Lack of an Association between a Polymorphism in the KRAS 3' Untranslated Region (rs61764370) and Endometriosis in a Large European Case-Control Study.

BACKGROUND: Endometriosis is a common disorder that affects 6-10% of reproductive age women. In a previous study, we demonstrated that a polymorphism in let-7 microRNA-binding site in the 3' untranslated region of the KRAS gene was found in 31% of subjects with endometriosis resistant to medical therapy. This polymorphism was now tested in a large, case-control study. METHODS: Peripheral blood or peritoneal biopsies from 2,077 European subjects with or without endometriosis and known infertility were tested for the presence of the variant allele using polymerase chain reaction. RESULTS: Histologically proven endometriosis was found in 1,140 subjects, while 937 subjects were disease free. Variant allele carrier rates in subjects with and without endometriosis were 15.7 and 15.1%, respectively. No association between the variant KRAS allele and stage of the disease, age at surgery, body mass index, or type of infertility was identified. CONCLUSION: A germ-line single-nucleotide polymorphism in the let-7 microRNA-binding site of the KRAS gene was not associated with sporadic endometriosis in an infertile Caucasian population in this large case-control study. However, it remains possible that this gene variant may be a marker of treatment resistance. Further studies on the role of this polymorphism in endometriosis are needed.

The relative importance of genetic parenthood.

RESEARCH QUESTION: How much do patients with severe infertility and their gynaecologists value genetic parenthood relative to other key treatment characteristics? DESIGN: A discrete choice experiment included the following treatment characteristics: genetic parenthood, pregnancy rate, curing infertility, maternal health, child health and costs. The questionnaire was disseminated between 2015 and 2016 among Dutch and Belgian patients with severe infertility and their gynaecologists. RESULTS: The questionnaire was completed by 173 patients and 111 gynaecologists. When choosing between treatments that varied in safety, effectiveness and costs, the treatment's ability to lead to genetic parenthood did not affect the treatment preference of patients with severe infertility (n = 173). Genetic parenthood affected the treatment preference of gynaecologists (n = 111) less than all other treatment characteristics. Patients indicated that they would switch to a treatment that did not enable genetic parenthood in return for a child health risk reduction of 3.6%, a cost reduction of €3500, an ovarian hyperstimulation risk reduction of 4.6%, a maternal cancer risk reduction of 2.7% or a pregnancy rate increase of 18%. Gynaecologists made similar trade-offs. CONCLUSIONS: While awaiting replication of this study in larger populations, these findings challenge the presumed dominant importance of genetic parenthood. This raises questions about whether donor gametes could be presented as a worthy alternative earlier in treatment trajectories and whether investments in novel treatments enabling genetic parenthood, like in-vitro gametogenesis, are proportional to their future clinical effect.

Screening hysteroscopy in subfertile women and women undergoing assisted reproduction.

BACKGROUND: Screening hysteroscopy in infertile women with unexplained infertility, or prior to intrauterine insemination (IUI) or in vitro fertilisation (IVF) may reveal intrauterine pathology that may not be detected by routine transvaginal ultrasound. Hysteroscopy, whether purely diagnostic or operative may improve reproductive outcomes. OBJECTIVES: To assess the effectiveness and safety of screening hysteroscopy in subfertile women undergoing evaluation for infertility, and subfertile women undergoing IUI or IVF. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL CRSO, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (September 2018). We searched reference lists of relevant articles and handsearched relevant conference proceedings. SELECTION CRITERIA: Randomised controlled trials comparing screening hysteroscopy versus no intervention in subfertile women wishing to conceive spontaneously, or before undergoing IUI or IVF. DATA COLLECTION AND ANALYSIS: We independently screened studies, extracted data, and assessed the risk of bias. The primary outcomes were live birth rate and complications following hysteroscopy. We analysed data using risk ratio (RR) and a fixed-effect model. We assessed the quality of the evidence by using GRADE criteria. MAIN RESULTS: We retrieved 11 studies. We included one trial that evaluated screening hysteroscopy versus no hysteroscopy, in women with unexplained subfertility, who were trying to conceive spontaneously. We are uncertain whether ongoing pregnancy rate improves following a screening hysteroscopy in women with at least two years of unexplained subfertility (RR 4.30, 95% CI 2.29 to 8.07; 1 RCT; participants = 200; very low-quality evidence). For a typical clinic with a 10% ongoing pregnancy rate without hysteroscopy, performing a screening hysteroscopy would be expected to result in ongoing pregnancy rates between 23% and 81%. The included study reported no adverse events in either treatment arm. We are uncertain whether clinical pregnancy rate is improved (RR 3.80, 95% CI 2.31 to 6.24; 1 RCT; participants = 200; very low-quality evidence), or miscarriage rate increases (RR 2.80, 95% CI 1.05 to 7.48; 1 RCT; participants = 200; very low-quality evidence), following screening hysteroscopy in women with at least two years of unexplained subfertility.We included ten trials that included 1836 women who had a screening hysteroscopy and 1914 women who had no hysteroscopy prior to IVF. Main limitations in the quality of evidence were inadequate reporting of study methods and higher statistical heterogeneity. Eight of the ten trials had unclear risk of bias for allocation concealment.Performing a screening hysteroscopy before IVF may increase live birth rate (RR 1.26, 95% CI 1.11 to 1.43; 6 RCTs; participants = 2745; I² = 69 %; low-quality evidence). For a typical clinic with a 22% live birth rate, performing a screening hysteroscopy would be expected to result in live birth rates between 25% and 32%. However, sensitivity analysis done by pooling results from trials at low risk of bias showed no increase in live birth rate following a screening hysteroscopy (RR 0.99, 95% CI 0.82 to 1.18; 2 RCTs; participants = 1452; I² = 0%).Only four trials reported complications following hysteroscopy; of these, three trials recorded no events in either group. We are uncertain whether a screening hysteroscopy is associated with higher adverse events (Peto odds ratio 7.47, 95% CI 0.15 to 376.42; 4 RCTs; participants = 1872; I² = not applicable; very low-quality evidence).Performing a screening hysteroscopy before IVF may increase clinical pregnancy rate (RR 1.32, 95% CI 1.20 to 1.45; 10 RCTs; participants = 3750; I² = 49%; low-quality evidence). For a typical clinic with a 28% clinical pregnancy rate, performing a screening hysteroscopy would be expected to result in clinical pregnancy rates between 33% and 40%.There may be little or no difference in miscarriage rate following screening hysteroscopy (RR 1.01, 95% CI 0.67 to 1.50; 3 RCTs; participants = 1669; I² = 0%; low-quality evidence).We found no trials that compared a screening hysteroscopy versus no hysteroscopy before IUI. AUTHORS' CONCLUSIONS: At present, there is no high-quality evidence to support the routine use of hysteroscopy as a screening tool in the general population of subfertile women with a normal ultrasound or hysterosalpingogram in the basic fertility work-up for improving reproductive success rates.In women undergoing IVF, low-quality evidence, including all of the studies reporting these outcomes, suggests that performing a screening hysteroscopy before IVF may increase live birth and clinical pregnancy rates. However, pooled results from the only two trials with a low risk of bias did not show a benefit of screening hysteroscopy before IVF.Since the studies showing an effect are those with unclear allocation concealment, we are uncertain whether a routine screening hysteroscopy increases live birth and clinical pregnancy, be it for all women, or those with two or more failed IVF attempts. There is insufficient data to draw conclusions about the safety of screening hysteroscopy.

Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities.

BACKGROUND: Observational studies suggest higher pregnancy rates after the hysteroscopic removal of endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions, which are present in 10% to 15% of women seeking treatment for subfertility. OBJECTIVES: To assess the effects of the hysteroscopic removal of endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions suspected on ultrasound, hysterosalpingography, diagnostic hysteroscopy or any combination of these methods in women with otherwise unexplained subfertility or prior to intrauterine insemination (IUI), in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). SEARCH METHODS: We searched the following databases from their inception to 16 April 2018; The Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Studies Online, ; MEDLINE, Embase , CINAHL , and other electronic sources of trials including trial registers, sources of unpublished literature, and reference lists. We handsearched the American Society for Reproductive Medicine (ASRM) conference abstracts and proceedings (from 1 January 2014 to 12 May 2018) and we contacted experts in the field. SELECTION CRITERIA: Randomised comparison between operative hysteroscopy versus control for unexplained subfertility associated with suspected major uterine cavity abnormalities.Randomised comparison between operative hysteroscopy versus control for suspected major uterine cavity abnormalities prior to medically assisted reproduction.Primary outcomes were live birth and hysteroscopy complications. Secondary outcomes were pregnancy and miscarriage. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and risk of bias, and extracted data. We contacted study authors for additional information. MAIN RESULTS: Two studies met the inclusion criteria.1. Randomised comparison between operative hysteroscopy versus control for unexplained subfertility associated with suspected major uterine cavity abnormalities.In women with otherwise unexplained subfertility and submucous fibroids, we were uncertain whether hysteroscopic myomectomy improved the clinical pregnancy rate compared to expectant management (odds ratio (OR) 2.44, 95% confidence interval (CI) 0.97 to 6.17; P = 0.06, 94 women; very low-quality evidence). We are uncertain whether hysteroscopic myomectomy improves the miscarriage rate compared to expectant management (OR 1.54, 95% CI 0.47 to 5.00; P = 0.47, 94 women; very low-quality evidence). We found no data on live birth or hysteroscopy complication rates. We found no studies in women with endometrial polyps, intrauterine adhesions or uterine septum for this randomised comparison.2. Randomised comparison between operative hysteroscopy versus control for suspected major uterine cavity abnormalities prior to medically assisted reproduction.The hysteroscopic removal of polyps prior to IUI may have improved the clinical pregnancy rate compared to diagnostic hysteroscopy only: if 28% of women achieved a clinical pregnancy without polyp removal, the evidence suggested that 63% of women (95% CI 45% to 89%) achieved a clinical pregnancy after the hysteroscopic removal of the endometrial polyps (OR 4.41, 95% CI 2.45 to 7.96; P < 0.00001, 204 women; low-quality evidence). We found no data on live birth, hysteroscopy complication or miscarriage rates in women with endometrial polyps prior to IUI. We found no studies in women with submucous fibroids, intrauterine adhesions or uterine septum prior to IUI or in women with all types of suspected uterine cavity abnormalities prior to IVF/ICSI. AUTHORS' CONCLUSIONS: Uncertainty remains concerning an important benefit with the hysteroscopic removal of submucous fibroids for improving the clinical pregnancy rates in women with otherwise unexplained subfertility. The available low-quality evidence suggests that the hysteroscopic removal of endometrial polyps suspected on ultrasound in women prior to IUI may improve the clinical pregnancy rate compared to simple diagnostic hysteroscopy. More research is needed to measure the effectiveness of the hysteroscopic treatment of suspected major uterine cavity abnormalities in women with unexplained subfertility or prior to IUI, IVF or ICSI.

Optimization of Endometrial Decidualization in the Menstruating Mouse Model for Preclinical Endometriosis Research.

BACKGROUND: To induce endometrial decidualization in rodents, an intrauterine oil stimulus can be delivered via the nontraumatic vagina or via the traumatic laparotomy. However, there is considerable variation in amount of decidualization using these inducing methods. Therefore, we studied which oil delivery route could achieve the highest rate of endometrial decidualization along the full length of both uterine horns. METHODS: To induce decidualization, ovariectomized C57Bl/6J mice were injected with estrogen (100 ng/day; 3 days). A progesterone pellet (5 mg) was implanted subcutaneously, followed by estrogen injections (5 ng/day; 3 days). Oil (20 µL/horn) was injected in the uterus via laparotomy, laparoscopy, or vagina. Four days later, the pellet was removed, followed by hysterectomy after 4 to 6 hours. Endometrial decidualization was evaluated macroscopically and microscopically using hematoxylin and eosin and desmin staining. Furthermore, uterine weight and hormone levels were measured. RESULTS: The proportion of animals with macroscopic bicornuate decidualization was higher after laparoscopic (83%) and laparotomic (89%) injection than after sham injection (11%). Furthermore, macroscopic bicornuate decidualization was significantly higher after laparotomic injection (89%) compared to the vaginal injection (38%). Uterine weight and endometrial surface area were significantly higher in both laparotomy and laparoscopy groups compared to the sham group, while the relative desmin-positive endometrial surface area was only significantly different between the laparotomy and the sham animals. CONCLUSION: Methods using laparoscopic and laparotomic intrauterine oil injection resulted in a higher amount of decidualized endometrium compared to sham injection, although further optimization is needed to reach full bicornuate decidualization.

Of Mice and Women: A Laparoscopic Mouse Model for Endometriosis.

STUDY OBJECTIVE: To demonstrate how a novel laparoscopic approach allows the development of a mouse model for endometriosis after seeding menstrual endometrium from donor mice into the abdominal cavity of syngeneic recipient mice. DESIGN: A step-by-step video description of the techniques used to adapt the estrous cycle of mice towards a menstrual cycle and to subsequently induce endometriosis via laparoscopic seeding of menstrual endometrium. SETTING: University research institute. ETHICS: All animal experiments were ethically approved by KU Leuven, Belgium (ethical approval number: P031/2013). INTERVENTIONS, MEASUREMENTS, AND MAIN RESULTS: Oophorectomized female C57BL/6JRj mice received a series of estrogen injections. Next, a progesterone pellet was administered, together with a second series of estrogen injections. In addition, decidualization of the endometrium was induced with an intrauterine sesame oil stimulus. Four days later the progesterone pellet was removed and menstruation started [1]. Five hours after the progesterone pellet was removal the uterus was harvested, and the menstrual endometrium was dissected and seeded into the abdominal cavity of syngeneic recipient mice to induce endometriosis [2] using a laparoscopic approach [3]. Uterus and lesions were removed from the recipient mice 1 week after induction, and tissues were immunohistochemically stained for H&E, vimentin, and cytokeratin. CONCLUSION: In this video we show a novel methodology to induce endometriosis in mice using laparoscopic inoculation of syngeneic menstrual endometrium, mimicking Sampson's theory of retrograde menstruation [4]. Compared with currently available rodent models, our model offers a less invasive and more physiologic way for fundamental and preclinical endometriosis research, with a high endometriosis incidence and lesion take rate.

Anti-adhesion therapy following operative hysteroscopy for treatment of female subfertility.

BACKGROUND: Observational evidence suggests a potential benefit with several anti-adhesion therapies in women undergoing operative hysteroscopy (e.g. insertion of an intrauterine device or balloon, hormonal treatment, barrier gels or human amniotic membrane grafting) for decreasing intrauterine adhesions (IUAs). OBJECTIVES: To assess the effectiveness of anti-adhesion therapies versus placebo, no treatment or any other anti-adhesion therapy, following operative hysteroscopy for treatment of female subfertility. SEARCH METHODS: We searched the following databases from inception to June 2017: the Cochrane Gynaecology and Fertility Group Specialised Register; the Cochrane Central Register of Studies (CRSO); MEDLINE; Embase; CINAHL and other electronic sources of trials, including trial registers, sources of unpublished literature and reference lists. We handsearched the Journal of Minimally Invasive Gynecology, and we contacted experts in the field. We also searched reference lists of appropriate papers. SELECTION CRITERIA: Randomised controlled trials (RCTs) of anti-adhesion therapies versus placebo, no treatment or any other anti-adhesion therapy following operative hysteroscopy in subfertile women. The primary outcome was live birth. Secondary outcomes were clinical pregnancy, miscarriage and IUAs present at second-look hysteroscopy, along with mean adhesion scores and severity of IUAs. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, extracted data and evaluated quality of evidence using the GRADE method. MAIN RESULTS: The overall quality of the evidence was low to very low. The main limitations were serious risk of bias related to blinding of participants and personnel, indirectness and imprecision. We identified 16 RCTs comparing a device versus no treatment (two studies; 90 women), hormonal treatment versus no treatment or placebo (two studies; 136 women), device combined with hormonal treatment versus no treatment (one study; 20 women), barrier gel versus no treatment (five studies; 464 women), device with graft versus device without graft (three studies; 190 women), one type of device versus another device (one study; 201 women), gel combined with hormonal treatment and antibiotics versus hormonal treatment with antibiotics (one study; 52 women) and device combined with gel versus device (one study; 120 women). The total number of participants was 1273, but data on 1133 women were available for analysis. Only two of 16 studies included 100% infertile women; in all other studies, the proportion was variable or unknown.No study reported live birth, but some (five studies) reported outcomes that were used as surrogate outcomes for live birth (term delivery or ongoing pregnancy). Anti-adhesion therapy versus placebo or no treatment following operative hysteroscopy.There was insufficient evidence to determine whether there was a difference between the use of a device or hormonal treatment compared to no treatment or placebo with respect to term delivery or ongoing pregnancy rates (odds ratio (OR) 0.94, 95% confidence interval (CI) 0.42 to 2.12; 107 women; 2 studies; I² = 0%; very-low-quality evidence).There were fewer IUAs at second-look hysteroscopy using a device with or without hormonal treatment or hormonal treatment or barrier gels compared with no treatment or placebo (OR 0.35, 95% CI 0.21 to 0.60; 560 women; 8 studies; I² = 0%; low-quality evidence). The number needed to treat for an additional beneficial outcome (NNTB) was 9 (95% CI 5 to 17). Comparisons of different anti-adhesion therapies following operative hysteroscopyIt was unclear whether there was a difference between the use of a device combined with graft versus device only for the outcome of ongoing pregnancy (OR 1.48, 95% CI 0.57 to 3.83; 180 women; 3 studies; I² = 0%; low-quality evidence). There were fewer IUAs at second-look hysteroscopy using a device with or without graft/gel or gel combined with hormonal treatment and antibiotics compared with using a device only or hormonal treatment combined with antibiotics, but the findings of this meta-analysis were affected by evidence quality (OR 0.55, 95% CI 0.36 to 0.83; 451 women; 5 studies; I² = 0%; low-quality evidence). AUTHORS' CONCLUSIONS: Implications for clinical practiceThe quality of the evidence ranged from very low to low. The effectiveness of anti-adhesion treatment for improving key reproductive outcomes or for decreasing IUAs following operative hysteroscopy in subfertile women remains uncertain. Implications for researchMore research is needed to assess the comparative safety and (cost-)effectiveness of different anti-adhesion treatments compared to no treatment or other interventions for improving key reproductive outcomes in subfertile women.

Effect of simvastatin on baboon endometriosis.

Endometriosis, a common disorder affecting women of reproductive age, is characterized by ectopic growth of the endometrial tissues, altered steroid hormone response, and inflammation. Previous studies revealed that statins, selective inhibitors of the key step of mevalonate pathway, inhibit growth of endometrial stromal cells in vitro and reduce endometriotic lesions in murine models of endometriosis. This study evaluated the effects of simvastatin on the development of endometriosis in a baboon model of this disease. Sixteen baboons were randomly assigned to the treatment group (simvastatin, 20 mg daily) or to the control group. Endometriotic lesions were evaluated by laparoscopy after 3 months. The volume of red, orange-red, and white endometriotic lesions was significantly reduced by 78% in animals treated with simvastatin. The expression of a marker of proliferation, proliferating cell nuclear antigen (PCNA), was significantly reduced in animals receiving simvastatin in red lesions, white lesions, black lesions, and in adhesions. Simvastatin was also associated with an increase in the expression of estrogen receptor alpha in red lesions, and a decrease in the expression of estrogen receptor beta in black lesions, in adhesions, and in eutopic endometrium. Furthermore, simvastatin significantly reduced the expression of neopterin, a marker of inflammation, oxidative stress, and immune system activation. Collectively, the present findings indicate that the inhibition of the mevalonate pathway by simvastatin reduces the risk of developing endometriosis in the primate model of this disease by decreasing the growth of endometrial lesions, by modulating the expression of genes encoding for estrogen receptors, and by reducing inflammation.

Endometriosis is associated with aberrant metabolite profiles in plasma.

OBJECTIVE: To identify metabolites that are associated with and predict the presence of endometriosis. DESIGN: Metabolomics study using state-of-the-art mass spectrometry approaches. SETTING: University hospital and universities. PATIENT(S): Twenty-five women with laparoscopically confirmed endometriosis (cases) and 19 women with laparoscopically documented absence of endometriosis (controls). None of the women included in this study had received oral contraception or GnRH agonists for a minimum of 1 month before blood collection. INTERVENTION(S): Plasma collection. MAIN OUTCOME MEASURE(S): Metabolite profiles were generated and interrogated using multiple mass spectrometry methods, that is, high performance liquid chromatography coupled with negative mode electrospray ionization tandem mass spectrometry, UPLC-MS/MS, and ultra performance liquid chromatography-electroSpray ionization-quadrupole time-of-flight (UPLC-ESI-Q-TOF). Metabolite groups investigated included phospholipids, glycerophospholipids, ether-phospholipids, cholesterol-esters, triacylglycerol, sphingolipids, free fatty acids, steroids, eicosanoids, and acylcarnitines. RESULT(S): A panel of acylcarnitines predicted the presence of endometriosis with 88.9% specificity and 81.5% sensitivity in human plasma, with a positive predictive value of 75%. However, due to data limitations the outcome of the receiver operating characteristic curve analysis was not significant. CONCLUSION(S): A diagnostic model based on acylcarnitines has the potential to predict the presence and stage of endometriosis.

The Presence of Endometrial Cells in Peritoneal Fluid of Women With and Without Endometriosis.

To reinforce Sampson's theory of retrograde menstruation in the pathogenesis of endometriosis, proof should be provided that during menstruation endometrial cells are present in peritoneal fluid (PF). We hypothesize that the prevalence of PF samples containing endometrial cells is higher in patients with endometriosis than in controls without endometriosis during menstruation. We selected from our biobank PF samples of 17 reproductive-age women with (n = 9) or without (n = 8) endometriosis who had received a diagnostic laparoscopy for investigation of pain/infertility. Peritoneal fluid had been collected during laparoscopy in the menstrual phase of the cycle, centrifuged, and the resulting pellet was stored at -80°C. About 5-µm sections of frozen PF pellets were stained using the Dako Envision Flex system with primary antibodies against epithelial cell adhesion molecule (Ep-CAM; endometrial epithelial cells), CD10 (endometrial stromal cells), prekeratin (epithelial/mesothelial cells), vimentin (endometrial/mesothelial/immune cells), calretinin (mesothelial cells), and CD68 (macrophages). The PF cells positive for Ep-CAM were detected in 5 of 9 patients with endometriosis and 6 of 8 controls ( P = .62). CD10 stained positively in 6 of the 9 patients with endometriosis and 3 of the 8 controls ( P = .35). Calretinin and prekeratin staining showed the presence of mesothelial cells in all pellets. Vimentin stained approximately 100% of the PF cells. CD68+ macrophages represented >50% of cells in all pellets. The prevalence of PF samples containing endometrial epithelial and stromal cells was not higher in patients with endometriosis than in controls without endometriosis during menstruation. Our findings question the relevance of endometrial cells in PF for the pathogenesis of endometriosis and support the importance of other mechanisms such as immune dysfunction and/or endometrial stem cells.

Laparoscopic Surgery: A New Technique to Induce Endometriosis in a Mouse Model.

BACKGROUND: This prospective pilot study was designed to induce endometriosis in a mouse model using laparoscopy, a less invasive and more precise approach than laparotomy. We aimed to achieve a peritoneal implant rate of at least 50% by varying both duration of anesthesia and intra-abdominal insufflation pressure. METHODS: Female BALB/cANnCrl mice in metestrus or diestrus were used as donors (n = 5) or recipients (n = 20) of uterine transplant tissue. Each recipient mouse was laparoscopically inoculated with 10 uterine pieces (range: 10-12) from donor mice into the abdominal cavity. Before starting the study, recipient mice were randomly assigned to 4 groups with variable duration of anesthesia (ketamine/xylazine or pentobarbital) and variable intra-abdominal pressure (5 or 15 mm Hg). One week after laparoscopy, endometriosis incidence and peritoneal implant take rate were documented visually during laparotomy. The retrieved lesions were histologically analyzed. RESULTS: Laparoscopic inoculation of uterine pieces in recipient mice resulted in an endometriosis incidence of 100% (20/20 animals) and an individual peritoneal implant take rate of 60% (121/206), ranging from 17% (2/12) till 83% (10/12), without differences between the 4 subgroups, and with a histological confirmation rate of 92% (58/63). CONCLUSIONS: To the best our knowledge, this is the first report showing that endometriosis can be induced by laparoscopic surgery in rodents, with a 100% incidence and a median peritoneal implant take rate of 60%. This laparoscopic model offers important advantages over traditional laparotomy models that are limited by surgery-associated trauma and/or adhesion formation.

c-Jun NH2-terminal kinase inhibitor bentamapimod reduces induced endometriosis in baboons: an assessor-blind placebo-controlled randomized study.

OBJECTIVE: To test the hypothesis that the c-Jun NH2-terminal kinase (JNK) inhibitor (JNKI) bentamapimod (AS602801/PGL5001) can reduce induced endometriosis in baboons. DESIGN: Prospective randomized placebo-controlled study. SETTING: Nonhuman primate research center. ANIMAL(S): Twenty baboons each underwent four laparoscopies. Initial screening laparoscopy (L1) was followed after one rest cycle by an endometriosis-induction laparoscopy (L2). Fifty days after L2, the baboons were randomized just before staging laparoscopy (L3). Treatment lasted for 60 days, followed by a post-treatment staging laparoscopy (L4). INTERVENTION(S): Randomization before a 60-day treatment in four groups: daily placebo (n = 5), daily oral administration of 20 mg/kg JNKI (n = 5), concomitant daily oral administration of 20 mg/kg JNKI and 10 mg medroxyprogesterone acetate (MPA; n = 5), or subcutaneous administration of 3 mg cetrorelix every 3 days (n = 5). MAIN OUTCOME MEASURE(S): Type, surface area and volume of endometriotic lesions, and revised American Society for Reproductive Medicine score and stage were recorded during L3 and L4. Menstrual cycle length and serum hormonal concentration were recorded before and after treatment. RESULT(S): Compared with placebo, treatment with JNKI, JNKI + PMA, or cetrorelix resulted in lower total surface area and volume of endometriotic lesions. Remodeling of red active lesions into white lesions was observed more frequently in baboons treated with JNKI + MPA than in baboons treated with JNKI only. Menstrual cycle length and serum hormonal concentration were similar between placebo and JNKI groups. CONCLUSION(S): JNKI alone was as effective as JNKI + MPA or cetrorelix in reducing induced endometriosis in baboons, but without severe side effects or effect on cycle length or serum reproductive hormones.

Anti-adhesion therapy following operative hysteroscopy for treatment of female subfertility.

BACKGROUND: Limited observational evidence suggests potential benefit for subfertile women undergoing operative hysteroscopy with several anti-adhesion therapies (e.g. insertion of an intrauterine device (IUD) or balloon, hormonal treatment, barrier gels or human amniotic membrane grafting) to decrease intrauterine adhesions (IUAs). OBJECTIVES: To assess the effectiveness of anti-adhesion therapies versus placebo, no treatment or any other anti-adhesion therapy following operative hysteroscopy for treatment of female subfertility. SEARCH METHODS: We searched the following databases from inception to March 2015: the Cochrane Menstrual Disorders and Subfertility Specialised Register, the Cochrane Central Register of Controlled Trials (2015, Issue 2), MEDLINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and other electronic sources of trials, including trial registers, sources of unpublished literature and reference lists. We handsearched The Journal of Minimally Invasive Gynecology, and we contacted experts in the field. SELECTION CRITERIA: Randomised comparisons of anti-adhesion therapies versus placebo, no treatment or any other anti-adhesion therapy following operative hysteroscopy in subfertile women. The primary outcome was live birth or ongoing pregnancy. Secondary outcomes were clinical pregnancy, miscarriage and IUAs present at second look, along with their mean adhesion scores or severity. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, extracted data and evaluated quality of the evidence using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) method. MAIN RESULTS: We included 11 randomised studies on use of an inserted device versus no treatment (two studies; 84 women) or another inserted device (one study; 162 women), hormonal treatment versus no treatment or placebo (two studies; 131 women), gel versus no treatment (five studies; 383 women) and graft versus no graft (one study; 43 women). The total number of women randomly assigned was 924, but data on only 803 participants were available for analysis. The proportion of subfertile women varied from 0% (one study; 41 women), to less than 50% (six studies; 487 women), to 100% (one study; 43 women); the proportion was unknown in three studies (232 women). Most studies (9/11) were at high risk of bias with respect to one or more methodological criteria.We found no evidence of differences between anti-adhesion therapy and no treatment or placebo with respect to live birth rates (odds ratio (OR) 0.99, 95% confidence interval (CI) 0.46 to 2.13, P value = 0.98, three studies, 150 women; low-quality evidence) and no statistical heterogeneity (Chi(2) = 0.14, df = 2 (P value = 0.93), I(2) = 0%).Anti-adhesion therapy was associated with fewer IUAs at any second-look hysteroscopy when compared with no treatment or placebo (OR 0.36, 95% CI 0.20 to 0.64, P value = 0.0005, seven studies, 528 women; very low-quality evidence). We found no statistical heterogeneity (Chi(2) = 2.65, df = 5 (P value = 0.75), I(2) = 0%). The number needed to treat for an additional beneficial outcome (NNTB) was 9 (95% CI 6 to 20).No evidence suggested differences between an IUD and an intrauterine balloon with respect to IUAs at second-look hysteroscopy (OR 1.23, 95% CI 0.64 to 2.37, P value = 0.54, one study, 162 women; very low-quality evidence). AUTHORS' CONCLUSIONS: Implications for clinical practiceThe quality of the evidence retrieved was low or very low for all outcomes. Clinical effectiveness of anti-adhesion treatment for improving key reproductive outcomes or for decreasing IUAs following operative hysteroscopy in subfertile women remains uncertain. Implications for researchAdditional studies are needed to assess the effectiveness of different anti-adhesion therapies for improving reproductive outcomes in subfertile women treated by operative hysteroscopy.

Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities.

BACKGROUND: Observational studies suggest higher pregnancy rates after the hysteroscopic removal of endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions, which are detectable in 10% to 15% of women seeking treatment for subfertility. OBJECTIVES: To assess the effects of the hysteroscopic removal of endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions suspected on ultrasound, hysterosalpingography, diagnostic hysteroscopy or any combination of these methods in women with otherwise unexplained subfertility or prior to intrauterine insemination (IUI), in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Specialised Register (8 September 2014), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2014, Issue 9), MEDLINE (1950 to 12 October 2014), EMBASE (inception to 12 October 2014), CINAHL (inception to 11 October 2014) and other electronic sources of trials including trial registers, sources of unpublished literature and reference lists. We handsearched the American Society for Reproductive Medicine (ASRM) conference abstracts and proceedings (from January 2013 to October 2014) and we contacted experts in the field. SELECTION CRITERIA: Randomised comparisons between operative hysteroscopy versus control in women with otherwise unexplained subfertility or undergoing IUI, IVF or ICSI and suspected major uterine cavity abnormalities diagnosed by ultrasonography, saline infusion/gel instillation sonography, hysterosalpingography, diagnostic hysteroscopy or any combination of these methods. Primary outcomes were live birth and hysteroscopy complications. Secondary outcomes were pregnancy and miscarriage. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and risk of bias, and extracted data. We contacted study authors for additional information. MAIN RESULTS: We retrieved 12 randomised trials possibly addressing the research questions. Only two studies (309 women) met the inclusion criteria. Neither reported the primary outcomes of live birth or procedure related complications. In women with otherwise unexplained subfertility and submucous fibroids there was no conclusive evidence of a difference between the intervention group treated with hysteroscopic myomectomy and the control group having regular fertility-oriented intercourse during 12 months for the outcome of clinical pregnancy. A large clinical benefit with hysteroscopic myomectomy cannot be excluded: if 21% of women with fibroids achieve a clinical pregnancy having timed intercourse only, the evidence suggests that 39% of women (95% CI 21% to 58%) will achieve a successful outcome following the hysteroscopic removal of the fibroids (odds ratio (OR) 2.44, 95% confidence interval (CI) 0.97 to 6.17, P = 0.06, 94 women, very low quality evidence). There is no evidence of a difference between the comparison groups for the outcome of miscarriage (OR 0.58, 95% CI 0.12 to 2.85, P = 0.50, 30 clinical pregnancies in 94 women, very low quality evidence). The hysteroscopic removal of polyps prior to IUI can increase the chance of a clinical pregnancy compared to simple diagnostic hysteroscopy and polyp biopsy: if 28% of women achieve a clinical pregnancy with a simple diagnostic hysteroscopy, the evidence suggests that 63% of women (95% CI 50% to 76%) will achieve a clinical pregnancy after the hysteroscopic removal of the endometrial polyps (OR 4.41, 95% CI 2.45 to 7.96, P < 0.00001, 204 women, moderate quality evidence). AUTHORS' CONCLUSIONS: A large benefit with the hysteroscopic removal of submucous fibroids for improving the chance of clinical pregnancy in women with otherwise unexplained subfertility cannot be excluded. The hysteroscopic removal of endometrial polyps suspected on ultrasound in women prior to IUI may increase the clinical pregnancy rate. More randomised studies are needed to substantiate the effectiveness of the hysteroscopic removal of suspected endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions in women with unexplained subfertility or prior to IUI, IVF or ICSI.

Treating suspected uterine cavity abnormalities by hysteroscopy to improve reproductive outcome in women with unexplained infertility or prior to IUI, IVF, or ICSI.

Endometrial polyps, submucous fibroids, uterine septa, and intrauterine adhesions can be found by ultrasound (US), HSG, hysteroscopy, or any combined in 10-15 % of infertile women. Observational studies suggest a better reproductive outcome when these anomalies are removed by operative hysteroscopy. The current Cochrane review assesses the effectiveness of hysteroscopy for treating these suspected anomalies in women with otherwise unexplained infertility or prior to intrauterine insemination, in vitro fertilization, or intracytoplasmic sperm injection.

Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities.

BACKGROUND: Observational studies suggest higher pregnancy rates after the hysteroscopic removal of endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions, which are detectable in 10% to 15% of women seeking treatment for subfertility. OBJECTIVES: To assess the effects of the hysteroscopic removal of endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions suspected on ultrasound, hysterosalpingography, diagnostic hysteroscopy or any combination of these methods in women with otherwise unexplained subfertility or prior to intrauterine insemination (IUI), in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Specialised Register (6 August 2012), the Cochrane Central Register of Controlled Trials (T he Cochrane Library 2012, Issue 7), MEDLINE (1950 to October 2012), EMBASE (1974 to October 2012), CINAHL (from inception to October 2012) and other electronic sources of trials including trial registers, sources of unpublished literature and reference lists. We handsearched the American Society for Reproductive Medicine (ASRM) conference abstracts and proceedings (from January 2008 to October 2012) and we contacted experts in the field. SELECTION CRITERIA: Randomised comparisons between operative hysteroscopy versus control in women with otherwise unexplained subfertility or undergoing IUI, IVF or ICSI and suspected major uterine cavity abnormalities diagnosed by ultrasonography, saline infusion/gel instillation sonography, hysterosalpingography, diagnostic hysteroscopy or any combination of these methods. Primary outcomes were live birth and hysteroscopy complications. Secondary outcomes were pregnancy and miscarriage. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for inclusion and risk of bias, and extracted data. We contacted study authors for additional information. MAIN RESULTS: Two studies met the inclusion criteria and neither reported the primary outcomes of live birth and complications from the procedure. In women with otherwise unexplained subfertility and submucous fibroids, there is no evidence of benefit with hysteroscopic myomectomy compared to regular fertility-oriented intercourse during 12 months for clinical pregnancy (odds ratio (OR) 2.4, 95% confidence interval (CI) 0.97 to 6.2, P = 0.06, 94 women) and miscarriage (OR 1.5, 95% CI 0.47 to 5.0, P = 0.47, 94 women) (very low-quality evidence). The hysteroscopic removal of polyps prior to IUI increases the odds of clinical pregnancy (experimental event rate (EER) 63%) compared to diagnostic hysteroscopy and polyp biopsy only (control event rate (CER) 28%) (OR 4.4, 95% CI 2.5 to 8.0, P < 0.00001, 204 women, high-quality evidence). AUTHORS' CONCLUSIONS: Hysteroscopic myomectomy might increase the odds of clinical pregnancy in women with unexplained subfertility and submucous fibroids, but the evidence is at present not conclusive. The hysteroscopic removal of endometrial polyps suspected on ultrasound in women prior to IUI might increase the clinical pregnancy rate. More randomised studies are needed to substantiate the effectiveness of the hysteroscopic removal of suspected endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions in women with unexplained subfertility or prior to IUI, IVF or ICSI.

Baboon spermatology: basic assessment and reproducibility in olive baboons (Papio anubis).

BACKGROUND: Development of a reproducible baboon in vitro fertilization (IVF) system require optimized and reproducible sperm parameters. The objective of this study was to document basic spermatology values and investigate the reproducibility of these variables in the same baboons 1 or 3 months later in a larger number of baboons. METHODS: In this prospective study, sperm quality (semen volume, pH, concentration, motility, morphology and size) was evaluated in 27 sperm samples obtained from 9 baboons electroejaculated three times with a time interval of 1 month (between first and second sample collection) and 3 months (between second and third round sample collection). RESULTS: Baseline sperm values for semen volume (0.5 ± 0.3 ml), pH (7.5 ± 0.3), concentration (54.2 ± 19.3 million/ml), motility (67.3 ± 18.5%) and morphology (89.2 ± 4.8%) were similar to sperm samples obtained after 1 or 3 months (P > 0.05). Head, midpiece and tail abnormalities were rarely observed (0-9%). Sperm dimensions were characterized by a tail length of 69.6 ± 13.9 µm, a head width of 2.41 ± 0.43 µm and a head length of 3.49 ± 0.6 µm. CONCLUSION: Sperm quality was not affected by repeated electroejaculation with time intervals of 1 or 3 months, suggesting that the same baboon can participate multiple times in reproductive research.

Analysis of common variations in tumor-suppressor genes on chr1p36 among Caucasian women with endometriosis.

OBJECTIVE: Epidemiological data indicate that endometriosis increases the risk of epithelial ovarian cancer (EOC), but the mechanism of cancer transition is unknown. Results from genome-wide association studies (GWAS) and transcriptome sequencing have demonstrated that genes located in the 1p36 region are important in both endometriosis and endometriosis-associated cancer development. Therefore, we tested the hypothesis that SNPs in two tumor-suppressor genes (CHD5 and ARID1A) in the 1p36 region are associated with endometriosis. METHODS: Allele frequencies of SNPs were investigated in 1685 Caucasian women consisting of 947 women with endometriosis and 738 controls. Peripheral blood samples were retrieved, DNA extracted and allelic frequencies of SNPs in two tumor-suppressor genes (CHD5 and ARID1A) were analyzed using TaqMan Open Array technique. RESULTS: Associations were observed for 3 SNPs in the CHD5 gene: rs1883603 (OR 1.31, 95% CI 1.00-1.71), rs9434741 (OR 1.41, 95% CI 1.16-1.71) and rs17436816 (OR 1.24, 95% CI 1.02-1.50). After correction for multiple comparisons, rs9434741 (CHD5) remained significantly associated with endometriosis (p<0.01). No associations were detected for ARID1A. CONCLUSIONS: In this Caucasian population, endometriosis seems to be associated with the tumor-suppressor gene CHD5. Our findings support recent data, suggesting that the 1p36 region plays an important role in endometrios. To validate these data, replication in an independent population is warranted.

Clinical outcome after laparoscopic radical excision of endometriosis and laparoscopic segmental bowel resection.

PURPOSE OF REVIEW: To present the clinical outcome after laparoscopic radical excision of deeply infiltrative endometriosis (DIE) with colorectal extension and laparoscopic segmental bowel resection. RECENT FINDINGS: In three different studies including mostly patients with recurrent DIE with colorectal extension, we showed that radical reconstructive CO2 laser laparoscopic resection of DIE with colorectal extension in a multidisciplinary setting resulted in a low complication rate, a low cumulative reintervention and recurrence rate and a high cumulative pregnancy rate, also when bowel resection reanastomosis was performed. In a systematic review to assess the clinical outcome of surgical treatment of DIE with colorectal involvement, data were reported in such a way that comparison of different surgical techniques was not possible. A checklist is proposed to achieve standardized reporting of presenting symptoms, preoperative tests, inclusion criteria, preoperative and postoperative care, complications, follow-up, patient-centered assessment of pain and quality of life, fertility and recurrence corrected for postoperative use of hormonal suppression or infertility treatment. SUMMARY: CO2 laser laparoscopic radical excision of DIE with colorectal extension and laparoscopic segmental bowel resection in centers of expertise is associated with good clinical outcome. To make real progress, international agreement is needed on terms and definitions used in surgical endometriosis research.

Randomized comparison of different ovarian stimulation regimens for assisted reproductive technology in baboons (Papio anubis).

OBJECTIVE: To compare different methods of ovarian stimulation (OS) for assisted reproductive technology in baboons. DESIGN: Prospective randomized study. SETTING: Institute of primate research. ANIMAL(S): Baboons (n = 10) were randomized into two groups (of five animals each) during three different cycles to compare six protocols of OS. INTERVENTION(S): Cycle 1: clomiphene citrate (CC) alone (group CC) versus CC and GnRH agonist (group CC-Ag); cycle 2: recombinant gonadotropins (GON) without GnRH agonist (group GON) versus GON and depot GnRH agonist (group GON-AgDepo-1); cycle 3: GON and depot GnRH agonist (group GON-AgDepo-2) versus GON and daily GnRH agonist in a classic long protocol (group GON-Ag). Oocyte aspiration was performed 34-36 hours after injecting 5,000 IU rhCG, followed by fertilization via intracytoplasmic sperm injection (ICSI). MAIN OUTCOME MEASURE(S): Number and quality of oocytes retrieved and their fertilization rate. RESULT(S): More metaphase II (MII) oocytes were retrieved using the GON-AgDepo-1 (n = 12; 64% MII), GON-AgDepo-2 (n = 9; 79% MII), GON-Ag (n = 16; 88% MII), and GON (n = 6; 59% MII) protocols compared with the CC (n = 9; 15% MII) and CC-Ag (n = 14; 20% MII) protocols. Fertilization by ICSI varied between 43% and 71%. CONCLUSION(S): In baboons, long and depot protocols yield similar numbers of MII oocytes; however, depot protocol may be preferable because only one injection of GnRH agonist is needed.