Int J Cancer. 2006 Feb 27; [Epub ahead of print] Molecular genetic evidence that endometriosis is a precursor of ovarian cancer. Prowse AH, Manek S, Varma R, Liu J, Godwin AK, Maher ER, Tomlinson IP, Kennedy SH. Nuffield Department of Obstetrics and Gynaecology, The Women's Centre, John Radcliffe Hospital, University of Oxford, Oxford, ...
Fertil Steril.2012 Jun;97(6):1430-7. Epub 2012 Mar 28.
Retinoic acid suppresses growth of lesions, inhibits peritoneal cytokine secretion, and promotes macrophage differentiation in an immunocompetent mouse model of endometriosis.
Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia.
To determine the effects of all-trans-retinoic acid (RA) on establishment and growth of endometrial lesions, peritoneal interleukin-6 (IL-6) and macrophage chemotactic factor-1 (MCP-1) concentrations, and CD38, CD11b, and F4/80 expression on peritoneal macrophages in an immunocompetent mouse model of endometriosis.
Experimental transplantation study using mice.
Academic medical center.
C57BL/6 recipient mice and syngeneic green fluorescent protein transgenic (GFP+) mice.
Recipient mice were inoculated with GFP+ minced uterine tissue to induce endometriosis and treated with RA (400 nmol/day) or vehicle for 17 days (3 days before to 14 days after tissue injection).
MAIN OUTCOME MEASURE(S):
Total number of GFP+ implants in recipient mice, number of implants showing visible blood vessels, total volume of established lesions per mouse, concentrations of IL-6 and MCP-1 in peritoneal fluid, and expression of CD11b, F4/80, and CD38 on peritoneal macrophages.
Retinoic acid treatment for 17 days reduced the number of implants versus controls and decreased the frequency of lesions with vessels. Peritoneal washings in RA-treated animals had lower concentrations of IL-6 and MCP-1 than controls 3 days after endometrial inoculation and lower levels of IL-6 on day 14 after inoculation. Concomitant with these effects on day 14, CD38, CD11b, and F4/80 were higher on macrophages from RA-treated mice versus controls.
The development of endometriotic implants is inhibited by RA. This effect may be caused, at least in part, by reduced IL-6 and MCP-1 production and enhanced differentiation of peritoneal macrophages.
Front Biosci (Elite Ed).2012 Jun 1;4:2854-63.
Department of Obstetrics and Gynecology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Proposed hypothetical causes of endometriosis include retrograde menstruation, lymphatic and vascular metastasis, iatrogenic direct implantation, coelomic metaplasia, embryonic rest, and mesenchymal cell differentiation (induction). Each theory, individually, fails to account for all types of endometriotic lesions, thereby implicating combined and/or type-specific mechanisms. Recent evidence supports the presence of endometrial stem/progenitor cells and their possible involvement in eutopic endometrial regeneration and differentiation. Thus an additional novel mechanism for the origin of endometriotic lesions is that they arise from ectopic endometrial stem/progenitor cells.
Front Biosci (Schol Ed).2012 Jun 1;4:1568-81.
Department of Obstetrics and Gynecology, Kochi Medical School.
Impaired natural killer (NK) activity in women with endometriosis is thought to promote implantation and progression of endometrial tissue, in accord with Sampson’s hypothesis. However, the mechanisms responsible for decreased NK cell activity and the antigens recognized by NK cells are not clear.We focused on human leukocyte antigen (HLA)-G, a ligand of NK receptors, expression and its menstrual cycle changes by eutopic endometrium. Interestingly, HLA-G expression was identified on eutopic endometrium only in the menstrual phase but not in the proliferative or secretory phases. Furthermore, HLA-G expressing cells were also detected in peritoneal fluid during the menstrual period. During retrograde menstruation, HLA-G expressing endometrial tissue may enter the peritoneal cavity, and may be reduced by immunosurveillance system. Although peritoneal NK cells play an important role in this system, impairment of NK cytotoxicity via HLA-G may allow peritoneal endometrial cell survival and implantation. In this review, we discuss the pathogenesis of endometriosis from the viewpoint of intraperitoneal immune interaction between NK cell receptors and HLA-G that can enter into peritoneal cavity from eutopic endometrium through retrograde menstruation.
Front Biosci (Schol Ed).2012 Jun 1;4:1213-34.
Department of Obstetrics and Gynecology, Patras University School of Medicine, Patra, Greece.
The nuclear factor kappaB (NF-kappaB) is a ubiquitously expressed transcription factor playing vital roles in innate immunity and other processes involving cellular survival, proliferation, and differentiation. This review highlights the importance of NF-kappaB in the pathophysiology of endometriosis. Constitutive activation of NF-kappaB has been shown in endometriotic lesions. Complex interactions of NF-kappaB with steroid receptors and apoptotic molecules in endometriosis resulting in opposing roles of NF-kappaB are discussed. NF-kappaB regulates the expression of cytokines mediating autocrine self-amplifying cycles of cytokine release and NF-kappaB activation, leading to maintenance of inflammatory reactions in endometriosis. NF-kappaB can contribute to the increased ability of endometriotic cells to invade and adhere to the peritoneal surface by regulating the expression of matrix metaloproteinases. We are presenting the role of NF-kappaB to regulate vascularization and oxidative stress in endometriotic cells. Effects of drugs used for the treatment of endometriosis on NF-kappaB pathway are presented and we show how drugs that inhibit the NF-kappaB can mediate the progression of endometriosis. Novel therapeutic strategies involving the NF-kappaB and applied in endometriosis are also discussed.
Front Biosci (Schol Ed).2012 Jun 1;4:1201-12.
Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Proteinase-activated receptors (PARs) are G protein-coupled receptors activated by various proteinases. PARs play important roles in haemostasis, thrombosis, and inflammation. PAR1 and PAR2 are expressed in endometrial cells from the eutopic endometrium and endometriotic cells derived from endometriotic lesions. A typical activator of PAR1, thrombin, and a typical activator of PAR2, tryptase, are produced in the endometrium as well as endometriotic lesions. PAR1 activation in endometrial stromal cells induces production of vascular endothelial growth factor and matrix metalloproteinases, and increases activities of tissue-type and urokinase-type plasminogen activator. PAR2 activation in endometrial stromal cells stimulates interleukin (IL)-8 and stem cell factor production and proliferation of the cells. PAR1 activation in endometriotic stromal cells induces production of IL-8, monocyte chemotactic protein-1, and cyclooxygenase-2, and proliferation of the cells. PAR2 activation in endometriotic stromal cells increases secretion of IL-6 and IL-8, and the number of the cells. These findings indicate a wide range of function of PAR1 and PAR2 in the endometrium and endometriosis, and suggest PAR1 and PAR2 as possible therapeutic targets for endometriosis.
Gynecol Endocrinol.2012 Jun;28(6):451-4. Epub 2011 Dec 1.
A new oral contraceptive regimen for endometriosis management: preliminary experience with 24/4-day drospirenone/ethinylestradiol 3 mg/20 mcg.
The Minimally Invasive Gynaecological Surgery Unit, Gynaecology Department, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
We report our preliminary experience with the use of a low-dose oral contraceptive containing Drospirenone/Ethinylestradiol 3 mg/20 mcg, both in cyclic and continuous regimen for endometriosis management. A total of 93 women were retrospectively included: 52 were treated by medical therapy (exclusive combined oral contraceptives (COC)-users), while 41 were submitted to surgery followed by postoperative therapy (postoperative COC-users). A clinical examination was performed at baseline and at 6-months follow-up. Presence and intensity of endometriosis-related symptoms were assessed by a visual analogue scale. Presence and dimension of endometriotic lesions were evaluated by transvaginal ultrasonography. Adverse effects and tolerability were analysed. In exclusive COC-users, significant reductions in dysmenorrhoea and dyspareunia scores and in endometrioma mean diameter were observed at follow-up. In postoperative COC-users, anatomical and symptom recurrence rates at follow-up were 4.9% and 17%, respectively. The most frequent adverse effects were spotting and headache. No difference between cyclic and continuous regimen in terms of symptom relief, lesion progression and tolerability was observed. From our preliminary experience, Drospirenone/Ethinylestradiol 3 mg/20 mcg seems to be promising in endometriosis management.
Gynecol Endocrinol.2012 Jun;28(6):447-50. Epub 2011 Nov 30.
The vascular endothelial growth factor (VEGF) polymorphisms and the risk of endometriosis in northern Iran.
Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran.
Vascular endothelial growth factor (VEGF) is known to be a key molecule in the pathogenesis of endometriosis. In this study, we evaluated whether two polymorphisms -460T>C and +405G>C in VEGF are related with the susceptibility to endometriosis in northern Iran. Genomic DNA derived from patients with endometriosis and healthy women were analysed by polymerase chain reaction-restriction fragment length polymorphism. The total number of 1080 subjects (480 patients with endometriosis and 600 normal controls) was enrolled into the study. We used the Chi-square (χ(2)) test to evaluate each allele and genotype frequency of -460T>C and +405G>C polymorphisms among the cases and controls. The associations between the polymorphisms and the risk of endometriosis were estimated by odds ratio and their 95% confidence intervals. There was no significant differences in the VEGF -460T>C genotypes and allele frequencies between control women and endometriosis patients (P = 0.63). In contrast, an increased frequency of the +405CC genotype was observed in the patients with endometriosis as compared with the controls. The +405C allele was associated with the presence of endometriosis. It is concluded that the +405G>C polymorphism in VEGF may be associated with higher risk of endometriosis in northern Iran.
Gynecol Obstet Fertil.2012 Jun;40(6):337-43. Epub 2011 Oct 22.
Endometriosis and postoperative infertility. A prospective study (Auvergne cohort of endometriosis).
[Article in French]
Pôle de gynécologie-obstétrique, CHU Estaing Clermont-Ferrand, 1, place Lucie-Aubrac, 63003 Clermont-Ferrand cedex 1, France.
To evaluate in infertile women the benefit of laparoscopic surgical treatment of endometriosis.
PATIENTS AND METHODS:
All infertile patients aged 18 to 43 years old, operated between February 2004 and March 2008, with a minimal follow-up of 18 months, coming from the Auvergne cohort of endometriosis has been, were included. The primary end point was the achievement of a pregnancy.
One hundred and twenty-three patients have been included. Global pregnancy rate was 48%, which 47% was spontaneous with a mean postoperative delay of 6±4.5 months. Sixty-three patients had benefited from Assisted Reproductive Technology (ART) and 25 pregnancies were obtained (pregnancy rate: 39.7% with a mean delay of 10±3.8 months). Eighty-one percent of spontaneous pregnancies were obtained during the first 12 postoperative months. Duration of preoperative infertility and tubal involvement were significantly associated with lower spontaneous pregnancy rate. No significant differences were found between endometriosis stage I and II compared to stage III and IV, and between patient under 34 years old compared to older.
DISCUSSION AND CONCLUSION:
With this first study on infertility from the Auvergne cohort of endometriosis, we are confirmed that surgery is one of the central issues in the treatment of infertile endometriosis patient. The postoperative delay to obtain a spontaneous pregnancy requires a quick management by ART after 6 to 12 postoperative month and an immediate management by ART in case of tubal involvement or former infertility.
Gynecol Oncol.2012 Jun;125(3):667-72. Epub 2012 Mar 14.
Serum HE4 concentration is not dependent on menstrual cycle or hormonal treatment among endometriosis patients and healthy premenopausal women.
Department of Obstetrics and Gynecology, Turku University Hospital, FI-20520 Turku, Finland.
Human epididymal secretory protein E4 (HE4) is a new promising tumor marker developed for the diagnostics and follow up of ovarian cancer. It has yet to become widely accepted in clinical practice, and its biological properties have not been inclusively studied. The aim of this study was to investigate whether serum HE4 concentration varies within the normal menstrual cycle and whether common gynecological hormonal treatments have an effect on HE4 values.
Our study population consisted of 180 women, including 126 endometriosis patients and 54 healthy women. We measured their serum HE4 and CA125 concentrations and evaluated the effect of the menstrual cycle and the possible hormonal medication on these marker concentrations.
We found no significant variation in serum HE4 concentrations in samples taken at different phases of the menstrual cycle. The median HE4 concentrations in proliferative, secretory and menstrual phase were 41.5, 45.1 and 35.3pM in healthy women, and 43.4, 44.3 and 43.0pM in endometriosis patients, respectively. The use of combined estrogen and progestin contraceptives did not affect serum HE4 levels significantly.
The present study shows that the HE4 measurement in healthy premenopausal women as well as in women with endometriosis can be carried out at any phase of the menstrual cycle, and irrespective of hormonal medication, extending the benefits of HE4 use in clinical practice.
Gynecol Oncol.2012 Jun;125(3):683-6. Epub 2012 Mar 13.
Peritoneal washing cytology in patients with BRCA1 or BRCA2 mutations undergoing risk-reducing salpingo-oophorectomies: A 10-year experience and reappraisal of its clinical utility.
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
To evaluate the utility of peritoneal washing cytology (PWC) for detecting occult primary peritoneal carcinoma in patients with BRCA1 or BRCA2 mutations, we reviewed PWCs obtained during risk-reducing salpingo-oophorectomy (RRSO) from 117 patients at our institution and correlated the results with surgical pathology findings.
Records of 128 PWCs from 125 patients with BRCA1 or BRCA2 mutations undergoing RRSO at MD Anderson Cancer Center between 2000 and 2010 were obtained. Slides were available for review for 119 PWCs from 117 patients (2 patients had 2 PWCs each). Cytopathologists, blinded to the RRSO histopathologic diagnoses, categorized the PWCs as benign, atypical, suspicious for malignancy, or malignant. These results were correlated with the RRSO histopathologic diagnoses.
PWCs from 113 patients were benign. Of the remaining 4 patients, 2 had PWCs classified as atypical, 1 as suspicious for malignancy, and 1 as malignant. The corresponding RRSO histopathologic findings of the 2 atypical PWCs showed endosalpingiosis and cystadenofibroma in one case and showed no abnormalities in the other case. Both patients with suspicious or malignant PWCs, indicating the possibility of occult peritoneal carcinoma, had RRSO histopathologic diagnoses of endometriosis and endosalpingiosis. Nine patients had abnormal tubal or ovarian histologic findings, but all 9 of these patients had benign PWCs.
PWC has the potential to detect occult peritoneal carcinoma in patients with BRCA1 or BRCA2 mutations. The clinical significance of a positive PWC without abnormal RRSO histology remains unclear and will require long-term follow-up for determination.
Hum Reprod.2012 Jun;27(6):1878. Epub 2012 Apr 4.
Multidisciplinary Endometriosis Team, Department of Abdominal Surgery, Herestraat 49, 3000 Leuven, Belgium.
Hum Reprod.2012 Jun;27(6):1676-84. Epub 2012 Apr 3.
Paired-box gene 2 is down-regulated in endometriosis and correlates with low epidermal growth factor receptor expression.
GROW, School for Oncology and Developmental Biology, Maastricht University Medical Centre, Postbus 5800, 6202 AZ Maastricht, The Netherlands.
BACKGROUND Paired-box 2 (Pax2) is involved in the development of the female genital tract and has been associated with endometrial pathologies. The expression of Pax2 is induced by epidermal growth factor (EGF) and estrogens. In the present study, Pax2 expression and regulation were investigated in endometriosis. METHODS AND RESULTS Pax2 protein expression was assessed by immunohistochemistry in the eutopic (i.e. inside the uterus) and ectopic tissue (endometriosis) from 11 patients. Immunoreactivity was high in the endometrium, with strong epithelial and weaker stromal staining. Similar expression patterns of Pax2 were observed in the endometrium of women without endometriosis (n = 12). The mRNA level of Pax2 was assessed by real-time PCR in the eutopic and ectopic endometria of 14 patients and in the endometrium from women without endometriosis (n = 20). Pax2 expression was lower in endometriotic lesions than that in the eutopic endometrium of patients (P< 0.001) and controls (P= 0.007). Three possible mechanisms determining low Pax2 expression were investigated: EGF signalling, CpG DNA methylation of the Pax2 promoter and steroid response. The mRNA level of the EGF receptor (EGFR1) was assessed in the samples used for Pax2 mRNA assessment. A significant correlation between EGFR1 and Pax2 in both eutopic and ectopic tissues was observed (R = 0.58; slope regression line, 0.81; 95% CI: 0.09-1.52 and R = 0.54; slope regression line, 2.51; 95% CI: 0.02-4.99, respectively). CpG DNA methylation was analyzed by methyl-specific PCR in two regions of the Pax2 promoter but they were unmethylated in all samples. Steroid responsiveness was assessed using endometrial explant cultures and Pax2 was not regulated by either 17β-estradiol or progesterone. CONCLUSIONS In endometriosis patients, Pax2 is down-regulated in the lesions compared with the eutopic tissue, possibly due to low EGF signalling.
Hum Reprod.2012 Jun;27(6):1857-64. Epub 2012 Apr 3.
No evidence of somatic DNA copy number alterations in eutopic and ectopic endometrial tissue in endometriosis.
Department of Obstetrics and Gynecology, University of Tartu, L. Puusepa 8, 51014 Tartu, Estonia.
BACKGROUND De novo somatic copy number aberrations (SCNAs) in eutopic and ectopic endometria are thought to be involved in the pathogenesis of endometriosis. In this study we used, for the first time, high-density single nucleotide polymorphism-array technology for accurate detection of SCNAs, inherited DNA copy number variations (CNVs) and copy-neutral loss of heterozygosity (cn-LOH) patterns in patients with endometriosis. METHODS The Illumina HumanOmniExpress array was used to detect de novo somatic genomic alterations in eutopic and ectopic endometria from 11 women (eight with Stage I-II endometriosis and three with Stage III-IV endometriosis) by comparatively analysing DNA from peripheral blood, eutopic endometrium and a pure population of endometriotic cells harvested from endometriotic lesions by laser capture microdissection (LCM). The frequency of the CNV in 3p14.1 from blood DNA of 187 endometriosis patients (94 with Stage I-II endometriosis and 93 with Stage III-IV endometriosis) and 171 healthy women from the Estonian general population was evaluated. RESULTS Analysis of array data showed that LCM DNA can be used successfully for detection of genetic changes as all inherited CNVs were identified in all tissues studied. No unique SCNAs or cases of cn-LOH were found in either eutopic or ectopic endometrium when compared with blood DNA. The frequency of the deletion allele in 3p14.1 did not differ between studied groups. CONCLUSIONS In the present study no endometriosis-specific SCNAs or regions of cn-LOH in eutopic or ectopic endometrium were found. Nevertheless, as we studied only 17 endometriotic tissues derived from 11 patients we cannot entirely exclude the occurrence of rare SCNAs. Based on our results we suggest that molecular mechanisms other than chromosomal rearrangements most likely underlie the onset and progression of endometriosis.
Hum Reprod.2012 Jun;27(6):1735-44. Epub 2012 Mar 23.
Institute for Clinical & Experimental Surgery, University of Saarland, Homburg/Saar 66421, Germany.
BACKGROUND Xanthohumol is a prenylated flavonoid isolated from hops, which is known to act as a pleiotropic cancer chemopreventive agent owing to its anti-proliferative, anti-inflammatory and anti-angiogenic properties. In the present study, we analyzed, for the first time, whether this dietary compound may also be used for the treatment of endometriosis. METHODS Peritoneal and mesenteric endometriotic lesions were surgically induced in BALB/c mice by uterine tissue transplantation into the abdominal cavity. The animals were treated daily with 100 µM xanthohumol (n= 8) or vehicle (control, n= 8) via the drinking water, starting 3 days before tissue transplantations. Lesion growth, cyst formation and vascularization were subsequently analyzed by means of high-resolution ultrasound imaging (at Day 0 and then once per week for 28 days), caliper measurements, western blotting, histology and immunohistochemistry over 4 weeks. RESULTS In the treatment and control groups, uterine grafts developed typical endometriotic lesions with cyst-like dilated glands surrounded by a vascularized endometrial stroma. However, xanthohumol efficiently decreased the size of these lesions at Day 28, independent of their localization within the peritoneal cavity, compared with control (peritoneal: P =0.041; mesenteric: P =0.038). This was associated with a reduced level of phosphoinositide 3-kinase protein. Moreover, vascularization of xanthohumol-treated lesions was suppressed, as indicated by a significantly lower microvessel density at Day 28 when compared with vehicle-treated controls (peritoneal: P =0.026; mesenteric: P =0.004). Additional analyses revealed that treatment with xanthohumol did not affect the histomorphology, proliferation and vascularization of the uterine horns and ovaries. CONCLUSIONS Taken together, these experimental findings suggest that xanthohumol inhibits the development of endometriotic lesions in mice without inducing serious side effects in the reproductive organs. Thus, xanthohumol represents a promising dietary phytochemical that, after further testing, may be considered for the use in the selective treatment of endometriotic lesions.
Hum Reprod.2012 Jun;27(6):1668-75. Epub 2012 Mar 23.
BDNF Val66Met polymorphism is associated with Stage III-IV endometriosis and poor in vitro fertilization outcome.
Reproductive Medical Center, The Second Hospital Affiliated to Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250001, P.R. China.
BACKGROUND The recently identified human brain-derived neurotrophic factor (BDNF) Val66Met polymorphism was found to be associated with altered susceptibility to some neuropsychiatric disorders. Interestingly, BDNF together with its receptors TrkB and p75 are extensively expressed in female reproduction system. The aim of this study is to investigate whether the BDNF Val66Met polymorphism plays a role in endometriosis, endometriosis-related infertility and the outcomes of IVF and embryo transfer (IVF-ET). METHODS A case-control study included 425 endometriosis patients and 244 control Chinese Han women. The genotyping of the BDNF Val66Met polymorphism was performed by the fluorescence resonance energy transfer method. The plasma and follicular fluid concentrations of BDNF on the day of oocyte retrieval were measured by ELISA. The general clinical data from the endometriosis-related and tubal obstructed infertile patients treated with IVF-ET were analyzed. RESULTS There was no association between the BDNF Val66Met polymorphism and overall endometriosis (P> 0.05), whereas higher genotype and allele frequencies of the BDNF(Met) polymorphism were found in the Stage III-IV endometriosis (both P< 0.01) and endometriosis-related infertile patients (both P< 0.05). Moreover, during IVF and embryo transfer (IVF-ET) treatment, fewer mature oocytes (P< 0.05) and lower fertilization rate (P< 0.01) were found in BDNF(Met/Met) carriers compared with those in BDNF(Val/Val) carriers with infertility. Follicular-fluid BDNF concentration in BDNF(Met/Met) carriers was lower compared with that in BDNF(Val/Val) individuals (P< 0.01). CONCLUSIONS Our results suggest that the BDNF(Met) single-nucleotide polymorphism might contribute to the increased susceptibility to the Stage III-IV endometriosis and endometriosis-related infertility. Moreover, infertile patients with the BDNF(Met/Met) genotype had a poorer IVF outcome compared with the BDNF(Val/Val) genotype individuals, which might in part be due to the decreased BDNF levels in follicular fluids after controlled ovarian hyperstimulation.
Hum Reprod.2012 Jun;27(6):1712-22. Epub 2012 Mar 22.
Induction of endometriosis alters the peripheral and endometrial regulatory T cell population in the non-human primate.
Department of Animal Sciences, University of Illinois, 1207 W. Gregory Drive, Urbana, IL 61801, USA.
BACKGROUND Endometriosis is a gynecological condition that is characterized by extreme abdominal pain and also decreased fertility. Regulatory T cells (Tregs) have immunosuppressive activity critical for embryonic implantation and likewise the acceptance of tissue engraftment. Utilizing the induced non-human primate (Papio anubis) model of endometriosis, we hypothesize that endometriosis decreases the peripheral and endomet rial Treg profile, whereas ectopic lesions have increased Treg localization. METHODS Peripheral blood and endometrium were obtained throughout the menstrual cycle prior to and after induction of disease. Animals were randomly assigned to control (n = 7) or diseased (n = 16) treatment groups. Endometriosis was induced by i.p. injection of autologous menstrual tissue for 2 consecutive months during menses. Peripheral blood and endometrial tissue were collected at d9-11PO at 1, 3, 6, 9, 12 and 15 months post-induction of disease for fluorescence-activated cell sorting, quantitative RT-PCR and immunohistochemistry. Ectopic lesions were excised at 1 and 6 months post-inoculation and also harvested at necropsy (15 months) and processed for RNA of IHC. Identification of Tregs through analysis of FOXP3 expression was conducted utlilizing several methodologies. Differences were determined by non-parametric statistical analysis between all treatment groups and time points. RESULTS In control animals, the proportion of peripheral natural Tregs (nTregs) was reduced (P < 0.05) during the mid- and late secretory stages of the menstrual cycle compared with menses. The induction of disease decreased peripheral Treg expression at early time points (P < 0.05) and this remained low throughout the time course, compared with the pre-inoculatory level of an individual. FOXP3 gene expression and Treg populations were also decreased in the eutopic endometrium (P < 0.05) compared with control animals, whereas these parameters were increased in ectopic lesions (P < 0.05), compared with the eutopic endometrium. CONCLUSIONS Our data suggest that a reduction in peripheral Tregs may be a causative factor for endometriosis-associated infertility, while the increase in ectopic Treg expression may aid lesion development. Furthermore, endometriosis appears to disrupt Treg recruitment in both eutopic and ectopic endometrium.
Hum Reprod.2012 Jun;27(6):1685-9. Epub 2012 Mar 20.
Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan.
BACKGROUND Endometriotic cells display invasive characteristics, despite their benign histological appearance. Recently, the epithelial-mesenchymal transition, in which epithelial cells acquire mesenchymal and migratory properties, has attracted attention as a mechanism of tumor invasion. We aimed to investigate the association between endometriosis and polymorphisms of the E-cadherin gene, a central player in the epithelial-mesenchymal transition, in Japanese women. METHODS Twelve single-nucleotide polymorphisms (SNPs) in the E-cadherin gene were identified by real-time polymerase chain reaction using a TaqMan assay in 511 women with endometriosis (the majority in Stages III and IV) and 498 healthy controls. RESULTS Allele frequency analysis indicated that there was a marginally higher frequency of the rs4783689 C allele in women with endometriosis compared with controls (corrected P = 0.007; odds ratio = 1.37; 95% confidence interval, 1.14-1.64). No significant associations with endometriosis were found for the other 11 SNPs. CONCLUSIONS Although this study was limited by sample size, the E-cadherin gene polymorphism rs4783689 was marginally associated with endometriosis in the Japanese population, suggesting that E-cadherin might be involved in genetic susceptibility to endometriosis.
Hum Reprod.2012 Jun;27(6):1624-7. Epub 2012 Mar 15.
The clinical features and management of perineal endometriosis with anal sphincter involvement: a clinical analysis of 31 cases.
Department of Obstetrics and Gynecology, Peking Union Medical College (PUMC) Hospital, No. 1 Shuaifuyuan Wangfujing, Dongcheng District, Beijing 100730, P.R. China.
BACKGROUND The aim of this study was to investigate the appropriate measures for diagnosing and treating perineal endometriosis (PEM) with anal sphincter involvement. METHODS Between January 1992 and April 2011, the clinical features, diagnosis and management of 31 patients who were diagnosed with PEM with anal sphincter involvement at the Peking Union Medical College Hospital were retrospectively analyzed using their clinical records. A range of 6-78 months of outpatient follow-up after surgery were conducted for these 31 patients but was extended by telephone interviews with 29 patients conducted in December 2011. RESULTS All 31 patients had a history of vaginal delivery. The level of serum CA(125) was elevated in only 2 (6.5%) cases. All cases received surgical treatment, which included narrow excision (NE, close to the edge of the endometrioma) with primary sphincteroplasty (PSp) for 30 cases and incomplete excision (IE) for 1 case. Of the 30 cases in the NE group, 20 (66.7%) received hormone therapy preoperatively. Up until December 2011, there was one recurrence (3.6%) of PEM in the NE group. PEM relapse occurred in the IE patient 6 years after the initial IE surgery. Perineal abscesses were found in one patient post-operatively. No complaint of dyspareunia and no fecal incontinence episodes were observed during follow-up. CONCLUSIONS Based on our own experience, NE and PSp may be indicated for the treatment of PEM with anal sphincter involvement.
Int J Gynaecol Obstet.2012 Jun;117(3):228-33. Epub 2012 Mar 27.
Detailed analysis of a randomized, multicenter, comparative trial of dienogest versus leuprolide acetate in endometriosis.
Department of Gynecological Endocrinology and Reproductive Medicine, University of Heidelberg, Vossstrasse 9, 69115 Heidelberg, Germany. email@example.com
To analyze the secondary efficacy and safety outcomes from a recent trial comparing dienogest (DNG) with leuprolide acetate (LA) in women with endometriosis.
A 24-week, open-label, randomized, multicenter study of DNG versus LA in women with endometriosis-related pain was assessed for outcomes such as responder rates (using predefined thresholds of pain relief), changes in single symptoms/signs and sum scores from the Biberoglu and Behrman (B&B) scale, clinical laboratory parameters, and measures of quality of life.
Dienogest was non-inferior to LA for treatment response using all predefined thresholds of pain relief and provided equivalent improvements in B&B symptoms and signs. No clinically relevant changes in laboratory parameters were observed during DNG treatment, whereas estrogen levels decreased in the LA group. Compared with LA, DNG was associated with pronounced improvements in specific quality-of-life measures.
The analyses provide supportive evidence that the efficacy of DNG is equivalent to that of LA for treating endometriosis symptoms, with specific quality-of-life benefits and a favorable safety profile.