Mol Med Rep. 2018 Mar 29. doi: 10.3892/mmr.2018.8823. [Epub ahead of print] Zearalenone regulates endometrial stromal…
Ann Ital Chir. 2012 Jul-Aug;83(4):353-6.
Intestinal occlusion caused by endometriosis of the sigmoid colon.
Endometriosis (E) is an estrogen-dependent inflammatory disorder that is observed in approximately 10% of women in childbearing age, and is the most common benign gynecological disorder requiring hospitalization. In 5% of cases, there is an involvement of the gastrointestinal tract, for the most part of the sigmoid colon and rectum (~ 90%). However intestinal obstruction due to severe stenosis of the sigmoid colon, as in the case described by the authors, is rare. The differential diagnosis should include cancer, inflammatory diseases and actinic colitis which has a similar clinical picture to E. Surgical treatment – resection and anastomosis or conservative procedures – provides better results especially when a multidisciplinary approach is used (colorectal surgeon, gynecologist, urologist). The authors report a case of obstruction of the sigmoid colon due to endometriosis and analyze the pathophysiology, diagnosis and surgical management of this disorder.
Menopause Int. 2012 Jun;18(2):68-72. doi: 10.1258/mi.2012.012008.
Gonadotrophin receptor hormone analogues in combination with add-back therapy: an update.
Gonadotrophin receptor hormone analogues (GnRHa) have been used in a range of sex hormone-dependent disorders. In the management of premenstrual syndrome, they can completely abolish symptoms. The success of GnRHa in the treatment of endometriosis and adjuvant therapy in the management of fibroids is proven. This efficacy does not come without a cost and the side-effects of the hypo-estrogenic state have limited their application. The use of add-back therapy to counter these effects has enabled wider application, longer durations of treatment and an increase in compliance. This review article is an update on the evidence supporting gonadotrophin receptor hormone analogues in combination with add-back therapy.
Potential strategies to avoid progestogen-induced premenstrual disorders.
Non-hormonal approaches to premenstrual syndrome (PMS) treatment such as selective serotonin reuptake inhibitors are by no means effective for all women and frequently we must resort to endocrine therapy. During many of the hormonal approaches, PMS-like symptoms can be introduced or re-introduced during the necessary cyclical or continuous progestogen component of the therapy. This is seen with combined oral contraception, progestogen only contraception, progestogen therapy for heavy menstrual bleeding and endometriosis, sequential hormone replacement therapy and any therapeutic strategy for premenstrual syndrome where it is necessary to provide endometrial protection, including estrogen suppression of ovulation or add-back during gonadotrophin releasing hormone suppression. The link to progestogen is very often missed by health professionals. When the pattern of symptoms mimics the cyclicity of PMS, it is termed progestogen-induced premenstrual disorder. The need to use progestogen to protect the endometrium from the proliferative actions of estrogen can pose insurmountable difficulties in managing premenstrual disorders. In the absence of any really useful evidence, nearly all practice in this area depends on clinician experience. We cannot afford to wait for adequate research evidence to be produced – it never will – and so we must rely on empirical findings, clinical experience, theoretical strategies and common sense.
Gynecol Surg. 2012 May;9(2):131-137. Epub 2011 Dec 28.
Is adenomyosis the neglected phenotype of an endomyometrial dysfunction syndrome?
Since the dissociation between adenomyoma and endometriosis in the 1920s and the laparoscopic progress in the diagnosis and surgery of endometriosis, the literature has been greatly focused on the disease endometriosis. The study of adenomyosis, on the other hand, has been neglected as the diagnosis remained based on hysterectomy specimens. However, since the introduction of magnetic resonance and sonographic imaging techniques in the 1980s, the myometrial junctional zone has been identified as a third uterine zone and interest in adenomyosis was renewed. This has also been the start for the interest in the role of the myometrial junctional zone dysfunction and adenomyosis in reproductive and obstetrical disorders.
Borderline clear cell adenofibroma of the ovary associated with ovarian endometriosis: a case report.
Clear cell tumours of the ovary are relatively uncommon. Most of them are clear cell carcinomas. Benign and borderline clear cell tumours are extremely rare and almost always fibromatous. We report a case of a 34-year-old woman. Ultrasound and computed tomography showed a right ovarian mass 8 cm in diameter. The patient underwent right salpingo-oophorectomy. Microscopic examination revealed glands and cysts different in size and shape within an abundant stromal component without evidence of stromal invasion. Many cysts and glands were lined by a single layer of flattened, cuboidal or hobnail cells with mild to moderate cytologic atypia and prominent nucleoli. Psammomatous calcifications were occasionally indentified. Features of endometriosis were also present adjacent to the tumour. Lesional cells were positive for Ker 7 and CA125. Staining for p53 was focally positive. Based on the above characteristic morphologic and immunohistochemical findings a diagnosis of borderline clear cell adenofibroma was made. The patient was free of recurrence four years after surgery.
Eur J Obstet Gynecol Reprod Biol. 2012 Sep;164(1):1-9. doi: 10.1016/j.ejogrb.2012.05.008. Epub 2012 May 20.
Association of endometriosis risk and genetic polymorphisms involving biosynthesis of sex steroids and their receptors: an updating meta-analysis.
The objective of our study is to assess the association of endometriosis risk and genetic polymorphisms involving biosynthesis of sex steroids and their receptors. A systematic search of three databases was conducted. Twenty-seven studies on the association of the cytochrome P450 subfamily 17 (CYP17), estrogen receptor gene (ER), progesterone receptor gene (PR), 17-beta-hydroxysteroid dehydrogenase type 1 gene (HSD17B1), and cytochrome P450 subfamily 19 (CYP19) polymorphisms with endometriosis risk were identified. When all groups were pooled, we found an association between HSD17B1 (A variant allele vs. G wild allele: odds ratio (OR)=1.42, 95% confidence interval (CI)=1.10-1.84, P=0.007) and PR (P2 variant allele vs. P1 wild allele, OR=1.43, 95% CI=0.99-2.08, P=0.058) polymorphisms and endometriosis risk, while failing to detect links with CYP17, ER, and CYP19 polymorphisms examined. In the subgroup analysis, a significant association of CYP17 and ERα-PvuII polymorphisms with endometriosis was found neither in a Caucasian population nor in an Asian population. The findings of our study suggest that HSD17B1 and PR polymorphisms are associated with an increased risk of endometriosis. Further investigation into the association between CYP17, ER, PR, HSD17B1, and CYP19 polymorphisms and endometriosis risk is warranted and should include larger sample sizes.
Update on the surgical management of adenomyosis.
PURPOSE OF REVIEW:
Adenomyosis is a benign gynaecological condition associated with menstrual symptoms and pelvic pain in premenopausal women, it has also been linked to subfertility. Improvement in ultrasound and MRI imaging has allowed accurate diagnosis of this condition prior to histological confirmation. Patients opting for surgical management need to be counselled regarding the surgical options available. This review summarizes the surgical management of adenomyosis and reviews the recent surgical developments.
For patients who wish to preserve their fertility, cytoreductive surgery is an option in centres with surgical expertise. Recently, modified surgical procedures to remove extensive adenomyosis known as an adenomyomectomy have been described. These operations may enhance subsequent fertility.
Access to accurate imaging modalities such as MRI and transvaginal ultrasound allows for adequate patient counselling preoperatively. Depending on the fertility requirements and the extent of adenomyosis, patients can be offered various surgical treatment options including laparoscopic hysterectomy or adenomyomectomy.
[Infertility and risk of cancer].
[Article in Finnish]
Ovulation problems, ovarian endometriosis and impaired sperm quality may be factors underlying infertility and possibly predisposing to cancer diseases. Infertility therapies utilize products that alter the hormonal balance and may in theory increase the risk of cancer. Handling of gametes in the laboratory is also likely to influence gene regulation. Ovulation induction therapies may increase the risk of uterine cancer, and in vitro fertilization (IVF) therapies may increase ovarian tumors. Children born after IVF therapies seem to have a statistically elevated risk of cancer. Instead of risk ratios, the use of clear figures is recommended in patient information.
Raf-1, a potential therapeutic target, mediates early steps in endometriosislesion development by endometrial epithelial and stromal cells.
Endometriosis is a hormone-sensitive gynecological disorder characterized by the benign growth of endometrial-like tissue in the pelvic cavity. Endometriotic lesions composed of endometrial stromal cells (ESC) and glandular epithelial cells (EEC) are thought to arise from menstrual endometrial tissue reaching the pelvic cavity via retrograde menstruation. The cause of endometriotic lesion formation is still not clear. Recent evidence suggest that cytokines may play a role in the early development of endometriosis lesions. Because cytokines and growth factors signal via the v-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) kinase pathway, we have examined the role of Raf-1 in early steps of endometriosis lesion formation, specifically attachment of endometrial cells to peritoneal mesothelial cells (PMC) and invasion of endometrial cells through PMC (trans-mesothelial invasion). Raf-1 antagonist GW5074 decreased attachment to PMC and trans-mesothelial invasion by primary EEC and ESC. Raf-1 also mediated TGFβ-induced trans-mesothelial invasion by the established, low-invasive EEC line EM42. TGFβ treatment of EEC resulted in Raf-1 phosphorylation at S338 and phosphorylation of ERK, suggesting that TGFβ activates Raf-1 signaling in these cells. GW5074 had little effect on ESC proliferation but inhibited EEC growth significantly under reduced serum conditions. Antagonizing Raf-1 activity and expression via GW5074 and specific Raf-1 small interfering RNA, respectively, did not alter EEC resistance to growth inhibition by TGFβ. Raf-1 inhibition blocked induction of EEC growth by epidermal growth factor. Our data suggest that Raf-1 may mediate pathologic steps involved in early endometriosis lesion formation and may be a mediator of TGFβ and epidermal growth factor actions in endometriosis.
Gynecol Endocrinol. 2012 Nov;28(11):903-5. doi: 10.3109/09513590.2012.683074. Epub 2012 May 24.
Costs of in-patient treatment for endometriosis in Germany 2006: an analysis based on the G-DRG-Coding.
The aim of this study was to estimate the financial burden of in-patients costs for endometriosistreatment in Germany in 2006.
Data from a national in-patient database for women of reproductive age who were admitted for surgical treatment for endometriosis were analysed retrospectively. The number and type of hospital admissions involving surgical interventions for endometriosis were identified, and the costs of these hospitalizations to funding bodies in Germany were estimated using the diagnosis-related group reimbursement rates.
A total of 20,835 patients were admitted to hospital for endometriosis treatment in Germany in 2006 (1.27 per 1,000 women in reproductive age). The average cost per patient was estimated at 3,056.21 €. The total in-patient costs for endometriosis treatment in 2006 were estimated at 40,708,716.26 €. The surgical procedure most often performed in treating endometriosis was hysterectomy (in 24.70% of cases).
The burden of admissions and the economic impact associated with the inpatients treatment of endometriosis in Germany is substantial. The results presented here may enable those responsible in the field of medicine and health-care policy to improve the allocation of resources and manage expenses on a more sustained basis.
Int J Gynecol Cancer. 2012 Jul;22(6):993-9. doi: 10.1097/IGC.0b013e3182534acf.
Management and prognosis of clear cell borderline ovarian tumor.
The clear cell borderline ovarian tumor (CCBOT) of the ovary is a rare tumor accounting for less than 1% of BOT. Fewer than 25 cases have been reported in the literature (including details on clinical management and outcomes). The aim of this study was to determine the prognosis of a series of CCBOTs collected in 2 reference centers.
PATIENTS AND METHODS:
This was a retrospective review of patients with CCBOT treated or referred to our institutions. A centralized histological review by a reference pathologist and data on the clinical characteristics, management, and outcomes of patients were required for inclusion.
Twelve patients were identified between 2000 and 2010. The median age of patients was 68 years (range, 36-83 years). Two had been treated conservatively and 9 radically (data unknown in 1). The tumor was unilateral in 11 cases. All patients had stage I disease. All cases were CCBOT with an adenofibromatous pattern. Stromal microinvasion or intraepithelial carcinoma was histologically associated in 2 and 3 cases, respectively. Four of the 12 patients had synchronous endometrial disorders (but no endometrioid carcinoma). No cases were histologically associated with endometriosis. Four patients were lost to follow-up. Among 8 other patients, after a median period of 28 months (range, 2-129 months), no recurrence had occurred (1 patient had died of another disease).
Clear cell borderline ovarian tumor carries a good prognosis. All tumors are stage I; therefore, surgical staging is not necessary in most of the cases. Conservative treatment could be proposed to young patients, but uterine curettage would then be required in cases of uterine preservation.
J Minim Access Surg. 2012 Apr;8(2):50-3. doi: 10.4103/0972-9941.95535.
Type-I complex regional pain syndrome of umbilical port site: An unforeseen complication of laparoscopic surgery.
Many complications have been observed after laparoscopic surgery. Persisting pain in the umbilical port site is due to infection, hernia, endometriosis, metastasis, etc. There is no case report due to neuralgic complex regional pain syndrome, and we have dealt a case which is described with relevant literature review and etiopathogenesis.
[Success rate of intrauterine insemination in patients with unknown infertility].
[Article in Serbian]
Unknown cause of infertility exists in 10%-26% of couples with infertility problems. Treatment of these couples depends on the posibility of correcting the unidentified defect over time. Intrauterine insemination (IUI) and ovaluation stimulation are methods of choice in treatment of unexplained fertility, but if a woman is older than 37 years, in vitro fertilization (IVF) could be directly recommended. The aim of this research was to compare the success rate of pregnancies with IUI between the patients with unexplained infertility and the patients with mild form endometriosis.
The study included on 50 patients diagnosed with mild form endometriosis (group A) and 50 patients with unknown cause infertility (group B). Using the same therapeutical protocol, human menopausal gonadothropin (hMG) stimulation and horionic gonadropin (hCG) induction were applied, as well as IUI.
The percentage of achieved ovulation was higher in the group B (p < 0.05). During the 3 simulated sequential periods 102 IUI were performed in the group A and 97 IUI in the group B. In the group A there were 6 single and 1 twin pregnancies sucesfully conceived (14%), while in group B there were 9 (18%) single pregnancies.
The use of a combination of controled ovarian hyperstimulation and IUI is an effective, cheap and safe method for treating infertility couples, especially couples with unknown cause infertility. Mild form endometriosis, as etiological infertility factor, has a negative impact on IUI success rate.
Hum Pathol. 2012 Nov;43(11):1964-72. doi: 10.1016/j.humpath.2012.02.005. Epub 2012 May 22.
Involvement of pelvic inflammation-related mismatch repair abnormalities and microsatellite instability in the malignant transformation of ovarian endometriosis.
Inflammation in the ovary, including ovulation and pelvic inflammatory disease, has been proposed to play a role in the pathogenesis of ovarian cancer. Endometriotic lesions trigger a local inflammatory reaction and have been reported to be associated with an increased risk of epithelial ovarian cancer. However, the precise molecular mechanisms of ovarian cancer arising from endometriosis are still to be elucidated. To clarify the involvement of mismatch repair (MMR) abnormalities in the inflammation-associated malignant transformation of endometriosis, the immunohistochemical expression of mismatch repair proteins (human mutL homolog 1 [hMLH1] and human mutS homolog 2 [hMSH2]) was examined in 27 cases of ovarian endometriosis, 25 cases of ovarian carcinoma accompanied by endometriosis, and 39 cases of solitary ovarian carcinoma. In addition, the relationship between mismatch repair abnormalities including the microsatellite instability, PTEN (phosphatase and tensin homolog) mutation, and clinicopathologic parameters was analyzed. The expression of mismatch repair proteins was stepwisely decreased in endometriosis, ovarian carcinoma accompanied by endometriosis, and ovarian carcinoma. Tumors harboring multiple microsatellite instability (high-frequency microsatellite instability [MSI-H]) were detected in 4 (14.8%) of 27 cases of endometriosis and 7 (30.4%) of 23 cases of ovarian carcinomas. The frequency of PTEN mutations was higher in MSI-H cases than in microsatellite instability-stable (MSI-S) cases. In 2 cases of ovarian carcinoma accompanied by endometriosis, the decreased expression of mismatch repair proteins and MSI-H was observed in both the endometriosis and carcinoma lesions. Clinicopathologically, the MSI-H cases were associated with elevated serum levels of C-reactive protein and higher white blood cell counts. These findings suggest that mismatch repair abnormalities might be involved in the malignant transformation of ovarian endometriosis and that inflammation induces mismatch repair abnormalities during ovarian carcinogenesis arising from endometriosis.
Arch Physiol Biochem. 2012 Oct;118(4):210-8. doi: 10.3109/13813455.2012.687003. Epub 2012 May 26.
Analysis of cytokines in the peritoneal fluid of endometriosis patients as a function of the menstrual cycle stage using the Bio-Plex® platform.
Endometriosis is a painful disease affecting 10-15% of reproductive-age women. Concentrations of several cytokines and angiogenic factors in peritoneal fluid (PF) have been found to correlate with the severity of the disease. However, levels of some analytes vary across the menstrual cycle, and an ideal biomarker of endometriosishas not yet been identified. We have compared the PF concentrations of different cytokines in proliferative and secretory phases in women with and without the disease using the Bio-Plex platform.
PF was aspirated during laparoscopy (N = 133) and the PF concentrations of 18 cytokines from Bio-Plex panels I and II determined with the serum protocol.
Increased PF concentrations of IL-6, IL-18, eotaxin, and MCP-1 were found in endometriosis with no changes with menstrual cycle. Levels of IL-12(p70), ICAM-1, and GRO-α were higher in the secretory phase, while eotaxin concentrations were lower.
Of the 18 cytokines tested, IL-6, IL-18 and MCP-1 were the best PF markers of endometriosis.
Eur J Obstet Gynecol Reprod Biol. 2012 Oct;164(2):121-6. doi: 10.1016/j.ejogrb.2012.05.004. Epub 2012 May 23. Review.
Association between TGF-β1-509C/T polymorphism and endometriosis: a systematic review and meta-analysis.
To evaluate the association between the transforming growth factor β1 gene-509C/T (TGF-β1-509C/T) polymorphism and the risk of endometriosis.
Relevant studies published before October 2011 were identified by searching PubMed and Embase. Studies were selected using prior defined criteria. The strength of the relationship between the TGF-β1-509C/T polymorphism and endometriosis risk was assessed by Odds Ratios (ORs). Fixed- or random-effects model was calculated according to study heterogeneity. Stratification analysis and sensitivity analysis were also conducted. Possible publication bias was tested by funnel plots and Egger’s test.
Of 49 potentially relevant studies, six case-control studies were identified in this meta-analysis. The integrated result showed that the TGF-β1-509C/T polymorphism was not associated with the endometriosis risk for the allele contrast (T vs. C: OR=1.57, 95%CI=0.88-2.79), the additive genetic model (T/T vs. C/C: OR=2.96, 95%CI=0.97-9.10), the dominant genetic model (T/T+T/C vs. C/C: OR=1.80, 95%CI=0.80-4.07) and the recessive genetic model (T/T vs. C/C+T/C: OR=1.91, 95%CI=0.89-4.12). In the stratified analysis by ethnicity, genotyping method and source of control, no significantly association was found. Publication bias was not detected in the included studies.
Meta-analyses of the available data showed that the association between TGF-β1-509C/T polymorphism and susceptibility of endometriosis was not significant. More studies are needed to elucidate its role in endometriosis.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
J Neuroimmunol. 2012 Aug 15;249(1-2):49-55. doi: 10.1016/j.jneuroim.2012.04.020. Epub 2012 May 25.
Eutopic endometrium from women with endometriosis does not exhibit neurotrophic properties.
The role of neurotrophins in eutopic endometrium from endometriosis-patients was investigated in a prospective study using immunofluorescence-staining, Western blot and a neuronal growth assay. The nerve growth factor is expressed in primary endometrial cell culture from women with and without endometriosis. Western blot analysis of endometrial biopsies or uterine fluid from patients with and without endometriosis shows no difference in the neurotrophin expression. We could not find a difference between patients with and without endometriosis with regards to the neurite outgrowth of sensory ganglia when treated with conditioned cultured medium or uterine fluid. This result refutes the assumed neurotrophic properties of eutopic endometrium of patients with endometriosis.
Fertil Steril. 2012 Aug;98(2):415-22.e1-12. doi: 10.1016/j.fertnstert.2012.04.047. Epub 2012 May 24.
The ferroimmunomodulatory role of ectopic endometriotic stromal cells in ovarian endometriosis.
To understand the role of ectopic endometriotic stromal cells in ovarian endometriosis (OEM) and the associated risks for infertility and carcinogenesis.
Analyses of secreted proteins and gene expression using immortalized eutopic/ectopic endometrial(-otic) stromal cells from OEM.
Women with and without OEM.
Samples of endometrial(-otic) tissue from women with or without OEM
MAIN OUTCOME MEASURE(S):
Immunohistochemical analysis of oxidative stress in OEM, gene expression profiles, and the identification of secreted proteins by mass spectrometry in immortalized endometrial(-otic) stromal cells.
4-Hydroxy-2-nonenal-modified proteins and carboxymethyllysine were abundant in the stroma, rather than epithelia, of OEM patients, indicating the presence of oxidative stress. Immortalized ectopic endometriotic stromal cells exhibited high IRP1/IRP2/HIF-1β expression and contained lower amounts of iron and copper than their eutopic counterparts. Expression profiles, in combination with protein identification, revealed that complement component 3 (C3) and pentraxin-3 (PTX3) are the major proteins secreted from immortalized ectopic endometriotic stromal cells. Complement-3/PTX3 promoted the secretion of various cytokines by THP1 macrophage cells and thus supported M1 differentiation.
Immortalized ectopic endometriotic stromal cells in OEM predominantly secrete C3 and PTX3 and exhibit a differential regulation of iron metabolism.
Med Glas (Zenica). 2012 Feb;9(1):10-6. Review.
Role of laparoscopic surgery in treatment of infertility.
The role of laparoscopy in assisted reproduction is disputed by many. A rising problem of infertility is battled by an increasing number of centres for reproductive medicine in the region. Nevertheless, there is a large number of indications and conditions where laparoscopic surgery should not be avoided as a therapeutic choice or an aid in assisted reproductive techniques (ART). The number of centres where laparoscopic surgery is performed is significantly higher than the number of reproductive centres; a number of gynaecologists educated in laparoscopic gynaecology is growing, making it more available for patients.
Minerva Ginecol. 2012 Jun;64(3):231-8.
The role of EHP-30 as specific instrument to assess the quality of life of Italian women with endometriosis.
Our goals were to assess the psychometrical characteristics of EHP-30, to test its higher degree of appropriateness compared to the generic Quality of Life-assessment tools for Italian women suffering from endometriosis, and to determine its ability to identify the disease’s effects on the patients’ psychosocial condition, highlighting critical points that can be modified for future linguistic validation.
Participants to our study were 98 women between 19 and 51-year-old (M=34.4, SD=7.5), selected from patients of the Department of Obstetrics and Gynecology, ARNAS Civico Hospital, Palermo, Italy. All of them had a surgical diagnosis of endometriosis with histological confirmation. Quality of Life was assessed through generic (SF-36) and specific (EHP-30) instruments.
Our study shows that the current Italian version of EHP-30 is affected by overall weaker construct validity than the English one; it seems that this has to be ascribed to the inadequacy of the EHP-30 translation into Italian. In particular, unsatisfactory reliability levels have been observed for social support and self-image scales. An incorrect order of response categories has been in addition found out for several items of the Italian version of EHP-30. Research results suggest solutions to adopt for a revision of the EHP-30 Italian version that can satisfy the requirements of validity and reliability.
Although requiring a structural and linguistic revision, also the Italian version of a specific measurement instrument as EHP-30 is, appears to be more appropriate than generic tools to assess the quality of life of Italian women suffering for endometriosis.
Mol Hum Reprod. 2012 Oct;18(10):467-76. Epub 2012 May 24.
Inhibition of IDO1 suppresses cyclooxygenase-2 and matrix metalloproteinase-9 expression and decreases proliferation, adhesion and invasion of endometrial stromal cells.
Indoleamine 2,3-dioxygenase-1 (IDO1) is an intracellular enzyme that catalyses essential amino acid tryptophan along the kynurenine pathway. The aim of this study was to determine the impact of IDO1 expression on the biological characteristic of the endometrial stromal cells (ESCs). IDO1, cyclooxygenase-2 (COX-2) and matrix metalloproteinases (MMPs) in endometriotic ectopic stromal cells, endometriosis-derived eutopic stromal cells and normal ESCs (control) were detected by the in-cell Western analysis. After being treated with lipopolysaccharide, levo-1-methyl-tryptophan (L-1-MT) alone or a combination, a comparative analysis of the above protein expression was evaluated. The effects of IDO1 on ESCs proliferation, adhesion and invasion were detected through ELISA, adhesion assay and Matrigel invasion assay, respectively. The results showed that, contrary to healthy ESCs from control women, the expression of IDO1 was significantly higher in eutopic and ectopic ESCs obtained from women with endometriosis. Inhibition of IDO1 by L-1-MT suppressed the expression of COX-2 and MMP-9 in ESCs. It could also decrease the ESCs proliferation, adhesion and invasion, while stimulating ESCs decidualization. Thus, IDO1 is possibly involved in endometriosis pathogenesis via promoting COX-2 and MMP-9 expression and regulation of ESCs biological characteristics. The information may be useful for developing a new therapeutic strategy for endometriosis.
J Obstet Gynaecol Res. 2013 Jan;39(1):217-22. doi: 10.1111/j.1447-0756.2012.01891.x. Epub 2012 May 28.
Robotic surgery and standard laparoscopy: a surgical hybrid technique for use in colorectal endometriosis.
The aim of our work was to assess the feasibility and possible benefits of a novel hybrid surgical technique in rectosigmoidal resection in patients with bowel endometriosis.
MATERIAL AND METHODS:
A total of seven symptomatic and infertile women with severe bowel endometriosis underwent segmental bowel resection using the da Vinci surgical system and conventional laparoscopy. Statistical analysis was performed by Friedman test for non-parametric multiple comparisons.
The surgical procedure has a determined short mean operative time (210min) and short postoperative hospitalization (five days). In 100% of patients, the resected area showed disease-free margins. Follow-up, carried out at three, six and 12months after operation, showed a regression of painful symptoms in all operated patients (100%). Two patients (28.6%) aged≥35years eventually had natural pregnancies.
To the best of our knowledge, this report is the first concerning the use of a hybrid technique for intestinal resection in severe endometriosis, and comparing our data with that in the literature, its methodological and clinical advantages are evident. Moreover, the complete removal of endometriotic implants seems to offer good results in terms of postoperative fertility, although the study data do not allow us to draw definitive conclusions on the management of fertility.
Ugeskr Laeger. 2012 May 21;174(21):1459-60. Danish.
[Atypical course of Budd-Chiari syndrome with hydrothorax].[Article in Danish]
Budd-Chiari syndrome is a very rare condition with an incidence and a prevalence of respectively 0.8 and 1.4 per million inhabitants per year. Significant large right-sided pleural effusion without significant ascites is well-known in portal hypertension and cirrhosis, where it occurs in 5-10% of the patients. Due to the presence of endometriosis and the dominant symptom in the form of hydrothorax up to 5 l per day delayed the correct diagnosis in a case with a 33 year-old woman. Reviews of the initially performed computed tomographies could have been made shortly after admission thus avoiding long time illness and hospitalization.
J Pharmacol Sci. 2012;119(1):40-51. Epub 2012 Apr 28.
Protease-activated receptor-stimulated interleukin-6 expression in endometriosis-like lesions in an experimental mouse model of endometriosis.
The present study was undertaken to investigate the function of protease-activated receptor (PAR) in endometriotic lesions using a mouse model of endometriosis. Unilateral ovariectomy (uOVX) was performed on female nude mice followed by intraperitoneal transplantation of a suspension mixture of immortalized human endometrial epithelial cells (EM-1) and stromal cells (EtsT-499). Endometriosis-like lesions were observed mostly around the dissection site after transplantation. The expression of interleukin (IL)-6 and cyclooxygenase-2 in the lesions was enhanced in uOVX mice compared to non-uOVX animals. In non-uOVX mice, IL-6 mRNA levels were higher in lesions formed with cells that were pretreated with PAR1/2 agonists (thrombin, 10 U/ml and PAR2-activating peptide, 30 µM) compared to untreated, intact cells. Peritoneal IL-6 concentrations were also increased in the PAR1/2 agonists-treated group. IL-6 expression induced by PAR activation was blocked by the treatment of cells with serine protease inhibitors. In cultured endometrial cells, simultaneous treatment with PAR1 and PAR2 agonists significantly increased the expression of IL-6. These results suggest that peritoneal bleeding may accelerate IL-6 expression in endometriotic lesions in part through the activation of PAR.
Ugeskr Laeger. 2012 May 21;174(21):1459-60. Danish.
[Atypical course of Budd-Chiari syndrome with hydrothorax].
Budd-Chiari syndrome is a very rare condition with an incidence and a prevalence of respectively 0.8 and 1.4 per million inhabitants per year. Significant large right-sided pleural effusion without significant ascites is well-known in portal hypertension and cirrhosis, where it occurs in 5-10% of the patients. Due to the presence of endometriosis and the dominant symptom in the form of hydrothorax up to 5 l per day delayed the correct diagnosis in a case with a 33 year-old woman. Reviews of the initially performed computed tomographies could have been made shortly after admission thus avoiding long time illness and hospitalization.
J Pharmacol Sci. 2012;119(1):40-51. Epub 2012 Apr 28
Quality of life and sexual function 1 year after laparoscopic rectosigmoid resection for endometriosis.
Endometriosis is relatively common condition in fertile women and may affect the alimentary tract. Laparoscopic rectosigmoid resection for endometriosis has been found to be both feasible and safe. The aim of the present study was to prospectively evaluate the quality of life and sexual function of patients who have undergone rectosigmoid resection for endometriosis.
All patients undergoing rectal or sigmoid resection for endometriosis in two specialist hospitals were prospectively recruited in the study. Details regarding demography, endometriosis-related symptoms, procedure and postoperative recovery were collected. One year after the operation patients were sent a postal questionnaire asking about endometriosis-related symptoms, quality of life and sexual functioning. The 15D Questionnaire and McCoy Female Sexuality Questionnaire were used for this purpose.
A total of 26 patients responded to the 15D questionnaire. Endometriosis-related bowel symptoms decreased significantly after the operation. The responses showed improvements in the overall score and scores for five different dimensions (usual activities, P = 0.04; discomfort and symptoms, P < 0.001; distress, P < 0.001; vitality, P < 0.001; sexual activity, P < 0.001). Sexual satisfaction was greater 1 year after the operation (P = 0.01). Sexual problems and partner satisfaction scores had not changed significantly.
Laparoscopic rectal and sigmoid resection for endometriosis significantly reduce endometriosis-related symptoms and improve quality of life and sexual well-being.
Kössi J, Setälä M, Mäkinen J, Härkki P, Luostarinen M.
Laparoscopic management of bowel endometriosis: predictors of severe disease and recurrence.
BACKGROUND AND OBJECTIVES:
The identification of highstage and recurrent cases of bowel endometriosis is critical, because these cases require careful surgical planning. We aim to describe the clinical characteristics of women with bowel endometriosis, our principles in laparoscopic management of this pathology, and to identify predictors of severe disease and recurrence.
This was a retrospective study of 193 patients with pathologically confirmed bowel endometriosis.
Predictors of higher-stage endometriosis include a history of previous laparoscopic surgery (P=.04) and a presenting complaint of abnormal uterine bleeding (P=.01). The higher the stage of endometriosis, the more likely there would be coexistent urinary tract endometriosis (P=.02), a need for enterolysis (P=.002), ovarian cystectomy (P<.001), and bowel resection (P=.01) performed during laparoscopy. Patients with higher body mass index (BMI) had significantly higher recurrence rates of endometriosis compared to those with lower BMI (P=.002). Within our cohort, 87% of our patients achieved amelioration of symptoms by the end of the first postoperative month.
Our study confirms that laparoscopic management of bowel endometriosis is safe and effective. We found 2 statistically significant predictors of higher-stage disease that should prompt careful surgical planning. Obesity is associated with a higher rate of recurrence of endometriosis.
JSLS. 2011 Oct-Dec;15(4):431-8. doi: 10.4293/108680811X13176785203752.
Outcomes of surgical management of deep infiltrating endometriosis of the ureter and urinary bladder.
To report the outcomes of surgical management of urinary tract endometriosis and discuss the choice between conservative and radical surgery.
MATERIALS AND METHODS:
We reviewed data concerning women managed for ureteral or bladder deep infiltrating endometriosis in 5 surgical departments participating in the CIRENDO prospective database. Preoperative data, surgical procedure data, and postoperative outcomes were analyzed.
Data from 30 women pooled in the database showed 15 women presenting with ureteral endometriosis, 14 women with bladder nodules, and 1 with both types of lesions. Ureterolysis was performed in 14 cases; the ureter was satisfactorily freed in 10 of these. In 4 women over 40 years old, who were undergoing definitive amenorrhea, moderate postoperative ureteral stenosis was tolerated and later improved in 3 cases, while the fourth underwent secondary ureteral resection and ureterocystoneostomy. Primary ureterectomy was carried out in 4 women. Two cases of intrinsic ureteral endometriosis were found in 5 ureter specimens. Four complications were related to surgical procedures on ureteral nodules, and 2 complications followed the removal of bladder endometriosis. Delayed postoperative outcomes were favorable with a significant improvement in painful symptoms and an absence of unpleasant urinary complaints, except for one patient with prolonged bladder denervation.
Conservative surgery, in association with postoperative amenorrhea, can be proposed in a majority of cases of urinary tract endometriosis. Although the outcomes are generally favorable, the risk of postoperative complications should not be overlooked, as surgery tends to be performed in conjunction with other complex procedures such as colorectal surgery.
JSLS. 2011 Oct-Dec;15(4):439-47. doi: 10.4293/108680811X13176785203798.
Laparoscopic supracervical hysterectomy versus laparoscopic-assisted vaginal hysterectomy.
To compare the incidence of perioperative complications and postoperative healthcare utilization and costs in laparoscopic supracervical hysterectomy (LSH) versus laparoscopic-assisted vaginal hysterectomy (LAVH) patients.
Women 18 years with LSH or LAVH were extracted using a large national commercial claims database from 1/1/2007 through 9/30/2008. Outcome was perioperative complications and gynecologic-related postoperative resource use and costs. Multivariate analysis was performed to compare postsurgical outcomes between the cohorts.
The final sample consisted of 6,198 LSH patients and 14,181 LAVH patients. LSH patients were significantly more likely to have dysfunctional uterine bleeding and leiomyomas and less likely to have endometriosis and prolapse as the primary diagnosis, and also significantly more likely to have a uterus that weighed 250 grams than LAVH patients. Compared with LAVH patients, LSH patients had significantly lower overall infection rates (7.4% versus 6.2%, P .002) and lower total gynecologic related postoperative costs ($252 versus $385, P .001, within 30 days of follow-up and $350 versus $569, P .001, within 180 days of follow-up). Significant cost differences remained following multivariate adjustment for patient characteristics.
LSH patients demonstrated fewer perioperative complications and lower GYN-related postoperative costs compared to LAVH patients.
Clin J Gastroenterol. 2012 Jun;5(3):220-4. doi: 10.1007/s12328-012-0302-9. Epub 2012 Apr 28
Rupture of appendiceal mucocele due to endometriosis: report of a case.
We report a rare case of a mucocele of the appendix due to endometriosis which accidentally ruptured prior to surgery. A 56-year-old woman was referred to our institution for further evaluation of a cecal tumor. Colonoscopy showed a submucosal tumor at the appendiceal orifice in the cecum. Computed tomography and magnetic resonance imaging showed a well-circumscribed mass measuring 4 cm in diameter in the right lower quadrant. A preoperative diagnosis of a simple mucocele of the appendix was established. At laparotomy, a mucocele was identified in the right side of the abdomen; however, part of the mucocele had ruptured and yellow mucin was seen around the cecum. An ileocecal resection was performed. Histopathological examination was consistent with a mucocele of the appendix due to endometriosis. Cytology specimens from the yellow mucin showed few proliferating epithelial cells with a mild degree of cytological and architectural atypia. Mechanical pressure due to excess anteflexion during administration of epidural anesthesia may have contributed to the rupture of the mucocele. It is important to handle a mucocele of the appendix with great care to avoid rupture at the time of operation, including during the administration of epidural anesthesia.
Acta Obstet Gynecol Scand. 2013 Jan;92(1):8-16. doi: 10.1111/j.1600-0412.2012.01470.x. Epub 2012 Nov 1. Review.
Long-term adjuvant therapy for the prevention of postoperative endometrioma recurrence: a systematic review and meta-analysis.
Ovulation seems crucial in the pathogenesis of ovarian endometriomas. Therefore, suppression of ovulation should be protective against cyst relapse after excision. The objective of this systematic review was to assess the effect of long-term postoperative medical treatment on the risk of endometrioma recurrence. A MEDLINE search was conducted to identify all the comparative studies published in the last 12 years in the English language literature on the relation between long-term postoperative adjuvant therapy and risk of endometrioma recurrence. Of the 12 articles assessed in detail, four were finally selected based on surgery for endometriotic cysts, postoperative medical treatment use for ≥ 12 months vs. expectant management, and ultrasonographic and/or histological diagnosis of endometrioma recurrence. A total of 965 women were enrolled, 726 of whom were in three cohort studies and 239 in one randomized controlled trial. Oral contraceptives (OCs) were always used as postoperative adjuvant treatment. The absolute effect of postoperative OC use was assessed by comparing “always” and “never” users. A recurrent endometrioma was identified in 33 of 423 (8%) “always” OC users and in 117 of 341 (34%) women who underwent expectant management (pooled odds ratio 0.12; 95% confidence interval 0.05-0.29). To define the effect of duration of use, “always” users were compared with “ever” users, and “ever” with “never” users, with a pooled odds ratio of, respectively, 0.21 (95% confidence interval 0.11-0.40) and 0.39 (95% confidence interval 0.23-0.66). Postoperative OC use dramatically decreased the risk of ovarian endometrioma recurrence, especially in women who used OCs regularly and for prolonged periods.
Best Pract Res Clin Obstet Gynaecol. 2012 Dec;26(6):747-55. doi: 10.1016/j.bpobgyn.2012.04.003. Epub 2012 May 29.
Role of reproductive surgery in the era of assisted reproductive technology.
Reproductive surgery could be divided into surgery as a primary treatment for infertility, surgery to enhance in-vitro fertilisation outcome, and surgery for fertility preservation. A shift has occurred away from surgery as a primary treatment of infertility to surgery playing a crucial part in enhancing in-vitro fertilisation outcome and for fertility preservation. A normal uterine cavity is a prerequisite for implantation, and hysteroscopic correction of intrauterine pathology, including polypectomy, myomectomy and metroplasty, increases the chances of having a successful pregnancy. Management of hydrosalpinx before in-vitro fertilisation treatment by laparoscopic salpingectomy or proximal tubal occlusion increases the in-vitro fertilisation delivery rate. Finally, surgery plays an important role in preservation of fertility. This includes laparoscopic ovarian transposition, ovarian tissue removal for cryopreservation and ovarian transplantation.
Arch Toxicol. 2012 Oct;86(10):1491-504. doi: 10.1007/s00204-012-0868-5. Epub 2012 May 31. Review.
Estrogen receptors and human disease: an update.
A myriad of physiological processes in mammals are influenced by estrogens and the estrogen receptors (ERs), ERα and ERβ. As we reviewed previously, given the widespread role for estrogen in normal human physiology, it is not surprising that estrogen is implicated in the development or progression of a number of diseases. In this review, we are giving a 5-year update of the literature regarding the influence of estrogens on a number of human cancers (breast, ovarian, colorectal, prostate, and endometrial), endometriosis, fibroids, and cardiovascular disease. A large number of sophisticated experimental studies have provided insights into human disease, but for this review, the literature citations were limited to articles published after our previous review (Deroo and Korach in J Clin Invest 116(3):561-570, 2006) and will focus in most cases on human data and clinical trials. We will describe the influence in which estrogen’s action, through one of or both of the ERs, mediates the aforementioned human disease states.
Med Sci Monit. 2012 Jun;18(6):CR361-7.
Increased expression of importin13 in endometriosis and endometrial carcinoma.
Importin13 (IPO13) is a novel potential marker of corneal epithelial progenitor cells. We investigated the expression and localization of IPO13 in endometrial, endometriotic and endometrial carcinoma tissue.
IPO13 expression in endometrial, endometriotic and endometrial carcinoma tissue was examined by immunohistochemistry, qPCR and Western blot.
Immunohistochemistry studies showed that IPO13 protein was expressed mainly in cytoplasm of glandular epithelial cell and stromal cells. The rate of importin13-positive cells in proliferative phase endometrium was higher (by about 6-fold) than that in secretory endometrium (P<0.05) and the rate of importin13-positive cells in endometriosis and endometrial carcinoma was higher than that in normal secretory phase endometrial tissues (by about 4- and 9-fold, respectively). Immunofluorescence microscopy revealed co-localization of IPO13 with CD34, CD45, c-kit, telomerase, CD90 and CD146. QPCR revealed significantly increased IPO13 mRNA in endometriosis and endometrial carcinoma versus secretory phase endometrium (by about 2- and 10-fold, respectively). Western blot analysis showed that IPO13 protein is enhanced in endometriosis and endometrial carcinoma versus secretory phase endometrium (p<0.05).
These results demonstrate an increased expression of IPO13 in endometriosis and endometrial carcinoma, which could be involved in the pathogenesis of endometriosis and endometrial carcinoma; IPO13 can serve as an endometrial progenitor/stem cell marker.
Arch Gynecol Obstet. 2012 Oct;286(4):939-46. doi: 10.1007/s00404-012-2379-2. Epub 2012 May 31.
Effect of mifepristone on COX-2 both in eutopic and ectopic endometrium in mouse endometriotic model.
To study the influence of mifepristone on the expression of cyclooxygenase 2 (COX-2) protein and COX-2 mRNA and then to evaluate the mechanism.
After the establishment of 30 mice endometriosis models, the mice were randomly divided into six groups with 5 mice each group and assigned to experimental and control groups of 1-, 4- and 6-week circle according to whether mifepristone (0.13 mg d(-1)) was taken or not. Small animal optical imaging system was used to detect the fluorescent intensity of the ectopic tissue. Reverse transcript-polymerase chain reaction and western blot was used to examine COX-2 protein and COX-2 mRNA expression. ELISA was used to examine concentration of PGE(2) in serum.
Mifepristone could not affect the fluorescent intensity of the ectopic endometrium after it was taken 1, 4, and 6 (P > 0.05). However, it could decrease the transcription of COX-2 mRNA in the 1 and 4 week groups (P < 0.05), while the difference in the 6 week group was not significant (P > 0.05). It could decrease the expression of COX-2 protein after it was taken 4 and 6 weeks (P < 0.05). The serous PGE(2) in the trial groups was lower than that in the control groups, but the difference was not significant (P > 0.05).
This study showed that mifepristone could not affect the size of the ectopic endometrium, but it could decrease the transcription of COX-2 gene and then reduce the expression of COX-2 protein and its product PGE(2) which is an important factor which mediate pain. This maybe another mechanism that mifepristone takes effect through anti-inflammatory path.
Arch Gynecol Obstet. 2012 Sep;286(3):777-83. doi: 10.1007/s00404-012-2390-7. Epub 2012 May 31.
Therapeutic efficiency of Atosiban, an oxytocin receptor blocking agent in the treatment of experimental endometriosis.
The current study investigated the potential therapeutic efficiency of atosiban, an oxytocin receptor antagonist, in an experimental endometriosis model.
Endometriosis was surgically induced in 35 female rats during estrus. Four weeks after this procedure, relaparotomy was performed. The viability and dimensions of the endometriosis foci were recorded. Rats were then randomly divided into three groups. In the first group (n = 8), a daily dose of 0.2 ml 0.9 % NaCl was injected intraperitoneally (i.p.) (control cases). In the second and third groups (n = 8 and n = 8), 0.5 mg/kg/day i.p. atosiban and 1 mg/day i.p. diltiazem were given, respectively. At the end of the treatment, laparotomy was performed, and the dimensions of the endometriosis foci were recorded. The endometrial implants were processed for histological and immunohistochemical studies. The volumes of endometriotic implants were measured, and immunohistochemical analyses were performed, and compared between the groups.
After the treatment with atosiban, volumes of endometriotic implants decreased significantly. Proliferating cell nuclear antigen expression levels were significantly reduced in the atosiban and diltiazem groups compared with the control group.
In a rat endometriosis model, atosiban, an agent used for the first time for the medical treatment of endometriosis, has shown significant therapeutic efficiency.
Lin SC, Wang CC, Wu MH, Yang SH, Li YH, Tsai SJ.
Hypoxia-induced microRNA-20a expression increases ERK phosphorylation and angiogenic gene expression in endometriotic stromal cells.
Aberrant activation of MAPK has been implicated to play important roles in pathological processes of endometriosis. However, how MAPK are constitutively activated in endometriotic tissues remains largely unknown. microRNA are small noncoding RNA that regulate the stability or translational efficiency of target mRNA by interacting with the 3′ untranslated region. Thus, miRNA are thought to be modulators of the transcriptional response, fine-tuning gene expression.
The aim of this study was to evaluate the functional roles of microRNA-20a (miR20a) in MAPK activation and the pathogenesis of endometriosis.
miR20a expression was analyzed in nonpaired (endometrium = 17; endometriosis = 37) and paired (n = 12) endometriotic tissues by quantitative RT-PCR. Overexpression of miR20a in eutopic endometrial stromal cells or inhibition of miR20a in ectopic endometriotic stromal cells was used to evaluate its impact on ERK phosphorylation and subsequently angiogenesis- and proliferation-related gene expression.
Levels of miR20a were up-regulated in endometriotic stromal cells. Elevation of miR20a was up-regulated by hypoxia inducible factor-1α. The up-regulation of miR20a causes the down-regulation of dual-specificity phosphatase-2, which leads to prolonged ERK phosphorylation and an increase in the expression of several angiogenic genes. Furthermore, the up-regulation of miR20a enhances the prostaglandin E(2)-induced expression of fibroblast growth factor-9, a potent mitogen that stimulates both endothelial and endometrial cell proliferation.
Our findings provide the novel mechanism that not only functionally links together hypoxic stress, miR20a expression, aberrant ERK phosphorylation, and angiogenesis but also demonstrates that miR20a is an important modulator in the development of endometriosis.
Ultrasound Obstet Gynecol. 2012 Dec;40(6):727-9. doi: 10.1002/uog.11198. Epub 2012 Nov 8. No abstract available.
Macrophage migration inhibitory factor antagonist blocks the development of endometriosis in vivo.
Endometriosis, a disease of reproductive age women, is a major cause of infertility, menstrual disorders and pelvic pain. Little is known about its etiopathology, but chronic pelvic inflammation is a common feature in affected women. Beside symptomatic treatment of endometriosis-associated pain, only two main suboptimal therapeutic approaches (hormonal and invasive surgery) are generally recommended to patients and no specific targeted treatment is available. Our studies led to the detection of a marked increase in the expression of macrophage migration inhibitory factor (MIF) in the eutopic endometrium, the peripheral blood and the peritoneal fluid of women with endometriosis, and in early, vascularized and active endometriotic lesions. Herein, we developed a treatment model of endometriosis, where human endometrial tissue was first allowed to implant into the peritoneal cavity of nude mice, to assess in vivo the effect of a specific antagonist of MIF (ISO-1) on the progression of endometriosis and evaluate its efficacy as a potential therapeutic tool. Administration of ISO-1 led to a significant decline of the number, size and in situ dissemination of endometriotic lesions. We further showed that ISO-1 may act by significantly inhibiting cell adhesion, tissue remodeling, angiogenesis and inflammation as well as by altering the balance of pro- and anti-apoptotic factors. Actually, mice treatment with ISO-1 significantly reduced the expression of cell adhesion receptors αv and ß3 integrins (P<0.05), matrix metalloproteinases (MMP) 2 and 9 (P<0.05), vascular endothelial cell growth factor (VEGF) (P<0.01), interleukin 8 (IL8) (P<0.05), cyclooxygenease (COX)2 (P<0.001) and the anti-apoptotic protein Bcl2 (P<0.01), but significantly induced the expression of Bax (P<0.05), a potent pro-apoptotic protein. These data provide evidence that specific inhibition of MIF alters endometriotic tissue growth and progression in vivo and may represent a promising potential therapeutic avenue.
PLoS One. 2012;7(5):e37264. doi: 10.1371/journal.pone.0037264. Epub 2012 May 23.
Distal ileal endometriosis as a cause of ileus: a case report.
Endometriosis is a benign condition affecting females of reproductive age. Although intestinal endometriosis is common, it is rarely manifested as an acute bowel obstruction secondary to ileal endometriosis. Enteric endometriosis should be considered as a differential diagnosis when assessing females of reproductive age with acute small bowel obstruction.
A 41-year-old woman presented with symptoms and signs of an acute small bowel obstruction requiring emergency surgery. A small bowel resection was performed with end-to-end anastomosis. Histological examination demonstrated endometriosis with fibrosis and stricture of the ileal segment. This case is important to report as it highlights the diagnostic difficulty this particular condition pre sents to an emergency surgeon.
In the differential diagnosis, endometriosis should be taken into consideration when assessing females of reproductive age who present with abdominal pain and small bowel obstruction.
Front Biosci (Elite Ed). 2012 Jun 1;4:2754-63. Review.
Stem cell theory for the pathogenesis of endometriosis.
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;4:1201-12. Review.
Proteinase-activated receptors in the endometrium and endometriosis.
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.
Front Biosci (Schol Ed). 2012 Jun 1;4:1213-34. Review.
The role of NF-kappaB in endometriosis.
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;4:1568-81. Review.
Role of NK cells and HLA-G in endometriosis.
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.
Int J Gynecol Pathol. 2012 Jul;31(4):297-303. doi: 10.1097/PGP.0b013e31823f8482.
Endocervical-type mucinous borderline tumors are related to endometrioid tumors based on mutation and loss of expression of ARID1A.
Nongastrointestinal-type mucinous borderline tumors have been described as displaying endocervical and serous differentiation and hence have been termed “endocervical-type” mucinous borderline tumors, “mixed-epithelial papillary cystadenoma of borderline malignancy of mullerian type,” or “atypical proliferative seromucinous tumors.” A striking feature of these tumors is their frequent association with endometriosis, which has been reported in a third to a half of cases. This is an unusual finding, as pure endocervical and serous tumors are not usually associated with endometriosis. ARID1A is a recently identified tumor suppressor, which frequently loses its expression and is mutated in endometrium-related carcinomas including ovarian clear cell, ovarian endometrioid, and uterine endometrioid carcinomas. Although ARID1A mutations and their expression have been studied in gynecologic cancer, the expression pattern of ARID1A has not been investigated in ovarian atypical proliferative (borderline) tumors. In this study, we analyzed ARID1A expression in serous, gastrointestinal-type and endocervical-type (seromucinous) mucinous, and endometrioid atypical proliferative (borderline) tumors using immunohistochemistry and performed mutational analysis in selected cases. We observed loss of ARID1A staining in 8 (33%) of 24 seromucinous tumors. In contrast, ARID1A staining was retained in all the other 32 tumors except in 1 endometrioid tumor (P<0.01). Mutational analysis was performed on 2 representative seromucinous tumors, which showed complete loss of ARID1A. Both tumors harbored somatic inactivating ARID1A mutations. Previous studies have reported loss of expression and/or mutation of ARID1A in 30% to 57% of endometrioid and clear cell carcinomas but only rarely in serous tumors. In summary, these tumors often contain endocervical-type mucinous epithelium, but they typically display papillary architecture, unlike most endocervical neoplasms, and their immunophenotype is different from both endocervical and serous tumors. Moreover, they frequently contain ciliated cells, endometrial-type cells, cells with abundant eosinophilic cytoplasm, and hobnail-shaped cells, all of which can be found in endometrioid tumors. The loss of expression of ARID1A and the presence of inactivating mutations of the ARID1A gene further link this tumor to endometrioid and clear cell tumors, as does the frequent association with endometriosis. Accordingly, we suggest designating these tumors “atypical proliferative (borderline) papillary müllerian tumors” as this designation more accurately reflects their clinicopathologic, immunohistochemical, and molecular genetic features.
Int J Gynecol Pathol. 2012 Jul;31(4):304-12. doi: 10.1097/PGP.0b013e318243a97b.
The dichotomy in the histogenesis of endometriosis-associated ovarian cancer: clear cell-type versus endometrioid-type adenocarcinoma.
The histogenesis of endometriosis and endometriosis-associated ovarian cancer is one of the most mysterious aspects of pathology. To better understand the histogenesis of endometriosis and endometriosis-associated ovarian cancer, we analyzed the possibility of a link of endometrium, ovarian surface epithelium, and a cortical inclusion cyst to ovarian endometriosis and endometriosis-associated ovarian cancer by immunohistochemistry using the epithelial membrane antigen (an epithelial marker), calretinin (a mesothelial marker), and hepatocyte nuclear factor (HNF)-1β (a clear cell carcinoma-specific transcription factor). During ovarian surface epithelium invagination, cortical inclusion cyst epithelial cells may, in some cases, undergo mesothelial-epithelial transition and subsequently differentiate into endometriosis. This case of endometriosis that has undergone Müllerian metaplasia arises from the HNF-1β-negative cells. The remaining endometriosis may develop from the late secretory and menstrual endometria, with HNF-1β-positive staining, by retrograde menstruation. Endometrioid adenocarcinoma and clear cell carcinoma arise from the HNF-1β-negative and HNF-1β-positive epithelial cells of endometriosis, respectively. It has been proposed that clear cell and endometrioid-type adenocarcinomas arise from distinct types of endometriosis with different cells of origin.
Int J Gynecol Pathol. 2012 Jul;31(4):328-34. doi: 10.1097/PGP.0b013e318240505e.
Chromosomal aberrations detected by chromogenic in situ hybridization in abdominal wall endometriosis after cesarean section.
The goal of this study is to evaluate the chromosomal loss in abdominal wall endometriosis by chromogenic in situ hybridization (CISH). Twenty-four cases of abdominal wall endometriosis that developed after cesarean section at the Korea University Medical Center between January 1997 and December 2006 were selected. CISH was performed in the sections of tissue microarray block using the Zymed CISH centromeric probes for chromosomes 3, 7, 8, 9, 10, 11, 17, and 18. Monosomy was defined when the percentage of the nuclei with a single dot was more than mean+3 SD of the respective probe in normal control endometrium. CISH study was possible in more than half of the endometriosis samples, except for chromosome 9, and was most successful for chromosome 17. The frequency of monosomy was high for chromosomes 9 (75.0%) and 17 (73.9%), moderate for chromosomes 10 (57.1%) and 18 (56.3%), and low for chromosomes 3 (12.5%), 7 (22.2%), 8 (10.5%), and 11 (10.5%). Monosomy for >2 and 3 chromosomes occurred in 66.7% and 42.9% of the cases, respectively. It is concluded that CISH method may be considered a useful laboratory technique in detecting chromosomal loss, and multiple chromosomal loss is involved in the formation of ectopic endometrium in abdominal wall endometriosis.
Genet Mol Res. 2012 May 15;11(2):1401-8. doi: 10.4238/2012.May.15.10
Association of TP53 gene codon 72 polymorphism with endometriosis in Mexican women.
The TP53 tumor suppressor gene plays an important role in cell cycle regulation; polymorphisms of this gene have been associated with endometriosis. We examined the role of TP53 codon 72 polymorphism by comparing genotypes of 235 healthy Mexican women (controls with surgically excluded endometriosis) with the genotypes of 151 Mexican women with endometriosis. The observed genotype frequencies for controls and endometriosis patients were 8 and 22% for proline/proline (Pro/Pro), 30 and 34% for proline/arginine (Pro/Arg), and 62 and 44% for arginine/arginine (Arg/Arg), respectively. We found that odds ratio (OR) = 3.3; 95% confidence intervals (95%CI) = 1.7-6.4; P = 0.0001. The association was also evident in the comparison of the distributions of genotypes Pro/Pro and Pro/Arg in patients with moderate-to-severe endometriosis; OR = 1.9; 95%CI = 0.95-3.9; P = 0.049. We suggest that genotype Pro/Pro of codon 72 polymorphism in TP53 contributes significantly to endometriosis susceptibility in the Mexican population.
J Exp Clin Cancer Res. 2012 Jun 1;31:53. doi: 10.1186/1756-9966-31-53. Review.
Clear cell carcinoma of the ovary: is there a role of histology-specific treatment?
Several clinical trials to establish standard treatment modality for ovarian cancers included a high abundance of patients with serous histologic tumors, which were quite sensitive to platinum-based chemotherapy. On the other hand, ovarian tumor with rare histologic subtypes such as clear cell or mucinous tumors have been recognized to show chemo-resistant phenotype, leading to poorer prognosis. Especially, clear cell carcinoma of the ovary (CCC) is a distinctive tumor, deriving from endometriosis or clear cell adenofibroma, and response rate to platinum-based therapy is extremely low. It was implied that complete surgical staging enabled us to distinguish a high risk group of recurrence in CCC patients whose disease was confined to the ovary (pT1M0); however, complete surgical staging procedures could not lead to improved survival. Moreover, the status of peritoneal cytology was recognized as an independent prognostic factor in early-staged CCC patients, even after complete surgical staging. In advanced cases with CCC, the patients with no residual tumor had significantly better survival than those with the tumor less than 1 cm or those with tumor diameter more than 1 cm. Therefore, the importance of achieving no macroscopic residual disease at primary surgery is so important compared with other histologic subtypes. On the other hand, many studies have shown that conventional platinum-based chemotherapy regimens yielded a poorer prognosis in patients with CCC than in patients with serous subtypes. The response rate by paclitaxel plus carboplatin (TC) was slightly higher, ranging from 22% to 56%, which was not satisfactory enough. Another regimen for CCC tumors is now being explored: irinotecan plus cisplatin, and molecular targeting agents. In this review article, we discuss the surgical issues for early-staged and advanced CCC including possibility of fertility-sparing surgery, and the chemotherapy for CCC disease.
Urology. 2012 Jun;79(6):e84-5. doi: 10.1016/j.urology.2011.02.034.
Clear cell adenocarcinoma arising from abdominal wall endometriosismimicking urachal tumor.
A 41-year-old woman presented with severe lower abdominal pain. She had a history of 2 cesarean deliveries. Magnetic resonance imaging (MRI) revealed a 4.3 × 4.6 × 4.8-cm mass on the urinary bladder dome. Preoperative diagnosis was invasive urachal tumor. Wide resection of the tumor was performed. The histopathological diagnosis was clear cell adenocarcinoma with endometriosis. MRI revealed normal-sized ovaries and uterus. The definite diagnosis of clear cell carcinoma arising from abdominal wall endometriosiswas made. Adjuvant chemotherapy with paclitaxel and carboplatin (total 6 courses) was planned. The patient has thus far received 4 courses of this treatment.