aoki, Daisuke

    2016-01-01

    Germline mutation of DNA mismatch repair (MMR) genes is a cause of Lynch syndrome. Methylation of MutL homolog 1 (MLH1) and MutS homolog 2 (MSH2) has been detected in peripheral blood cells of patients with colorectal cancer. This methylation is referred to as epimutation. Methylation of these genes has not been studied in an unselected series of endometrial cancer cases. Therefore, we examined methylation of MLH1, MSH2, and MSH6 promoter regions of peripheral blood cells in 206 patients with endometrial cancer using a methylation-specific polymerase chain reaction (MSP). Germline mutation of MMR genes, microsatellite instability (MSI), and immunohistochemistry (IHC) were also analyzed in each case with epimutation. MLH1 epimutation was detected in a single patient out of a total of 206 (0.49%)—1 out of 58 (1.72%) with an onset age of less than 50 years. The patient with MLH1 epimutation showed high level MSI (MSI-H), loss of MLH1 expression and had developed endometrial cancer at 46 years old, complicated with colorectal cancer. No case had epimutation of MSH2 or MSH6. The MLH1 epimutation detected in a patient with endometrial cancer may be a cause of endometrial carcinogenesis. This result indicates that it is important to check epimutation in patients with endometrial cancer without a germline mutation of MMR genes. PMID:27754426

  16. Oxytocin Increases Invasive Properties of Endometrial Cancer Cells Through Phosphatidylinositol 3-Kinase/AKT-Dependent Up-Regulation of Cyclooxygenase-1, -2, and X-Linked Inhibitor of Apoptosis Protein1

    PubMed Central

    Déry, Marie-Claude; Chaudhry, Parvesh; Leblanc, Valérie; Parent, Sophie; Fortier, Anne-Marie; Asselin, Eric

    2011-01-01

    Traditionally, oxytocin (OT) is well known to play a crucial role in the regulation of cyclic changes in the uterus, implantation of the embryo, and parturition. Recently, an additional role for OT has been identified in several types of cancer cells in which OT acts as a growth regulator. In endometrial cancer cells, OT is known to efficiently inhibit cellular proliferation. In the present study, we show that OT increases invasiveness of human endometrial carcinoma (HEC) cells, which are otherwise resistant to the growth-inhibiting effects of OT. Using pharmacological inhibitors, invasion assay, RNA interference, and immunofluorescence, we found that OT enhances the invasive properties of HEC cells through up-regulation of X-linked inhibitor of apoptosis protein (XIAP), matrix-metalloproteinase 2 (MMP2), and matrix-metalloproteinase 14 (MMP14). In addition, we show that OT-mediated invasion is both cyclooxygenase 1 (PTGS1) and cyclooxygenase-2 (PTGS2) dependent via the phosphatidylinositol 3-kinase/AKT (PIK3/AKT) pathway. PTGS2 knockdown by shRNA resulted in XIAP down-regulation. We also show that OT receptor is overexpressed in grade I to III endometrial cancer. Taken together, our results describe for the first time a novel role for OT in endometrial cancer cell invasion. PMID:21816851

  17. Lifetime physical activity and risk of endometrial cancer

    PubMed Central

    John, Esther M.; Koo, Jocelyn; Horn-Ross, Pamela L.

    2010-01-01

    Background The role of moderate physical activity and life patterns of activity in reducing endometrial cancer risk remains uncertain. Methods We assessed lifetime histories of activity from recreation, transportation, chores, and occupation and other risk factors in a population-based case-control study of endometrial cancer conducted in the San Francisco Bay area. The analysis was based on 472 newly diagnosed cases ascertained by the regional cancer registry and 443 controls identified by random-digit dialing who completed an in-person interview. Results Reduced risks associated with greater lifetime physical activity (highest vs. lowest tertile) were found for both total activity (odds ratio (OR) = 0.61 (95% confidence interval (CI) = 0.43–0.87, ptrend = 0.01) and activity of moderate intensity (OR=0.44, 95% CI=0.30–0.64, ptrend < 0.0001). Compared to women with low lifetime physical activity (below median), those with greater activity throughout life had the highest reduction in risk (OR=0.62, 95% CI=0.44–0.88). Inverse associations were stronger in obese and overweight women, but differences were not statistically significantly different from those in normal weight women. Conclusion These findings suggest that physical activity in adulthood, even of moderate intensity, may be effective in lowering the risk of endometrial cancer, particularly among those at highest risk for this disease. Impact The results emphasize the importance of evaluating lifetime histories of physical activity from multiple sources, including both recreational and non-recreational activities of various intensities, in order to fully understand the relation between physical activity and disease risk. PMID:20406960

  18. Transvaginal ultrasound examination of myometrial infiltration by endometrial cancer.

    PubMed

    Miklos, P; Klacko, M; Babala, P; Masak, L; Ondrus, D; Waczulikova, I

    2014-01-01

    The depth of myometrial infiltration by endometrial cancer is an important prognostic factor. The examination of the depth of infiltration classifies the patients in the low- and high-risk groups, which influences the therapeutic approach. Transvaginal ultrasonography represents a first-choice diagnostic test for the assessment of the depth of myometrial infiltration as the time consumption and financial demands of magnetic resonance imaging need to be taken into account. In comparison with the MRI, the diagnostic accuracy of the transvaginal ultrasound depends more on the individual experience and professional potential of the examining physician. This fact can contribute to the heterogeneity of published results of transvaginal ultrasound on the determination of infiltration depth. Having in mind the aim to verify these indicators in our local conditions and environment, we decided to prospectively study 150 endometrial cancer patients who were examined with the transvaginal ultrasound in the period 1/2009 - 10/ 2011. Correlated firstly with the preoperative and then secondly with the definitive histopathological examination was the depth-of-infiltration-related data that had been taken from the ultrasound findings. The output being monitored was the exclusion or confirmation of the invasion exceeding half the thickness of myometrium. In our study, the diagnostic accuracy of the method reached 82.67 %, while the other indicators were as follows: sensitivity 92.31 %, specificity 79.28 %, positive predictive value (PPV) 61.02 %, negative predictive value (NPV) 96.7 %, the likelihood ratio of a positive test 4.455 and the likelihood ratio of a negative test 0.097. The results of the depth of myometrial infiltration examination and their comparison with the data from similarly oriented clinical studies entitle us to include this examination in the set of standard preoperative methods used for the examination of patients with endometrial cancer (Tab. 3, Fig. 5, Ref

  19. Odds ratio analysis in women with endometrial cancer

    PubMed Central

    Żak, Ewa; Pięta, Beata

    2016-01-01

    Introduction Despite the progress in diagnosis and treatment of malignant tumours, the effects of treatment are insufficient. Reduction of the risk of cervical, ovarian, and endometrial cancer is possible by introducing preventative actions. Aim of the study The aim of the thesis is the analysis of selected risk factors that may affect the increase or decrease in the odds ratio of developing endometrial cancer. Material and methods The study was conducted among patients of the Gynaecology and Obstetrics Hospital of Poznań University of Medical Sciences in the years 2011-2013. The research included a total of 548 female respondents aged between 40 and 84 years. Women responded to questions assessing elements of lifestyle such as consumption of alcohol, smoking, and eating certain groups of foods. Results The respondents consuming fruits and vegetables several times a week have a reduced risk of odds ratio and the OR is 0.85; 95% CI: 0.18-4.09, compared to the women who rarely consume vegetables and fruits. Consumption of whole-wheat bread several times a week reduces the risk of developing the cancer, OR = 0.59; 95% CI: 0.14-2.47, compared to women not consuming wholegrain bread at all. Respondents who consumed red meat, such as veal, pork, and lamb in the amount of 101-200 g per day have an increased risk of developing the disease: OR = 2.16; 95% CI: 1.09-4.28, compared to women not consuming red meat at all. Conclusions A diet rich in fruit and vegetables, onions, garlic, whole grains, and beans should be introduced in order to reduce the risk of endometrial cancer. The consumption of red meat and white pasta should be reduced or even eliminated. PMID:27095953

  20. Induction of 11β-HSD 1 and activation of distinct mineralocorticoid receptor- and glucocorticoid receptor-dependent gene networks in decidualizing human endometrial stromal cells.

    PubMed

    Kuroda, Keiji; Venkatakrishnan, Radha; Salker, Madhuri S; Lucas, Emma S; Shaheen, Fozia; Kuroda, Masako; Blanks, Andrew; Christian, Mark; Quenby, Siobhan; Brosens, Jan J

    2013-02-01

    The actions of glucocorticoids at the feto-maternal interface are not well understood. Here, we show that decidualization of human endometrial stromal cells (HESCs) in response to progesterone and cAMP signaling is associated with a strong induction of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) expression and enzyme activity. Decidualization also triggered a gradual decrease in glucocorticoid receptor (GR) expression and reciprocal increase in mineralocorticoid receptor (MR) levels. Gene expression profiling of differentiating HESCs after small interfering RNA (siRNA)-mediated knockdown of either GR or MR identified 239 and 167 significantly regulated genes, respectively. Interestingly, GR-repressed genes were enriched for Krüppel-associated box domain containing zinc-finger proteins, transcriptional repressors involved in heterochromatin formation. In agreement, GR knockdown was sufficient to enhance trimethylated H3K9 levels in decidualizing cells. Conversely, we identified several MR-dependent genes implicated in lipid droplet biogenesis and retinoid metabolism. For example, the induction in differentiating HESCs of DHRS3, encoding a highly conserved enzyme that catalyzes the oxidation/reduction of retinoids and steroids, was enhanced by aldosterone, attenuated in response to MR knockdown, and abolished upon treatment with the MR antagonist RU26752. Furthermore, we demonstrate that decidualization is associated with dynamic changes in the abundance and distribution of cytoplasmic lipid droplets, the formation of which was blocked by RU26752. In summary, progesterone drives local cortisol biosynthesis by decidual cells through induction of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), leading to transcriptional regulation of distinct GR and MR gene networks involved in epigenetic programming and lipid and retinoid metabolism, respectively. PMID:23275455

  1. Endometrial decidualization: a rare cause of acute appendicitis during pregnancy

    PubMed Central

    Murphy, Skyle J.; Kaur, Anupinder; Wullschleger, Martin E.

    2016-01-01

    Appendicular endometriosis is a rare and poorly understood pathology that affects women in their reproductive years. In the gravid woman, ectopic endometrial tissue undergoes decidualization. This physiological process can result in acute appendicitis in exceptional cases. Here we describe a patient in her second trimester of pregnancy who presented with right iliac fossa pain and clinical, laboratory and imaging findings consistent with acute appendicitis. A laparoscopic appendectomy was performed with intraoperative findings suspicious for malignancy. Histological analysis made the surprising diagnosis of decidualized endometriosis causing luminal constriction resulting in acute appendicitis. We also detail the challenging diagnostic and management issues faced by clinicians in such cases. PMID:27106612

  2. Progesterone Reduces Secondary Damage, Preserves White Matter, and Improves Locomotor Outcome after Spinal Cord Contusion

    PubMed Central

    Garcia-Ovejero, Daniel; González, Susana; Paniagua-Torija, Beatriz; Lima, Analía; Molina-Holgado, Eduardo; De Nicola, Alejandro F.

    2014-01-01

    Abstract Progesterone is an anti-inflammatory and promyelinating agent after spinal cord injury, but its effectiveness on functional recovery is still controversial. In the current study, we tested the effects of chronic progesterone administration on tissue preservation and functional recovery in a clinically relevant model of spinal cord lesion (thoracic contusion). Using magnetic resonance imaging, we observed that progesterone reduced both volume and rostrocaudal extension of the lesion at 60 days post-injury. In addition, progesterone increased the number of total mature oligodendrocytes, myelin basic protein immunoreactivity, and the number of axonal profiles at the epicenter of the lesion. Further, progesterone treatment significantly improved motor outcome as assessed using the Basso-Bresnahan-Beattie scale for locomotion and CatWalk gait analysis. These data suggest that progesterone could be considered a promising therapeutical candidate for spinal cord injury. PMID:24460450

  3. Role of progesterone and progestin therapy in threatened abortion and preterm labour.

    PubMed

    Szekeres-Bartho, Julia; Wilczynski, Jacek R; Basta, Pawel; Kalinka, Jaroslaw

    2008-01-01

    Progesterone (P) has been widely used in an attempt to prevent threatened miscarriage, recurrent miscarriage and pre-term labour. Successful pregnancy depends on maternal tolerance of the fetal "semi-allograft". Along with its endocrine effects, P also acts as an "immunosteroid", by controlling the bias towards a pregnancy protective immune milieu. A protein called progesterone-induced blocking factor (PIBF), by inducing a Th2 dominant cytokine production mediates the immunological effects of progesterone. Progesterone plays a role in uterine homing of NK cells and up-regulates HLA-G gene expression, the ligand for various NK inhibitory receptors. At high concentrations, progesterone is a potent inducer of Th2-type cytokines as well as of LIF and M-CSF production by T cells. The possible mechanisms by which progesterone contributes to the maintenance of early and late pregnancy are discussed. PMID:17981685

  4. Progesterone augments cell susceptibility to HIV-1 and HIV-1/HSV-2 co-infections.

    PubMed

    Ragupathy, Viswanath; Xue, Wang; Tan, Ji; Devadas, Krishnakumar; Gao, Yamei; Hewlett, Indira

    2016-10-01

    In human immunodeficiency virus type 1 (HIV-1)-infected women, oral or injectable progesterone containing contraceptive pills may enhance HIV-1 acquisition in vivo, and the mechanism by which this occurs is not fully understood. In developing countries, Herpes simplex virus type-2 (HSV-2) co-infection has been shown to be a risk for increase of HIV-1 acquisition and, if co-infected women use progesterone pills, infections may increase several fold. In this study, we used an in vitro cell culture system to study the effects of progesterone on HIV-1 replication and to explore the molecular mechanism of progesterone effects on infected cells. In our in vitro model, CEMss cells (lymphoblastoid cell line) were infected with either HIV-1 alone or co-infected with HSV-2. HIV-1 viral load was measured with and without sex hormone treatment. Progesterone-treated cells showed an increase in HIV-1 viral load (1411.2 pg/mL) compared with cells without progesterone treatment (993.1 pg/mL). Increased cell death was noted with HSV-2 co-infection and in progesterone-treated cells. Similar observations were noted in peripheral blood mononuclear cells (PBMC) cells derived from three female donors. Progesterone-treated cells also showed reduced antiviral efficacy. Inflammatory cytokines and associations with biomarkers of disease progression were explored. Progesterone upregulated inflammatory cytokines and chemokines conversely and downregulated anti-apoptotic Bcl-2 expression. Nuclear protein analysis by electrophoretic mobility shift assay showed the association of progesterone with progesterone response element (PRE), which may lead to downregulation of Bcl-2. These data indicate that progesterone treatment enhances HIV-1 replication in infected cells and co-infection with HSV-2 may further fuel this process. PMID:27538988

  5. Disseminated intravascular coagulation induced by progesterone in the pregnant rat. Prevention by estogens.

    PubMed Central

    Stamler, F. W.

    1977-01-01

    Fatal disseminated intravascular coagulation (DIC) was induced in female rats by administration of progesterone in late pregnacy. This prevented parturition, with intrauterine fetal death 2 to 4 days past term and subsequent retention of dead fetuses. Concomitantly with or closely following the intrauterine death of their litters, a large proportion of pregnant rats died with histologically evident DIC. Administration of cortisone, heparin, or disoumarin did not prevent DIC, and xi-aminocaproic acid, acetylsalicylic acid, or an onion-rich diet tended to increase its incidence. Antibiotic regimens gave variable results, with significant decrease in DIC only with a combination of two wide-spectrum penicillins. Neomycin and polymyxin had little effect on susceptible Sprague-dawley derived rats, but polymxin caused a significant increase in DIC in a resistant strain of hooded rats. Fatal maternal DIC was completely prevented only by use of natural or synthetic estrogens concurrently with progesterone, although this did not alter the sequence of abnormally prolonged pregnacy with intrauterine fetal death and retention of dead fetuses. Potencies of estrogens varied greatly, but all compounds tested prevented DIC at adequate dosage levels. Diethylstilbestrol, the most potent drug tested, was completely protective at 1 mug daily given subcutaneously. beta-Estradiol was the most effective natural estrogen, giving complete protection with a 10-mug daily subcutaneous injection. Estrogens were much more potent by subcutaneous injection than by oral ingestion, and toxic side effects were sometimes noted with higher levels of the latter. For estrogen therapy to be effective, it was necessary to begin its use before the expected onset of DIC, and in no instance was there evidence of reversal of this process after signs of illness were observed. Images Figure 3 Figure 4 Figure 1 Figure 2 PMID:65916

  6. Enhanced Human Decidual Cell-Expressed FKBP51 May Promote Labor-Related Functional Progesterone Withdrawal.

    PubMed

    Schatz, Frederick; Guzeloglu-Kayisli, Ozlem; Basar, Murat; Buchwalder, Lynn F; Ocak, Nehir; Guzel, Elif; Guller, Seth; Semerci, Nihan; Kayisli, Umit A; Lockwood, Charles J

    2015-09-01

    Sustained plasma progesterone (P4) levels suggest initiation of human term labor by functional P4 withdrawal, reflecting reduced progesterone receptor (PR) and/or glucocorticoid receptor (GR) expression or activity. The steroid-induced immunophilin cochaperone FKBP51 inhibits PR- and GR-mediated transcription, suggesting a labor-initiating role. Gestational age-matched decidual sections were immunostained for FKBP51 and decidual cell (DC) and interstitial trophoblast (IT) markers, vimentin and cytokeratin, respectively. Term DC cultures were incubated with vehicle (control), estradiol (E2) with or without medroxyprogesterone acetate, dexamethasone (Dex), or Organon 2058. FKBP51 histologic scoring was significantly higher in DC nuclei during labor versus prelabor decidua, whereas FKBP51 immunostaining was undetected in interstitial trophoblasts (P < 0.05). In term DC cultures, E2 + medroxyprogesterone acetate or E2 + Dex enhanced FKBP51 expression (P < 0.01), whereas E2 + Organon 2058 inhibited PR expression (P < 0.05), and E2 + Dex inhibited GR expression (P < 0.05). Unlike term DCs, FKBP51 was undetected in control or Dex-treated cultured third-trimester trophoblasts. Electrophoretic mobility shift assays revealed that FKPB51 overexpression or silencing in cultured DCs altered PR-DNA binding. Increased FKBP51 levels in term DCs during labor complement our prior in situ observations of significantly lower PR in labor versus prelabor DCs. In a milieu of sustained plasma P4 levels, these reciprocal changes will amplify functional P4 withdrawal in DCs via FKBP51-mediated PR resistance coupled with declining PR levels, whereas the lack of FKBP51 expression in interstitial trophoblasts suggests unopposed constitutive GR action.

  7. Disseminated intravascular coagulation induced by progesterone in the pregnant rat. Prevention by estogens.

    PubMed

    Stamler, F W

    1977-03-01

    Fatal disseminated intravascular coagulation (DIC) was induced in female rats by administration of progesterone in late pregnacy. This prevented parturition, with intrauterine fetal death 2 to 4 days past term and subsequent retention of dead fetuses. Concomitantly with or closely following the intrauterine death of their litters, a large proportion of pregnant rats died with histologically evident DIC. Administration of cortisone, heparin, or disoumarin did not prevent DIC, and xi-aminocaproic acid, acetylsalicylic acid, or an onion-rich diet tended to increase its incidence. Antibiotic regimens gave variable results, with significant decrease in DIC only with a combination of two wide-spectrum penicillins. Neomycin and polymyxin had little effect on susceptible Sprague-dawley derived rats, but polymxin caused a significant increase in DIC in a resistant strain of hooded rats. Fatal maternal DIC was completely prevented only by use of natural or synthetic estrogens concurrently with progesterone, although this did not alter the sequence of abnormally prolonged pregnacy with intrauterine fetal death and retention of dead fetuses. Potencies of estrogens varied greatly, but all compounds tested prevented DIC at adequate dosage levels. Diethylstilbestrol, the most potent drug tested, was completely protective at 1 mug daily given subcutaneously. beta-Estradiol was the most effective natural estrogen, giving complete protection with a 10-mug daily subcutaneous injection. Estrogens were much more potent by subcutaneous injection than by oral ingestion, and toxic side effects were sometimes noted with higher levels of the latter. For estrogen therapy to be effective, it was necessary to begin its use before the expected onset of DIC, and in no instance was there evidence of reversal of this process after signs of illness were observed.

  8. Fludeoxyglucose F 18 PET Scan, CT Scan, and Ferumoxtran-10 MRI Scan Before Chemotherapy and Radiation Therapy in Finding Lymph Node Metastasis in Patients With Locally Advanced Cervical Cancer or High-Risk Endometrial Cancer

    ClinicalTrials.gov

    2016-09-19

    Cervical Adenocarcinoma; Cervical Adenosquamous Cell Carcinoma; Cervical Small Cell Carcinoma; Cervical Squamous Cell Carcinoma; Endometrial Clear Cell Carcinoma; Endometrial Papillary Serous Carcinoma; Stage I Endometrial Carcinoma; Stage IB Cervical Cancer; Stage II Endometrial Carcinoma; Stage IIA Cervical Cancer; Stage IIB Cervical Cancer; Stage III Cervical Cancer; Stage III Endometrial Carcinoma; Stage IVA Cervical Cancer

  9. Endometrial and cervical cancer: incidence and mortality among women in the Lodz region

    PubMed Central

    Leśniczak, Beata; Krasomski, Grzegorz; Oszukowski, Przemysław; Woźniak, Piotr

    2015-01-01

    Introduction By the early 21st century the most common cancer of female genitals in Poland was cervical cancer. Now endometrial cancer ranks first. The aim of this study was to analyse the incidence and mortality of endometrial and cervical cancer among women in the Lodz region. Material and methods Data on the incidence and mortality of endometrial and cervical cancer among inhabitants of the Lodz region were obtained from the National Cancer Registry and Bulletin of Cancer Cases in the Lodz region. The analysis covered ten consecutive years beginning in 2001. Results The number of new cases reported in 2010 exceeded that observed in 2001 by 181. The standardized incidence rate of endometrial cancer increased by 6.3, while the standardized incidence rate of cervical cancer decreased by 1.4. Conclusions In the years 2001-2010, the incidence of endometrial cancer increased by 88.3% and that of cervical cancer decreased by 6.5% among inhabitants of the Lodz region. In the years 2001-2010, mortality of endometrial cancer increased by 24.5% and that of cervical cancer decreased by 12.6%. In 2010, the highest crude incidence rates in the Lodz region of both endometrial and cervical cancer at 39.1 were recorded in the district town of Piotrków. PMID:26528109

  10. Joint Effect of Genotypic and Phenotypic Features of Reproductive Factors on Endometrial Cancer Risk

    PubMed Central

    Wang, Zhanwei; Risch, Harvey; Lu, Lingeng; Irwin, Melinda L.; Mayne, Susan; Schwartz, Peter; Rutherford, Thomas; De Vivo, Immaculata; Yu, Herbert

    2015-01-01

    Prolonged estrogen exposure is believed to be the major cause of endometrial cancer. As possible markers of estrogen exposure, various menstrual and reproductive features, e.g., ages at menarche and menopause, are found to be associated with endometrial cancer risk. In order to assess their combined effects on endometrial cancer, we created the total number of menstrual cycles (TNMC) that a woman experienced during her life or up to the time of study and two genetic risk scores, GRS1 for age at menarche and GRS2 for age at menopause. Comparing 482 endometrial cancer patients with 571 population controls, we found TNMC was associated with endometrial cancer risk and that the association remained statistically significant after adjustment for obesity and other potential confounders. Risk increased by about 2.5% for every additional 10 menstrual-cycles. The study also showed that high GRS1 was associated with increased risk. This relationship, however, was attenuated after adjustment for obesity. Our study further indicated women with high TNMC and GRS1 had twice the risk of endometrial cancer compared to those low in both indices. Our results provided additional support to the involvement of estrogen exposure in endometrial cancer risk with regard to genetic background and lifestyle features. PMID:26498156

  11. Genetic imbalances in precursor lesions of endometrial cancer detected by comparative genomic hybridization.

    PubMed

    Kiechle, M; Hinrichs, M; Jacobsen, A; Lüttges, J; Pfisterer, J; Kommoss, F; Arnold, N

    2000-06-01

    Endometrial hyperplasia is regarded as a precursor lesion of endometrioid adenocarcinomas of the endometrium. The genetic events involved in the multistep process from normal endometrial glandular tissue to invasive endometrial carcinomas are primarily unknown. We chose endometrial hyperplasia as a model for identifying chromosomal aberrations occurring during carcinogenesis. Comparative genomic hybridization (CGH) was performed on 47 formalin-fixed, paraffin-embedded specimens of endometrial hyperplasia using the microdissection technique to increase the number of tumor cells in the samples and reduce contamination from normal cells. CGH analysis revealed that 24 out of 47 (51%) samples had detectable chromosomal imbalances, whereas 23 (49%) were in a genetically balanced state. The incidence of aberrant CGH profiles tended to parallel dysplasia grade, ranging from 22% aberrant profiles in simple hyperplasia to 67% in complex hyperplasia with atypia. The most frequent imbalances were 1p, 16p, and 20q underrepresentations and 4q overrepresentations. Copy number changes in 1p were more frequent in atypical complex hyperplasia than in complex lesions without atypical cells or simple lesions (42% versus 20% and 0%). Our results show that endometrial hyperplasia reveals recurrent chromosomal imbalances which tend to increase with the presence of atypical cells. The most frequent aberrations in endometrial cancer, 1q and 8q overrepresentations, are not present or are rare in its precursor lesions. This analysis provides evidence that tumorigenesis proceeds through the accumulation of a series of genetic alterations and suggests a stepwise mode of tumorigenesis. PMID:10854205

  12. Regulation of inflammatory and angiogenesis mediators in a functional model of decidualized endometrial stromal cells.

    PubMed

    Bourdiec, Amélie; Ahmad, Syed-Furquan; Lachhab, Asmaa; Akoum, Ali

    2016-01-01

    The mechanisms involving the expression of interleukin (IL) 1 family members in the process of preparing the endometrium to receive an embryo remain unclear. In this study, decidualization differentially skewed the balance of IL1 family receptor expression in a pattern that increases endometrial stromal cell receptivity to IL1, IL18 and IL33. Additionally, endometrial cells showed increased expression of homeobox HOXA10 and HOXA11 and LIFR, which are known to be involved in endometrial embryo receptivity. Further analyses of decidual endometrial cells revealed a significant increase in the release of potent proinflammatory, remodelling and angiogenic factors implicated in the embryo invasion process, such as VEGF (P = 0.0305), MMP9 (P = 0.0003), TIMP3 (P = 0.0001), RANTES (P = 0.0020), MCP1 (P = 0.0001) and MIF (P = 0.0068). No significant changes in endogenous IL1B secretion were observed. Decreased secretion of IL18 and decidualization increased secretion of IL33. These findings reveal a significant modulation of endometrial cell receptivity to IL1 family members during endometrial stromal cell decidualization, and suggest that the involvement of IL1 family members is important in physiological processes of endometrial receptivity, including adaptive immunology. This may be relevant to establishing a favourable uterine microenvironment for embryo implantation. PMID:26602943

  13. Cyto-histologic evaluation of the endometrium in climacteric women at risk for endometrial carcinoma.

    PubMed

    de Aloysio, D; Rocca, G; Miliffi, L

    1986-08-31

    The authors evaluated the diagnostic effectiveness of a triple specimen technique (cyto-histologic) performed by the Perma device. The incidence of endometrial hyperplasia (according to Dallenbach-Hellweg's classification) was estimated in 254 climacteric women selected from outpatients who come spontaneously to the Menopause Clinic of the Obstetrics and Gynecology Department (Bologna University). The selection criterion was the evidence of risk factors for endometrial carcinoma, climacteric bleedings (obesity, late menopause, high blood pressure, diabetes), or endometriotropic estrogen therapy in the postmenopause. Results showed that the cyto-histologic sampling is most useful for diagnosing endometrial hyperplasia and early carcinoma (diagnostic effectiveness: 89.0-93.8%). Also, endometrial hyperplasia was found to have a significant incidence in the group we examined. This incidence was highest in women with climacteric bleedings, secondly in women using high-dose estrogens, and thirdly in women with risk factors for endometrial carcinoma. When evaluating the different kinds of endometrial hyperplasia, we never found adenomatous hyperplasia in women on estrogen therapy. Affinity between histologic and cytologic classes was around 50% in endometrial hyperplasia and 100% in early carcinoma. This emphasizes that both samplings are needed to perform an accurate diagnosis.

  14. Factors Influencing the Recurrence Potential of Benign Endometrial Polyps after Hysteroscopic Polypectomy

    PubMed Central

    Yang, Jehn-Hsiahn; Chen, Chin-Der; Chen, Shee-Uan; Yang, Yu-Shih; Chen, Mei-Jou

    2015-01-01

    Background An endometrial polyp is a frequently encountered gynecologic disease with abnormal uterine bleeding and infertility being the two common presenting problems, and hysteroscopic polypectomy is an effective method to remove them. The postoperative polyp recurrence might result in reappearance of abnormal uterine bleeding or infertility, whereas factors influencing the postoperative recurrence potential have limited data. Methods This case-series report included 168 premenopausal women who suffered from endometrial polyps and underwent hysteroscopic polypectomy. All of them were awaiting a future pregnancy. Office hysteroscopy was done before and after hysteroscopic polypectomy, in which preoperative hysteroscopy examined the number, type, and location of endometrial polyps, and postoperative hysteroscopy checked the polyp recurrence. Surgical indications, either infertility or the presentation of abnormal uterine bleeding, and follow-up duration were recorded. Results Seventy-three out of 168 (43%) women had polyp recurrence after hysteroscopic polypectomy. Multivariate logistic regression analysis revealed that more endometrial polyps (P = 0.015) and longer duration of follow-up (P = 0.004) were significantly associated with an increased risk of postoperative polyp recurrence. The type of endometrial polyps was not correlated with polyp recurrence potential, whereas pedunculated type endometrial polyps were closely related to the presentation of abnormal uterine bleeding (P = 0.001). Conclusions A higher number of endometrial polyps and longer follow-up duration are associated with a greater potential of polyp recurrence after hysteroscopic polypectomy. PMID:26660149

  15. Malignant and premalignant changes in the endometrium of women with an ultrasound diagnosis of endometrial polyp.

    PubMed

    Gambadauro, P; Martínez-Maestre, M Á; Schneider, J; Torrejón, R

    2014-10-01

    The association between polyps and endometrial cancer is under debate. The main objectives of this study were to study the frequency and the characteristics of malignant and premalignant endometrial changes in women with endometrial polyp at ultrasound. The study population consisted of 1,390 consecutive patients that were referred to office hysteroscopy because of the ultrasonographic diagnosis of endometrial polyps. A total of 16 cases of endometrial neoplasia were diagnosed (1.15%). The frequencies of atypia and cancer in our population were 0.14% and 1.01%, respectively. All patients, except one, were postmenopausal (93.8%). All had undergone the initial ultrasonographic assessment because of symptoms (bleeding in the 93.8%). The neoplasia was not confined to the polyp in 75% of the cases. Nine cases had a lower risk disease (56.25%; atypical hyperplasia or endometrial cancer stage IA-G1,2), while seven had a higher risk cancer (43.75%; ≥ stage IA-G3). Patients with a higher risk disease were found to be significantly younger, and their polyps were smaller, albeit non-significantly. In spite of the common practice to refer all women with an ultrasound diagnosis of polyp to hysteroscopy, our data show how the prevalence of endometrial neoplasia in these patients is low (1.15%). Moreover, the malignancy is not confined to a polyp in most of the cases.

  16. Neuroactive Steroids in First-Episode Psychosis: A Role for Progesterone?

    PubMed Central

    Pagotto, Uberto; Bonora, Elena; Triolo, Federico; Chiri, Luigi; Menchetti, Marco; Mondelli, Valeria; Pariante, Carmine; Berardi, Domenico

    2016-01-01

    Neuroactive steroids may play a role in the pathophysiology of psychotic disorders, but few studies examined this issue. We compared serum levels of cortisol, testosterone, dehydroepiandrosterone, and progesterone between a representative sample of first-episode psychosis (FEP) patients and age- and gender-matched healthy subjects. Furthermore, we analyzed the associations between neuroactive steroids levels and the severity of psychotic symptom dimensions. Male patients had lower levels of progesterone than controls (p = 0.03). Progesterone levels were inversely associated with the severity of positive symptoms (p = 0.007). Consistent with preclinical findings, results suggest that progesterone might have a role in the pathophysiology of psychotic disorders. PMID:27747103

  17. Absence of progesterone effects on chlamydial genital infection in female guinea pigs.

    PubMed

    Pasley, J N; Rank, R G; Hough, A J; Cohen, C; Barron, A L

    1985-01-01

    The effect of progesterone alone and in combination with estradiol was investigated in ovariectomized and gonadally intact female guinea pigs infected with the chlamydial agent of guinea pig inclusion conjunctivitis (GPIC). The course of the infection, as determined by the percentage of cells with GPIC (chlamydia) inclusions in Giemsa-stained vaginal scrapings, was not affected in animals receiving 5.0 mg of progesterone daily. Progesterone had no influence on the enhancement of infection by estradiol. In comparison with sesame oil-treated controls, infection was prolonged by four to six days (P less than .05) in animals receiving a combination of 5.0 mg of progesterone plus 1.0 microgram of estradiol or 1.0 microgram of estradiol alone each day. In ovariectomized animals, estradiol delayed the appearance of IgA antibody in genital secretions, whereas progesterone alone had no effect. Guinea pigs treated with estradiol or progesterone plus estradiol manifested an acute endometritis not observed in animals treated with progesterone alone or in controls receiving sesame oil. Although cervical ectopy, analogous to that seen in women with high levels of progesterone, was identified by histopathology in animals treated with progesterone, no enhancement of the chlamydial infection was observed.

  18. Association of leukocyte telomere length in peripheral blood leukocytes with endometrial cancer risk in Caucasian Americans.

    PubMed

    Sun, Yuhui; Zhang, Liren; Zhao, Lina; Wu, Xifeng; Gu, Jian

    2015-11-01

    Telomeres are the protective structure at the ends of each chromosome and play an important role in maintaining genomic integrity. Interindividual variation of telomere length in peripheral blood leukocytes has been associated with the risks of developing many human diseases including several cancers. The association between leukocyte telomere length (LTL) and endometrial cancer risk is still inconsistent. Using a case-control study of endometrial cancer patients (n = 139) and control subjects (n = 139) in a Caucasian population, we assessed the association of relative LTL with the risk of endometrial cancer. We calculated odds ratios and 95% confidence intervals using multivariate logistic regression. We also determined the joint effects of LTL with established risk factors of endometrial cancer. The normalized LTL was significantly longer in endometrial cancer cases (median, 0.93; range, 0.19-1.62) than in controls (median, 0.70; range, 0.03-2.14) (P < 0.001). When individuals were dichotomized into long and short groups based on the median LTL value in the controls, individuals with long LTL had a significantly increased risk of endometrial cancer (adjusted OR, 3.84; 95%CI, 2.16-6.85; P < 0.001) compared to those with short LTL. When individuals were categorized into three groups or four groups according to tertile or quartile LTL value in the controls, there was a significant dose-response association between LTL and the risk of endometrial cancer (P < 0.001). Joint effects between LTL and smoking status, body mass index and a history of hypertension or diabetes in elevating endometrial cancer risk were observed. Long telomere length in peripheral blood leukocytes is associated with a significantly increased risk of endometrial cancer.

  19. The impact of low-volume uterine lavage on endometrial biopsy classification.

    PubMed

    Linton, J K; Sertich, P L

    2016-09-01

    In the mare, the low-volume uterine lavage technique allows for bacterial sampling of the entire uterine lumen and is usually performed after obtaining the traditional double-guarded endometrial swab for aerobic culture and cytology and before procurement of an endometrial biopsy sample during a breeding soundness examination. The purpose of this study was to explore the potential effects of the low-volume lavage on the endometrial biopsy classification and polymorphonuclear cell (PMNs) infiltration in the context of a breeding soundness examination. Fourteen light horse mares of mixed breed, age 7 to 21 years, with known reproductive history, were included in the study, matched by age and reproductive history, and then divided into treatment and control groups. Transrectal palpation and ultrasonography, endometrial swabbing, and the first endometrial biopsy were performed in all mares. Low-volume uterine lavage was performed in the treatment group but not the control group. After either the lavage or a 15-minute rest, a second endometrial biopsy was obtained from both the control and treatment groups. Endometrial swabs and effluent from the low-volume lavages were submitted for aerobic culture and sensitivity. Biopsy samples were fixed in Bouin's solution for 24 hours, processed, stained with hematoxylin and eosin, and then viewed under bright light microscopy. Additional staining with anti-neutrophil elastase antibody (ab68672) was performed for indirect immunohistochemistry. All samples were interpreted by a blinded observer. When the first (pre-uterine lavage) and second (post-uterine lavage) biopsies were compared using a mixed-effects logistic regression, there was no difference in endometrial biopsy classification (P = 0.74), presence of PMNs in blood vessels (P = 0.728), or infiltration of PMNs in the tissue (P = 0.934) between the treatment and control groups. In this study, the low-volume uterine lavage did not affect the endometrial biopsy

  20. Evidence of a Causal Association Between Insulinemia and Endometrial Cancer: A Mendelian Randomization Analysis

    PubMed Central

    Nead, Kevin T.; Sharp, Stephen J.; Thompson, Deborah J.; Painter, Jodie N.; Savage, David B.; Semple, Robert K.; Barker, Adam; Perry, John R. B.; Attia, John; Dunning, Alison M.; Easton, Douglas F.; Holliday, Elizabeth; Lotta, Luca A.; O’Mara, Tracy; McEvoy, Mark; Pharoah, Paul D. P.; Scott, Rodney J.; Spurdle, Amanda B.; Langenberg, Claudia; Wareham, Nicholas J.

    2015-01-01

    Background: Insulinemia and type 2 diabetes (T2D) have been associated with endometrial cancer risk in numerous observational studies. However, the causality of these associations is uncertain. Here we use a Mendelian randomization (MR) approach to assess whether insulinemia and T2D are causally associated with endometrial cancer. Methods: We used single nucleotide polymorphisms (SNPs) associated with T2D (49 variants), fasting glucose (36 variants), fasting insulin (18 variants), early insulin secretion (17 variants), and body mass index (BMI) (32 variants) as instrumental variables in MR analyses. We calculated MR estimates for each risk factor with endometrial cancer using an inverse-variance weighted method with SNP-endometrial cancer associations from 1287 case patients and 8273 control participants. Results: Genetically predicted higher fasting insulin levels were associated with greater risk of endometrial cancer (odds ratio [OR] per standard deviation = 2.34, 95% confidence internal [CI] = 1.06 to 5.14, P = .03). Consistently, genetically predicted higher 30-minute postchallenge insulin levels were also associated with endometrial cancer risk (OR = 1.40, 95% CI = 1.12 to 1.76, P = .003). We observed no associations between genetic risk of type 2 diabetes (OR = 0.91, 95% CI = 0.79 to 1.04, P = .16) or higher fasting glucose (OR = 1.00, 95% CI = 0.67 to 1.50, P = .99) and endometrial cancer. In contrast, endometrial cancer risk was higher in individuals with genetically predicted higher BMI (OR = 3.86, 95% CI = 2.24 to 6.64, P = 1.2x10-6). Conclusion: This study provides evidence to support a causal association of higher insulin levels, independently of BMI, with endometrial cancer risk. PMID:26134033

  1. Role of Liquid-based Cytology and Cell Block in the Diagnosis of Endometrial Lesions

    PubMed Central

    Zhang, Hui; Wen, Jia; Xu, Pi-Li; Chen, Rui; Yang, Xi; Zhou, Lian-Er; Jiang, Ping; Wan, An-Xia; Liao, Qin-Ping

    2016-01-01

    Background: Liquid-based cytology (LBC) offers an alternative method to biopsy in screening endometrial cancer. Cell block (CB), prepared by collecting residual cytological specimen, represents a novel method to supplement the diagnosis of endometrial cytology. This study aimed to compare the specimen adequacy and diagnostic accuracy of LBC and CB in the diagnosis of endometrial lesions. Methods: A total of 198 women with high risks of endometrial carcinoma (EC) from May 2014 to April 2015 were enrolled in this study. The cytological specimens were collected by the endometrial sampler (SAP-1) followed by histopathologic evaluation of dilatation and curettage or biopsy guided by hysteroscopy. The residual cytological specimens were processed into paraffin-embedded CB after LBC preparation. Diagnostic accuracies of LBC and CB for detecting endometrial lesions were correlated with histological diagnoses. Chi-square test was used to compare the specimen adequacies of LBC and CB. Results: The specimen inadequate rate of CB was significantly higher than that of LBC (22.2% versus 7.1%, P < 0.01). There were 144 cases with adequate specimens for LBC and CB preparation. Among them, 29 cases were atypical endometrial hyperplasia (11 cases) or carcinoma (18 cases) confirmed by histology evaluation. Taking atypical hyperplasia and carcinoma as positive, the diagnostic accuracy of CB was 95.1% while it was 93.8% in LBC. When combined LBC with CB, the diagnostic accuracy was improved to 95.8%, with a sensitivity of 89.7% and specificity of 97.4%. Conclusions: CB is a feasible and reproducible adjuvant method for screening endometrial lesions. A combination of CB and LBC can improve the diagnostic accuracy of endometrial lesions. PMID:27270542

  2. Presence of HHV-6A in Endometrial Epithelial Cells from Women with Primary Unexplained Infertility

    PubMed Central

    Bortolotti, Daria; Lo Monte, Giuseppe; Caselli, Elisabetta; Bolzani, Silvia; Rotola, Antonella; Di Luca, Dario; Rizzo, Roberta

    2016-01-01

    To elucidate the roles of human herpesvirus (HHV)-6 primary unexplained infertile women, a prospective randomized study was conducted on a cohort of primary unexplained infertile women and a cohort of control women, with at least one successful pregnancy. HHV-6 DNA was analyzed and the percentage and immune-phenotype of resident endometrial Natural Killer (NK) cells, as the first line of defense towards viral infections, was evaluated in endometrial biopsies. Cytokine levels in uterine flushing samples were analyzed. HHV-6A DNA was found in 43% of endometrial biopsies from primary unexplained infertile women, but not in control women. On the contrary, HHV-6B DNA was absent in endometrial biopsies, but present in PBMCs of both cohorts. Endometrial NK cells presented a different distribution in infertile women with HHV6-A infection compared with infertile women without HHV6-A infection. Notably, we observed a lower percentage of endometrial specific CD56brightCD16- NK cells. We observed an enhanced HHV-6A-specific endometrial NK cell response in HHV-6A positive infertile women, with a marked increase in the number of endometrial NK cells activating towards HHV-6A infected cells. The analysis of uterine flushing samples showed an increase in IL-10 levels and a decrease of IFN-gamma concentrations in infertile women with HHV6-A infection. Our study indicates, for the first time, that HHV-6A infection might be an important factor in female unexplained infertility development, with a possible role in modifying endometrial NK cells immune profile and ability to sustain a successful pregnancy. PMID:27367597

  3. Endometrial ablation using SideFire laser fiber

    NASA Astrophysics Data System (ADS)

    Everett, Royice B.

    1996-05-01

    The first successful report using the neodymium:yttrium-aluminum-garnet (Nd:YAG) Laser to control hypermenorrhea was reported in 1981. Variations on the treatment technique have been attempted to improve the amenorrhea rate. Reports using the Nd:YAG laser with the blanching or non-touch technique seem to result in a better outcome and higher rate of total amenorrhea than using the dragging technique. Due to the report of improved rates of amenorrhea when using the blanching technique and the Nd:YAG laser, a fiber was developed to direct the laser energy at right angles to the axis of the fiber, therefore allowing a total treatment of the entire uterus in a perpendicular fashion. The theoretic benefit of this would be a more complete and predictable destruction of the endometrial lining, avoiding fluid overload by coagulating and sealing of the vessels and lymphatic. After a follow-up of 12 to 36 months, 56 of the 60 patients (93%) who underwent complete endometrial ablation with the SideFireTM technique had excellent results. Total absolute amenorrhea resulted in 50 patients (83%). Contrary to earlier reports, using the rollerball electrode, this procedure technique resulted in no decrease in results in younger patients. In conclusion, this seems to be a reasonable alternative which offers improved results when compared to previously available methods using electrosurgery or the Nd:YAG laser without the use of the SideFireTM device.

  4. Endometrial regenerative cells: a novel stem cell population.

    PubMed

    Meng, Xiaolong; Ichim, Thomas E; Zhong, Jie; Rogers, Andrea; Yin, Zhenglian; Jackson, James; Wang, Hao; Ge, Wei; Bogin, Vladimir; Chan, Kyle W; Thébaud, Bernard; Riordan, Neil H

    2007-01-01

    Angiogenesis is a critical component of the proliferative endometrial phase of the menstrual cycle. Thus, we hypothesized that a stem cell-like population exist and can be isolated from menstrual blood. Mononuclear cells collected from the menstrual blood contained a subpopulation of adherent cells which could be maintained in tissue culture for >68 doublings and retained expression of the markers CD9, CD29, CD41a, CD44, CD59, CD73, CD90 and CD105, without karyotypic abnormalities. Proliferative rate of the cells was significantly higher than control umbilical cord derived mesenchymal stem cells, with doubling occurring every 19.4 hours. These cells, which we termed "Endometrial Regenerative Cells" (ERC) were capable of differentiating into 9 lineages: cardiomyocytic, respiratory epithelial, neurocytic, myocytic, endothelial, pancreatic, hepatic, adipocytic, and osteogenic. Additionally, ERC produced MMP3, MMP10, GM-CSF, angiopoietin-2 and PDGF-BB at 10-100,000 fold higher levels than two control cord blood derived mesenchymal stem cell lines. Given the ease of extraction and pluripotency of this cell population, we propose ERC as a novel alternative to current stem cells sources. PMID:18005405

  5. ECGene: A Literature‐Based Knowledgebase of Endometrial Cancer Genes

    PubMed Central

    Liu, Yining; O'Mara, Tracy A

    2016-01-01

    ABSTRACT Endometrial cancer (EC) ranks as the sixth common cancer for women worldwide. To better distinguish cancer subtypes and identify effective early diagnostic biomarkers, we need improved understanding of the biological mechanisms associated with EC dysregulated genes. Although there is a wealth of clinical and molecular information relevant to EC in the literature, there has been no systematic summary of EC‐implicated genes. In this study, we developed a literature‐based database ECGene (Endometrial Cancer Gene database) with comprehensive annotations. ECGene features manual curation of 414 genes from thousands of publications, results from eight EC gene expression datasets, precomputation of coexpressed long noncoding RNAs, and an EC‐implicated gene interactome. In the current release, we generated and comprehensively annotated a list of 458 EC‐implicated genes. We found the top‐ranked EC‐implicated genes are frequently mutated in The Cancer Genome Atlas (TCGA) tumor samples. Furthermore, systematic analysis of coexpressed lncRNAs provided insight into the important roles of lncRNA in EC development. ECGene has a user‐friendly Web interface and is freely available at http://ecgene.bioinfo‐minzhao.org/. As the first literature‐based online resource for EC, ECGene serves as a useful gateway for researchers to explore EC genetics. PMID:26699919

  6. Enolase-1 is a therapeutic target in endometrial carcinoma

    PubMed Central

    Shu, Luyun; Wang, Lijing; Chen, YiYu; Fu, Qiaofen; Liu, Yan; Hua, Shengni; Fan, Yue; Liu, Yiyi; Deng, Xiaojie; Luo, Rongcheng; Mei, Zhong; Jiang, Qinping; Liu, Zhen

    2015-01-01

    ENO1 plays a paradoxical role in driving the pathogenesis of tumors. However, the clinical significance of ENO1 expression remains unclear and its function and modulatory mechanisms have never been reported in endometrial carcinoma (EC). In this study, ENO1 silencing significantly reduced cell glycolysis, proliferation, migration, and invasion in vitro, as well as tumorigenesis and metastasis in vivo by modulating p85 suppression. This in turn mediated inactivation of PI3K/AKT signaling and its downstream signals including glycolysis, cell cycle progression, and epithelial-mesenchymal transition (EMT)-associated genes. These effects on glycolysis and cell growth were not observed after ENO1 suppression in normal human endometrial epithelial cells (HEEC). Knocking down ENO1 could significantly enhance the sensitivity of EC cells to cisplatin (DDP) and markedly inhibited the growth of EC xenografts in vivo. In clinical samples, EC tissues exhibited higher expression levels of ENO1 mRNA and protein compared with normal endometrium tissues. Patients with higher ENO1 expression had a markedly shorter overall survival than patients with low ENO1 expression. We conclude that ENO1 favors carcinogenesis, representing a potential target for gene-based therapy. PMID:25951350

  7. Single-cell transcriptome analysis of endometrial tissue

    PubMed Central

    Krjutškov, K.; Katayama, S.; Saare, M.; Vera-Rodriguez, M.; Lubenets, D.; Samuel, K.; Laisk-Podar, T.; Teder, H.; Einarsdottir, E.; Salumets, A.; Kere, J.

    2016-01-01

    STUDY QUESTION How can we study the full transcriptome of endometrial stromal and epithelial cells at the single-cell level? SUMMARY ANSWER By compiling and developing novel analytical tools for biopsy, tissue cryopreservation and disaggregation, single-cell sorting, library preparation, RNA sequencing (RNA-seq) and statistical data analysis. WHAT IS KNOWN ALREADY Although single-cell transcriptome analyses from various biopsied tissues have been published recently, corresponding protocols for human endometrium have not been described. STUDY DESIGN, SIZE, DURATION The frozen-thawed endometrial biopsies were fluorescence-activated cell sorted (FACS) to distinguish CD13-positive stromal and CD9-positive epithelial cells and single-cell transcriptome analysis performed from biopsied tissues without culturing the cells. We studied gene transcription, applying a modern and efficient RNA-seq protocol. In parallel, endometrial stromal cells were cultured and global expression profiles were compared with uncultured cells. PARTICIPANTS/MATERIALS, SETTING, METHODS For method validation, we used two endometrial biopsies, one from mid-secretory phase (Day 21, LH+8) and another from late-secretory phase (Day 25). The samples underwent single-cell FACS sorting, single-cell RNA-seq library preparation and Illumina sequencing. MAIN RESULTS AND THE ROLE OF CHANCE Here we present a complete pipeline for single-cell gene-expression studies, from clinical sampling to statistical data analysis. Tissue manipulation, starting from disaggregation and cell-type-specific labelling and ending with single-cell automated sorting, is managed within 90 min at low temperature to minimize changes in the gene expression profile. The single living stromal and epithelial cells were sorted using CD13- and CD9-specific antibodies, respectively. Of the 8622 detected genes, 2661 were more active in cultured stromal cells than in biopsy cells. In the comparison of biopsy versus cultured cells, 5603

  8. Endometrial biopsy in the infertility investigation. The experience at two institutions.

    PubMed

    Wild, R A; Sanfilippo, J S; Toledo, A A

    1986-10-01

    The combined experience at two institutions was reviewed to evaluate endometrial biopsy and the prognosis for pregnancies affected by endometrial sampling during the cycle of conception. In the evaluation of 1,084 patients, 1,174 biopsies were performed. Twenty-seven endometrial biopsies were done during the cycle of conception, with spontaneous abortion occurring in six cases (22.2%). Multiple diagnoses were made (including luteal phase defects, endometritis and polyps), and interruption of pregnancy occurred. Several cases illustrate disturbing complications. Methods of minimizing pregnancy interruption and patient discomfort are available.

  9. Progesterone Receptor-A and -B Have Opposite Effects on Proinflammatory Gene Expression in Human Myometrial Cells: Implications for Progesterone Actions in Human Pregnancy and Parturition

    PubMed Central

    Tan, Huiqing; Yi, Lijuan; Rote, Neal S.; Hurd, William W.

    2012-01-01

    Context: Progesterone promotes uterine relaxation during pregnancy and its withdrawal induces labor. Progesterone withdrawal in human parturition is mediated in part by changes in the relative levels of the nuclear progesterone receptor isoforms, PR-A and PR-B, in myometrial cells. Parturition also involves myometrial inflammation; however, the functional link between nuclear PR-mediated progesterone actions and inflammation in human myometrial cells is unclear. Objective: Our objective was to determine how PR-A and PR-B regulate progesterone action in human myometrial cells and specifically the expression of genes encoding contraction-associated proteins and proinflammatory mediators. Design: Effects of PR-A and PR-B on the capacity for progesterone to modulate gene expression was determined using an immortalized human myometrial cell line stably transfected with inducible PR-A and PR-B expression transgenes and conditioned to express various PR-A and PR-B levels. Gene expression was assessed by genome wide transcriptome analysis, quantitative RT-PCR and immunoblotting. Results: PR-A and PR-B were each transcriptionally active in response to progesterone and affected the expression of distinct gene cohorts. The capacity for progesterone to affect gene expression was dependent on the PR-A to PR-B ratio. This was especially apparent for the expression of proinflammatory genes. Progesterone decreased proinflammatory gene expression when the PR-A to PR-B ratio favored PR-B and increased proinflammatory gene expression when the ratio favored PR-A. Progesterone via PR-B increased expression of inhibitor-κBα, a repressor of the nuclear factor-κB transcription factor, and inhibited basal and lipopolysaccharide-induced proinflammatory gene expression. Both of those PR-B-mediated effects were inhibited by PR-A. Conclusions: Our data suggest that during most of human pregnancy, when myometrial cells are PR-B dominant, progesterone promotes myometrial quiescence through PR

  10. Progesterone Synthesis in the Nervous System: Implications for Myelination and Myelin Repair

    PubMed Central

    Schumacher, Michael; Hussain, Rashad; Gago, Nathalie; Oudinet, Jean-Paul; Mattern, Claudia; Ghoumari, Abdel M.

    2011-01-01

    Progesterone is well known as a female reproductive hormone and in particular for its role in uterine receptivity, implantation, and the maintenance of pregnancy. However, neuroendocrine research over the past decades has established that progesterone has multiple functions beyond reproduction. Within the nervous system, its neuromodulatory and neuroprotective effects are much studied. Although progesterone has been shown to also promote myelin repair, its influence and that of other steroids on myelination and remyelination is relatively neglected. Reasons for this are that hormonal influences are still not considered as a central problem by most myelin biologists, and that neuroendocrinologists are not sufficiently concerned with the importance of myelin in neuron functions and viability. The effects of progesterone in the nervous system involve a variety of signaling mechanisms. The identification of the classical intracellular progesterone receptors as therapeutic targets for myelin repair suggests new health benefits for synthetic progestins, specifically designed for contraceptive use and hormone replacement therapies. There are also major advantages to use natural progesterone in neuroprotective and myelin repair strategies, because progesterone is converted to biologically active metabolites in nervous tissues and interacts with multiple target proteins. The delivery of progesterone however represents a challenge because of its first-pass metabolism in digestive tract and liver. Recently, the intranasal route of progesterone administration has received attention for easy and efficient targeting of the brain. Progesterone in the brain is derived from the steroidogenic endocrine glands or from local synthesis by neural cells. Stimulating the formation of endogenous progesterone is currently explored as an alternative strategy for neuroprotection, axonal regeneration, and myelin repair. PMID:22347156

  11. Luteal phase support in intrauterine insemination cycles: a prospective randomized study of 300 mg versus 600 mg intravaginal progesterone tablet.

    PubMed

    Biberoglu, Ebru H; Tanrıkulu, Filiz; Erdem, Mehmet; Erdem, Ahmet; Biberoglu, Kutay Omer

    2016-01-01

    Vaginal progesterone (P) has been suggested to be used for luteal phase support (LPS) in controlled ovarian stimulation (COH)-intrauterine insemination (IUI) cycles, however, no concensus exists about the best P dose. Therefore, considering the fecundability rate as the primary end point, our main objective was to find the optimal dose of P in COH-IUI cycles, comparing the two groups of women, each of which comprised of 100 women either on 300 mg or 600 mg of intravaginal P tablets, in a prospective randomized study design. The mean age of the women, duration of infertility, basal and day of hCG injection hormone levels in the female and sperm parameters were similar in the two study groups. Also, duration and dose of gonadotropin given, number of follicles, endometrial thickness, the total, ongoing and multiple pregnancy rates were comparable in both groups. We, therefore, claim that 300 mg of intravaginal micronized P should be the maximum dose of LPS in IUI cycles. PMID:26291817

  12. Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer

    PubMed Central

    Mehnert, Janice M.; Panda, Anshuman; Zhong, Hua; Hirshfield, Kim; Damare, Sherri; Lane, Katherine; Sokol, Levi; Stein, Mark N.; Rodriguez-Rodriquez, Lorna; Kaufman, Howard L.; Ali, Siraj; Ross, Jeffrey S.; Pavlick, Dean C.; Bhanot, Gyan; White, Eileen P.; DiPaola, Robert S.; Lovell, Ann; Cheng, Jonathan

    2016-01-01

    Antibodies that target the immune checkpoint receptor programmed cell death protein 1 (PD-1) have resulted in prolonged and beneficial responses toward a variety of human cancers. However, anti–PD-1 therapy in some patients provides no benefit and/or results in adverse side effects. The factors that determine whether patients will be drug sensitive or resistant are not fully understood; therefore, genomic assessment of exceptional responders can provide important insight into patient response. Here, we identified a patient with endometrial cancer who had an exceptional response to the anti–PD-1 antibody pembrolizumab. Clinical grade targeted genomic profiling of a pretreatment tumor sample from this individual identified a mutation in DNA polymerase epsilon (POLE) that associated with an ultramutator phenotype. Analysis of The Cancer Genome Atlas (TCGA) revealed that the presence of POLE mutation associates with high mutational burden and elevated expression of several immune checkpoint genes. Together, these data suggest that cancers harboring POLE mutations are good candidates for immune checkpoint inhibitor therapy. PMID:27159395

  13. The cytoskeleton and the cellular traffic of the progesterone receptor.

    PubMed

    Perrot-Applanat, M; Lescop, P; Milgrom, E

    1992-10-01

    Previous studies on glucocorticoid receptors have suggested the existence of interactions between the receptor and microtubule or actin networks. It was hypothesized that such interactions may contribute to the guidance of steroid hormone receptors towards the nucleus. We used a permanent L cell line expressing the delta 638-642 progesterone receptor. This mutant has all the characteristics of the wild type receptor except that the deletion of five amino acids inactivates the constitutive karyophilic signal. Consequently, the receptor is cytoplasmic in the absence of hormone but is shifted into the nucleus when administration of hormone activates the second karyophilic signal. Optical microscopy and confocal laser microscopy were used in intact cells or in cells depleted of soluble elements by permeabilization with detergents. By immunofluorescence, the receptor was found to be mainly concentrated in the perinuclear area. A small fraction of progesterone receptor (PR) persisted in this region after Triton X100 treatment. These observations suggested that the receptor could interact with some insoluble constituent(s) of the cytoplasm. However, careful colocalization studies showed that this heterogenous distribution was not due to interactions with microtubule, microfilament, or intermediate filament networks. Functional involvement of these networks in the translocation of the receptor into the nucleus was studied after cell treatment with cytoskeletal drugs such as nocodazole, demecolcine and cytochalasin. None of these compounds prevented or even delayed the hormone-dependent transfer of delta 638-642 PR into the nucleus. Similar conclusions were reached with the wild type receptor expressed by transfection in Cos-7 cells. PR was shifted from the nucleus into the cytoplasm by administration of energy-depleting drugs. After disruption of the various cytoskeletal networks normal nuclear reaccumulation of the receptor was observed when these drugs were removed. The

  14. Testosterone decreases the expression of endometrial pinopode and L-selectin ligand (MECA-79) in adult female rats during uterine receptivity period

    PubMed Central

    Mokhtar, Helmy Mohd; Giribabu, Nelli; Muniandy, Sekaran; Salleh, Naguib

    2014-01-01

    Pinopode, a progesterone-dependent endometrial projection which appears during uterine receptivity period, participates in blastocyst implantation. Blastocyst loosely attaches to pinopode via L-selectin ligand (MECA-79). We hypothesized that pinopode and MECA-79 expressions were affected by testosterone. Therefore, the effect of testosterone on pinopode and MECA-79 expressions during uterine receptivity period were investigated. Methods: Ovariectomized adult female rats received 8 days sex-steroid replacement intended to mimic hormonal changes in early pregnancy with day 6 to 8 represents uterine receptivity period. Testosterone (1 mg/kg/day) was injected together with flutamide or finasteride during the period of uterine receptivity. At the end of treatment, rats were sacrificed and uteri were removed. The existence of pinopodes in the endometrium was visualized by electron microscopy and uterine expression and distribution of MECA-79 protein were examined by Western blotting and immunohistochemistry (IHC) respectively. Results: Abundant pinopodes and MECA-79 expressions were observed in rats received normal steroid replacement regime. Administration of testosterone during uterine receptivity period reduced pinopodes and MECA-79 expressions, which were antagonized by flutamide and not finasteride. Conclusions: The decrease in uterine pinopodes and MECA-79 expressions during uterine receptivity period by testosterone may cause failure of blastocyst to implant in conditions associated with high level of this hormone. PMID:24966906

  15. Endometrial adenocarcinoma: an analysis of treatment and outcome.

    PubMed

    Byrd, Louise M; Swindell, Richard; Webber-Rookes, Daniel; Hannon, R; Hunter, Robin D; Livsey, Jac; Davidson, Susan E

    2008-11-01

    This study aims to review the survival and morbidity in patients treated for endometrial cancer, at a single centre and analyses the effects of co-morbidity on these outcomes. Case notes of all patients referred to the Christie Hospital with endometrial carcinoma from January 1, 1993 to December 31, 1995 (n=499) were reviewed. Twenty patients presented with recurrence and were not included in this analysis. Three hundred and seventy-five patients had previously undergone a total abdominal hysterectomy and bilateral salpingoophorectomy (+/- pelvic lymphadenectomy). Of these, 175 received adjuvant external beam radiotherapy (XRT) only, 49 received XRT and brachytherapy, 30 received brachytherapy alone and 121 patients had no further therapy. One hundred and four patients were referred for primary treatment. Radical radiotherapy was administered to 63 patients who were unfit for surgery, with 10 of these receiving XRT + brachytherapy and 53 receiving brachytherapy alone. Thirteen patients received palliative XRT and 28 supportive care only. The overall 5-year survival for those treated radically was 73.3%. There was no significant survival difference between patients who underwent surgery and adjuvant radiotherapy, in whatever form (p=0.115). Patients who did not undergo surgery did less well as a group, although there was no significant survival difference between those treated with combination therapy or brachytherapy alone (p=0.33). Survival was significantly associated with FIGO stage, tumour grade, age (especially those >75 years) and co-morbidity (ACE-27 score). Late morbidity occurred in 46 patients, with severe toxicity affecting 12 (3.8%). Toxicity was associated with ACE-27 score (p=0.0019), treatment dose and modality, with 50% (n=6) of severe toxicity seen in patients receiving adjuvant XRT + ICT. These data demonstrate that survival in patients with endometrial carcinoma treated radically remains good, with the stage and grade of tumour being significant

  16. Restraint stress delays endometrial adaptive remodeling during mouse embryo implantation.

    PubMed

    Liu, Guanhui; Dong, Yulan; Wang, Zixu; Cao, Jing; Chen, Yaoxing

    2015-01-01

    In mice, previously, we showed that restraint stress reduces the number of embryo implantation sites in the endometrium. Here, we hypothesized that the uterine microenvironment is altered by restraint stress and consequently is suboptimal for embryo implantation. On embryonic day 1 (E1), 60 of 154 pregnant CD1 mice underwent restraint stress (4 h), repeated daily to E3, E5 or E7 (n = 10 mice per group). Restraint stress decreased food intake and suppressed body weight gain on E3, E5 and E7. Restraint stress decreased the actual and relative weight (percent body weight) of uterus and ovary on E5 (by 14.9%, p = 0.03; 16.1%, p = 0.004) and E7 (by 16.8%, p = 0.03; 20.0%, p = 0.01). Morphologically, restraint stress decreased relative endometrial area (by 8.94-18.8%, p = 0.003-0.021) and uterine gland area (by 30.6%, p < 0.01 on E3 and 44.5%, p < 0.01 on E5). Immunohistochemistry showed that restraint stress decreased microvessel density (by 12.9-70.5%, p < 0.01) and vascular endothelial growth factor expression (by 14.6-45.9%, p = 0.007-0.02). Restraint stress decreased by 32.4-39.8% (p = 0.002-0.01) the mean optical density ratio for proliferating cell nuclear antigen/terminal deoxynucleotidyl transferase dUTP nick end labeling. Methyl thiazolyl tetrazolium assay showed a dose-dependent decrease in proliferative activity of endometrial stromal cells (from 52 of 154 pregnant E5 control mice) incubated with H2O2 (100-1000 μM) in vitro. These findings supported the hypothesis that restraint stress negatively influences endometrial adaptive remodeling via an oxidative stress pathway, which resulted in fewer implantation sites.

  17. Generation of human endometrial knockout cell lines with the CRISPR/Cas9 system confirms the prostaglandin F2α synthase activity of aldo-ketoreductase 1B1.

    PubMed

    Lacroix Pépin, Nicolas; Chapdelaine, Pierre; Rodriguez, Yoima; Tremblay, Jacques-P; Fortier, Michel A

    2014-07-01

    Prostaglandins (PGs) are important regulators of female reproductive function. The primary PGs produced in the endometrium are PGE2 and PGF2α. Relatively little is known about the biosynthetic pathways leading to the formation of PGF2α. We have described the role of aldo-ketoreductase (AKR)1B1 in increased PGF2α production by human endometrial cells following stimulation with interleukin-1β (IL-1β). However, alternate PGF synthases are expressed concurrently in endometrial cells. A definite proof of the role of AKR1B1 would require gene knockout; unfortunately, this gene has no direct equivalent in the mouse. Recently, an efficient genome-editing technology using RNA-guided DNase Cas9 and the clustered regularly interspaced short palindromic repeats (CRISPR) system has been developed. We have adapted this approach to knockout AKR1B1 gene expression in human endometrial cell lines. One clone (16-2) of stromal origin generated by the CRISPR/Cas9 system exhibited a complete loss of AKR1B1 protein and mRNA expression, whereas other clones presented with partial edition. The present report focuses on the characterization of clone 16-2 exhibiting deletion of 68 and 2 nucleotides, respectively, on each of the alleles. Cells from this clone lost their ability to produce PGF2α but maintained their original stromal cell (human endometrial stromal cells-2) phenotype including the capacity to decidualize in the presence of progesterone (medroxyprogesterone acetate) and 8-bromo-cAMP. Knockout cells also maintained their ability to increase PGE2 production in response to IL-1β. In summary, we demonstrate that the new genome editing CRISPR/Cas9 system can be used in human cells to generate stable knockout cell line models. Our results suggest that genome editing of human cell lines can be used to complement mouse KO models to validate the function of genes in differentiated tissues and cells. Our results also confirm that AKR1B1 is involved in the synthesis of PGF2α.

  18. Endometrial adult/progenitor stem cells: pathogenetic theory and new antiangiogenic approach for endometriosis therapy.

    PubMed

    Pittatore, G; Moggio, A; Benedetto, C; Bussolati, B; Revelli, A

    2014-03-01

    The cyclical arrival of endometrial cells into the abdominal cavity through retrograde flux at menstruation represents the etiopathogenetic basis of endometriosis. The endometrium has peculiar regenerative properties linked to the presence of adult stem cells similar to mesenchymal stem cells (MSCs). Once in the abdominal cavity, these MSCs could proliferate, invade, and differentiate into endometrial cells, finally generating ectopic implants. As only differentiated endometrial cells, and not endometrial MSCs, possess steroid hormone receptors, MSCs could be responsible for the high rate of persistence/recurrence of the disease after hypoestrogenism-inducing therapies. Even angiogenesis promoted by MSCs could play an important role, as survival and proliferation of endometriotic tissue depend on the formation of new blood vessels. Inhibition of angiogenesis represents, in fact, a new, promising therapeutic approach for the disease. Further, medications directly targeting endometriosis MSCs could be effective, alone or in association with hormonal treatments, in increasing the success of medical treatment.

  19. Global Endometrial Ablation in the Presence of Essure® Microinserts

    PubMed Central

    Aldape, Diana; Chudnoff, Scott G; Levie, Mark D

    2013-01-01

    Abnormal uterine bleeding (AUB) affects 30% of women at some time during their reproductive years and is one of the most common reasons a woman sees a gynecologist. Many women are turning to endometrial ablation to manage their AUB. This article reviews the data relating to the available endometrial ablation techniques performed with hysteroscopic sterilization, and focuses on data from patients who had Essure® (Conceptus, San Carlos, CA) coils placed prior to performance of endometrial ablation. Reviewed specifically are data regarding safety and efficacy of these two procedures when combined. Data submitted to the US Food and Drug Administration for the three devices currently approved are reviewed, as well as all published case series. Articles included were selected based on a PubMed search for endometrial ablation (also using the brand names of the different techniques currently available), hysteroscopic sterilization, and Essure. PMID:24358407

  20. Let7a inhibits the growth of endometrial carcinoma cells by targeting Aurora-B.

    PubMed

    Liu, Ping; Qi, Meiyan; Ma, Chengbin; Lao, Guoying; Liu, Yu; Liu, Yan; Liu, Yingzi

    2013-08-19

    MicroRNAs negatively regulate target gene expression at the post-transcriptional level during carcinogenesis. Recent advances revealed that the expression levels of several miRNAs are up- or down-regulated in endometrial carcinoma (EC). Here we identify dysregulated miRNAs in EC and we elucidate the essential role of let-7a. The expression of 86 miRNAs in EC was found to be different from adjacent normal endometrial tissues. Moreover, miR-let-7 members are down-regulated in EC and let-7 miRNAs are highly associated with endometrial cancer. A functional investigation revealed that let-7a suppressed proliferation of HeLa cells by targeting Aurora-B. Let-7a also antagonizes Aurora-B functions in promoting carcinoma cell proliferation by down-regulating Aurora-B protein level. Let-7a could be applied for gene therapy against endometrial carcinogenesis. PMID:23769985

  1. Participation of WNT and β-Catenin in Physiological and Pathological Endometrial Changes: Association with Angiogenesis

    PubMed Central

    Kiewisz, Jolanta; Wasniewski, Tomasz; Kmiec, Zbigniew

    2015-01-01

    WNT proteins are involved in embryonic development, sex determination, stem cell recruitment, angiogenesis, and cancer. They take part in morphological changes in the endometrium during development, regulate processes of endometrial proliferation and differentiation. This review presents current knowledge about implication of WNT proteins and β-catenin in physiological endometrial functions as well as their involvement in uterine carcinogenesis. Influence of WNT proteins on the formation of blood vessel, taking place both under healthy and pathological conditions, is also considered. Participation of WNT proteins, β-catenin, and inhibitors and inducers of WNT signaling in the process of endometrial angiogenesis is largely unknown. Thus, confirmation of their local and systemic participation in the process of endometrial angiogenesis may in the long term help to establish new diagnostic and therapeutic approaches in conditions associated with the pathology of the female reproductive system. PMID:26366420

  2. Boots for Achilles: progesterone's reduction of cholesterol is a second-order adaptation.

    PubMed

    Amir, Dorsa; Fessler, Daniel M T

    2013-06-01

    Progesterone and cholesterol are both vital to pregnancy. Among other functions, progesterone downregulates inflammatory responses, allowing for maternal immune tolerance of the fetal allograft. Cholesterol a key component of cell membranes, is important in intracellular transport, cell signaling, nerve conduction, and metabolism Despite the importance of each substance in pregnancy, one exercises an antagonistic effect on the other, as periods of peak progesterone correspond with reductions in cholesterol availability, a consequence of progesterone's negative effects on cholesterol biosynthesis. This arrangement is understandable in light of the threat posed by pathogens early in pregnancy. Progesterone-induced immunomodulation entails increased vulnerability to infection, an acute problem in the first trimester, when fetal development is highly susceptible to insult. Many pathogens rely on cholesterol for cell entry, egress, and replication. Progesterone's antagonistic effects on cholesterol thus partially compensate for the costs entailed by progesterone-induced immunomodulation. Among pathogens to which the host's vulnerability is increased by progesterone's effects, approximately 90% utilize cholesterol, and this is notably true of pathogens that pose a risk during pregnancy. In addition to having a number of possible clinical applications, our approach highlights the potential importance of second-order adaptations, themselves a consequence of the lack of teleology in evolutionary processes. PMID:23909226

  3. Sphenoid wing meningioma progression after placement of a subcutaneous progesterone agonist contraceptive implant.

    PubMed

    Piper, J G; Follett, K A; Fantin, A

    1994-04-01

    A causal relationship between sex steroids and meningioma proliferation has long been suspected. We report a case of the clinical progression of a sphenoid wing meningioma after the placement of Norplant, a subcutaneous contraceptive implant containing levonorgestrel, a progesterone agonist. Although not proof of causation, this observation lends further credence to the importance of progesterone receptors in the growth and possible treatment of meningiomas.

  4. Secretion of progesterone and 20 alpha-dihydroprogesterone during pregnancy in goats.

    PubMed

    Sawada, T; Nakatani, T; Tamada, H; Mori, J

    1994-08-01

    The relationships between the secretion of progesterone and 20 alpha-dihydroprogesterone and the sites of their production in pregnant goats were investigated. The progesterone concentration in the peripheral plasma increased after the goats mated, and was high from day 10 to day 140 of pregnancy. The 20 alpha-dihydroprogesterone concentration increased gradually from day 0 to day 140 after mating. The progesterone co