Arkh Patol. 2014 Nov-Dec;76(6):37-43.

The morphological substrate and pathogenetic mechanisms of pelvic pain syndrome in endometriosis.

Kogan EA¹, Paramonova NB¹, Demura TA¹, Faĭzullina NM², Ovakimian AS², Adamian LV².

 

Abstract

in English, Russian

OBJECTION:

To study the origin and morphological substrate of pain syndrome in deep infiltrating endometriosisinvolving the bowel.

SUBJECTS AND METHODS:

The investigation was conducted using the intraoperative material (resected portions of the large and small bowels, appendix) obtained from 40 women diagnosed as having deep infiltrating endometriosis involving the bowel, which was accompanied by pain syndrome. Paraffin sections were immunohistochemically examined using the standard protocol. Antibodies to Ki-67, PTEN, ER, PR, (“Dako”), CD34 (“Cell Marque”, USA), VEGF, EGF, EGFR, COX-2 (“Abcam”), and MMP 1 and 2 (“Abbiotec”) were applied. Dako REAL EnVision Detection System kits (“Dako”, Denmark) were used as secondary antibodies.

RESULTS:

The morphological substrate of pelvic pain syndrome in deep infiltrating endometriosis was established to be factors that acted in situ at the location of endometriotic foci and those caused by the infiltrative perivascular, intravascular, and perineural growth of endometrioid heterotopies.

CONCLUSION:

Inflammation and fibrosis in the endometriotic foci contribute to the accumulation of algogenes, which gives rise to somatogenic pain syndrome, and chronic nerve fiber injury as a source of nociceptive stimulation leads to neuropathic pain syndrome.

 

 

Mol Cell Endocrinol. 2015 Jul 5;409:51-8.

Selective inhibition of prostaglandin E2 receptors EP2 and EP4 modulates DNA methylation and histone modification machinery proteins in human endometriotic cells.

Arosh JA¹, Lee J², Starzinski-Powitz A³, Banu SK².

 

Abstract

Endometriosis is an inflammatory gynecological disease of reproductive-age women. The prevalence of endometriosis is 5-10% in reproductive-age women. Modern medical treatments are directed to inhibit the action of estrogen in endometriotic cells. However, hormonal therapies targeting estrogen can be prescribed only for a short time because of their undesirable side effects. Recent studies from our laboratory, using human endometriotic epithelial cell line 12Z and stromal cell line 22B derived from red lesion, discovered that selective inhibition of prostaglandin E2 (PGE2) receptors EP2 and EP4 inhibits adhesion, invasion, growth, and survival of 12Z and 22B cells by modulating integrins, MMPs and TIMPs, cell cycle, survival, and intrinsic apoptotic pathways, suggesting multiple epigenetic mechanisms. The novel findings of the present study indicate that selective pharmacological inhibition of EP2 and EP4: (i) decreases expression of DNMT3a, DNMT3b, H3K9me3, H3K27me3, SUV39H1, HP1a, H3K27, EZH2, JMJD2a, HDAC1, HDAC3, MeCP2, CoREST and Sin3A; (ii) increases expression of H3K4me3, H3H9ac, H3K27ac; and (iii) does not modulate the expression of DNMT1, hSET1, LSD1, MBD1, p300, HDAC2, and JMJD3 epigenetic machinery proteins in an epithelial and stromal cell specific manner. In this study, we report for the first time that inhibition of PGE2-EP2/EP4 signaling modulates DNA methylation, H3 histone methylation and acetylation, and epigenetic memory machinery proteins in human endometriotic epithelial cells and stromal cells. Thus, targeting EP2 and EP4 receptors may emerge as long-term nonsteroidal therapy for treatment of active endometriotic lesions in women.

 

 

J Steroid Biochem Mol Biol. 2015 Sep;153:160-9.

Estrogen O-sulfamates and their analogues: Clinical steroid sulfatase inhibitors with broad potential.

Thomas MP¹, Potter BV².

 

Abstract

Estrogen sulfamate derivatives were the first irreversible active-site-directed inhibitors of steroid sulfatase (STS), an emerging drug target for endocrine therapy of hormone dependent diseases that catalyzes inter alia the hydrolysis of estrone sulfate to estrone. In recent years this has stimulated clinical investigation of the estradiol derivative both as an oral prodrug and its currently ongoing exploration in endometriosis. 2-Substituted steroid sulfamate derivatives show considerable potential as multi-targeting agents for hormone-independent disease, but are also potent STS inhibitors. The steroidal template has spawned nonsteroidal STS inhibitors one of which, Irosustat, has been evaluated clinically in breast cancer, endometrial cancer and prostate cancer and there is potential for innovative dual-targeting approaches. This review surveys the role of estrogen sulfamates, their analogues and current status.

 

 

Acta Obstet Gynecol Scand. 2015 Jun;94(6):646-53.

Intrafollicular iron and ferritin in women with ovarian endometriomas.

Benaglia L¹, Paffoni A¹, Mangiarini A¹, Restelli L¹, Bettinardi N², Somigliana E¹, Vercellini P^1,3, Fedele L^1,3.

 

Abstract

OBJECTIVE:

To evaluate whether iron contained in ovarian endometriomas can diffuse through the cyst wall and negatively affect ovarian function.

DESIGN:

Prospective case series.

SETTING:

Infertility unit in an academic setting.

POPULATION:

Thirty-nine infertile women with unilateral endometriomas who underwent in vitro fertilization.

METHODS:

Iron and ferritin assessments in pools of follicular fluids obtained from affected and contralateral intact gonads.

MAIN OUTCOME MEASURES:

Iron and ferritin concentrations.

RESULTS:

Follicular fluid iron content did not differ between the two gonads. The median [interquartile range (IQR)] follicular concentrations in the affected and unaffected ovaries were 59 (IQR 44-74) and 59 (IQR 47-73) μg/dL, respectively (p = 0.77). Conversely, ferritin concentration was significantly higher in affected gonads. The median (IQR) concentrations of ferritin in the affected and unaffected ovaries were 57 (IQR 31-146) and 33 (IQR 23-67) μg/mL, respectively (p = 0.026). When considering together the 78 studied ovaries, no significant correlations emerged between follicular iron and ferritin and variables reflecting ovarian responsiveness and oocyte developmental competence.

CONCLUSIONS:

Iron may diffuse from ovarian endometriomas into the adjacent ovarian tissue. However, this phenomenon does not appear to markedly affect ovarian function. Some effective biological mechanisms such as ferritin storage may effectively sequester free iron, so limiting its detrimental effects.

 

J Minim Invasive Gynecol. 2015 Jul-Aug;22(5):834-40.

Adolescent Endometriosis: Report of a Series of 55 Cases With a Focus on Clinical Presentation and Long-Term Issues.

Audebert A¹, Lecointre L², Afors K³, Koch A⁴, Wattiez A⁴, Akladios C⁴.

 

Abstract

STUDY OBJECTIVE:

To report the clinical presentation and long-term issues of adolescent endometriosis.

DESIGN:

Retrospective cohort study.

SETTING:

Single private clinical center, Bordeaux, France.

PATIENTS:

Adolescents with a confirmed diagnosis of endometriosis.

INTERVENTIONS:

Surgical excision or ablation or lesions performed at laparoscopy.

MEASUREMENTS AND MAIN RESULTS:

Fifty-five adolescents, ages from 12 to 19 years (mean age 17.8), who were diagnosed with endometriosis from March 1998 to April 2013 were included in the study. Pain of various types was the leading symptom in all patients, except 2. Twenty-three patients had an adnexal mass identified preoperatively, and 5 had an associated infertility issue at the time of diagnostic laparoscopy. Four patients had an associated genital malformation. Fifty-one percent of the patients had a history of appendectomy. A familial history of endometriosis was reported by 19 patients (34.5%), with a first-degree relative affected in 14 cases (25.45%), and 47.3% of patients were smoking at least 5 cigarettes a day. Superficial implants was encountered in 31 cases (56.4%), endometriomas in 18 cases (32.72%), and deep infiltrating endometriosis (DIE) in 6 cases (10.90%). Sixty percent of patients were scored as stages I to II and 40% as stages III to IV. Five patients were lost to follow-up, and 37 had a follow-up ranging from 36 to 315 months (mean follow-up 125.5 months). Among the 50 patients not lost to follow-up, 13 (26%) had either no pain, or improved and had acceptable pain with medical treatment. Seventeen patients of the 50 adolescents not lost to follow-up (34%) underwent a repeat laparoscopy. A subsequent laparoscopic and/or magnetic resonance imaging scan was performed in 35 patients because of persistent pain. Among these, there was 12 endometriomas (7 recurrences) and 12 DIEs (3 recurrences), giving recurrence rates for endometriomas and DIEs of 36.84% and 50%, respectively. During the study, 18 patients wished to have a child. Thirteen had a delivery (72.2%), and 9 pregnancies occurred in patients who initially presented with stage I to II endometriosis. Of the 11 patients who had subfertility, 6 successfully conceived (54.5%).

CONCLUSIONS:

Adolescent endometriosis is not a rare condition. In our study a familial history was reported in more than one-third of patients. Among those patients treated for DIE, there was a trend for higher rates of recurrences (symptoms or lesions) that required repeat laparoscopy. However, the impact on subsequent fertility appeared to have been limited.

 

 

J Minim Invasive Gynecol. 2015 Jul-Aug;22(5):827-33.

Laparoscopic Ureteroneocystostomy: Be Prepared!

Bourdel N¹, Cognet S², Canis M³, Berdugo O⁴, Botchorishvili R³, Rabischong B³, Jardon K⁵.

 

Abstract

STUDY OBJECTIVE:

To assess the outcomes and complications of laparoscopic ureteroneocystotomy in gynecologic surgery.

DESIGN:

We retrospectively reviewed all medical records of patients who underwent ureteroneocystostomy between April 2008 and May 2012.

DESIGN CLASSIFICATION:

Retrospective case series study.

SETTING:

A university tertiary care hospital.

PATIENTS:

Nine patients underwent ureteroneocystostomy: 3 patients had ureteral endometriosis stenoses; and 6 patients had iatrogenic ureter injuries.

INTERVENTIONS:

All procedures were performed laparoscopically. The ureterovesical re-implantation was unilateral in 8 cases and bilateral for 1 patient.

MEASUREMENTS AND MAIN RESULTS:

The mean operating time was 226.7 min (range, 120-480). Average blood loss was 114.4 mL (range, 30-400). The mean duration of the in-dwelling catheter was 10.4 days (range, 7-21); the average hospital stay was 12.6 days (range, 6-26). The mean duration of the ureteral double J stent was 7.8 weeks (range, 6-16). One patient was re-operated for vaginal and laparoscopic drainage of a pelvic abscess on the sixth postoperative day. The median follow-up time was 20.8 months (range, 9-36), No patient had stenosis or breakdown of a suture line.

CONCLUSIONS:

Our series confirms the feasibility and the effectiveness of laparoscopic ureteroneocystostomy. This minimally invasive approach, which avoids laparotomy, requires a multidisciplinary team.

 

 

Reprod Sci. 2015 Sep;22(9):1143-52.

The Targeted Delivery of Interleukin 4 Inhibits Development of Endometriotic Lesions in a Mouse Model.

Quattrone F¹, Sanchez AM¹, Pannese M¹, Hemmerle T², Viganò P³, Candiani M³, Petraglia F⁴, Neri D², Panina-Bordignon P⁵.

 

Abstract

Endometriosis is caused by the displacement of endometrium outside the uterus contributing heavily to infertility and debilitating pelvic pain. Ectopic adhesion and growth are believed to occur under the influence of a favorable hormonal environment and immunological factors. The objective of this study is to analyze the effect of a targeted therapy with an antibody-based pharmacodelivery of interleukin 4 (F8-IL4) in a mouse model of experimentally induced endometriosis. Endometriosis-like lesions were induced in Balb/c mice. The animals were treated intravenously with F8-IL4 or with untargeted IL4 (KSF-IL4). Twelve days after disease induction, the lesions were isolated. A significant reduction in the number of total lesions/mouse and in the total volume of lesions/mouse was observed in mice treated with F8-IL4 compared to controls (P = .029 and P = .006, respectively), while no difference was found between KSF-IL4-treated mice and their controls. Gene expression was evaluated by quantitative real-time polymerase chain reaction. Expression of genes involved in cell adhesion, extracellular matrix invasion, and neovascularization was significantly downregulated in F8-IL4-treated mice compared to their controls (integrin β1: P = .02; metalloproteinase [MMP] 3: P = .02; MMP9: P = .04; vascular endothelial growth factor: P = .04). Gene expression of inflammatory cytokines (tumor necrosis factor α, IL1β, IL1α, and IL6) did not vary in the ectopic lesions isolated from F8-IL4-treated mice compared to their controls. Immunohistochemistry demonstrated a significantly reduced expression of E-cadherin and β-catenin in the lesions of mice treated with F8-IL4. Our results show that the antibody-mediated targeted delivery of IL4 inhibits the development of endometriosis in a syngeneic mouse model by likely impairing adhesion, invasion, and vascularization of the ectopic endometrium.

 

 

 

 

 

Int J Gynecol Pathol. 2015 Sep;34(5):480-6

Differential Expression Patterns of GATA3 in Uterine Mesonephric and Nonmesonephric Lesions.

Roma AA¹, Goyal A, Yang B.

 

Abstract

GATA binding protein 3 (GATA3) is a recently described immunohistochemical marker that has proven useful in the characterization of breast and urothelial carcinomas. However, the expression pattern of GATA3 in mesonephric proliferations is largely unknown. The aim of this study was to examine the immunohistochemical expression of GATA3 in cervicovaginal mesonephric lesions and compare it to its expression in endocervical and endometrial adenocarcinomas and cervicovaginal endometriosis. A cohort of 107 cases, including 33 cases of mesonephric lesions and 74 cases of nonmesonephric lesions, was selected for the study. Of 33 mesonephric lesions, 31 (94%) cases (16 remnants, 12 hyperplasias, and 3 adenocarcinomas) were strongly and diffusely positive in tumor cell nuclei for GATA3. The remaining 2 mesonephric carcinosarcomas showed focal nuclear staining and rare nuclear positivity, respectively. Of 36 endocervical adenocarcinomas, 33 (92%) were negative for GATA3 and the remaining revealed focal weak nuclear staining. Of 34 endometrial adenocarcinomas, 32 (94%) were negative, whereas 2 showed rare nuclear positivity. All 4 cases of endometriosis were negative. The benign endocervical epithelium and the benign endometrium in most cases lacked GATA3 expression, whereas the benign squamous epithelium in the majority exhibited nuclear basal and parabasal staining pattern. Our study demonstrates that GATA3 protein is expressed in most mesonephric lesions, regardless of them being benign or malignant. In contrast, GATA3 is absent in the majority of endometrial and endocervical adenocarcinomas. These results support that GATA3 immunostain can be a useful tool in differentiating mesonephric lesions from endocervical and endometrial adenocarcinomas.

 

 

Am J Physiol Endocrinol Metab. 2015 Jun 1;308(11):E950-9.

Estradiol-mediated hepatocyte growth factor is involved in the implantation of endometriotic cells via the mesothelial-to-mesenchymal transition in the peritoneum.

Ono YJ¹, Hayashi M², Tanabe A¹, Hayashi A¹, Kanemura M¹, Terai Y¹, Ohmichi M¹.

 

Abstract

The pathogenesis of endometriosis, a chronic painful gynecological disease characterized by the presence of endometrial tissue located outside of the uterus and often adhering to the peritoneum, is known to be estrogen dependent. However, the precise pathophysiology of endometriosis remains elusive. Recent studies indicate that the epithelial-to-mesenchymal transition (EMT) of human endometrial cells is important for the progression of endometriosis, and another previous study has implicated hepatocyte growth factor (HGF) in endometriosisprogression. The aim of the present study was to examine the role of estradiol in the regulation of HGF production and progression of peritoneal endometriosis, focusing on the interactions between the peritoneum and endometriotic cells. Consequently, estradiol was found to promote the proliferation, invasion, and migration of immortalized human endometrial epithelial cells (hEECs) via HGF upregulation, and the estradiol-induced direct binding of estrogen receptor-α to the HGF promoter was confirmed on a chromatin immunoprecipitation (ChIP) assay. Estradiol also induced the EMT in hEECs by promoting HGF production. Furthermore, human mesothelial cells underwent the mesothelial-to-mesenchymal transition (MMT) during culture with estradiol-stimulated hEEC conditioned medium. Importantly, estradiol itself did not induce the MMT, and the estradiol-stimulated hEEC-conditioned medium in the presence of HGF antibodies reversed the MMT process. These results, which were obtained using immortalized hEECs, indicate that estradiol-induced HGF production may play a crucial role in the peritoneal implantation of human endometriotic cells by exerting proliferative and invasive effects via the EMT in hEECs and promoting the MMT in mesothelial cells.

 

 

Abdom Imaging. 2015 Oct;40(7):2541-56.

Complex abdominopelvic endometriosis: the radiologist’s perspective.

Barrow TA¹, Elsayed M², Liong SY², Sukumar SA³.

 

Abstract

Endometriosis is a multifocal gynecological disorder affecting approximately 6%-10% of women during their reproductive years (Giudice and Kao in: Lancet 364:1789-1799, 2004). Presenting symptomatology often relates to the anatomical structures involved. Given the complexity of both the management and pain control of patients with complex endometriosis, the British Society of Gynaecological Endoscopy has issued guidelines on the establishment of a multidisciplinary team approach to these cases (http://www.bsge.org.uk/ec-requirements-BSGE-accredited-endometriosis-centre.php). The ovaries are the most common site affected, but the gastrointestinal, genitourinary tract, chest and other soft tissues are not infrequently involved. Less well-recognized features of the disease include the deep infiltrative form of endometriosis, malignant transformation and decidualization of endometriomas under progesterone. In this pictorial essay, we will discuss the clinical presentation and review the imaging features of these complex and under appreciated forms of endometriotic disease.

 

 

Abdom Imaging. 2015 Oct;40(7):2667-82.

Herlyn-Werner-Wunderlich syndrome: pre- and post-surgical MRI and US findings.

Dias JL^1,2, Jogo R³.

 

Abstract

Herlyn-Werner-Wunderlich syndrome (HWWS) is a rare congenital anomaly of the female urogenital tract that associates Müllerian duct anomalies with mesonephric duct anomalies. The triad of uterus didelphys, obstructed hemivagina, and ipsilateral renal agenesis characterizes this syndrome. Patients generally present with non-specific symptoms after menarche. Pelvic pain, dysmenorrhea, and palpable mass due to hematocolpos or hematometra are the most common findings. Pyohematocolpos and pyosalpinx may appear as acute complications, while endometriosis and pelvic adhesions constitute potential long-term complications. When a prenatal diagnosis of unilateral renal agenesis in newborn girls is known, a gynecological imaging study should be performed to exclude uterine and vaginal abnormalities. These patients should be followed up to ensure that a timely surgical correction is performed. The diagnosis of HWWS is difficult due to the lack of specific symptoms or findings upon physical examination. An accurate imaging description of these congenital anomalies is crucial to guide patients toward surgical treatment, relieving acute complications, and preserving the normal fertility. The authors provide a pictorial review of the magnetic resonance imaging and ultrasonography findings of the HWWS with correlation to embryological, clinical, and surgical features.

 

 

Arch Gynecol Obstet. 2015 Oct;292(4):923-9.

The clinical characteristics and outcomes of cases with pure ovarian clear cell, mixed type and high-grade serous adenocarcinoma.

Kucukgoz Gulec U¹, Paydas S, Guzel AB, Vardar MA, Khatib G, Gumurdulu D.

 

Abstract

PURPOSE:

This study aimed to compare the clinical characteristics and outcomes of the cases with pure ovarian clear cell adenocarcinoma (OCCC), mixed type (clear plus serous or clear plus endometrioid or serous plus clear plus endometrioid) ovarian adenocarcinoma (MOC) and high-grade serous ovarian adenocarcinoma (HGSOC).

METHODS:

A retrospective comparison was conducted in 32 cases with pure OCCC, 23 cases with MOC and 28 cases with HGSOC followed between January 1999 and October 2011. Clinico-pathologic characteristics including histopathologic subtypes, age, stage, presence of ascites and/or peritoneal carcinomatosis, endometriosis and optimal cytoreduction, and also survival rates were compared in these three groups.

RESULTS:

The cases with pure OCCC were younger than the cases with MOC and HGSOC (p = 0.004). The median pre-operative CA-125 level was lower in the pure OCCC than in MOC and HGSOC (p = 0.006) (p = 0.001, p = <0.001, respectively). Bilaterality and peritoneal carcinomatosis were more frequently seen in the HGSOC group (p = 0.001, p < 0.001, respectively). The majority of the cases (65 %) had stage I or II disease in the pure OCCC group, but most of the cases in the HGSOC group had advanced stage disease (p < 0.001). Endometriosis was found in 16 cases (16/55, 29 %) in the OCCC group. No significant difference was detected with regard to the median survival rate among three groups (p = 0.517), while the stage of disease was found to be the only important factor for survival (p = 0.002).

CONCLUSION:

Pure OCCC, MOC and HGSOC represent distinct clinical characteristics. Clinical characteristics of MOC are more similar to those of HGSOC.

 

 

J Clin Diagn Res. 2015 Feb;9(2):QC01-3.

Outcome of ovarian drilling in women with polycystic ovary syndrome.

Yanamandra NK¹, Gundabattula SR².

 

Abstract

OBJECTIVE:

To determine the effectiveness and safety of laparoscopic ovarian drilling (LOD) in inducing ovulation in women with polycystic ovary syndrome (PCOS) who failed to conceive after medical methods of ovulation induction.

MATERIALS AND METHODS:

A retrospective study of all women who underwent LOD as a treatment for anovulatory infertility between January 2010 and December 2011 was conducted. Women diagnosed to have PCOS by the Rotterdam criteria were considered for the study. Those who had PCOS but were associated with male factor infertility, deep infiltrating endometriosis and submucous fibroids were excluded.

RESULTS:

A total of 43 women underwent LOD during the study period. Majority were aged 26 to 30 years and two-thirds were overweight or obese. Most (72%) of them had primary infertility. Other factors which could have contributed to infertility such as superficial endometriosis, septate uterus and unilateral tubal block were observed in 30.2% of the women, which were dealt with concomitantly. When we excluded the 14% who were lost to follow up, 23 of 43 (53.5%) women achieved pregnancy and almost 70% of them did so within the first 6 months. None of our study population had ovarian hyperstimulation or multiple pregnancy.

CONCLUSION:

LOD thus not only helps in regulating ovulation and enhancing conception rates but also provides an opportunity to assess the pelvis for other potential causes of subfertility which could be treated at the same time. We therefore believe that diagnostic hysteroscopy and laparoscopy should be offered quite high-up in the hierarchy of infertility investigations and treatment.

 

 

Arch Gynecol Obstet. 2015 Oct;292(4):843-51.

Association of the intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms with endometriosis: a systematic review and meta-analysis.

Pabalan N¹, Jarjanazi H, Christofolini DM, Barbosa CP, Bianco B.

 

Abstract

BACKGROUND:

Reported associations of the G241R and K469E polymorphisms of the intercellular adhesion molecule-1 gene (ICAM-1) gene with endometriosis have differed in magnitude.

MATERIALS AND METHODS:

In a meta-analysis of six published case-control studies (from five articles), we estimated risk [odds ratio (OR) 95 % confidence intervals (CI)] of associations with these polymorphisms using the Review Manager 5.3 software.

RESULTS:

Based on 1213 cases and 1103 controls, overall analysis showed significant increased risk in the homozygous (OR 2.83, 95 % CI 0.99-8.10, p = 0.05), dominant (OR 1.86, 95 % CI 1.00-3.46, p = 0.05) and codominant (OR 2.15, 95 % CI 1.06-4.35, p = 0.03) models. Confined to the studies in Hardy-Weinberg Equilibrium erased the significance (OR 1.59-2.59, 95 % CI 0.81-8.22, p = 0.10-0.15). Asian effects were variable (OR 0.93-1.09, p = 0.50-0.57), but Caucasian effects were not (OR 4.09-13.60, p < 0.0001). Independent data for the late stages of endometriosis suggest protection of the ICAM-1 K469E polymorphism among the Asians (OR 0.91-0.95, p = 0.35-0.71). These effects were weak but non-heterogeneous (P heterogeneity = 0.17-0.57, I (2) = 0-40 %).

CONCLUSION:

In summary, strengths of the overall effects were consistency, significance and robustness but limited by their high heterogeneity. These strengths and limitations were also observed in the Caucasian subgroup which when tested for interaction against the contrasting Asian effects, highlighted Caucasian susceptibility (p = 0.004-0.01). The findings are an interplay of strengths and limitations, which warrant awareness of their interpretation as susceptibility markers for this disorder.

 

 

Arq Bras Cir Dig. 2015;28(1):61-7.

New alternative for wound protection in laparoscopic colectomy.

da Silva JJ¹, Silva RM¹, Costa KK¹.

 

Abstract

BACKGROUND:

Large number of surgical services use laparoscopy to approach the colon. One of the concerns on the resection using this way is the high rate of cancer relapse at in- and outlet site of the surgical instruments.

AIM:

To describe a protective device for surgical isolation in laparoscopic colectomy.

METHODS:

The device is made of sterile polyethylene plastic cover used to protect the fiber optic cable in laparoscopic surgery and one 20 Fr. urethral catheter working as a conduit.

RESULTS:

The device was used in six laparoscopic colectomies, three for adenocarcinoma of the colon and three for intestinal endometriosis. It was effective to avoid contact of the specimen with the abdominal wall, in order to reduce the risk of implantation of cancer or endometriotic cells and surgical site infection. The device was made intraoperative at all surgeries and allowed good visualization in laparoscopy and maintenance of the pneumoperitoneum. It cost R$ 22,00 (approximately US$ 10), R$14.50 related to the plastic cover and R$7.50, the urethral tube. The production time of the device and its installation in the abdominal cavity was measured in each procedure and was, on average, respectively, of 66 s and 25 s.

CONCLUSION:

The device proved to be feasible, not requiring any special training and can be performed by the surgical team itself, even at institutions with limited resources.

 

 

Clin Exp Obstet Gynecol. 2015;42(1):106-7.

Intrauterine endometriotic cyst at the site of previous cesarean scar; scar endometriosis.

Isci H, Gonenc G, Yigiter AB, Guducu N, Dünder I.

 

Abstract

Uterine scar endometriosis is an extremely rare entitiy. As the surgical procedures of the uterus increases through time, scar endometriosis may be diagnosed more often in the future. A case of uterine scar endometriosis is presented with complaints of menstruation lasting one day with associated pelvic pain. When a cystic mass in the site of previous surgery is diagnosed, scar endometriosis must be considered.

 

 

Acta Obstet Gynecol Scand. 2015 Jul;94(7):693-700

Use of hormonal therapy is associated with reduced nerve fiber density in deep infiltrating, rectovaginal endometriosis.

Tarjanne S¹, Ng CH², Manconi F², Arola J³, Mentula M¹, Maneck B², Fraser IS², Heikinheimo O¹.

 

Abstract

OBJECTIVE:

To study the density of nerve fibers in cases of deep infiltrating endometriosis (DIE) of the rectovaginal septum in relation to various clinical factors.

DESIGN:

A research laboratory-based study.

SETTING:

A tertiary center together with a research laboratory.

METHODS:

Archived DIE tissue samples from 45 women operated upon for rectovaginal septum DIE were re-examined histologically, and by immunohistochemistry.

MAIN OUTCOME MEASURES:

The effect of progestogens or combined oral contraceptives on the density of nerve fibers, and the expression of nerve growth factor (NGF) and its high-affinity receptor (tyrosine kinase receptor A, Trk-A).

RESULTS:

The use of hormonal therapy was associated with reduced densities of sympathetic, parasympathetic and sensory nerve fibers in DIE lesions. Density of total nerve fibers (with pan-neuronal marker PGP9.5) was significantly lower (p < 0.05) in lesions collected from hormone-treated women (8.6/mm², 4.2-20.8/mm²; median density, from 25th to 75th quartiles) compared with that in lesions from untreated women (24.9/mm², 11.2-34.9/mm²). DIE lesions stained strongly for NGF and its receptor Trk-A. Expression of NGF, but not of Trk-A, was significantly reduced during use of hormonal therapy.

CONCLUSIONS:

Use of hormonal therapy was associated with significantly reduced nerve fiber density in DIE lesions. This may be an important mechanism of action of hormonal therapy for controlling DIE pain symptoms. The expression of estrogen-regulated NGF and its receptor was only partially suppressed during the use of hormonal therapy, suggesting that local estrogen action is often maintained during conventional hormonal therapy in cases of DIE.

 

 

J Med Life. 2015 Apr-Jun;8(2):129-31

Fallopian tubes–literature review of anatomy and etiology in female infertility.

Briceag I¹, Costache A², Purcarea VL³, Cergan R⁴, Dumitru M⁵, Briceag I⁶, Sajin M⁶, Ispas AT⁴.

 

Abstract

RATIONALE:

Around 30% of the infertile women worldwide have associated Fallopian tubes pathology. Unfortunately, for a long time, this aspect of infertility has been neglected due to the possibility of bypassing this deadlock through IVF.

OBJECTIVE:

Up to date free full text literature was reviewed, meaning 4 major textbooks and around 100 articles centered on tubal infertility, in order to raise the awareness on this subject.

METHODS AND RESULTS:

The anatomy of the Fallopian tube is complex starting from its embryological development and continuing with its vascular supply and ciliated microstructure, that is the key to the process of egg transport to the site of fertilization. There are many strongly documented causes of tubal infertility: infections (Chlamydia Trachomatis, Gonorrhea, and genital tuberculosis), intrauterine contraceptive devices, endometriosis, and complications after abdominal surgery, etc.

DISCUSSIONS:

Although there are still many controversies about the etiology of tubal sterility with the advent of molecular diagnosis of infections there has been cleared the pathway of infection through endometriosis or through ciliary immobility towards the tubal obstruction.

 

Gynecol Oncol. 2015 Jun;137(3):412-7.

The clinical value of surgeons’ efforts of preventing intraoperative tumor rupture in stage I clear cell carcinoma of the ovary: A Korean multicenter study.

Suh DH¹, Park JY², Lee JY³, Kim BG⁴, Lim MC⁵, Kim JW³, Bae DS⁴, Park SY⁵, Nam JH², Kim K¹, No JH¹, Kim YB⁶.

 

Abstract

OBJECTIVE:

To demonstrate the survival impact of intraoperative tumor rupture in women with stage I clear cell carcinoma (CCC) of the ovary.

METHODS:

A total of 193 patients with stage I CCC of the ovary who had undergone a complete staging operation followed by ≥three cycles of adjuvant platinum-based chemotherapy, were retrospectively reviewed. Survival analysis was performed and compared between three stage groups: IA/IB, IC1, and IC2/IC3.

RESULTS:

There were 70, 51, and 72 women with ovarian CCC in stages IA/IB, IC1, and IC2/IC3, respectively. Intraoperative tumor rupture occurred in 69 (35.8%) patients. Gross endometriosis (p=0.020) and significant peritumoral adhesion (p<0.001) were associated with intraoperative tumor rupture. However, neither laparoscopic approach nor large tumor size >10cm were associated with intraoperative tumor rupture. Patients with stage IC2/IC3 compared to those with stage IC1, had poorer progression-free survival (PFS) (5-year PFS, 68.5% versus 91.7%; p=0.010) and overall survival (OS) (5-year OS, 81.1% versus 95.4%; p=0.027). However, there was no significant difference between patients with stages IA/IB and IC1 CCC in PFS (5-year PFS 88.8% versus 91.7%; p=0.291) and OS (5-year OS 94.6% versus 95.4%; p=0.444). Stage IC2/IC3 was the only independent poor prognostic factor for OS (hazard ratio, 3.50; 95% confidence interval, 1.31 to 9.36).

CONCLUSION:

Surgical spillage of tumor cells does not appear to have a negative impact on survival outcomes of women with stage I ovarian CCC who received ≥three cycles of adjuvant platinum-based chemotherapy.

 

 

 

Gynecol Obstet Invest. 2015;79(4):234-8.

Characteristics, expectations and needs of the dutch endometriosis society members.

Roos-Eysbouts Y¹, De Bie-Rocks B, Van Dijk J, Nap AW.

 

Abstract

BACKGROUND/AIM STUDY QUESTION: Endometriosis is associated with a significant reduction in the quality of life and higher depression and anxiety rates. The Dutch Endometriosis Society (ES) was founded to increase the recognition and knowledge in patients and health care professionals, stimulate research and improve care. This study was conducted to explore the characteristics of the members and evaluate their needs and expectations.

METHODS:

A descriptive questionnaire-based survey was conducted among all members of the ES. The response rate was 51% (n = 571).

RESULTS:

ES members appear to be highly educated women with a wide variety of endometriosis-related symptoms resulting in considerable restrictions in daily life. Information transmission was considered the main aim of ES (97%), whereas 56% expected social support, and 38% expected advocacy. The majority (71%) reported an improvement in their quality of life after contact with the ES.

CONCLUSION:

The results of this study underline patients’ primary quest for information about endometriosis. Patient support groups such as ES can fulfil a useful role in disseminating knowledge from medical professionals to those suffering a chronic illness, resulting in a greater understanding and ultimately increasing their quality of life.

 

 

Eur J Gynaecol Oncol. 2015;36(1):21-4.

Prevalence of endometriosis in epithelial ovarian cancer. Analysis of the associated clinical features and study on molecular mechanisms involved in the possible causality.

Machado-Linde F, Sánchez-Ferrer ML, Cascales P, Torroba A, Orozco R, Silva Sánchez Y, Nieto A, Fiol G.

 

Abstract

PURPOSE OF INVESTIGATION:

To determine the prevalence of endometriosis in patients with epithelial ovarian cancer and explore the differences between women with endometrioid and clear-cell histologic subtypes with and without associated endometriosis.

MATERIALS AND METHODS:

The medical charts of 496 patients with epithelial ovarian cancer at the Hospital Virgin de la Arrixaca (Murcia, Spain) between 1971 and 2010 were reviewed.

RESULTS:

Endometriosis was present in 27 (5.4%) of the 496 cases (p < 0001), and was associated with the endometrioid histotype in 13/45 cases (29%) and with the clear cell histotype in 7/22 (32%). The prevalence of an association with endometriosis according to histologic type was 28.8% (13/45) for endometrioid carcinoma and 31.8% (7/22) for clear-cell carcinoma.

CONCLUSION:

Both endometrioid and clear-cell ovarians tumours are associated with pelvic endometriosis. Patients with endometiosis associated ovarian cancer differ from non-endometiosis associated ovarian cancer in their clinical characteristics.

 

 

Int J Gynaecol Obstet. 2015 Jul;130(1):23-6.

Endometrial ILKAP expression among patients with endometriosis and its association with clinical characteristics.

Shao G¹, Zheng Q², Xu X², Zhao J², Liu P³.

 

Abstract

OBJECTIVE:

To investigate expression of ILKAP among women with endometriosis and its association with clinical characteristics.

METHODS:

A retrospective study was conducted at a center in China in 2012, using samples of ectopic (n=55) and eutopic (n=33) endometrium from women with endometriosis, and control endometrium samples (n=33) from women without endometriosis. Information on clinical characteristics was obtained from records. The expression of ILKAP was tested by immunohistochemistry.

RESULTS:

The expression of ILKAP was higher in the secretory phase of the menstrual cycle than in the proliferative phase, and it was lower in eutopic and ectopic endometriosis tissue than in control endometrium (P<0.001 for both). A lower expression of ILKAP in ectopic endometrium was associated with moderate-to-severe dysmenorrhea, infertility for more than 1year, a cancer antigen 125 level of more than 35 U/mL, a disease duration of at least 1year, and American Fertility Society grade IV disease (P<0.05 for all).

CONCLUSION:

A low level of ILKAP could facilitate the pathogenesis of endometriosis. Additionally, the level of ILKAP expression in ectopic endometrium might reflect the severity of endometriosis.

 

 

Cancer Epidemiol Biomarkers Prev. 2015 Jul;24(7):1094-100.

African Americans and Hispanics Remain at Lower Risk of Ovarian Cancer Than Non-Hispanic Whites after Considering Nongenetic Risk Factors and Oophorectomy Rates.

Wu AH¹, Pearce CL², Tseng CC³, Pike MC⁴.

 

Abstract

BACKGROUND:

Risk factors for invasive epithelial ovarian cancer (IEOC) among Hispanics and African Americans are understudied despite notable differences in incidence relative to non-Hispanic whites.

METHODS:

We used multivariate logistic regression to examine parity, oral contraceptive use, tubal ligation, endometriosis, family history of ovarian cancer, and talc use and risk of IEOC among Hispanics (308 cases and 380 controls), African Americans (128 cases and 143 controls), and non-Hispanic whites (1,265 cases and 1,868 controls) using four case-control studies we conducted in Los Angeles County. We expressed each of these factors in the form of increasing risk and calculated population attributable risk percentage (PAR%) estimates for the six risk factors separately and jointly in the three groups.

RESULTS:

The risk associations with these six well-accepted factors were comparable in the three groups. The significant racial/ethnic differences in the prevalence of these factors and differences in their oophorectomy rates explained 31% of the lower incidence in African Americans compared with non-Hispanic whites, but only 13% of the lower incidence in Hispanics. The PAR%s ranged from 27.5% to 31.0% for no tubal ligation, 15.9% to 22.2% for not using oral contraceptives, and 12.2% to 15.1% for using talc in the three groups.

CONCLUSIONS:

All six risk factors are comparably important in the three groups. Differences in the prevalence of these factors and their oophorectomy rates explained approximately one third of the difference in incidence between African Americans and non-Hispanic whites.

IMPACT:

Devising strategies to lessen the burden of IEOC will be applicable to all three racial/ethnic groups.

 

 

 

Arch Gynecol Obstet. 2015 Oct;292(4):869-73.

The role of ovarian fossa evaluation in patients with ovarian endometriosis.

De Cicco Nardone C¹, Terranova C, Plotti F, Ricciardi R, Capriglione S, Luvero D, Caserta D, Moscarini M, Benedetti Panici P, Angioli R.

 

Abstract

PURPOSE:

The aim of this study is to evaluate prospectively the presence of endometriosis in the peritoneum of the ovarian fossa of patients affected by endometriomas and its correlation with the adhesion between this peritoneum and endometrioma.

METHODS:

Patients presenting ovarian endometriomas and candidate to laparoscopy were considered for inclusion in the study. Patients underwent laparoscopic excision of endometriomas. The presence of adherence of the ovarian fossa to endometrioma was investigated. In all patients, the removal of a peritoneum fragment from the ovarian fossa of the affected ovary was carried out.

RESULTS:

68 patients were enrolled in the study. 48 patients presented adhesions to the ovarian fossa. Histopathologic examination of the peritoneum of the ovarian fossa revealed the presence of endometriosis in 87 % of patients presenting adhesions of the endometriomas with ovarian fossa; surprisingly it was present only in 15 % of patients not presenting this condition (p < 0.0001). Pain symptoms were more frequent in patients with endometriomas adhesion to the ovarian fossa. CA125 levels were not statistically significantly different between groups. At 12-month follow-up, four patients presented endometrioma recurrence. All of them presented adhesion of the ovarian fossa to the endometrioma in the first operation.

CONCLUSIONS:

There is a strong association between adhesion of the endometriomas to the ovarian fossa and the presence of endometriosis on the peritoneal surface of the fossa. This condition significantly correlates with pain symptoms and may predict endometrioma recurrence. The removal of this peritoneum in case of adherent endometrioma may potentially reduce the incidence of recurrence.

 

 

Zhonghua Fu Chan Ke Za Zhi. 2015 Jan;50(1):48-53.

Small hairpin RNA targeting inhibition of NF-κB gene in endometriosistherapy of Macaca fascicularis.

Zhu F¹, Liu M², Pan Y¹, Wang X¹, Chen Y¹.

 

Abstract

OBJECTIVE:

To observe the therapeutic effect of NF-κB gene short hairpin RNA (shRNA) on endometriosis and identify the function of NF-κB on the maintenance and development of endometriosis in Macaca fascicularis.

METHODS:

The Macaca fascicularis model of endometriosis was developed, which divided into experimental group, negative control group and simple model group. The high specificity adenovirus vector mediated shRNA targeting NF-κB gene and negative control shRNA adenovirus with no-load NF-κB gene were synthesised. The experimental group injected the adenovirus which carried the NF-κB shRNA into the endometriosis lesions under laparoscopy surgery, the negative control group with no-load shRNA adenovirus and the simple models group injected with normal saline. Four weeks later after the injection, an observed operation was performed through laparoscopy and some lesions were collected. The CD34 immunohistochemistry of these lesions were done to detect the microvessel density, then the variation of the microvessel density among each group were observed. The expression of the NF-κB and proliferating cell nuclear antigen (PCNA) were detected through western blot.

RESULTS:

First, the Macaca fascicularis model of endometriosis was successful developed, and the experimental group has an evident atrophy in ectopic lesions compared with the previous. The lesions’ microvessel density in experimental group decreased evidently compared with the negative control group and simple model group (0.002 0±0.000 3 versus 0.021 9±0.002 6 versus 0.024 5±0.003 3), and the differences was statistically significant (P < 0.01). The expression of PCNA (0.37±0.17 versus 0.57±0.26 versus 0.57±0.28) and NF-κB (0.338±0.174 versus 0.678±0.021 versus 0.645±0.098) in experiment group was lower than the negative control group and simple model group, the differences were statistically significant (all P < 0.01).

CONCLUSION:

Through targeting suppressed the NF-κB gene expression by NF-κB shRNA, we can inhibit the development of endometriosis through reducing the ability of angiogenesis and cell proliferation of ectopic endometrial cells.

 

 

Reprod Biol Endocrinol. 2015 Apr 15;13:31.

Infertility etiologies are genetically and clinically linked with other diseases in single meta-diseases.

Tarín JJ¹, García-Pérez MA^2,3, Hamatani T⁴, Cano A^5,6.

 

Abstract

The present review aims to ascertain whether different infertility etiologies share particular genes and/or molecular pathways with other pathologies and are associated with distinct and particular risks of later-life morbidity and mortality. In order to reach this aim, we use two different sources of information: (1) a public web server named DiseaseConnect ( http://disease-connect.org ) focused on the analysis of common genes and molecular mechanisms shared by diseases by integrating comprehensive omics and literature data; and (2) a literature search directed to find clinical comorbid relationships of infertility etiologies with only those diseases appearing after infertility is manifested. This literature search is performed because DiseaseConnect web server does not discriminate between pathologies emerging before, concomitantly or after infertility is manifested. Data show that different infertility etiologies not only share particular genes and/or molecular pathways with other pathologies but they have distinct clinical relationships with other diseases appearing after infertility is manifested. In particular, (1) testicular and high-grade prostate cancer in male infertility; (2) non-fatal stroke and endometrial cancer, and likely non-fatal coronary heart disease and ovarian cancer in polycystic ovary syndrome; (3) osteoporosis, psychosexual dysfunction, mood disorders and dementia in premature ovarian failure; (4) breast and ovarian cancer in carriers of BRCA1/2 mutations in diminished ovarian reserve; (5) clear cell and endometrioid histologic subtypes of invasive ovarian cancer, and likely low-grade serous invasive ovarian cancer, melanoma and non-Hodgkin lymphoma in endometriosis; and (6) endometrial and ovarian cancer in idiopathic infertility. The present data endorse the principle that the occurrence of a disease (in our case infertility) is non-random in the population and suggest that different infertility etiologies are genetically and clinically linked with other diseases in single meta-diseases. This finding opens new insights for clinicians and reproductive biologists to treat infertility problems using a phenomic approach instead of considering infertility as an isolated and exclusive disease of the reproductive system/hypothalamic-pituitary-gonadal axis. In agreement with a previous validation analysis of the utility of DiseaseConnect web server, the present study does not show a univocal correspondence between common gene expression and clinical comorbid relationship. Further work is needed to untangle the potential genetic, epigenetic and phenotypic relationships that may be present among different infertility etiologies, morbid conditions and physical/cognitive traits.

 

 

Fertil Steril. 2015 Jun;103(6):1537-43.

Endometriosis and assisted reproductive technology: United States trends and outcomes 2000-2011.

Kawwass JF¹, Crawford S², Session DR³, Kissin DM⁴, Jamieson DJ⁴; National ART Surveillance System Group.

Abstract

OBJECTIVE:

To assess endometriosis-associated infertility trends among assisted reproductive technology (ART) cycles, and to compare cancellation and hyperstimulation risks and pregnancy and live birth rates among women using ART for endometriosis-associated vs. male factor infertility.

DESIGN:

Descriptive and multivariable analyses of Centers for Disease Control and Prevention (CDC) National ART Surveillance System data.

SETTING:

Fertility centers.

PATIENT(S):

All reported fresh autologous ART cycles in the United States between 2000 and 2011 (n = 1,589,079).

INTERVENTION(S):

None.

MAIN OUTCOME MEASURE(S):

Oocyte yield, hyperstimulation, cancellation, implantation, pregnancy, live birth.

RESULT(S):

The absolute number of ART cycles with an endometriosis diagnosis fell in recent years, from 16,751 (2000) to 15,311 (2011); the percentage fell over time, from 17.0% (2000) to 9.6% (2011) of all cycles. Compared with male factor (n = 375,557), endometriosis-associated cycles (n = 112,475) yielded fewer oocytes (50.5% vs. 42.5% of cycles with only 0-10 oocytes retrieved), lower risk of hyperstimulation (1.1% vs. 1.3%, adjusted risk ratio [aRR] 0.82, 95% confidence interval [CI] 0.74-0.91), and an increased risk of cancellation (12.9% vs. 10.1%, aRR 1.30, 95% CI 1.25-1.35). Endometriosis was associated with a statistically decreased but likely clinically insignificant difference in the following outcomes: chance of pregnancy per transfer (43.7% vs. 44.8%, aRR 0.96, 95% CI 0.95-0.98) among couples who did not also have tubal factor infertility and live birth per transfer (37.2% vs. 37.6%, aRR 0.96, 95% CI 0.94-0.98).

CONCLUSION(S):

The percentage of endometriosis-associated ART cycles has decreased over time. As compared with male factor infertility, endometriosis is associated with increased cancellation and decreased hyperstimulation risks. Despite decreased oocyte yield and higher medication dose, the difference in pregnancy and live birth rates may be of limited clinical significance, suggesting comparable pregnancy outcomes per transfer.

 

 

J Minim Invasive Gynecol. 2015 Jul-Aug;22(5):846-52.

Sensitivity of Narrow Band Imaging Compared With White Light Imaging for the Detection of Endometriosis.

Barrueto FF¹, Audlin KM¹, Gallicchio L², Miller C³, MacDonald R⁴, Alonsozana E⁵, Johnston M⁶, Helzlsouer KJ⁷.

 

Abstract

STUDY OBJECTIVE:

To evaluate the ability of narrow band imaging (NBI) in conjunction with standard white light imaging to improve the detection and diagnosis of endometriosis during laparoscopic evaluation compared with white light imaging alone. Sensitivity of NBI in detecting endometriosis was assessed and compared with white light imaging.

DESIGN:

Randomized controlled trial.

CLASSIFICATION OF STUDY DESIGN:

LEVEL I: Evidence obtained from a properly designed, randomized, controlled trial.

SETTING:

The trial was conducted in 2 medical centers.

PATIENTS:

One hundred sixty-seven women undergoing laparoscopic evaluation for suspected endometriosisand/or infertility were recruited. Of these, 150 were assessable to determine sensitivity of NBI compared with white light imaging for the detection of endometriotic lesions.

INTERVENTIONS:

Patients were randomized in a 3:1 ratio to receive white light imaging followed by NBI or white light imaging only. The pelvis was systematically visualized with each assigned imaging modality; lesions were recorded under each visualization and then resected. All patients had white light imaging on the first visualization followed by either a second white light examination (control arm) or NBI examination (intervention arm).

MEASUREMENTS:

Pathology of resected lesions was the criterion standard for evaluating sensitivity and was conducted at each institution. The method of detection of the lesion (white light or NBI) was masked. Central pathology review was conducted for a randomly selected 10% sample of specimens and for those lesions visualized under only 1 imaging modality among patients assigned to the intervention arm. The sensitivity was assessed for each modality (white light and NBI) and compared using a McNemar’s test.

MAIN RESULTS:

Among the group randomized to receive both white light and NBI, 4 patients had lesions detected with NBI but no lesions detected with white light. Among the 255 lesions confirmed as endometriosis by pathologic review, all were detected by NBI for a sensitivity of 100%; 79% were detected by white light imaging (p < .001).

CONCLUSION:

The addition of NBI to white light imaging increased the number of endometriotic lesions identified during laparoscopy and the diagnosis of endometriosis compared with the use of white light imaging alone.

 

 

Mol Hum Reprod. 2015 Jul;21(7):594-602.

Genetic burden associated with varying degrees of disease severity in endometriosis.

Sapkota Y¹, Attia J², Gordon SD³, Henders AK³, Holliday EG², Rahmioglu N⁴, MacGregor S³, Martin NG³, McEvoy M², Morris AP⁴, Scott RJ⁵, Zondervan KT⁶, Montgomery GW³, Nyholt DR⁷.

 

Abstract

Endometriosis is primarily characterized by the presence of tissue resembling endometrium outside the uterine cavity and is usually diagnosed by laparoscopy. The most commonly used classification of disease, the revised American Fertility Society (rAFS) system to grade endometriosis into different stages based on disease severity (I to IV), has been questioned as it does not correlate well with underlying symptoms, posing issues in diagnosis and choice of treatment. Using two independent European genome-wide association (GWA) datasets and top-level classification of the endometriosis cases based on rAFS [minimal or mild (Stage A) and moderate-to-severe (Stage B) disease], we previously showed that Stage B endometriosis has greater contribution of common genetic variation to its aetiology than Stage A disease. Herein, we extend our previous analysis to four endometriosis stages [minimal (Stage I), mild (Stage II), moderate (Stage III) and severe (Stage IV) disease] based on the rAFS classification system and compared the genetic burden across stages. Our results indicate that genetic burden increases from minimal to severe endometriosis. For the minimal disease, genetic factors may contribute to a lesser extent than other disease categories. Mild and moderate endometriosis appeared genetically similar, making it difficult to tease them apart. Consistent with our previous reports, moderate and severe endometriosis showed greater genetic burden than minimal or mild disease. Overall, our results provide new insights into the genetic architecture of endometriosis and further investigation in larger samples may help to understand better the aetiology of varying degrees of endometriosis, enabling improved diagnostic and treatment modalities.

 

 

Hum Reprod. 2015 Jun;30(6):1280-6.

Fertility preservation in women with endometriosis: for all, for some, for none?

Somigliana E¹, Viganò P², Filippi F³, Papaleo E², Benaglia L³, Candiani M², Vercellini P⁴.

 

Abstract

The increasing confidence with the techniques of oocyte and ovarian cortex freezing has prompted their potential use for patient categories other than those at risk of early menopause due to cancer treatments. Women affected by every iatrogenic or pathologic condition known to compromise ovarian function severely have been considered as potential candidates for fertility preservation. Among them, women with endometriosis may represent a particularly suitable group since they are at increased risk of premature ovarian exhaustion and about half of them will experience infertility. Based on the currently available notions on the intricate relationships between endometriosis, infertility and damage to the ovarian reserve, we speculate that fertility preservation may be of interest for women with endometriosis, in particular for those with bilateral unoperated endometriomas and for those who previously had excision of unilateral endometriomas and require surgery for a contralateral recurrence. Young age at diagnosis may be an independent but pivotal additional factor to be taken into consideration in the balance of the pros and cons of fertility preservation. On the other hand, we argue against the introduction of fertility preservation for endometriosis in routine clinical practice. To date, only few cases have been reported and there are insufficient data for robust cost-utility analyses. It is noteworthy that endometriosis is a relatively common disease and systematically including affected women in a fertility preservation program would have profound clinical, logistic and financial effects. More clinical data and in-depth economic analysis are imperative prior to recommending its routine use.

 

 

J Fam Plann Reprod Health Care. 2015 Apr 16. pii: jfprhc-2014-100993.

Sexual function in women undergoing surgery for deep infiltrating endometriosis: a comparison with healthy women.

Di Donato N¹, Montanari G¹, Benfenati A¹, Monti G², Leonardi D², Bertoldo V², Facchini C¹, Raimondo D¹, Villa G³, Seracchioli R⁴.

 

Abstract

BACKGROUND:

Endometriosis is a chronic and progressive condition of women of reproductive age. It is strongly associated with significant impairment of sexual function.

AIM:

To objectively evaluate the impact of laparoscopic excision of endometriosis on sexual function in patients with deep infiltrating endometriosis (DIE) compared to healthy women.

SETTING AND DESIGN:

Prospective study, including 250 patients with a diagnosis of DIE scheduled for laparoscopic surgery and 250 healthy women.

METHODS:

A sexual activity questionnaire, SHOW-Q (Sexual Health Outcomes in Women Questionnaire), was used to collect data pertaining to women’s satisfaction, orgasm, desire and pelvic problem interference with sexual function. Women with DIE underwent complete excision of endometriotic lesions. All participants were asked to complete the SHOW-Q questionnaire before and after surgery.

RESULTS:

SHOW-Q scores in the endometriosis group before and 6 months after surgery were compared with the healthy group scores. A significant improvement was found between pre- and post-treatment in the scores of the satisfaction scale, desire scale and pelvic problem interference scale of SHOW-Q. The distribution of post-surgery SHOW-Q scores was comparable to healthy women’s scores apart from the orgasm scale score, which was unchanged in the post-surgery group.

CONCLUSIONS:

The surgical approach to treatment has a positive impact not only on organ impairment but also on sexual function in women affected by DIE.

 

 

Eur J Med Res. 2015 Apr 4;20:48.

Hepatic endometriosis: a rare case and review of the literature.

Liu K¹, Zhang W², Liu S³, Dong B⁴, Liu Y⁵.

 

Abstract

Hepatic endometriosis is one of the rarest disorders characterized by the presence of ectopic endometrium in the liver. To our knowledge, only 21 cases of hepatic endometrioma have been described in the medical literature. We report a case of a 36-year-old primiparous female with hepatic endometriosis forming a large cystic mass. The patient presented once with severe right quadrant pain as her only symptom and no history of endometriosis. Complete blood count and biochemical tests were normal. Abdominal ultrasonography and computed tomography scans suggested the presence of a 6.5 × 6.0 cm cystic mass in segment III of the liver. The mass was completely removed by local liver resection. The intraoperative frozen sections suggested a diagnosis of hepatic endometriosis. The diagnosis was confirmed through histological immunostaining without intrinsic abnormality. A preoperative diagnosis of hepatic endometriosis is made on the basis of considering the possibility in advance. Hepatic endometriosis should be considered in the differential diagnosis of a cystic liver mass despite conducting exhaustive investigations in the absence of characteristic clinical and radiological features. Histological examination is essential, and surgery remains the treatment of choice.

 

 

 

Eur J Obstet Gynecol Reprod Biol. 2015 Jun;189:73-8.

TP53 Arg72Pro polymorphism (rs1042522) and risk of endometriosis among Asian and Caucasian populations.

Li J¹, Chen Y², Mo Z², Li L³.

 

Abstract

This study was conducted to investigate the association between TP53 Arg72Pro polymorphism (rs1042522) and risk of endometriosis. Studies were retrieved from Pubmed, Embase and HuGENet, and four models [dominant (AA+AG vs. GG), recessive (AA vs. AG+GG), co-dominant (AA vs. AG, AA vs. GG) and allele analysis (A vs. G), combined with odds ratios (OR) and 95% confidence intervals (CI)], were applied to evaluate this association. Fourteen eligible studies from eight countries were included. The pooled analysis identified a significant association between TP53 Arg72Pro polymorphism (rs1042522) and risk of endometriosis [dominant: OR 0.746, 95% CI 0.585-0.952, I(2)=59%; recessive: OR 0.650, 95% CI 0.510-0.829, I(2)=73%; co-dominant (GG vs. GC): OR 0.676, 95% CI 0.637-0.851, I(2)=67%; co-dominant (GG vs. CC): OR 0.564, 95% CI 0.395-0.806, I(2)=74%; allele analysis: OR 0.762, 95% CI 0.654-0.888, I(2)=71%]. In the subgroup analysis, the same positive associations were found among Asians. After removing studies that did not satisfy Hardy-Weinberg equilibrium, significant correlations were confirmed in both the pooled analysis and the Asian subgroup. Three bioinformatic methods (TagSNP calculations, functional prediction and linkage disequilibrium analysis) were used to determine the importance of TP53 Arg72Pro polymorphism (rs1042522), and suggested that this locus may be equally important regardless of ethnicity. In conclusion, TP53 Arg72Pro polymorphism (rs1042522) was positively associated with risk of endometriosis, particularly among Asians. However, its potential role in Caucasians should not be ignored.

 

 

Mol Med Rep. 2015 Aug;12(2):1611-6.

Epigenetic dysregulation of endometriosis susceptibility genes (Review).

Koike N¹, Higashiura Y¹, Akasaka J¹, Uekuri C¹, Ito F¹, Kobayashi H¹.

 

Abstract

The aim of the present review was to illustrate how dysregulation of hormonal signaling regulates expressional changes of spatially associated genes in endometriosis. From a multi‑platform endometriosis dataset, an integrated analysis was performed of epigenomic changes of several biologically relevant genes that have been validated in the literature. Estrogen receptor (ER) may act as a direct epigenetic driver for endometriosisestablishment, maintenance and progression. A majority of endometriosis susceptibility genes may be present in functional downstream targets of ER and located near the known imprinting genes. Previous studies have shed light on the overlapping genetic signatures between endometriosis development and the defective decidualization process. The steroid hormone‑mediated decidualization signaling pathway was shown to be frequently dysregulated in endometriosis. DNA methylation is associated with various intragenic or intergenic epigenetic modifications of chromatin. Chromatin architecture may be established in temporal and spatial orchestration of the recruitment of genes specifically downregulated in endometriosis. In conclusion, defective chromatin architecture at the ER target locus may have a key role in endometriosis. Endometriosis represents an interesting model to explore the variation of expression of spatially associated genes.

 

 

 

Int J Gynecol Cancer. 2015 Jul;25(6):968-76.

The Risks for Ovarian, Endometrial, Breast, Colorectal, and Other Cancers in Women With Newly Diagnosed Endometriosis or Adenomyosis: A Population-Based Study.

Kok VC¹, Tsai HJ, Su CF, Lee CK.

 

Abstract

OBJECTIVE:

Recent studies report a link between endometriosis and ovarian cancer (OC). Using a population-based cohort study to confirm the association between endometriosis and cancer is desirable. We thus examined the magnitude of the risks of OC, endometrial cancer (EC), breast cancer, colorectal cancer (CRC), and other cancers in women with newly diagnosed endometriosis or adenomyosis (internal endometriosis).

METHODS/MATERIALS:

Women older than 20 years with claims data between 2003 and 2005 were identified from the Longitudinal Health Insurance Dataset containing 1 million individuals randomly sampled from the National Health Insurance Research Database. Those with preexisting malignancies, hysterectomy, or oophorectomy were excluded. The endometriosis cohort (n = 2266, including 768 cases of pure adenomyosis) and comparison cohort (n = 9064), formed by 1:4 matching, were followed up until incidence cancer, dropout, or December 31, 2008. Outcome measures included cancer incidence and adjusted hazard ratio by Cox model adjusted for age group, comorbidities, and endometriosis medication use.

RESULTS:

With 9842 person-years of follow-up in endometriosis cohort and 36,274 person-years of follow-up in comparison cohort, there were increased risks of all cancers (adjusted hazard ratio, 1.8; 95% confidence interval, 1.4-2.4), OC (4.56, 1.72-12.11), and EC (4.05, 1.20-13.66). The ovarian endometriosis group was associated with increased risk of subsequent OC (4.37, 1.07-17.83). The adenomyosis group was strongly associated with both OC (5.50, 1.95-15.50) and EC (5.13, 1.36-19.40). Increased risk of subsequent CRC was observed in women with adenomyosis with coexistent endometriosis at other sites (13.04, 2.21-77.04). However, no statistically significant increased risk of breast or other cancers was observed.

CONCLUSIONS:

Having limitations such as lacking of parity information which may affect the magnitude of risk estimates, this study demonstrates that ovarian endometriosis has a 4-fold increased risk of OC. Adenomyosis may associate with a 4- to 5-fold increased risk of OC and EC, and unexpectedly, a 13-fold increased risk of CRC.

 

 

Trends Pharmacol Sci. 2015 May;36(5):270-6

Menstruation pulls the trigger for inflammation and pain in endometriosis.

Laux-Biehlmann A¹, d’Hooghe T², Zollner TM³.

 

Abstract

Endometriosis is a chronic, hormone-dependent, inflammatory disease, characterized by the presence and growth of endometrial tissue outside the uterine cavity. It affects 5-10% of the female population of reproductive age and is frequently associated with moderate to severe pain, subfertility, and a marked reduction in health-related quality of life. Here, we propose a new pathophysiological concept of endometriosis, summarizing recent findings in one unifying picture. We propose menstruating tissue as the trigger for inflammatory pain in endometriosis through the activation of innate immune cells and peripheral nerve endings. We speculate how innovative treatment modalities beyond hormonal treatment will improve patients’ lives.

 

 

BMJ Case Rep. 2015 Apr 22;2015.

Endometriosis masquerading as Crohn’s disease in a patient with acute small bowel obstruction.

Dong C¹, Ngu WS², Wakefield SE³.

 

Abstract

A 45-year-old woman, a smoker, presented acutely with subacute small bowel obstruction. Abdominal CT scan showed features of ileocaecal Crohn’s disease. She was treated with high dose steroids and her symptoms rapidly settled. A few days later she was discharged on a reducing steroid course in addition to azathioprine. Outpatient colonoscopy was performed and reported as normal but there was failed terminal ileal intubation. Three months later, she represented as an emergency with complete small bowel obstruction. On laparoscopy, a terminal ileal stricture was found resulting in an ileocolic resection. Histopathology reported an endometriotic stricture with no evidence of Crohn’s disease. She was advised to stop steroids and azathioprine. A subsequent pelvic MRI scan showed no further endometrial deposits and she remained symptom free. This case highlights that endometriosis should always be considered when women of childbearing age present with bowel obstruction, even if the patient has no other evidence of the disease.

 

 

Thromb Res. 2015 Feb;135 Suppl 1:S38-40.

MicroRNAs and angiogenesis in endometriosis.

Marí-Alexandre J¹, García-Oms J², Barceló-Molina M¹, Gilabert-Aguilar J³, Estellés A¹, Braza-Boíls A¹, Gilabert-Estellés J⁴.

 

Abstract

miRNAs function as important regulators of a wide range of cellular processes, such as angiogenesis and fibrinolysis, by postranscriptional modulation of gene expression. We present a review on the role of miRNAs and angiogenesis in endometriosis. Endometriosis, defined as the implantation of endometrial tissue outside the uterine cavity, is one of the most frequent benign gynecological diseases and it has important consequences on the quality of life and fertility of patients. Similarly to tumor metastasis, the ectopic endometrium acquires the capability to adhere, proliferate and infiltrate the extracellular matrix. Endometriosis is a multifactorial and polygenic disease in which angiogenesis and proteolysis may be involved, and emerging data provide evidence that a dysregulation of miRNA expression may be implicated in these processes. The detection of circulating miRNAs in plasma and other body fluids and their relative stability has raised the possibility that they might serve as non-invasive biomarkers for the diagnosis of the disease. On the other hand, the development of therapies that might block the expression or mimic the functions of miRNAs could represent new therapeutic strategies for the treatment of endometriosis.

 

 

 

Biol Reprod. 2015 Jun;92(6):140.

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

Heard ME¹, Velarde MC², Giudice LC², Simmen FA¹, Simmen RC³.

Abstract

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

 

 

J Minim Invasive Gynecol. 2015 Jul-Aug;22(5):853-63

A Randomized Controlled Trial on the Efficacy and Safety of a New Crosslinked Hyaluronan Gel in Reducing Adhesions after Gynecologic Laparoscopic Surgeries.

Liu C¹, Lu Q¹, Zhang Z¹, Xue M², Zhang Y³, Zhang Y⁴, Wang H⁵, Li H⁶, Zhou Y⁷, Zhang Z⁸, Li W⁹; HyaRegen Adhesion Study Group.

 

Abstract

STUDY OBJECTIVE:

To evaluate the safety and efficacy of a new crosslinked hyaluronan (NCH) gel in reducing postoperative adhesions.

DESIGN:

Randomized controlled trial (Canadian Task Force classification I).

SETTINGS:

Seven departments of obstetrics and gynecology in China.

PATIENTS:

A total of 216 women scheduled for gynecologic laparoscopic surgery for primary removal of adhesions, myomas, ovarian cysts, or endometriotic cysts.

INTERVENTIONS:

Patients were randomized to receive either NCH gel or saline with 1:1 allocation.

MEASUREMENTS AND MAIN RESULTS:

All patients were evaluated using a modified American Fertility Society (mAFS) scoring system for the incidence, extent, and severity of pre-existing and postoperative adhesions at the 10 anatomic sites of ovaries/tubes and at the expanded 23 or 24 anatomic sites throughout the abdominopelvic cavity by laparoscopy. A total of 215 randomized patients were treated with either saline solution (108 of 108) or NCH gel (107 of 108), composing the full analysis set (FAS), and 196 patients (94 of 108 in the saline control group and 102 of 108 in the NCH gel group) completed the entire study, composing the per protocol set (PPS). The postoperative incidence of moderate or severe adhesions evaluated at the 10 sites (the primary endpoint for efficacy) was 27.7% in the control group and 9.8% in the NCH gel group, a difference of 14.4% (95% confidence interval [CI], 2.6%-20.6%) in the PPS, and 37.0% in the control group and 14.0% in the NCH gel group, a difference of 20.0% (95% CI, 8.9%-26.8%) in the FAS. The postoperative incidence of moderate or severe adhesions evaluated at the 24 sites was also significantly lower in the NCH gel group compared with the control group (5.9% vs 14.9%; p = .036) in the PPS. Also in the PPS, the NCH gel group had significantly lower postoperative adhesion scores of severity, extent, and mAFS: 60.0%, 50.8%, and 76.9%, respectively (median scores of the 10 sites; p = .002) and 48.5%, 50.0%, and 72.2% (median scores of the 24 sites; p = .001) lower than those recorded in the control group. No serious adverse events were observed, and the safety profile of NCH gel was comparable to that of saline control.

CONCLUSION:

This study demonstrates that NCH gel is safe and significantly reduces adnexal adhesion formation and global adhesion formation throughout the abdominopelvic cavity after gynecologic laparoscopic surgery.

 

 

Am J Pathol. 2015 May;185(5):1409-22.

Seminal Plasma Promotes Lesion Development in a Xenograft Model of Endometriosis.

McGuane JT, Watson KM, Zhang J, Johan MZ, Wang Z, Kuo G, Sharkey DJ, Robertson SA, Hull ML.

 

Abstract

The factors that predispose one-tenth of reproductive-aged women to endometriosis are poorly understood. We determined that genetic deficiency in transforming growth factor β1 impairs endometriosis-like lesion growth in mice. Given that seminal plasma is an abundant source of transforming growth factor β, we evaluated the effect of exposure to seminal plasma on the growth of endometrial lesions. Human endometrial explants were exposed to seminal plasma or to control medium before transfer to Prkdc(scid)-mutant (severe combined immunodeficient) mice. Xenografts exposed to seminal plasma showed an eightfold increase in volume and a 4.3-fold increase in weight after 14 days. These increases were associated with increased proliferation of endometrial epithelial cells and enhanced survival and proliferation of human stromal cells compared with those in control lesions, in which human stromal cell persistence was negligible. Although the distribution of macrophages was altered, their number and activation status did not change in response to seminal plasma. Seminal plasma stimulated the production of a variety of cytokines in endometrial tissue, including growth-regulated oncogene, granulocyte macrophage colony-stimulating factor, and IL-1β. These data suggest that seminal plasma enhances the formation of endometriosis-like lesion via a direct effect on endometrial cell survival and proliferation, rather than via macrophage-mediated mechanisms. These findings raise the possibility that endometrial exposure to seminal plasma could contribute to endometriotic disease progression in women.

 

 

Minerva Ginecol. 2016 Dec;68(6):713-21.

Improved surgical management through optimized imaging of pelvic endometriosis.

Garabedian C¹, Rubod C, Faye N, Ledu NK, Merlot B, Collinet P.

 

Abstract

Deep infiltrating endometriosis is a frequent benign pathology that is found in 10-15% of fertile women and in 20% of infertile women. It has an impact on fertility but also on everyday life. In case of failure of medical treatment, surgical treatment can be offered to the patient. To provide adequate treatment and give the clearest information to patients, it seems essential to achieve optimal preoperative imaging. The aim of this work was to define for each compartment the surgeon’s expectations and the indications of iconographic work-ups before surgical management of pelvic endometriosis. We do not discuss technical examinations nor surgical indications and techniques.

 

 

Hum Reprod. 2015 Jun;30(6):1331-41.

Quality of life outcomes in women with endometriosis are highly influenced by recruitment strategies.

De Graaff AA¹, Dirksen CD², Simoens S³, De Bie B⁴, Hummelshoj L⁵, D’Hooghe TM⁶, Dunselman GA⁷.

 

Abstract

STUDY QUESTION:

To what extent are outcome measures in endometriosis-related quality of life studies influenced by the setting in which patient recruitment is performed?

SUMMARY ANSWER:

Quality of life outcomes in women with endometriosis are highly influenced by recruitment strategies.

WHAT IS KNOWN ALREADY:

Most studies on quality of life in women with endometriosis are conducted in tertiary care centres or patient associations. It is conceivable that the setting in which patient recruitment is performed influences the quality of life results. This has not been investigated before.

STUDY DESIGN, SIZE, DURATION:

Retrospective questionnaire based cohort study (part of the World Endometriosis Research Foundation (WERF) EndoCost study). The investigated women were recruited in three settings: a tertiary care centre for endometriosis (n = 135); five secondary care centres (n = 63); an endometriosispatient association (n = 291).

PARTICIPANTS/MATERIALS, SETTING, METHODS:

The secondary and tertiary care population included women with a laparoscopic and/or histological diagnosis of endometriosis. The patient association population consisted of women with a self-reported diagnosis of surgically confirmed endometriosis.

MAIN RESULTS AND THE ROLE OF CHANCE:

The populations did not differ in terms of age, co-morbidities and education level. Delay of diagnosis was the longest in the patient association (median 7 years) (tertiary care 2 years; secondary care 1.5 years) (P < 0.001). The tertiary care population reported more laparotomies (64%) than the other populations (secondary care 43%; patient association 47%) (P = 0.002). Affected job was least prevalent in the secondary care setting (35%) (patient association 64%; tertiary care 56%) (P < 0.001). Affected relationships were most prevalent in the patient association setting (52%) (tertiary care 38%; secondary care 22%) (P < 0.001). Chronic pain was least prevalent in patients in secondary care (44%) (tertiary care 65%; patient association 61%) (P = 0.009). Substantial differences in quality of life were detected between secondary care (median physical component 50.4, mental component 49.6); tertiary care (physical component 46.2, mental component 46.2) and the patient association (physical component 45.0, mental component 44.6) (P < 0.001, P = 0.018).

LIMITATIONS, REASONS FOR CAUTION:

The response rate was relatively low (35%). Analysis of the hospital populations revealed that non-responders and responders did not differ with respect to age or revised American Fertility Society classification, indicating that the non-responder bias is limited. However, other factors, such as social and marital status or symptomatology, might be different for non-responders. Missing values were analysed as if the symptom was not present. Missing values never exceeded 10%, except for one value. Therefore, it can be expected that the effect of missing data on the outcome is negligible. Twenty-five patients belonged to more than one category. A sensitivity analysis showed that the influence of assigning patients to another category was limited.

WIDER IMPLICATIONS OF THE FINDINGS:

Outcomes regarding quality of life are highly influenced by recruitment strategy. None of the groups appeared to be a representative selection of the total population of women with endometriosis. An alternative strategy for creating a representative population for cost and quality of life studies is probably to recruit women who live in a specific geographic area rather than women that visit a specific hospital or are a member of a patient association.

STUDY FUNDING/COMPETING INTERESTS:

The WERF EndoCost study was funded by the World Endometriosis Research Foundation. The sponsors did not have a role in the design and conduct of this study: collection, management, analysis, interpretation of the data; preparation, review, approval of the manuscript. L.H. is the chief executive and T.M.D. was a board member of WERF at the time of funding. T.M.D holds the Merck-Serono Chair and the Ferring Chair in Reproductive Medicine in Leuven, Belgium and has served as consultant for Merck-Serono, Schering-Plough, Astellas, and Arresto.