Colorectal Dis. 2015 Oct;17 Suppl 3:7-11.

Diverse applications for near infra-red intraoperative imaging.

Gossedge G¹, Vallance A¹, Jayne D¹.

 

Abstract

BACKGROUND:

Near infra-red angiography using Indocyanine Green (ICG) has increasingly used as a tool for intraoperative diagnostics.

AIMS:

The aim of this review is to explore the applications of ICG fluorescence angiography with particular emphasis on general surgical applications.

MATERIALS AND METHODS:

A literature review was conducted to identify and summarise the diverse range of applications of ICG fluorescence.

RESULTS:

ICG fluorescence angiography is increasingly used in a number of general surgical applications, including identification of colorectal liver metastases, assessment of skin flap perfusion, diagnosis of peritoneal endometriosis, ureteric identification, and localisation of colonic pathology.

DISCUSSION:

ICG fluorescence angiography has clinical application in many areas as a tool for guiding surgical resection.

CONCLUSION:

With the technological developments in near infra-red imaging it is likely that ICG fluorescence will play an increasing role in many routine surgical procedures.

 

 

Womens Health (Lond). 2015 Aug;11(5):603-10

Serum markers for the noninvasive diagnosis of endometriosis.

Luisi S¹, Pinzauti S¹, Regini C¹, Petraglia F¹.

 

Abstract

Endometriosis is a disease that affects millions of women worldwide and its diagnosis is still challenging. Medical history, symptoms together with imaging data may address the correct diagnosis, but the gold standard remains laparoscopic assessment with histological confirmation. The development of serum markers as diagnostic tools for endometriosis may allow a prompt and noninvasive diagnosis. Several serum biomarkers have been investigated over the years, but none of these have shown a clinical utility and nowadays the more realistic diagnostic biomarker consists in a panel of biomarkers. The recent introduction of new technologies such as genomics and proteomics may represent the future perspective of endometriosis diagnosis.

 

 

Womens Health (Lond). 2015 Aug;11(5):633-41.

In vitro fertilization for endometriosis-associated infertility.

Polat M¹, Yaralı ݹ, Boynukalın K¹, Yaralı H^1,2.

 

Abstract

Endometriosis is an enigmatic disease affecting 10-15% of reproductive aged women and is encountered in 25-35% of women suffering from infertility. IVF is an effective tool to overcome endometriosis-associated infertility when expectant management or surgery fails. Direct IVF should be envisioned if the female age is greater than 38 year and infertility is long lasting. Likewise, semen characteristics or tubal status that is incompatible with natural conception mandates going straight to IVF. IVF, not only bypasses the distortion of pelvic anatomy associated with advanced stage endometriosis, but also removes gametes from a hostile peritoneal environment. In this article, we address the impact, if any, of endometriosis and endometriomason IVF outcome, whether surgical treatment of early-stage disease, endometriomas or deep infiltrating endometriosis would enhance pregnancy rates in IVF, which protocol to employ for controlled ovarian hyperstimulation for IVF and finally the impact, if any, of controlled ovarian hyperstimulation for IVF on progression of endometriosis.

 

 

Hum Reprod Update. 2016 Jan-Feb;22(1):104-15

Infertility and reproductive disorders: impact of hormonal and inflammatory mechanisms on pregnancy outcome.

Vannuccini S¹, Clifton VL², Fraser IS³, Taylor HS⁴, Critchley H⁵, Giudice LC⁶, Petraglia F¹.

 

Abstract

BACKGROUND:

Reproductive disorders and infertility are associated with the risk of obstetric complications and have a negative impact on pregnancy outcome. Affected patients often require assisted reproductive technologies (ART) to conceive, and advanced maternal age is a further confounding factor. The challenge is to dissect causation, correlation and confounders in determining how infertility and reproductive disorders individually or together predispose women to poor pregnancy outcomes.

METHODS:

The published literature, to June 2015, was searched using PubMed, summarizing all evidences concerning the perinatal outcome of women with infertility and reproductive disorders and the potential mechanisms that may influence poor pregnancy outcome.

RESULTS:

Reproductive disorders (endometriosis, adenomyosis, polycystic ovary syndrome and uterine fibroids) and unexplained infertility share inflammatory pathways, hormonal aberrations, decidual senescence and vascular abnormalities that may impair pregnancy success through common mechanisms. Either in combination or alone, these disorders results in an increased risk of preterm birth, fetal growth restriction, placental pathologies and hypertensive disorders. Systemic hormonal aberrations, and inflammatory and metabolic factors acting on endometrium, myometrium, cervix and placenta are all associated with an aberrant milieu during implantation and pregnancy, thus contributing to the genesis of obstetric complications. Some of these features have been also described in placentas from ART.

CONCLUSIONS:

Reproductive disorders are common in women of childbearing age and rarely occur in isolation. Inflammatory, endocrine and metabolic mechanisms associated with these disorders are responsible for an increased incidence of obstetric complications. These patients should be recognized as ‘high risk’ for poor pregnancy outcomes and monitored with specialized follow-up. There is a real need for development of evidence-based recommendations about clinical management and specific obstetric care pathways for the introduction of prompt preventative care measures.

 

 

 

Biomark Cancer. 2015 Sep 6;7(Suppl 2):1-13

Tissue Factor-Factor VII Complex As a Key Regulator of Ovarian Cancer Phenotypes.

Koizume S¹, Miyagi Y¹.

 

Abstract

Tissue factor (TF) is an integral membrane protein widely expressed in normal human cells. Blood coagulation factor VII (fVII) is a key enzyme in the extrinsic coagulation cascade that is predominantly secreted by hepatocytes and released into the bloodstream. The TF-fVII complex is aberrantly expressed on the surface of cancer cells, including ovarian cancer cells. This procoagulant complex can initiate intracellular signaling mechanisms, resulting in malignant phenotypes. Cancer tissues are chronically exposed to hypoxia. TF and fVII can be induced in response to hypoxia in ovarian cancer cells at the gene expression level, leading to the autonomous production of the TF-fVII complex. Here, we discuss the roles of the TF-fVII complex in the induction of malignant phenotypes in ovarian cancer cells. The hypoxic nature of ovarian cancer tissues and the roles of TF expression in endometriosis are discussed. Arguments will be extended to potential strategies to treat ovarian cancers based on our current knowledge of TF-fVII function.

 

 

Mol Med Rep. 2015 Nov;12(5):7109-15.

Polymorphic variants in vitamin D signaling pathway genes and the risk of endometriosis-associated infertility.

Szczepańska M¹, Mostowska A², Wirstlein P¹, Skrzypczak J¹, Misztal M², Jagodziński PP².

 

Abstract

It has recently been reported that vitamin D blood plasma levels are associated with reduced risk of endometriosis. The present study aimed to investigate whether the vitamin D binding protein (GC), vitamin D receptor (VDR), and retinoid X receptor (RXR) gene variants may be genetic risk factors for endometriosis‑associated infertility. The subjects consisted of 154 women with endometriosis‑associated infertility and 347 controls. Using polymerase chain reaction restriction fragment length polymorphism and high resolution melt techniques, the GC rs1155563, rs2298849 and rs7041; RXRA rs10881578, rs10776909 and rs749759; VDR BsmI rs1544410; and FokI rs2228570 single nucleotide polymorphisms (SNPs) were investigated in the patients with endometriosis and the healthy controls. The results indicated that no significant differences were observed between the genotype and allele frequencies of all experimental SNPs in the vitamin D signaling pathway genes in women with endometriosis-associated infertility and controls. However, a significant association was present between the A‑T haplotype, consisting of VDR rs1544410 and rs222857 minor alleles, and endometriosis-associated infertility [OR=1.659 (1.122‑2.453), P=0.011]. The results of the present study suggested that VDR gene variants act as genetic risk factors for endometriosis‑associated infertility.

 

 

 

Acta Obstet Gynecol Scand. 2015 Dec;94(12):1297-306.

Can we improve the prediction of pouch of Douglas obliteration in women with suspected endometriosis using ultrasound-based models? A multicenter prospective observational study.

Reid S¹, Lu C², Condous G^1,3.

 

Abstract

INTRODUCTION:

A negative “sliding sign” during transvaginal sonography (TVS) is associated with pouch of Douglas (POD) obliteration at laparoscopy in women with suspected endometriosis. The aim of the current study was to develop and validate mathematical ultrasound models to determine whether a combination of TVS markers could improve the prediction of POD obliteration as compared with the TVS “sliding sign” alone.

MATERIAL AND METHODS:

Multicenter prospective observational study. In all, 189 women (100 in the training set and 89 in the test set) with suspected endometriosis underwent pre-operative TVS and laparoscopy. More than 50 historical, clinical and TVS end points were recorded for analysis. Univariate/multivariate analysis was performed to determine significant TVS variables associated with POD obliteration at laparoscopy. Two logistic regression models were developed on a training set: POD1 – posterior compartment deep infiltrating endometriosis, right ovarian fixation, negative “sliding sign” (i.e. POD obliteration); and POD2 model – unilateral ovarian fixation, unilateral endometrioma, negative “sliding sign.” The two models were then applied to a test set to predict POD obliteration. POD1/POD2 performance was evaluated using receiver operating characteristic curves (probability cut-off value at 0.5) and compared with “sliding sign” alone for prediction of POD obliteration.

RESULTS:

Respective values for POD1 vs. POD2 vs. “sliding sign” alone for training/test sets: accuracy – 96/96% vs. 93/97% vs. 93/97%; sensitivity – 93/88% vs. 83/88% vs. 83/88%; specificity – 97/97% vs. 97/99% vs. 97/99%; positive predictive value – 93/88% vs. 93/94% vs. 93/94%; negative predictive ratio – 97/97% vs. 93/97% vs. 93/97%; positive likelihood ratio – 32.7/32.2 vs. 29.2/63.5 vs. 29.2/63.5; negative likelihood ratio – 0.07/0.12 vs. 0.17/0.12 vs. 0.17/0.12.

CONCLUSIONS:

Incorporation of TVS markers such as bowel endometriosis, endometrioma and ovarian fixation into mathematical models does not appear to improve the prediction of POD obliteration as compared with the TVS “sliding sign” alone.

 

 

Clin Chim Acta. 2015 Oct 23;450:362-5.

High CA-125 and CA19-9 levels in spontaneous ruptured ovarian endometriomas.

Dai X¹, Jin C², Hu Y¹, Zhang Q¹, Yan X¹, Zhu F¹, Lin F³.

 

Abstract

BACKGROUND:

To evaluate the clinical significance of serum CA-125 and CA19-9 in women with spontaneous ruptured ovarian endometriomas.

METHODS:

From January 2006 to April 2015, a total of 1653 women were diagnosed with ovarian endometriomas, and 43 women were diagnosed with the spontaneous rupture of their ovarian endometrioma. In addition, 70 women diagnosed with unruptured ovarian endometriomas were chosen to serve as control subjects. Serum CA-125 and CA19-9 levels, together with the clinical materials, were collected.

RESULTS:

Serum CA-125, CA19-9, and the combined biomarkers were shown to be obviously elevated in the spontaneous ruptured ovarian endometrioma group (p=0.001, p=0.001, p=0.001, respectively). The AUC value for the combined biomarkers was 0.992 (95% CI, 0.981-1.000), with a high sensitivity and specificity of nearly 100% and 93.6%, respectively. Moreover, the maximum diameter of the mass was significantly (p=0.001) increased in the ruptured group.

CONCLUSIONS:

Serum CA-125 and CA19-9 were significantly increased in patients with spontaneous ruptured ovarian endometriomas. Moreover, the combined biomarkers were better than either CA-125 or CA19-9 alone in the diagnosis of a spontaneous rupture of the ovarian endometrioma.

 

 

Obstet Gynecol Surv. 2015 Sep;70(9):587-95.

Evidence for the Relationship Between Endometriosis and Epithelial Ovarian Cancer.

del Carmen MG¹.

 

Abstract

Endometriosis may be a precursor lesion for some epithelial ovarian cancers (EOCs), especially those of clear cell and endometrioid histologies. The causality of this relationship remains controversial and in need of further investigation because the high prevalence of endometriosis and high mortality of EOC carry significant public health implications if the association is real. Endometriosis-associated ovarian cancer (EAOC) often presents at an earlier stage and with lower-grade lesions than non-EAOC. After surgical resection, these patients also tend to have less residual disease than do patients with non-EAOC. Survival has been reported to be better for women with EAOC. The tumor suppression gene, ARID1A, is frequently disrupted in EAOC. The ARID1A mutation has been reported in preneoplastic lesions and may be an early marker in the transformation of endometriosis into cancer. The current evidence in respect to critical molecular pathways underscores the need to investigate possible role of targeted therapies in the treatment of EAOC.

 

 

J Pharm Pharmacol. 2015 Dec;67(12):1744-55.

The oil-resin of the tropical rainforest tree Copaifera langsdorffii reduces cell viability, changes cell morphology and induces cell death in human endometriotic stromal cultures.

Henriques da Silva J¹, Borges VR², Pereira Lda C³, Ferrari R⁴, de Mattos RM¹, Barros EG¹, Palmero CY¹, Fernandes PD⁵, de Carvalho PR⁵, Pereira de Sousa V², Cabral LM², Nasciutti LE¹.

 

Abstract

OBJECTIVES:

The hormonal treatment for endometriosis frequently fails to completely eradicate endometriotic implants. A new therapeutic treatment is needed. This study investigates the in-vitro effect of Copaifera langsdorffii oil-resin on human eutopic and ectopic endometrium stromal cell cultures (EuESCs and EctESCs).

METHODS:

A nanocomposite system containing the copaiba oil-resin (NanoCOR) was developed and acute toxicity test was performed. Endometrial stromal cells (ESCs) from non-endometriotics controls (CESCs), EuESCs and EctESCs were isolated and treated with different concentrations of NanoCOR, at different time intervals to evaluate its effect on cell morphology, proliferation, viability, necrosis and apoptosis induction.

KEY FINDINGS:

When treated with 50 μg/ml of NanoCOR, the morphology of EctESCs changed, as the actin microfilaments were disorganized, disassembled or disrupted. Moreover, at 24 h of treatment with NanoCOR, the EctESCs viability was inhibited, and a significant number of these cells underwent apoptosis. In EuESCs, these effects were observed only at 48 h. Finally, the treatment of EctESCs with NanoCOR increased the lactate dehydrogenase release into the extracellular medium more than in EuESCs.

CONCLUSIONS:

Our data indicate that NanoCOR has a greater impact on the behaviour of human endometriotic stromal cells than on the eutopic endometrium stromal cells, supporting the idea that NanoCOR should be further investigated as a novel and valuable alternative to treat endometriosis.

 

 

J Steroid Biochem Mol Biol. 2016 Jan;155(Pt A):35-46.

Endometriosis as a detrimental condition for granulosa cell steroidogenesis and development: From molecular alterations to clinical impact.

Sanchez AM¹, Somigliana E², Vercellini P², Pagliardini L¹, Candiani M³, Vigano P⁴.

 

Abstract

Endometriosis is an estrogen-dependent chronic inflammatory condition that affects women in their reproductive period. Alterations in ovarian follicle morphology and function have been documented in affected women. The local intrafollicular environment has been as well examined by various groups. In the present review, we aimed to summarize the molecular evidence supporting the idea that endometriosis can negatively influence growth, steroidogenesis and the function of the granulosa cells (GCs). Reduced P450 aromatase expression, increased intracellular ROS generation and altered WNT signaling characterize the GCs of women with endometriosis. Clear evidence for an increased level of GC apoptosis has been provided in association with the downregulation of pro-survival factors. Other potentially negative effects include decreased progesterone production, locally decreased AMH production and lower inflammatory cytokine expression, although these have been only partially clarified. The possibility that endometriosis per se may influence IVF clinical results as a consequence of the detrimental impact on the local intrafollicular environment is also discussed.

 

 

Reprod Sci. 2016 Apr;23(4):492-7.

Different Expression of Hypoxic and Angiogenic Factors in Human Endometriotic Lesions.

Filippi I¹, Carrarelli P², Luisi S², Batteux F³, Chapron C⁴, Naldini A¹, Petraglia F⁵.

 

Abstract

Endometriosis is associated with local angiogenic and hypoxic mechanisms. Indeed, peritoneal fluid of women with endometriosis generates a specific microenvironment to support the growth and development of ectopic endometrial tissues. The association between proangiogenic markers and hypoxic processes in different endometriosis phenotypes was investigated in the present study, analyzing the expression of several genes, related to hypoxic signaling pathway and involved in angiogenic processes, in nonpregnant women with different forms of endometriosis. Samples of ovarian endometrioma (OMA; n = 16) or deep infiltrating endometriosis (DIE; n = 11) were collected, and in addition, control endometrium was collected from healthy women by hysteroscopy. The gene expression of the hypoxia-inducible factors (HIF) 1/2α, protease-activated receptors (PARs) ¼, and vascular endothelial growth factor (VEGF) A was evaluated by quantitative reverse-transcription polymerase chain reaction. Ovarian endometrioma expresses high levels of HIF-1/2α, PAR-1/4, and VEGF-A, while DIE did not show significantly different gene expression compared to endometrium from unaffected women. A positive correlation between the expression of HIF-1/2α and VEGF-A mRNA was observed in OMA. The overall data point out that the heterogeneity of the disease reflects differences in expression levels of genes associated with hypoxia and angiogenesis, suggesting that such conditions may have an active role in the development of the disease.

 

 

Fertil Steril. 2016 Jan;105(1):119-28.e1-5

Assessing brain-derived neurotrophic factor as a novel clinical marker of endometriosis.

Wessels JM¹, Kay VR¹, Leyland NA¹, Agarwal SK², Foster WG³.

 

Abstract

OBJECTIVE:

To evaluate novel clinical markers of endometriosis including the neurotrophins brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin 4/5 (NT4/5) and compare them to others previously reported in the literature including cancer antigen 125 (CA-125) and C-reactive protein (CRP).

DESIGN:

Prospective study.

SETTING:

University hospital.

PATIENT(S):

One hundred thirty-eight women were prospectively and consecutively recruited (April 2011-April 2015; cases: undergoing endometriosis surgery, n = 96; controls: benign gynecological surgery, n = 24 combined with healthy women, no history of pelvic pain, not undergoing surgery, n = 18).

INTERVENTION(S):

Collection of peripheral blood, gynecological and demographic information, eutopic biopsy in women undergoing laparoscopy.

MAIN OUTCOME MEASURE(S):

Circulating BDNF, NGF, NT4/5, CA-125, and CRP were quantified by ELISA.

RESULT(S):

Plasma concentrations of BDNF were significantly greater in women with endometriosis (1,091.9 pg/mL [640.4-1,683.1]; n = 68, untreated) than in controls (731.4 pg/mL [352.1-1,176.2]; n = 36), whereas circulating NGF, NT4/5, CA-125, and CRP were not different. When assessed for their ability to differentiate between women with revised Classification of the American Society of Reproductive Medicine stage 1 and 2 or stage 3 and 4 disease and controls, BDNF was the only putative marker able to identify stage 1 and 2 disease, with a sensitivity and specificity of 91.7% and 69.4%, respectively, using an arbitrary cutoff value of 1,000 pg/mL. We also demonstrated that circulating BDNF in women with endometriosis who were receiving ovarian suppression for disease was equivalent to that in the control group. This suggests that BDNF may also offer the opportunity to monitor patient response to treatment.

CONCLUSION(S):

Plasma BDNF is a potentially useful clinical marker of endometriosis that is superior to NGF, NT4/5, CA-125, and CRP.

 

 

Akush Ginekol (Sofiia). 2015;54(4):57-60.

LAPAROSCOPIC SURGERY IN PELVIC ENDOMETRIOSIS AND STERILITY.

Totev T, Tihomirova T, Tomov S, Gorchev G.

 

Abstract

Endometriosis associated sterility affects 30%-50% of patients with pelvic endometriosis and the pathogenesis is complicated and controversial. The laparoscopic approach in modern surgical conservative treatment includes laser/diathermy ablation to endometriotic implants, adhesiolysis, excision of endometriotic cyst, cyst wall ablation and drainage. In case of patient with bilateral tubal occlusion, recurrence, or if conception has not occurred by 12 months after surgery, assisted reproductive techniques should be considered.

 

 

 

Clin Exp Obstet Gynecol. 2015;42(4):495-7.

Serum YKL-40 levels as a novel marker of inflammation in patients with endometriosis.

Ural UM, Tekin YB, Cüre M, Şahin FK.

 

Abstract

PURPOSE:

To establish serum YKL-40 concentrations in patients with endometriosis compared to age-matched healthy subjects.

MATERIALS AND METHODS:

This was a cross-sectional clinical study conducted in a tertiary care center. Demographics and serum YKL levels were determined and noted in a total of 63 cases (33 endometriosispatients, 30 healthy controls). Measurement of YKL-40 levels was made using a YKL-40 enzyme-linked immunosorbent assay (ELISA) kit according to the manufacturer’s protocol.

RESULTS:

The mean serum YKL-40 levels of the patient group was 106.0 +/- 15.9 (range 23.44 to 382.55) years, while the mean serum YKL-40 levels of the controls was 52.2 +/- 7.0 (range 22.35 to 160.0) years (p = 0.003).

CONCLUSIONS:

This is the first study evaluating serum YKL-40 levels in endometriosis. The present results indicate that YKL-40 levels were increased in patients with endometriosis compared to controls. The authors propose that circulating YKL-40 levels could be a novel biomarker for diagnosis and follow-up of endometriosis.

 

 

Clin Exp Obstet Gynecol. 2015;42(4):543-4.

Endometriosis of episiotomy scar: a case report.

Mihmanli V, Ózkan T, Genc S, Cetinkaya N, Uctas H.

 

Abstract

Endometriosis is characterized by the presence of histologically normal endometrial glands and stroma outside the uterine cavity. Endometriosis predominantly locates on peritoneal surfaces, but it also affects the vagina, vulva, and perineum, usually secondary to surgical or obstetric trauma. Endometriosis in an episiotomy scar is a fairly rare phenomenon. The authors present a case of endometriosis in an episiotomy scar.

 

 

Ochsner J. 2015 Fall;15(3):251-5.

 

Abdominal Wall Endometriosis on the Right Port Site After Laparoscopy: Case Report and Literature Review.

Cozzolino M¹, Magnolfi S¹, Corioni S¹, Moncini D², Mattei A¹.

 

Abstract

BACKGROUND:

Endometriosis can be intrapelvic or, rarely, extrapelvic. Endometriosis involving the rectus abdominis muscle on the trocar port site is a rare event; until now, only 16 cases have been reported in the literature. The majority of cases were associated with previous abdominal surgery such as diagnostic laparoscopy, cyst excision, appendectomy, myomectomy, or cholecystectomy. We review all the reported cases of this unusual form of extrapelvic endometriosis.

CASE REPORT:

We report a new case of abdominal wall endometriosis at the trocar port site in the rectus abdominis muscle in a woman who had undergone 2 laparoscopies for endometriosis in the 3 years before coming to our attention. The diagnosis was made by sonography. We performed a surgical resection of the lesion with a free macroscopic margin of 5-10 mm.

CONCLUSION:

Endometriosis should be considered in the differential diagnosis of any abdominal swelling. In our experience, surgery is the treatment of choice.

 

 

Arch Gynecol Obstet. 2016 Apr;293(4):845-50.

Agreement between the preoperative findings and the operative diagnosis in patients with deep endometriosis.

Barcellos MB¹, Lasmar B², Lasmar R³.

 

Abstract

INTRODUCTION:

During the evaluation of patients with endometriosis, recognizing the location and characteristics of lesions is fundamental to define the type and evaluate the response of treatment, as well as for the preoperative surgical planning. However, the non-invasive diagnostic tests have specific limitations making the diagnostic laparoscopy been recommended as a tool necessary for the diagnosis of endometriosis lesions despite the high cost and the risks involved in this procedure.

OBJECTIVE:

To evaluate the feasibility of mapping endometriosis lesions using clinical signs and image evaluation, comparing the pre- and postoperative findings of patients submitted to surgical treatment.

METHOD:

A retrospective and prospective study included all patients who underwent surgical treatment for deep endometriosis between March 2011 and November 2014, at two centers of endometriosis in Rio de Janeiro. The positive finds registered during the clinical and image evaluation were compared with the surgical and histopathological results using a new instrument: the Lasmar’s MAP of endometriosis

RESULTS:

46 patients were included, age ranging from 23 to 47 years. For each site of endometriosis lesions, sensitivity, specificity, positive and negative predictive value, the positive and negative likelihood ratios and accuracy were calculated.

DISCUSSION:

The results show a high sensitivity, specificity and accuracy of the preoperative clinical evaluation to identify the main sites of endometriosis lesions without the use of diagnostic laparoscopy.

 

 

Ochsner J. 2015 Fall;15(3):262-4.

Endometriosis-Related Hemoperitoneum in Pregnancy: A Diagnosis to Keep in Mind.

Cozzolino M¹, Corioni S¹, Maggio L¹, Sorbi F¹, Guaschino S¹, Fambrini M¹.

 

Abstract

BACKGROUND:

Endometriosis is an important gynecologic clinical entity, pathologically defined by the ectopic presence of endometrium and frequently associated with pelvic pain, that affects approximately 10% of females of reproductive age. A rare but severe complication of endometriosis during pregnancy is spontaneous hemoperitoneum in pregnancy (SHiP), severe intraabdominal bleeding that can be life threatening.

CASE REPORT:

We present the case of a patient with SHiP at 29 weeks of pregnancy. A supraumbilical midline laparotomy was performed, and pelvic exploration revealed a lacerated and bleeding right ovary. Right annessiectomy was performed, and a cesarean section was performed because hemostasis was not achievable. A healthy baby was born, and hemostasis was finally achieved.

CONCLUSION:

We believe that in gravid females with a history of endometriosis, severe abdominal pain, and a reduction of hemoglobin, physicians should always suspect SHiP. Because SHiP is a life-threatening condition for both the mother and the baby, a prompt diagnosis must lead to prompt treatment.

 

Biomed Res Int. 2015;2015:751571

The Association between Endometriomas and Ovarian Cancer: Preventive Effect of Inhibiting Ovulation and Menstruation during Reproductive Life.

Grandi G¹, Toss A², Cortesi L², Botticelli L³, Volpe A¹, Cagnacci A¹.

 

Abstract

Although endometriosis frequently involves multiple sites in the pelvis, malignancies associated with this disease are mostly confined to the ovaries, evolving from an endometrioma. Endometriomas present a 2-3-fold increased risk of transformation in clear-cell, endometrioid, and possibly low-grade serous ovarian cancers, but not in mucinous ovarian cancers. These last cancers are, in some aspects, different from the other epithelial ovarian cancers, as they do not appear to be decreased by the inhibition of ovulation and menstruation. The step by step process of transformation from typical endometrioma, through atypical endometrioma, finally to ovarian cancer seems mainly related to oxidative stress, inflammation, hyperestrogenism, and specific molecular alterations. Particularly, activation of oncogenic KRAS and PI3K pathways and inactivation of tumor suppressor genes PTEN and ARID1A are suggested as major pathogenic mechanisms for endometriosis associated clear-cell and endometrioid ovarian cancer. Both the risk for endometriomas and their associated ovarian cancers seems to be highly and similarly decreased by the inhibition of ovulation and retrograde menstruation, suggesting a common pathogenetic mechanism and common possible preventive strategies during reproductive life.

 

 

Chin Med J (Engl). 2015 Oct 5;128(19):2617-24.

Phosphoproteomics Analysis of Endometrium in Women with or without Endometriosis.

Xu HM, Deng HT, Liu CD, Chen YL, Zhang ZY¹.

 

Abstract

BACKGROUND:

The molecular mechanisms underlying the endometriosis are still not completely understood. In order to test the hypothesis that the approaches in phosphoproteomics might contribute to the identification of key biomarkers to assess disease pathogenesis and drug targets, we carried out a phosphoproteomics analysis of human endometrium.

METHODS:

A large-scale differential phosphoproteome analysis, using peptide enrichment of titanium dioxide purify and sequential elution from immobilized metal affinity chromatography with linear trap quadrupole-tandem mass spectrometry, was performed in endometrium tissues from 8 women with or without endometriosis.

RESULTS:

The phosphorylation profiling of endometrium from endometriosis patients had been obtained, and found that identified 516 proteins were modified at phosphorylation level during endometriosis. Gene ontology annotation analysis showed that these proteins were enriched in cellular processes of binding and catalytic activity. Further pathway analysis showed that ribosome pathway and focal adhesion pathway were the top two pathways, which might be deregulated during the development of endometriosis.

CONCLUSIONS:

That large-scale phosphoproteome quantification has been successfully identified in endometrium tissues of women with or without endometriosis will provide new insights to understand the molecular mechanisms of the development of endometriosis.

 

 

Int Urogynecol J. 2016 Mar;27(3):445-51.

Bladder symptoms and urodynamic observations of patients with endometriosis confirmed by laparoscopy.

Panel P¹, Huchon C^2,3, Estrade-Huchon S², Le Tohic A⁴, Fritel X⁵, Fauconnier A^2,3.

 

Abstract

INTRODUCTION AND HYPOTHESIS:

Patients with deep infiltrating pelvic endometriosis (DIE) often describe having lower urinary tract symptoms (LUTS). Bladder pain syndrome in women is also often associated with endometriosis. In this study, we aimed to describe the characteristics of LUTS and urodynamic observations in patients with posterior endometriosis versus those with posterior and anterior endometriosis.

METHODS:

This was a prospective observational study of 30 patients from two gynecologic surgical settings with experience in DIE surgery. All patients underwent preoperative standardized investigation including detailed evaluation of LUTS and urodynamic studies. During surgery, endometriosis locations were recorded and correlated to symptoms and urodynamic observations.

RESULTS:

Twenty-three patients (76.7 %) had one or more LUTS symptoms and 29 (96.7 %) had one or more abnormalities at urodynamic examination. At surgery, all patients had posterior endometriosis and ten of them also had anterior endometriosis. Patients with anterior endometriosis had increased bladder sensation (90.0 % versus 45.0 %, p = 0.024) and painful bladder filling (70.0 % versus 30.0, p = 0.04) compared with patients with posterior endometriosis only. Voiding symptoms (60.0 %), impairment of flowmetry (30.0 %), and increased maximum urethral closure pressure (90.0 %) were frequent and not correlated with any specific location.

CONCLUSIONS:

Endometriosis infiltrating the bladder wall is associated with painful bladder symptoms. Dysfunctional voiding suggests an impairment of the inferior hypogastric plexus by posterior DIE. Clinical preoperative evaluation of bladder function should be systematic; urodynamic tests could be of interest in selected patients with DIE. Endometriosis may be a major cause of bladder pain syndrome.

 

 

 

Minim Invasive Surg. 2015;2015:702631.

How Predictable Is the Operative Time of Laparoscopic Surgery for Ovarian Endometrioma?

Gambadauro P¹, Campo V², Campo S².

 

Abstract

Endometriosis is a tricky albeit common disease whose management largely relies on laparoscopy. We have studied the operative times of laparoscopic endometrioma surgery in order to assess their predictability and possible predictors. One hundred forty-eight laparoscopies were included, with a median operative time of 70 minutes (mean 75.14; 95% CI: 70.03-80.24). Half of the cases had a duration within 15-20 minutes above or below the median (IQR: 55-93.75), but the whole dataset ranged from 20 to 180 minutes, and the standard deviation was relatively large (31.4). Surgical times were significantly related to technical (number and size of the cysts) and nontechnical factors (age, parity, dysmenorrhea, and family history). At multiple logistic regression, after adjusting for number and size of the cysts, surgical times below the first quartile were associated with older age (>30 years old: aOR: 3.590; 95% CI: 1.417-9.091) and parity (≥1 delivery: aOR: 3.409; 95% CI: 1.343-8.651). Longer times, above the third quartile, were instead predicted by a familial anamnesis of endometriosis (aOR: 3.639; 95% CI: 1.246-10.627). Our findings indicate highly variable surgical times, which are predicted by unexpected nontechnical factors. This is consistent with the complexity of endometriosis and its treatment. Productivity and efficiency in endometriosis surgery should focus on the quality of healthcare outcomes rather than on the time spent in the operating theatres.

 

J Obstet Gynaecol Res. 2015 Dec;41(12):1998-2001.

Long-lasting analgesic effect of transcranial direct current stimulation in treatment of chronic endometriosis pain.

Rostami R^1,2,3, Badran BW¹, Kazemi R^3,4, Habibnezhad M^3,5, George MS^1,6.

 

Abstract

Approximately 10-20% of women of reproductive age suffer from endometriosis, with 70-90% of these women reporting chronic pain symptoms that persist during their menstrual cycle. We are presenting a case in which a novel form of noninvasive brain stimulation called transcranial direct current stimulation was used as an intervention in a 32-year-old woman with persistent, chronic pain symptoms caused by endometriosis for 20 years. Ten daily, 20-min sessions of 2-mA anodal transcranial direct current stimulation were applied over the left primary motor cortex. Acutely, visual analog scale pain symptoms were reduced by 60%. There were also significant decreases in modules of the Endometriosis Health Profile. At the 4-month follow-up, the patient still expressed an overall decrease in pain symptoms of 30%.

 

 

J Obstet Gynaecol Res. 2015 Nov;41(11):1773-8.

Surgical excision of ovarian endometriomas: Does it truly impair ovarian reserve? Long term anti-Müllerian hormone (AMH) changes after surgery.

Vignali M¹, Mabrouk M², Ciocca E¹, Alabiso G¹, Barbasetti di Prun A¹, Gentilini D³, Busacca M¹.

 

Abstract

AIM:

The long-term effects of laparoscopic cystectomy on ovarian reserve in patients with unilateral and bilateral ovarian endometriomas were evaluated.

METHODS:

A total of 22 patients undergoing laparoscopic cystectomy for unilateral endometrioma (n = 10) and bilateral endometriomas (n = 12) were included in the study.

RESULT(S):

Serum anti-Müllerian hormone (AMH) levels significantly decreased from the baseline value (3.98 ± 3.27 ng/mL) one (1.67 ± 1.56 ng/mL), three (2.01 ± 1.70 ng/mL), and six months (2.43 ± 2.39 ng/mL) postoperatively. There was no difference between preoperative and 12 month postoperative AMH levels (4.01 ± 3.39 ng/mL) (P > 0.05). Patients with bilateral endometriomas had a significantly higher rate of decline in AMH levels 12 months after surgery than patients with monolateral endometriomas (P = 0.035), but in both groups there was no difference in AMH levels at one and 12 months postoperatively (P > 0.05).

CONCLUSION(S):

AMH levels temporarily decreased after laparoscopic cystectomy for ovarian endometriomas, with complete recovery of preoperative AMH values at 12 months postoperatively. This pattern was equal in patients with bilateral and unilateral ovarian involvement. Patients with bilateral cysts have higher rates of decline of AMH levels compared to patients with unilateral affection.

 

 

Acta Med Port. 2015 May-Jun;28(3):347-56.

Validation of the Portuguese Version of EHP-30 (The Endometriosis Health Profile-30).

Nogueira-Silva C¹, Costa P², Martins C³, Barata S⁴, Alho C⁴, Calhaz-Jorge C⁵, Osório F⁵.

 

Abstract

INTRODUCTION:

Endometriosis Health Profile Questionnaire-30 is currently the most used questionnaire for quality of life measurement in women with endometriosis. The aim of this study is to evaluate the psychometric properties and to validate the Portuguese Endometriosis Health Profile Questionnaire-30 version.

MATERIAL AND METHODS:

A sequential sample of 152 patients with endometriosis, followed in a Portugal reference center, were asked to complete a questionnaire on social and demographic features, the Portuguese version of the Endometriosis Health Profile Questionnaire-30 and of the Short Form Health Survey 36 Item â version 2. Appropriate statistical analysis was performed using descriptive statistics, factor analysis, internal consistency, item-total correlation and convergent validity.

RESULTS:

Factorial analysis confirmed the validity of the five-dimension structure of the Endometriosis Health Profile Questionnaire-30 core questionnaire, which explained 83.2% of the total variance. All item-total correlations presented acceptable results and high internal consistency, with Cronbach’s alpha ranging between 0.876 and 0.981 for the core questionnaire and between 0.863 and 0.951 for the modular questionnaire. Significant negative associations between similar scales of Endometriosis Health Profile Questionnaire-30 and Short Form Health Survey 36 Item â version 2 were demonstrated. Data completeness achieved was high for all dimensions. The emotional well-being scale in the core questionnaire and the infertility scale in the modular section had the highest median scores, and therefore the most negative impact on the quality of life of participating women.

DISCUSSION:

The test-retest reliability and responsiveness of the questionnaire should be evaluated in future studies.

CONCLUSION:

The present study demonstrates that the Portuguese version of the Endometriosis Health Profile Questionnaire-30 is a valid, reliable and acceptable tool for evaluating the health-related quality of life of Portuguese women with endometriosis.

 

 

Surg Endosc. 2016 Jun;30(6):2626-7.

Deep shaving and transanal disc excision in large endometriosis of mid and lower rectum: the Rouen technique.

Roman H^1,2, Abo C³, Huet E⁴, Tuech JJ^4,5.

 

Abstract

BACKGROUND:

Colorectal resection is performed in a majority of patients presenting with large endometriosis of mid and lower rectum; however, it may negatively and irreversibly impact postoperative rectal function. To avoid such unfavourable outcomes, we propose an original technique combining laparoscopic deep rectal shaving and transanal disc excision using a semi-circular stapler.

METHODS:

The video presents the procedure performed in a 29-year-old nullipara referred with a large endometriotic nodule infiltrating the lower rectum on more than 30 mm length. The first step is laparoscopic and involves deep rectal shaving performed using exclusively the plasma energy. Then, transanal excision of shaved area is performed, by placing traction parachute sutures in the middle and outside the shaved area. Their traction induces the prolapse of shaved area that is resected using a semicircular stapler. Insufflating the rectum with air checks the integrity of the staple line.

RESULTS:

Operative time was 210 min. Immediate postoperative outcomes were uneventful, and bowel movements were normal beginning with day 6. Our technique is suitable in large rectal nodules located up to 10 cm above the anus, infiltrating the rectum on up to 6 cm length, and these parameters are preoperatively assessed using MRI and computed tomography. To date, it was successfully carried out in 29 women with large deep endometriosis of the mid and lower rectum. Rectovaginal fistula was recorded in one patient (3.6 %) and transitory bladder dysfunction in seven patients (25 %). Digestive function assessment using standardized questionnaires revealed an overall improvement, without de novo anal continence troubles. Postoperative pregnancy rate was 78 % with a majority of patients having conceived spontaneously.

CONCLUSIONS:

Based on our experience, we believe that our conservative technique is feasible and reproducible in large mid and lower rectal endometriosis and might avoid the risk of unfavourable outcomes related to low colorectal resection.

 

 

Gynecol Oncol Rep. 2015 Jul 15;13:68-70.

Endometrioid adenocarcinoma arising from deep infiltrating endometriosisinvolving the bladder: A case report and review of the literature.

Tarumi Y¹, Mori T², Kusuki I², Ito F², Kitawaki J².

 

Abstract

• Malignant transformation of deep infiltrating endometriosisinvolving the bladder is quite rare.•We review eight relevant cases which have been reported.•This is the second case fulfilling Sampson and Scott criteria.

 

 

Gynecol Endocrinol. 2016;32(1):82-6

Expression of stem cell-related genes in the endometrium and endometriotic lesions: a pilot study.

Fettback PB¹, Pereira RM², Rocha AM³, Soares JM Jr¹, Smith GD³, Baracat EC¹, Serafini PC^1,2.

 

Abstract

OBJECTIVE:

To compare the expression of stem cell-related genes in the endometrium (END), superficial endometriosis (SE), and deep infiltrating endometriosis (DIE).

STUDY DESIGN:

We performed a prospective pilot study of six women suffering from SE and DIE who gave consent for laparoscopy surgery, endometrial biopsies, and participation in this study. Quantitative RT-PCR analysis of 84 stem cell-related genes was performed in 18 biopsy samples.

RESULTS:

A total of 40 of 84 genes were expressed in SE and DIE, but were different from END as follows. Seven genes were over-expressed in SE and 33 genes were under-expressed in DIE compared with END. Two genes were only over-expressed in SE and three genes were only over-expressed in DIE. Six under-expressed genes were exclusively located in SE and one was only located in DIE. The remaining 31 genes were not different among the groups. There was no significant difference in gene expression between SE and DIE samples.

CONCLUSION:

Tissue of DIE and SE appears to have similar stem cell-related genes. Nevertheless, there are differences in gene expression between SE and DIE.

 

 

Medicine (Baltimore). 2015 Sep;94(39):e1633.

The Risk of Epithelial Ovarian Cancer of Women With Endometriosis May be Varied Greatly if Diagnostic Criteria Are Different: A Nationwide Population-Based Cohort Study.

Lee WL¹, Chang WH, Wang KC, Guo CY, Chou YJ, Huang N, Huang HY, Yen MS, Wang PH.

 

Abstract

This article aims to test the hypothesis that the risk of epithelial ovarian cancer (EOC) in women with endometriosis might be changed by enrolling different population. A nationwide 14-year historic cohort study using the National Health Insurance Research Database (NHIRD) of Taiwan and the Registry for Catastrophic Illness Patients was conducted. A total of 239,385 women aged between 20 and 51 years, with at least 1 gynecologic visit after 2000, were analyzed. Cases included women with a diagnosed endometriosis, which was established along a spectrum from at least 1 medical record of endometriosis (recalled endometriosis) to tissue-proved ovarian endometriosis (n = X). Controls included women without any diagnosis of endometriosis (n = 239,385 – X). We used Cox regression, and computed hazard ratios (HRs) with 95% confidence intervals (95% CI) to determine the risk of EOC in patients. The EOC incidence rates (IRs, per 10,000 person-years) of women with endometriosisranged from 1.90 in women with recalled endometriosis to 18.70 in women with tissue-proved ovarian endometrioma, compared with those women without any diagnosis of endometriosis (0.77-0.89), contributing to crude HRs ranging from 2.59 (95% CI, 2.09-3.21; P < 0.001) to 24.04 (95% CI, 17.48-33.05; P < 0.001). After adjustment for pelvic inflammatory disease, infertility, Charlson co-morbidity index, and age, adjusted HRs were ranged from the lowest of 1.90 (95% CI, 1.51-2.37; P < 0.001) in recalled endometriosis to the highest of 18.57 (95% CI, 13.37-25.79; P < 0.001) in tissue-proved ovarian endometrioma, which was inversely related to the prevalence rate of endometriosis (from the highest of 30.80% in recalled endometriosis to the lowest of 1.54% in tissue-proved ovarian endometrioma). The risk of EOC in women with endometriosis varied greatly by different criteria used. Women with endometriosis might have a more apparently higher risk than those reported by systematic review and meta-analysis.

 

J Minim Invasive Gynecol. 2016 Feb 1;23(2):164-85.

Adenomyosis: A Clinical Review of a Challenging Gynecologic Condition.

Struble J¹, Reid S², Bedaiwy MA³.

 

Abstract

Adenomyosis is a heterogenous gynecologic condition. Patients with adenomyosis can have a range of clinical presentations. The most common presentation of adenomyosis is heavy menstrual bleeding and dysmenorrhea; however, patients can also be asymptomatic. Currently, there are no standard diagnostic imaging criteria, and choosing the optimal treatment for patients is challenging. Women with adenomyosis often have other associated gynecologic conditions such as endometriosis or leiomyomas, therefore making the diagnosis and evaluating response to treatment challenging. The objective of this review was to highlight current clinical information regarding the epidemiology, risk factors, pathogenesis, clinical manifestations, diagnosis, imaging findings, and treatment of adenomyosis. Several studies support the theory that adenomyosis results from invasion of the endometrium into the myometrium, causing alterations in the junctional zone. These changes are commonly seen on imaging studies such as transvaginal ultrasound (TVUS) and magnetic resonance imaging (MRI). The second most common theory is that adenomyosis results from embryologic-misplaced pluripotent mullerian remnants. Traditionally, adenomyosis was only diagnosed after hysterectomy; however, studies have shown that a diagnosis can be made with biopsies at hysteroscopy and laparoscopy. Noninvasive imaging can be used to help guide the differential diagnosis. The most common findings on 2-dimensional/3-dimensional TVUS and MRI are reviewed. Two-dimensional TVUS and MRI have a respectable sensitivity and specificity; however, recent studies indicate that 3-dimensional TVUS is superior to 2-dimensional TVUS for the diagnosis of adenomyosis and may allow for the diagnosis of early-stage disease. Management options for adenomyosis, both medical and surgical, are reviewed. Currently, the only definitive management option for patients is hysterectomy.

 

 

J Minim Invasive Gynecol. 2016 Jan;23(1):113-9.

Impact of Laparoscopic Surgical Management of Deep Endometriosis on Pregnancy Rate.

Centini G¹, Afors K², Murtada R², Argay IM², Lazzeri L³, Akladios CY⁴, Zupi E⁵, Petraglia F³, Wattiez A².

 

Abstract

STUDY OBJECTIVE:

To evaluate the impact of laparoscopic excision of lesions on deep endometriosis-related infertility.

DESIGN:

Retrospective study.

SETTING:

Endometriosis tertiary referral center (Canadian Task Force II-2).

PATIENTS:

A group of 115 patients who had undergone laparoscopic surgery for infertility with histologic confirmation of deep endometriosis.

INTERVENTIONS:

Patient medical records and operative reports were reviewed. Telephone interviews were conducted for long-term follow-up of fertility outcomes.

MEASUREMENTS AND MAIN RESULTS:

Evaluation of fertility outcome after laparoscopic treatment of deep endometriosis by spontaneous conception and by assisted reproductive technology (ART) correlated with lesion number, size, and location (anterior, posterolateral, pouch of Douglas, and multiple locations). After a mean follow-up of 22 months the overall pregnancy rate was 54.78% (n = 63) with a live-birth rate of 42.6% (n = 49). Among those patients given the chance to conceive spontaneously (n = 70), the overall pregnancy rate was 60% (n = 42): 38.5% (n = 27) spontaneously and 21.4% (n = 15) by ART. The removal of multiple lesions was associated with a higher pregnancy rate after surgery. When comparing isolated lesion size and disease location, there was no difference in pregnancy rate. Furthermore, those patients who underwent surgical eradication of the disease for the first time had a higher pregnancy rate (odds ratio, 4.18).

CONCLUSION:

This study demonstrates that laparoscopic excision of deep endometriosis enhances pregnancy rate, by both spontaneous conception and ART. First surgical treatment of multiple lesions was associated with higher pregnancy rates, whereas isolated lesions influenced the pregnancy rate irrespective of their location and size.

 

 

Hum Reprod. 2015 Dec;30(12):2846-52

Risk of ectopic pregnancy is linked to endometrial thickness in a retrospective cohort study of 8120 assisted reproduction technology cycles.

Rombauts L¹, McMaster R², Motteram C³, Fernando S⁴.

 

Abstract

STUDY QUESTION:

Is endometrial combined thickness (ECT) measured prior to embryo transfer (ET) associated with ectopic pregnancy (EP)?

SUMMARY ANSWER:

Following IVF, the risk of EP is 4-fold increased in women with an ECT of <9 mm compared with women with an ECT of >12 mm.

WHAT IS KNOWN ALREADY:

Known risk factors for EP include tubal damage, maternal cigarette smoking and endometriosis. EP is also more common following IVF but the underlying causes for this remain unclear.

STUDY DESIGN, SIZE, DURATION:

Retrospective cohort study restricted to all IVF cycles leading to a pregnancy (βhCG > 50 IU/l) between January 2006 and December 2014. A total of 6465 patients achieved a pregnancy in 8120 cycles. Cycles using preimplantation genetic screening or donor oocytes were excluded.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

This cohort consists of 6465 patients achieving a pregnancy in 6920 stimulated cycles with fresh embryo transfers (STIM ET) and 1200 hormone replacement therapy frozen embryo transfers (HRT-FET) cycles at a private IVF unit (Monash IVF, Melbourne, Australia). ECT was the primary independent variable of interest; the primary outcome was a diagnosis of EP. The dataset was analysed using binary logistic general estimating equations (SPSS v22.0) to calculate odds ratio (OR) for EP adjusted for known confounders (aOR). There was no loss to follow-up in the dataset.

MAIN RESULTS AND THE ROLE OF CHANCE:

The study groups did not differ significantly prior to IVF treatment. After adjusting for confounders, ECT remained statistically significant as an independent risk factor for EP. Compared with women with an ECT of <9 mm, women with an ECT of 9-12 mm had an aOR of 0.44 (95% CI 0.29-0.69, P < 0.01) and women with an ECT > 12 mm had an aOR of 0.27 (95% CI 0.10-0.77, P = 0.01). These differences remained statistically significant after performing a sensitivity analysis excluding HRT-FET, smokers and patients with tubal infertility.

LIMITATIONS, REASONS FOR CAUTION:

The study design is retrospective, and it is possible that not all confounders have been accounted for. Measurement of ECT was performed by highly trained sonographers, but some inconsistency between individuals may be present.

WIDER IMPLICATIONS OF THE FINDINGS:

Our group has previously demonstrated an increased risk of placenta praevia with increased ECT. These new findings suggest that the directionality of the uterine peristalsis waves matters more than their frequency or amplitude. Combining the data from both studies we now hypothesize that increased ECT is a marker for increased fundus-to-cervix uterine peristalsis, explaining both the increased placenta praevia risk and the lower EP risk. Further prospective studies are required to confirm these observations.

 

 

Reproduction. 2015 Dec;150(6):507-16.

Estradiol promotes cells invasion by activating β-catenin signaling pathway in endometriosis.

Xiong W¹, Zhang L¹, Yu L¹, Xie W¹, Man Y¹, Xiong Y¹, Liu H¹, Liu Y².

 

Abstract

Endometriosis is an estrogen-dependent disease that involves the adhesion, invasion, and angiogenesis of endometrial tissues outside of the uterine cavity. We hypothesized that a link exists between estrogen and beta-catenin (β-catenin) signaling in the pathogenesis of endometriosis. Human endometrial stromal cells (HESCs) were separated from eutopic endometrial tissues that were obtained from patients with endometriosis. β-catenin expression and cells invasiveness ability were up-regulated by 17β-estradiol (E2) in an estrogen receptor (ESR)-dependent manner, whereas β-catenin siRNA abrogated this phenomenon. Moreover, co-immunoprecipitation and dual immunofluorescence studies confirmed ESR1, β-catenin, and lymphoid enhancer factor 1/T cell factor 3 co-localization in the nucleus in HESCs after E2 treatment. To determine the role of β-catenin signaling in the implantation of ectopic endometrium, we xenotransplanted eutopic endometrium from endometriosis patients into ovariectomized severe combined immunodeficiency mice. The implantation of the endometrium was suppressed by β-catenin siRNA. Collectively, studies regarding β-catenin signaling are critical for improving our understanding of the pathogenesis of estrogen-induced endometriosis, which can translate into the development of treatments and therapeutic strategies for endometriosis.

 

 

Mol Hum Reprod. 2015 Dec;21(12):894-904

Coordination of AUF1 and miR-148a destabilizes DNA methyltransferase 1 mRNA under hypoxia in endometriosis.

Hsiao KY¹, Wu MH², Chang N¹, Yang SH¹, Wu CW¹, Sun HS³, Tsai SJ⁴.

 

Abstract

STUDY HYPOTHESIS:

DNA methylation is regulated by hypoxia in endometriosis.

STUDY FINDING:

Hypoxia causes global hypomethylation through AU-rich element binding factor 1 (AUF1)/microRNA-148a (miR-148a)-mediated destabilization of DNA methyltransferase 1 (DNMT1) mRNA.

WHAT IS KNOWN ALREADY:

Eutopic endometrial and ectopic endometriotic stromal cells have the same genetic background, but differ in several cellular and molecular responses. Both hypoxia and DNA methylation regulate several genes involved in the development of endometriosis.

STUDY DESIGN, SAMPLES/MATERIALS, METHODS:

This laboratory study included 15 patients of reproductive age with endometriosis or normal menstrual cycles. Paired endometrial and endometriotic tissues were collected for assaying the levels of DNMT1, 3a and 3b using quantitative RT-PCR, western blot and immunohistochemical (IHC) staining. Primary cultured endometrial stromal cells maintained in normoxia/hypoxia (1% O2) or treated with hypoxia-mimetic compounds were also assayed. The levels of DNA 5-methylcytosine were assayed by using IHC in clinical specimens and murine tissues, and by ELISA in cultured stromal cells. The 3′-untranslated region reporter assay was used to evaluate the effect of hypoxia, microRNAs (miRNAs) and human antigen R (HuR)/AUF1 on DNMT1 mRNA stability. RNA immunoprecipitation was used to assess the interaction of HuR/AUF1 and miR-148a/DNMT1 mRNA under hypoxia. Finally, a transplant-induced mouse model of endometriosis using 20 mice was used to elucidate the alteration of Dnmt1 levels and DNA methylation in the endometriotic tissues.

MAIN RESULTS AND THE ROLE OF CHANCE:

Levels of DNMT1 mRNA and protein and 5-methylcytosine were lower in the ectopic stromal cells (P < 0.05) than in the eutopic cells. Treatment with hypoxia and its mimetic compounds recapitulated the reduced levels of DNMT1 and 5-methylcytosine levels (P < 0.05 versus control). Hypoxia treatment destabilized DNMT1 mRNA through recruitment of miR-148a and AUF1. Mutations introduced to the miR-148a targeting site or AU-rich element (ARE) restored the hypoxia-suppressed DNMT1 3′-untranslated region (3′-UTR) reporter activity (P < 0.05 versus control). Levels of proteins of three hypermethylated genes in endometrial stroma cells, GATA6, HOXA3 and SLC16A5, were elevated after 72 h of hypoxia treatment (P < 0.05 versus control). Finally, a transplant-induced model of endometriosis demonstrated the down-regulation of DNMT1 and a decrease in 5-methylcytosine in the endometriotic tissues (P < 0.05, eutopic versus ectopic).

LIMITATIONS, REASONS FOR CAUTION:

Primary human cell cultures and a murine model were used in this study, and thus the results may not fully represent the situation in vivo.

WIDER IMPLICATIONS OF THE FINDINGS:

This is the first study to elucidate how microenvironmental hypoxia links to the epigenetic effects of DNA methylation in the endometriosis, and to delineate the molecular mechanism of hypoxia-coordinated AUF1/miR-148a interaction and recruitment to DNMT1 mRNA during the pathogenesis of endometriosis. The development of future therapeutics in endometriosis may aim at disrupting this specific interaction and eventually restore the epigenetic regulation.

STUDY FUNDING AND COMPETING INTERESTS:

This work was supported by the National Science Council of Taiwan (NSC101-2320-B-006-030-MY3). The author declares that there are no conflicts of interest.

 

 

Hum Reprod. 2015 Dec;30(12):2802-7.

Should a detailed ultrasound examination of the complete urinary tract be routinely performed in women with suspected pelvic endometriosis?

Pateman K¹, Holland TK², Knez J¹, Derdelis G¹, Cutner A¹, Saridogan E¹, Jurkovic D¹.

 

Abstract

STUDY QUESTION:

Is there any benefit to including the routine examination by ultrasound of the bladder, ureters and kidneys of women with endometriosis?

SUMMARY ANSWER:

The benefit of examination of the complete urinary tract of women with suspected endometriosis is that ureteric endometriosis, with or without hydronephrosis, can be detected which facilitates early intervention to prevent nephropathy.

WHAT IS ALREADY KNOWN:

Women with endometriosis can get ureteric obstruction but there is no clear consensus on the correct diagnostic technique. Ultrasound is accurate at detecting women with bladder endometriosis but ureteric involvement has not been assessed previously.

STUDY DESIGN, SIZE, DURATION:

This was a prospective observational study, conducted at a teaching hospital over a period of 14 months. A total of 848 women presenting with chronic pelvic pain were included into the study.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

All women with chronic pelvic pain underwent a detailed transvaginal and transabdominal pelvic ultrasound examination to investigate possible causes of their symptoms. This included a systematic assessment of the urinary bladder, pelvic sections of the ureters and kidneys. The ultrasound findings were compared with findings at surgery and the results of targeted urological imaging and interventions.

MAIN RESULTS AND THE ROLE OF CHANCE:

A total of 848 women presenting with chronic pelvic pain were included into the study. 28/848 women (3.3% 95% CI 2.1-4.5) had evidence of urinary tract abnormalities on initial ultrasound scan. Among these 17/848 (2.0% 95% CI 1.06-2.94) had evidence of urinary tract endometriosis, whilst 11/848 (1.3% 95% CI 0.54-2.06) women had other urinary tract abnormalities. Among women with urinary tract endometriosis 11/17 (65%) had evidence of ureteric involvement, 3/17 (18%) had both ureteric and bladder disease and 3/17 (18%) had bladder disease only. 12/17 (59%) women with urinary tract endometriosis also had evidence of hydronephrosis. The diagnosis of ureteral endometriosis had a sensitivity of 12/13 (92%) (95% CI 63.9-99.8), specificity 151/151 100% (95% CI 97.6-100), PPV 100% (95% CI 73.5-100), NPV 99.3% (95% CI 96.3-99.9%) LR- 0.08 (95% CI 0.01-0.39).

LIMITATIONS, REASONS FOR CAUTION:

The routine examination of the complete urinary tract including the distal ureters is a novel technique that should be evaluated in different populations.

WIDER IMPLICATIONS OF THE FINDINGS:

Ultrasound is an accurate test to diagnose urinary tract involvement in women with suspected pelvic endometriosis and examination of the complete urinary tract should become an integral part of ultrasound assessment of women with suspected endometriosis.

 

 

BJOG. 2017 Jan;124(2):220-229.

Endometriosis diagnosis and staging by operating surgeon and expert review using multiple diagnostic tools: an inter-rater agreement study.

Schliep KC^1,2, Chen Z¹, Stanford JB², Xie Y¹, Mumford SL¹, Hammoud AO³, Boiman Johnstone E³, Dorais JK³, Varner MW³, Buck Louis GM¹, Peterson CM³.

 

Abstract

OBJECTIVE:

To determine agreement on endometriosis diagnosis between real-time laparoscopy and subsequent expert review of digital images, operative reports, magnetic resonance imaging (MRI), and histopathology, viewed sequentially.

DESIGN:

Inter-rater agreement study.

SETTING:

Five urban surgical centres.

POPULATION:

Women, aged 18-44 years, who underwent a laparoscopy regardless of clinical indication. A random sample of 105 women with and 43 women without a postoperative endometriosis diagnosis was obtained from the ENDO study.

METHODS:

Laparoscopies were diagnosed, digitally recorded, and reassessed.

MAIN OUTCOME MEASURES:

Inter-observer agreement of endometriosis diagnosis and staging according to the revised American Society for Reproductive Medicine criteria. Prevalence and bias-adjusted kappa values (κ) were calculated for diagnosis, and weighted κ values were calculated for staging.

RESULTS:

Surgeons and expert reviewers had substantial agreement on diagnosis and staging after viewing digital images (n = 148; mean κ = 0.67, range 0.61-0.69; mean κ = 0.64, range 0.53-0.78, respectively) and after additionally viewing operative reports (n = 148; mean κ = 0.88, range 0.85-0.89; mean κ = 0.85, range 0.84-0.86, respectively). Although additionally viewing MRI findings (n = 36) did not greatly impact agreement, agreement substantially decreased after viewing histological findings (n = 67), with expert reviewers changing their assessment from a positive to a negative diagnosis in up to 20% of cases.

CONCLUSION:

Although these findings suggest that misclassification bias in the diagnosis or staging of endometriosis via visualised disease is minimal, they should alert gynaecologists who review operative images in order to make decisions on endometriosis treatment that operative reports/drawings and histopathology, but not necessarily MRI, will improve their ability to make sound judgments.

TWEETABLE ABSTRACT:

Endometriosis diagnosis and staging agreement between expert reviewers and operating surgeons was substantial.

 

 

J Clin Diagn Res. 2015 Aug;9(8):QD09-11.

Catamenial Pain in Umbilical Hernia with Spontaneous Reduction: An Unusual Presentation of a Rare Entity.

Pandey D¹, Sharma R¹, Salhan S².

 

Abstract

Spontaneous umbilical endometriosis occurring in absence of any previous abdominal or uterine surgery is extremely atypical. Its association with umbilical hernia is very rare and hernia getting spontaneously resolved has not been reported in literature so far. Here we report a case of a patient with spontaneous umbilical endometriosisassociated with umbilical hernia which led to spontaneous hernia reduction. This was also associated with multiple uterine fibromyoma and bilateral ovarian endometrioma which were simultaneously treated by total abdominal hysterectomy with bilateral salpingo-oopherectomy along with surgical excision of the endometriotic tissue and repair of the abdominal wall defect. To the best of our knowledge, this is the first described case of spontaneous umbilical hernia reduction due to development of endometriosis.

 

 

 

J Clin Endocrinol Metab. 2015 Dec;100(12):E1502-11

Possible Role of Phthalate in the Pathogenesis of Endometriosis: In Vitro, Animal, and Human Data.

Kim SH¹, Cho S¹, Ihm HJ¹, Oh YS¹, Heo SH¹, Chun S¹, Im H¹, Chae HD¹, Kim CH¹, Kang BM¹.

 

Abstract

CONTEXT:

Although phthalates were shown to have several negative effects on reproductive function in animals, its role in the pathogenesis of endometriosis remains to be elucidated.

OBJECTIVE:

We aimed to investigate the in vitro and in vivo effects of di-(2-ethylhexyl)-phthalate (DEHP) and to compare the urinary levels of several phthalate metabolites between women with and without endometriosis.

DESIGN:

For experimental studies, we used endometrial cell culture and nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse models. We also performed a prospective case-control study for human sample analyses.

SETTING:

The study was conducted at an academic center.

MAIN OUTCOME MEASURES:

The activities of matrix metalloproteinase (MMP)-2 and 9, cellular invasiveness, phosphorylation of extracellular signal-regulated kinase (Erk), and expression of p21-activated kinase 4 were analyzed in endometrial cells treated with DEHP. The implant size was compared between NOD/SCID mice fed with and without DEHP. Urinary concentrations of several phthalate metabolites were compared between women with and without endometriosis.

RESULTS:

In vitro treatment of endometrial cells with DEHP led to significant increases of MMP-2 and 9 activities, cellular invasiveness, Erk phosphorylation, and p21-activated kinase 4 expression. The size of the endometrial implant was significantly larger in the NOD/SCID mice fed with DEHP compared with those fed with vehicle. The urinary concentration of mono (2-ethyl-5-hydroxyhexyl) phthalate, mono (2-ethyl-5-oxohexyl) phthalate, and mono (2-ethyl-5-carboxyphentyl) phthalate were significantly higher in women with endometriosis compared with controls.

CONCLUSION:

These findings strongly suggest that exposure to phthalate may lead to establishment of endometriosis by enhancing invasive and proliferative activities of endometrial cells.

 

 

Womens Health (Lond). 2015 Aug;11(5):693-9.

Recurrence of endometriosis: risk factors, mechanisms and biomarkers.

Bozdag G¹.

 

Abstract

While the incidence of endometriosis is up to 40-60% in women with severe dysmenorrhea/chronic pelvic pain, patients with subfertility carries a risk up to 20-30%. In symptomatic patients, although medical therapy is preferred in women with endometriosis, surgery might be needed in nonresponders or patients with an endometrioma. Following the surgery, recurrence of the disease and/or symptoms might be still noticed which will progressively increase as times goes by. Nevertheless, some risk factors have been identified for the risk of recurrence that decreases the success of the procedure. Those risk factors might be classified as patient-disease related and surgery-associated variables. Herein, we will address about the management of endometriosisregarding the risk factors for relapse, mechanisms of recurrence and potential biomarkers to predict the event.

 

 

 

PLoS One. 2015 Oct 6;10(10):e0139388.

Nickel Allergy Is a Risk Factor for Endometriosis: An 11-Year Population-Based Nested Case-Control Study.

Yuk JS¹, Shin JS², Shin JY³, Oh E⁴, Kim H⁵, Park WI⁶.

 

Abstract

BACKGROUND:

A cross-sectional study has reported that nickel allergy is associated with endometriosis. However, causal studies of this association are limited.

OBJECTIVE:

The objective of this study was to compare the prevalence of nickel allergy in women with and without endometriosis.

METHODS:

We used a National Health Insurance Service (NHIS) sample cohort dataset that included approximately 1 million individuals from South Korea; the data were obtained between January 01, 2002, and December 31, 2013. We selected the endometriosis group according to diagnosis code (N80.X), surgery codes, and drug codes during the years 2009~2013. The controls were randomly matched to the endometriosis patients at a ratio of 4:1 by age and socioeconomic status. Patients with nickel allergy were defined in the cohort dataset as those with a simultaneous diagnosis code (L23.0) and patch test code during 2002~2008.

RESULTS:

In total, 4,985 women were selected from the NHIS cohort database and divided into an endometriosisgroup (997 women) and a control group (3,988 women). The number of patients with nickel allergy in the endometriosis group was eight (0.8%), and that in the control group was thirteen (0.3%). After adjustment for age and socioeconomic status, the rate of nickel allergy in was higher in the endometriosis group than in the control group [odds ratio: 2.474; 95% confidence interval: 1.023~5.988; p = 0.044].

CONCLUSIONS:

We found that nickel allergy is a risk factor for endometriosis.

 

 

Fertil Steril. 2015 Dec;104(6):1475-83.e1-3.

Ultramicro-trauma in the endometrial-myometrial junctional zone and pale cell migration in adenomyosis.

Ibrahim MG¹, Chiantera V¹, Frangini S¹, Younes S¹, Köhler C², Taube ET³, Plendl J⁴, Mechsner S⁵.

 

Abstract

OBJECTIVE:

To determine if ultrastructural tissue trauma occurs in the junctional zone in uteri in adenomyosis.

DESIGN:

A case-control experimental study.

SETTING:

Endometriosis research center.

PATIENT(S):

Twelve uteri with adenomyosis, and 9 uteri without adenomyosis, were gained during laparoscopy-assisted vaginal hysterectomy.

INTERVENTION(S):

Transmission electron microscopic study of the junctional zone, as well as immunohistochemical staining for epithelial cadherin, and van Gieson staining and immunofluorescence for CD45 and CD68.

MAIN OUTCOME MEASURE(S):

Analysis of the electron microscopy photos and the immunoreactive scores of the staining.

RESULT(S):

The inner myometrial muscle fibers were diversely arranged in adenomyosis; they were parallel to the basal endometrial glands in nonadenomyosis. Nuclear membrane infolding of the basal glandular epithelium and the disruption of the interface between basal endometrium and inner myometrium in adenomyosis (but not in nonadenomyosis) were evident. Intraepithelial pale cells were seen in the basal endometrial glands in both groups, but they lacked CD45 and CD68 expression. They were seen actively migrating into the stroma in adenomyosis only.

CONCLUSION(S):

The myofiber disarray in the inner myometrium, and the nuclear membrane irregularities in adenomyosis, are evidence for ultramicro-trauma in adenomyosis. The migrating nonleukocytic pale cells may be involved in pathogenesis of adenomyosis.

 

 

Gynecol Endocrinol. 2016;32(2):128-31.

Serum leptin concentration in women of reproductive age with euthyroid autoimmune thyroiditis.

Drobniak A¹, Kanecki K², Grymowicz M¹, Radowicki S¹.

 

Abstract

INTRODUCTION:

Autoimmune thyroid disease (AITD) with elevated anti-thyroid peroxidase antibody (aTPO) levels appears in 12-25% of all women, apart from thyroid dysfunction. High titers of aTPO are more common in women with polycystic ovary syndrome and endometriosis. Elevated aTPO has been associated with infertility and poorer quality of life among euthyroid women, and may be related to other factors.

OBJECTIVES:

The aim of the study was to measure differences in serum leptin concentration between AITD+ and AITD- patients. Setting, patients and main outcome measures: The sample was comprised of 74 women who were hospitalized in the Department of Gynecological Endocrinology, Medical University of Warsaw. Data collected included age, body mass index (BMI), and serum aTPO, serum thyroid stimulating hormone (TSH), serum fT4, serum follitropin (FSH), serum estradiol and serum leptin. AITD positive status was defined as serum aTPO greater than 5.6 mIU/ml.

RESULTS:

Serum leptin concentrations were significantly higher in AITD+ patients compared to AITD- patients (17.13 ng/ml [SD 7.66] versus 12.78 ng/ml [SD 7.28]; p < 0.05). No differences by AITD status were found in age, BMI, TSH, FSH, estradiol and fT4.

CONCLUSIONS:

Serum leptin concentrations were higher in patients with AITD than in patients without AITD.

 

 

Womens Health (Lond). 2015 Aug;11(5):577-86

Genetics of endometriosis.

Rahmioglu N¹, Montgomery GW², Zondervan KT^1,3.

 

Abstract

Endometriosis is a heritable complex disorder that is influenced by multiple genetic and environmental factors. Identification of these genetic factors will aid a better understanding of the underlying biology of the disease. In this article, we describe different methods of studying genetic variation of endometriosis, summarize results from genetic studies performed to date and provide recommendations for future studies to uncover additional factors contributing to the heritable component of endometriosis.

 

 

Diagn Interv Imaging. 2015 Oct;96(10):997-1007.

Chronic pelvic pain: An imaging approach.

Juhan V¹.

 

Abstract

Chronic pelvic pain is defined as disabling pain of at least six months duration. Chronic pelvic pain has often multiple causative factors. Careful analysis of clinical history and detailed clinical examination must be carried out to guide further imaging investigations. Endometriosis is a common cause of chronic pelvic pain, although there is no correlation between the severity of lesions and pain intensity. Pelvic ultrasonography should be the first line imaging examination to search for causative conditions that include endometriosis, adenomyosis, pelvic varices and chronic infection. Magnetic resonance imaging (MRI) is useful for making the positive diagnosis and assessing the spread of endometriosis. MRI is more accurate than ultrasonography for the diagnosis of tubo-ovarian abscess when an adnexal mass is identified. Duplex and color Doppler ultrasonography as well as MR angiography are the best imaging technique for the diagnosis of pelvic congestion syndrome. In patients with pudendal neuralgia, cross-sectional imaging help exclude nerve compression.

 

 

Int J Gynecol Pathol. 2015 Nov;34(6):507-16.

Morphologic Features Suggestive of Endometriosis in Nondiagnostic Peritoneal Biopsies.

Harrison BT¹, Mittal K.

 

Abstract

Endometriosis is a common disorder that causes significant morbidity from dysmenorrhea, pelvic pain, and subfertility. Establishment of a definitive diagnosis has important therapeutic implications; however, only approximately 50% of biopsies of laparoscopically suspicious areas provide a diagnosis of endometriosis. Histologic criteria for diagnosis require the presence of endometrial glands or endometrial-type stroma. We hypothesize that other frequently present, but nondiagnostic, histologic features of endometriosis suggest its presence in patients with nondiagnostic peritoneal biopsies. We performed a retrospective clinicopathologic study of morphologic and immunohistochemical features that may improve the histologic diagnosis of endometriosis on laparoscopic peritoneal biopsies. We compared diagnostic (n=88) and nondiagnostic (n=54) peritoneal biopsies from pathologically confirmed endometriosis cases with negative peritoneal biopsies (n=84) from early-stage gynecologic cancer cases. Statistical analysis utilized the Fisher exact test. Multiple morphologic features were significantly increased in nondiagnostic biopsies from patients with endometriosis in comparison with those from negative controls, including foamy macrophages (P=0.0001) and submesothelial stromal clusters (SSCs) (P=0.0008). SSCs ranged from subtle aggregates of spindle cells to nodules of whorled spindle cells with small vessels and extravasated red blood cells resembling stromal endometriosis. Immunohistochemical studies confirmed that ER and CD10-positive SSCs were present in a greater proportion of both nondiagnostic and diagnostic peritoneal biopsies and at a greater number of lesions per biopsy. The overall histologic detection rate of peritoneal biopsies for endometriosis was 62.0%, and inclusion of SSCs with or without foamy macrophages in the diagnostic criteria appreciably increased this rate to between 72.5% and 76.8%. We describe SSCs, which appear to be an early or less developed form of stromal endometriosis, and, when included in the diagnostic criteria, improve the histologic detection rate of endometriosis in peritoneal biopsies.

 

J Ovarian Res. 2015 Oct 7;8:66.

Identification of germ cell-specific VASA and IFITM3 proteins in human ovarian endometriosis.

Fraunhoffer NA^1,2,3, Meilerman Abuelafia A^4,5, Stella I⁵, Galliano S^5,6, Barrios M⁵, Vitullo AD^4,7.

 

Abstract

BACKGROUND:

Endometriosis is a gynaecological disorder that affects 6-10 % of female population. It is characterized by the presence of endometrial tissue outside the uterus, most often in the pelvic peritoneum or ovaries. Recent studies have indicated that mesenchymal endometrial stem cells might get involved in endometriosis progression. Although germ line stem cells have been proved to exist in the ovary, their involvement in ovarian endometriosis has not been investigated. In this preliminary report we aimed to identify germinal stem cell markers in ovarian endometriosis.

FINDINGS:

Ten paraffin-embedded ovarian endometriosis samples were screened for germ cell-specific proteins DDX4 (VASA) and IFITM3, and its relation with stem cell marker OCT4, proliferation marker PCNA and estrogen receptor alpha (ESR1), by immunohistochemistry, immunofluorescence and PCR. DDX4 and IFITM3 proteins were expressed in isolated cells and clusters of cells in the cortical region of ovarian endometriotic cysts. DDX4 and IFITM3 co-localized in cells from endometriotic stroma, and DDX4/IFITM3-expressing cells were positive for ESR1, OCT4 and PCNA. No cells expressing neither DDX4 nor IFITM3 were detected in normal endometrial tissue.

CONCLUSION:

The identification of germ cell-specific proteins DDX4 and IFITM3 provides the first evidence of ovarian-sourced cells in ovarian endometriotic lesions and opens up new directions towards understanding the still confusing pathogenesis of endometriosis.