Assessing ovarian stimulation with letrozole and levonorgestrel intrauterine system after combined fertility-sparing approach for atypical endometrial lesions: a retrospective case-control study.

RESEARCH QUESTION: Is ovarian stimulation with levonorgestrel intrauterine system (LNG-IUS) in situ and co-treatment with letrozole safe and effective in patients undergoing fertility-sparing combined treatment for atypical endometrial hyperplasia (AEH) or early endometrial cancer limited to the endometrium? DESIGN: Retrospective case-control study recruiting women who had undergone fertility-sparing 'combined' treatment and ovarian stimulation with letrozole and LNG-IUS in situ. The 'three steps' hysteroscopic technique was used. Once complete response was achieved, the ovaries were stimulated, and mature oocytes cryopreserved. The LNG-IUS was removed, and embryos transferred. A comparative analysis was conducted between the two control groups of the initial outcomes of ART (number of oocytes and MII oocytes retrieved): healthy infertile women undergoing ovarian stimulation for IVF/ICSI (control group A); and patients diagnosed with breast cancer who underwent ovarian stimulation with letrozole (control group B). RESULTS: Of the 75 patients analysed, 15 underwent oocyte cryopreservation after achieving a complete response to fertility-sparing treatment (study group); 30 patients in control group A and B, respectively. No statistically significant differences were observed in retrieved oocytes and mature oocytes between the study and control groups. In the nine patients who underwent embryo transfer, clinical pregnancy (55.6%), cumulative live birth (44.4%) and miscarriage (20%) rates were reported. In three patients with AEH, recurrence occurred (12%) at 3, 6 and 16 months after removing the LNG-IUS to attempt embryo transfer, respectively. CONCLUSION: Fertility-sparing hysteroscopic combined treatment and subsequent ovarian stimulation with letrozole and LNG-IUS in situ could be suggested to women with AEH or early endometrial cancer who ask for future fertility preservation.

"RAIL BIOPSY" A Novel and Useful Technique for Hysteroscopic Endometrial Target Biopsy.

STUDY OBJECTIVE: Endometrial biopsy (EB) is one of the most common gynecologic procedures. Office-based EB has replaced procedures involving general/loco-regional anesthesia and cervical dilatation performed in the operating room [1-3]. The Grasp Biopsy seems to be the most appropriate EB technique for reproductive-aged women [1,2,4]. Recently, the Visual D&C performed with hysteroscopic tissue removal devices has shown to be a valid alternative [5]. However, it is often difficult to obtain an adequate specimens in peri/post-menopausal women with hypo/atrophic endometrium [2]. Our aim is to show a novel hysteroscopic EB technique called "Rail Biopsy" which requires widespread and cheap instruments. DESIGN: A step-by-step explanation of surgical techinque with narrated video footage. SETTING: Tertiary Level Academic Hospital "IRCCS Azienda Ospedaliero-Universitaria di Bologna" Bologna, Italy. INTERVENTIONS: We performed the "Rail Biopsy" technique with a 5.0 mm Continuous Flow Operative Hysteroscope with a 30° Lens and a 5Fr operative channel. We identify the endometrial target area (ETA), and we create a first track cutting through the endometrium in a caudo-cranial direction using cold scissors. We repeat the procedure, creating a second parallel track, thus completing our "rail" and isolating a wide ETA. Then, in the caudo-cranial direction, we cut through the stromal layer beneath the ETA. With a 5Fr cold grasping forceps, we clench the cranial edge of the ETA, and we remove it from the uterine cavity. A high-quality specimen, even in the case of hypo/atrophic endometrium or focal sessile lesions, can be obtained with this technique. The crucial aspect of the "Rail Biopsy" indeed is cutting through the stromal tissue while the endometrium is minimally touched, avoiding thermal damage deriving from electrosurgery. The instruments required are widespread and cheap. Moreover, this technique can be performed on any wall of the uterus, under vision, and, in the majority of patients, in an office-setting without cervical dilatation or general/loco-regional anesthesia, making it an attractive alternative to hysteroscopy performed in the operating room setting. Further studies comparing "Rail Biopsy" to other EB techniques are needed. CONCLUSION: We showed a novel approach for hysteroscopic EB that may be particularly useful in patients with hypo/atrophic endometrium, easy to learn and with low costs. VIDEO ABSTRACT.

Uterine Tumors Resembling Ovarian Sex Cord Tumors (UTROSCTs): A Scoping Review of 511 Cases, Including 2 New Cases.

Uterine Tumors Resembling Ovarian Sex Cord Tumors (UTROSCTs) are rare uterine mesenchymal neoplasms with uncertain biological potential. These tumors, which affect both premenopausal and postmenopausal women, usually have a benign clinical course. Nevertheless, local recurrences and distant metastases have been described. By analyzing 511 cases retrieved from individual reports and cases series, we provide here the most comprehensive overview of UTROSCT cases available in the literature, supplemented by two new cases of UTROSCTs. Case 1 was an asymptomatic 31-year-old woman who underwent a laparoscopic resection of a presumed leiomyoma. Case 2 was a 58-year-old postmenopausal woman with abnormal vaginal bleeding who underwent an outpatient hysteroscopic biopsy of a suspicious endometrial area. In both cases, immunohistochemical positivity for Calretinin and Inhibin was noted, typical for a sex cord differentiation. In both cases, total laparoscopic hysterectomy with bilateral salpingo-oophorectomy was performed. In light of the available literature, no pathognomonic clinical or imaging finding can be attributed to UTROSCT. Patients usually present with abnormal uterine bleeding or pelvic discomfort, but 20% of them are asymptomatic. In most cases, a simple hysterectomy appears to be the appropriate treatment, but for women who wish to become pregnant, uterus-preserving approaches should be discussed after excluding risk factors. Age, tumor size, lymphovascular space invasion, nuclear atypia, and cervical involvement are not reliable prognostic factors in UTROSCT. The current research suggests that aggressive cases (with extrauterine spread or recurrence) can be identified based on a distinct genetic and immunohistochemical phenotype. For instance, UTROSCTs characterized by GREB1::NCOA1-3 fusions and PD-L1 molecule expression appear to be predisposed to more aggressive behaviors and recurrence, with GREB1::NCOA2 being the most common gene fusion in recurrent tumors. Hence, redefining the criteria for UTROSCTs may allow a better selection of women suitable for fertility-sparing treatments or requiring more aggressive treatments in the future.

Hysteroscopy and weight loss in treatment of endometrial cancer: case report and literature review.

Fertility-sparing treatments have become important for young women with atypical endometrial hyperplasia (AEH) or endometrial carcinoma (EC) who wish to preserve their reproductive potential. Evidence indicates a strong relationship between weight and EC and the effect of weight loss on reducing the risk of EC. We report the case of a young obese woman with a body mass index (BMI) of 46.6 kg/m2, diagnosed with grade 2 endometrial endometrioid adenocarcinoma, who underwent a combined fertility-sparing treatment with hysteroscopic resection followed by insertion of a levonorgestrel intrauterine system. After twelve months of failure to achieve a complete response, bariatric surgery was proposed to lose weight and improve the response to treatment. Histologic regression was achieved three months after surgery, with a weight loss of 30 kg and fifteen months after combined treatment of endometrial cancer. We reviewed the literature to summarize the evidence on the role of bariatric surgery and weight loss in modifying the oncologic and reproductive outcomes of women undergoing fertility-sparing treatment for atypical endometrial lesions.

Uterine contractile activity in healthy women throughout the menstrual cycle measured using a novel quantitative two-dimensional transvaginal ultrasound speckle tracking method.

RESEARCH QUESTION: To explore normal uterine contractile function across the menstrual cycle using a novel quantitative ultrasound method. DESIGN: This multicentre prospective observational study took place in three European centres from 2014 to 2022. Uterine contraction frequency (contractions/minute), amplitude, direction (cervix-to-fundus, C2F; fundus-to-cervix; F2C), velocity and coordination were investigated. Features were extracted from transvaginal ultrasound recordings (TVUS) using speckle tracking. Premenopausal women ≥18 years of age, with normal, natural menstrual cycles were included. A normal cycle was defined as: regular (duration 28 ± 2 days), no dysmenorrhoea, no menometrorrhagia. Four-minute TVUS were performed during the menstrual phase, mid-follicular, late follicular phase, early luteal phase and/or late luteal phase. Of the 96 recordings available from 64 women, 70 were suitable for inclusion in the analysis. RESULTS: Contraction frequency (for the posterior wall) and velocity (for the anterior uterine wall in the F2C direction) were highest in the late follicular phase and lowest in the menstrual and late luteal phases (1.61 versus 1.31 and 1.35 contractions/min, P < 0.001 and 0.81 versus 0.67 and 0.62 mm/s, P < 0.001, respectively). No significant difference was found for contraction amplitude. Contraction coordination (simultaneous contraction of the anterior and posterior walls in the same direction) was least coordinated in the mid-follicular phase (P = 0.002). CONCLUSIONS: This is the first study to objectively measure uterine contraction features in healthy women during the natural menstrual cycle on TVUS. Likewise, it introduces contraction coordination as a specific feature of uterine peristalsis. Differences in uterine contractility across the menstrual cycle are confirmed, with highest activity seen in the late follicular phase, and lowest in the late luteal phase.

Hysteroscopic resection vs ultrasound-guided dilation and evacuation for treatment of cesarean scar ectopic pregnancy: a randomized clinical trial.

BACKGROUND: Cesarean scar ectopic pregnancy is a type of ectopic pregnancy in which the fertilized egg is implanted in the muscle or fibrous tissue of the scar after a previous cesarean delivery. The condition can be catastrophic if not managed on time and can lead to significant morbidity and mortality. Several approaches have been studied for the management of cesarean scar ectopic pregnancy in women who opted for termination of pregnancy with no consensus on the best treatment modality reached so far. OBJECTIVE: This study aimed to compare the success rate of hysteroscopic resection vs ultrasound-guided dilation and evacuation for the treatment of cesarean scar ectopic pregnancy. STUDY DESIGN: This was a parallel group, nonblinded, randomized clinical trial conducted at a single center in Italy. Women with singleton gestations at <8 weeks and 6 days of gestation were included in the study. Inclusion criteria were women with a cesarean scar ectopic pregnancy with positive embryonic heart activity who opted for termination of pregnancy. Patients were randomized 1:1 to receive either hysteroscopic resection (ie, intervention group) or ultrasound-guided dilation and evacuation (ie, control group). Both groups received 50 mg/m2 of methotrexate intramuscularly at the time of randomization (day 1) and another dose at day 3. A third dose of methotrexate was planned in case of persistence of positive fetal heart activity at day 5. Participants received either ultrasound-guided dilation and evacuation or hysteroscopic resection from 1 to 5 days after the last dose of methotrexate. Hysteroscopic resection was performed under spinal anesthesia using a 15 Fr bipolar mini-resectoscope. Dilation and evacuation were performed by vacuum aspiration with a Karman cannula, followed by sharp curettage, if necessary, under ultrasound guidance. The primary outcome was the success rate of the treatment protocol, defined as no further treatment required until the complete resolution of the cesarean scar ectopic pregnancy. Resolution of the cesarean scar ectopic pregnancy was evaluated based on decline of beta-hCG and the absence of residual gestational material in the endometrial cavity. Treatment failure was defined as the necessity for further treatment required until the complete resolution of the cesarean scar ectopic pregnancy. A sample size calculation indicated that 54 participants were required to test the hypothesis RESULTS: A total of 54 women were enrolled and randomized. Number of previous cesarean deliveries ranged from 1 to 3. Overall, 10 women received a third dose of methotrexate with 7 of 27 (25.9%) participants in the hysteroscopic resection group and 3 of 27 (11.1%) in the dilation and evacuation group. The success rate was 100% (27/27) in the hysteroscopic resection group and 81.5% (22/27) in the dilation and evacuation group (relative risk, 1.22; 95% confidence interval, 1.01-1.48). Additional procedures were required in 5 cases of the control group, namely 3 hysterectomies, 1 laparotomic uterine segmental resection, and 1 hysteroscopic resection. The length of stay in the hospital was 9.0±2.9 days in the intervention group and 10.0±3.5 days in the control group (mean difference, -1.00 days; 95% confidence interval, -2.71 to 0.71). No cases of admission to intensive care unit or maternal death were reported. CONCLUSION: Hysteroscopic resection was associated with an increased success rate in the treatment of cesarean scar ectopic pregnancy when compared with ultrasound-guided dilation and evacuation.

Risk of endometrial cancer in asymptomatic postmenopausal women in relation to ultrasonographic endometrial thickness: systematic review and diagnostic test accuracy meta-analysis.

OBJECTIVE: This study aimed to evaluate the risk of endometrial carcinoma and atypical endometrial hyperplasia in asymptomatic postmenopausal women concerning the endometrial thickness measured by stratified threshold categories used for performing subsequent endometrial sampling and histologic evaluation. DATA SOURCES: MEDLINE, Scopus, ClinicalTrials.gov, SciELO, Embase, the Cochrane Central Register of Controlled Trials, LILACS, conference proceedings, and international controlled trials registries were searched without temporal, geographic, or language restrictions. STUDY ELIGIBILITY CRITERIA: Studies were selected if they had a crossover design evaluating the risk of atypical endometrial hyperplasia and endometrial carcinoma in postmenopausal asymptomatic women and calculated the diagnostic accuracy of transvaginal ultrasonography thresholds (at least 3.0 mm) confirmed by histopathologic diagnosis. METHODS: This was a systematic review and diagnostic test accuracy meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy and Synthesizing Evidence from Diagnostic Accuracy Tests guidelines. Endometrial thickness thresholds were grouped as follows: from 3.0 to 5.9 mm; between 6.0 and 9.9 mm; between 10.0 and 13.9 mm; and ≥14.0 mm. Quality assessment was performed using the Quality Assessment Tool for Diagnostic Accuracy Studies 2 tool. Publication bias was quantified using the Deek funnel plot test. Coprimary outcomes were the risk of atypical endometrial hyperplasia or endometrial carcinoma according to the endometrial thickness and diagnostic accuracy of each threshold group. RESULTS: A total of 18 studies provided the data of 10,334 women who were all included in the final analysis. Overall, at an endometrial thickness threshold of at least 3.0 mm, the risk of atypical endometrial hyperplasia or endometrial carcinoma was increased 3-fold relative to women below the cutoff (relative risk, 3.77; 95% confidence interval, 2.26-6.32; I2=74%). Similar degrees of risk were reported for thresholds between 3.0 and 5.9 mm (relative risk, 5.08; 95% confidence interval, 2.26-11.41; I2=0%), 6.0 and 9.9 mm (relative risk, 4.34; 95% confidence interval, 1.68-11.23; I2=0%), 10.0 and 13.9 mm (relative risk, 4.11; 95% confidence interval, 1.55-10.87; I2=86%), and ≥14.0 mm (relative risk, 2.53; 95% confidence interval, 1.04-6.16; I2=78%) with no significant difference among subgroups (P=.885). Regarding diagnostic accuracy, the pooled sensitivity decreased from thresholds below 5.9 mm (relative risk, 0.81; 95% confidence interval, 0.49-0.85) to above 14.0 mm (relative risk, 0.28; 95% confidence interval, 0.18-0.40). Furthermore, the specificity increased from 0.70 (95% confidence interval, 0.61-0.78) for endometrial thickness between 3.0 and 5.9 mm to 0.86 (95% confidence interval, 0.71-0.94) when the endometrial thickness is ≥14.0 mm. For 3.0 to 5.9 mm and 10.0 to 13.9 mm thresholds, the highest diagnostic odds ratios of 10 (95% confidence interval, 3-41) and 11 (95% confidence interval, 2-49), with areas under the curve of 0.81 (95% confidence interval, 0.77-0.84) and 0.82 (95% confidence interval, 0.79-0.86), respectively, were retrieved. The summary point analysis revealed that the 3.0 to 5.9 mm cutoff point was placed higher in the summary receiver operator curve space than the other subgroups, indicating increased endometrial carcinoma or atypical endometrial hyperplasia diagnosis using these cutoffs. CONCLUSION: Both low and high endometrial thickness thresholds in postmenopausal asymptomatic women seem equally effective in detecting endometrial carcinoma and atypical endometrial hyperplasia. However, although using a 3.0 to 5.9 mm cutoff results in a lower specificity, the offsetting improvement in sensitivity may justify using this cutoff for further endometrial evaluation in patients with suspected endometrial malignancy.

ESGO/ESHRE/ESGE Guidelines for the fertility-sparing treatment of patients with endometrial carcinoma.

The standard surgical treatment of endometrial carcinoma, consisting of total hysterectomy with bilateral salpingo-oophorectomy, drastically affects the quality of life of patients and creates a challenge for clinicians. Recent evidence-based guidelines of the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) provide comprehensive information on all relevant issues of diagnosis and treatment in endometrial carcinoma in a multidisciplinary setting. While addressing also work-up for fertility preservation treatments and the management and follow-up for fertility preservation, it was considered relevant to further extend the guidance on fertility-sparing treatment.A collaboration was set up between the ESGO, the European Society of Human Reproduction and Embryology (ESHRE), and the European Society for Gynaecological Endoscopy (ESGE), aiming to develop clinically relevant and evidence-based guidelines focusing on key aspects of fertility-sparing treatment (patient selection, tumor clinicopathological characteristics, treatment, special issues) in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.ESGO/ESHRE/ESGE nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (11 experts from across Europe). To ensure that the guidelines are evidence-based, the literature published since 2016, identified by a systematic search, was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 95 independent international practitioners in cancer care delivery and patient representatives.

Step-by-Step Hysteroscopic Treatment of Complete Uterine Septum Associated or Not with Cervical Anomalies.

STUDY OBJECTIVE: To demonstrate our hysteroscopic technique using the mini-resectoscope for the treatment of complete uterine septum with or without cervical anomalies. DESIGN: A step-by-step video demonstration of the technique with the use of an educational video. SETTINGS: We present 3 patients diagnosed as having complete uterine septum (U2b according to the ESHRE/ESGE classification) with or without cervical anomalies (C0, normal cervix; C1, septate cervix; C2, double "normal" cervix"), 2 of them with a longitudinal vaginal septum (V1). The first case is a 33-year-old woman with history of primary infertility diagnosed as having a complete uterine septum with normal cervix (class U2bC0V0 according to the ESHRE/ESGE classification). Case 2 is a 34-year-old woman with infertility and abnormal uterine bleeding, diagnosed as having complete uterine and cervical septum and a partial nonobstructive vaginal septum (class U2bC1V1). Case 3 is a 28-year-old woman with infertility and dyspareunia, diagnosed as having a complete uterine septum, double "normal" cervix, and nonobstructive longitudinal vaginal septum (class U2bC2V1) Still 3. The procedures were performed in a tertiary care university hospital. INTERVENTION: The 3 procedures were performed in the operative room using a 15 Fr continuous flow mini-resectoscope and bipolar energy with the patient under general anesthesia Still 1 and Still 2. No complications were encountered in any of the 3 cases. After all procedures, a gel based on hyaluronic acid was applied to minimize postoperative adhesion formation. Patients were discharged home the same day of the procedure after a short period of observation. CONCLUSION: Hysteroscopic treatment of patients with uterine septa associated or not with cervical anomalies using miniaturized instruments is a feasible and effective option for the management of patients with these complex müllerian anomalies.

Restoring Fertility of Patients with Severe Asherman's Syndrome in the Office Setting: A Step-by-Step Recipe for Success.

OBJECTIVE: To describe an effective in-office hysteroscopic strategy to restore fertility of patients with severe Asherman's syndrome. DESIGN: A step-by-step video demonstration of the technique with an emphasis on the key portions of the procedure. A detailed narrated description of the steps is provided. SETTING: Tertiary care University Hospital. INTERVENTIONS: Three patients were managed by hysteroscopy performed in the office setting without anesthesia. Case 1 is a 34-year-old woman with obstetrical history of first-trimester incomplete abortion treated with Dilation and Curettage (D&C), followed by a tubal ectopic pregnancy treated with laparoscopic partial salpingectomy and a subsequent pregnancy on the tubal stump treated with uterine artery embolization. Case 2 is a 40-year-old woman with history of tubal ectopic pregnancy treated with salpingectomy, a surgical first-trimester voluntary termination of pregnancy with D&C and a full term vaginal delivery complicated with retained products of conception that were removed with D&C. Case 3 is a 35-year-old woman with two previous first-trimester spontaneous miscarriages both treated with D&C. Case 1 and 3 were treated using miniaturized mechanical instruments only; in case 2, miniaturized mechanical instruments and the 15 Fr bipolar mini-resectoscope were used. Preoperative 2D and 3D ultrasound were used to predict the complexity of the cases and to guide the surgeon during the procedure. Intrauterine lysis of adhesions was concluded when both tubal ostia were visualized, and the uterine cavity was determined to have adequate shape and volume. At the end of the procedures, hyaluronic acid-based gel was applied to prevent new intrauterine adhesion formation. Two weeks after the initial procedure, a second look diagnostic hysteroscopy was performed. Only one patient (#1) needed additional lysis of adhesions; in this case, at the end of the procedure, a Word catheter was inserted as a barrier method for the prevention of adhesion formation. Eight weeks later, the word catheter was removed, and additional lysis of adhesions was performed. All the surgical procedures were performed without complication, and a healthy endometrium was observed at the second look hysteroscopy, in all the three patients. All 3 patients conceived after the procedure. Pregnancy was achieved after one IVF cycle with the transfer of one frozen embryo in case 1 and spontaneously in cases 2 and 3. Patient 1 was delivered by elective caesarean section due to placenta previa, while the other two patients had normal vaginal deliveries. Patient 1 had Retained Products of Conception requiring hysteroscopic removal using a 27 Fr Resectoscope. CONCLUSION: When using innovative miniaturized instruments and adequate surgical technique, hysteroscopic lysis of adhesions is a feasible and effective in-office strategy to restore fertility in patients with severe Asherman's syndrome. The use of 2D and 3D ultrasound played an important role in the preoperative workup of the patient with Asherman's syndrome.

Efficacy of Hysteroscopy in Improving Fertility Outcomes in Women Undergoing Assisted Reproductive Technique: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Usefulness of hysteroscopy before assisted reproductive technique (ART) was considered debatable. However, over the last decade, several new trials have been added to available literature. We aimed to assess the impact of diagnostic and operative hysteroscopy on reproductive outcomes of infertile women with and without intrauterine abnormalities. MATERIALS AND METHODS: MEDLINE, Scopus, SciELO, Embase, Cochrane Library at CENTRAL, PROSPERO, CINAHL, grey literature, conference proceedings, and international controlled trials registries were searched without temporal, geographical, or language restrictions. Randomized controlled trials (RCTs) of infertile women comparing hysteroscopy versus no hysteroscopy prior to the first ART or after at least one failed attempt were included. RCTs of infertile women with intrauterine pathology comparing diagnostic versus operative hysteroscopy were included in separate analysis. Random-effect meta-analysis was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Grading of Recommendations, Assessment, Development and Evaluation and Cochrane criteria were used for quality of evidence and risk of bias assessment. Primary outcome was live birth rate (LBR). Secondary outcomes were clinical pregnancy (CPR) and pregnancy loss rate. RESULTS: Fifteen studies (5,038 women) were included. Compared to no hysteroscopy before first or after failed ART attempts, moderate-quality evidence showed that hysteroscopy increased the LBR (relative risk [RR] 1.24, 95% confidence interval [CI] 1.09-1.43, I2 = 21%), confirmed by subgroup analysis for women with failure after one or more ART cycles (RR 1.43, 95% CI: 1.19-1.72, I2 = 0%) but not before the first ART. Moderate-quality evidence showed that it increased the CPR (RR 1.36, 95% CI: 1.18-1.57; I2 = 51%), confirmed in subgroup analysis for both implantation failure (RR 1.40, 95% CI: 1.12-1.74, I2 = 52%) and before first ART (RR 1.32, 95% CI: 1.11-1.57, I2 = 42%). Low-quality data suggest that operative hysteroscopy increases CPR when used to treat intrauterine pathologies (RR 2.13, 95% CI: 1.56-2.92, I2 = 0%). CONCLUSIONS: Although moderate-quality evidence supports performing hysteroscopy before ART in women with history of implantation failure, hysteroscopic evaluation of uterine cavity should be considered a first-line technique in all infertile women undergoing ART. Additional high-quality RCTs are still needed, particularly to assess yield during couple's initial evaluation even before ART is considered.

Postsurgical barrier strategies to avoid the recurrence of intrauterine adhesion formation after hysteroscopic adhesiolysis: a network meta-analysis of randomized controlled trials.

OBJECTIVE: To assess the efficacy of mechanical strategies to avoid the recurrence of intrauterine adhesions, to evaluate the impact on subsequent fertility after hysteroscopic adhesiolysis and to rank the available antiadhesive options. DATA SOURCES: MEDLINE, Scopus, ClinicalTrials.gov, CINAHL, Scielo, EMBASE, PROSPERO, Cochrane Library, conference proceedings, and international controlled trials registries were searched without temporal, geographic, and language restrictions. STUDY ELIGIBILITY CRITERIA: Randomized trials that analyzed the recurrence, reproductive outcomes, or both in women undergoing hysteroscopic adhesiolysis followed by mechanical prevention of intrauterine adhesions were included. The exclusion criteria included the following: quasi-randomized trials and trials without randomization and studies including patients undergoing hysteroscopic surgery that was different from adhesiolysis. STUDY APPRAISAL AND SYNTHESIS METHODS: The Preferred Reporting Items for Systematic reviews and Meta-Analyses extension statement for network meta-analyses guidelines were followed. We performed a network meta-analysis based on the random effects model for mixed multiple treatment comparisons to rank the antiadhesive strategies by surface under the cumulative ranking curve area. Quality assessment was performed using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. The primary outcome was the recurrent presence of intrauterine adhesions. RESULTS: Eleven studies with data for 1596 women were identified as applicable. A copper intrauterine device together with an intrauterine balloon (surface under the cumulative ranking curve area=46.4%) or with cross-linked hyaluronic acid gel (surface under the cumulative ranking curve area=21.3%) seemed effective in preventing adhesions recurrence. Regarding the fecundity, hyaluronic acid gel demonstrated the highest pregnancy rates (surface under the cumulative ranking curve area=79.8%). The greatest degrees of change in the mean adhesions scores were found with the use of hyaluronic acid gel plus an intrauterine device (surface under the cumulative ranking curve area=38.9%). For postsurgical adhesion severity, hyaluronic acid gel plus intrauterine device (surface under the cumulative ranking curve area=49.9%) followed by intrauterine device alone (surface under the cumulative ranking curve area=30.8%) was ranked the highest. Dried amnion graft (surface under the cumulative ranking curve area=53.8%) and uterine balloon (surface under the cumulative ranking curve area=45%) showed the greatest menstrual pattern improvement. CONCLUSION: Cross-linked hyaluronic acid gel, with or without insertion of a copper intrauterine device, seems to be the most effective approach. However, the lack of a clear best therapy suggests the need for further studies to draw firm conclusions.

Unicornuate Uterus with Noncommunicating Rudimentary Horn (Class U4aC0V0/ESHRE/ESGE Classification) and a Communicating Bladder Endometriotic Nodule.

STUDY OBJECTIVE: To describe the diagnostic workup and laparoscopic management of a noncommunicating left uterine rudimentary horn (class U4aC0V0 European Society of Human Reproduction and Embryology/European Society of Gastrointestinal Endoscopy Classification) with communicating endometriotic bladder nodule. DESIGN: Step-by-step description of the surgical treatment. PATIENT: A 33-year-old woman with unicornuate uterus and a left-side noncommunicating rudimentary horn affected by primary infertility, mild dysmenorrhea (visual analog scale score 6), severe catamenial dysuria (visual analog scale score 10), and catamenial hematuria. SETTING: Noncommunicating rudimentary horns are rare Müllerian anomalies present in 20% to 25% of women with a unicornuate uterus. It is associated with severe dysmenorrhea, pelvic pain, subfertility, and poor obstetric outcomes and usually presents with cyclic pelvic pain that starts early after the menarche. Endometriotic bladder nodules are present in 1% to 2% of patients with endometriosis. In the literature, there are no reported cases of noncommunicating rudimentary horn with communicating endometriotic bladder nodules. Surgical excision of the rudimentary horn is the treatment of choice. In our case, the 2-dimensional/3-dimensional ultrasound revealed a right unicornuate uterus with a left noncommunicating rudimentary horn with hematometra. The uterine fundus presented «gamma sign¼ vascularization. In addition, a bladder endometriotic nodule (16 × 15 mm) communicating with hematometra was displayed. Magnetic resonance imaging demonstrated no additional malformations. Diagnostic hysteroscopy revealed a single cervix without vaginal malformation and small right uterine cavity with single tubal ostium. At laparoscopy, using hysteroscopic transillumination, a clear plane of dissection was identified between the rudimentary horn and the uterus confirming the presence of a noncommunicating horn. Evaluation of the abdominal cavity showed bilateral normal adnexa with normal ovaries. Chromopertubation showed a patent right Fallopian tube and obstructed left tube. INTERVENTIONS: A left salpingectomy using bipolar and the ultrasonic energy was performed. The utero-ovarian ligament was transected, and the left ovary was preserved. The left ovary was suspended at the pelvic wall, the retroperitoneum was opened, the ureter was identified, and the left uterine artery was temporary occluded. The left round ligament was transected and the left paravesical space was developed. With a lateromedial approach, we opened the vesicouterine septum to dissect the bladder from the rudimentary horn. The endometriotic bladder nodule was gently detached from the uterine horn with a lateromedial approach. The left uterine artery was coagulated and dissected at level of the cervix. A solution of vasopressin was injected between the uterine horn and the uterus. Resection of the rudimentary horn was performed. The peritoneum was closed. The temporary occlusion of the uterine artery was removed. The specimen was placed in a bag and removed using an extracorporeal tissue extraction technique. CONCLUSION: The late clinical presentation of our patient with only mild dysmenorrhea could be explained by the drainage of the hematometra from the noncommunicating horn into the endometriotic bladder nodule. The bladder symptoms in patients with Müllerian anomalies should be carefully investigated. The laparoscopic removal of rudimentary horn with mobilization of communicating bladder nodule when present is a safe and feasible method to improve symptomatology.

Mismatch repair-deficiency specifically predicts recurrence of atypical endometrial hyperplasia and early endometrial carcinoma after conservative treatment: A multi-center study.

OBJECTIVE: Deficient expression of mismatch repair proteins (MMR) has been suggested to be a predictor of resistance of atypical endometrial hyperplasia (AEH) and early endometrial carcinoma (EEC) to conservative treatment. AIMS: To assess the predictive value of MMR immunohistochemistry in patients conservatively treated for AEH and EEC, and to calculate its predictive accuracy. MATERIALS AND METHODS: All patients with AEH or EEC conservatively treated with hysteroscopic resection plus progestins in two referral centers from January 2004 to July 2019 were retrospectively assessed. Immunohistochemistry for MMR was ad hoc performed. Study outcomes were: (i) the association of a deficient immunohistochemical expression of MMR with resistance and recurrence of AEH and EEC after conservative treatment, and (ii) the accuracy of MMR immunohistochemistry in predicting the outcome of conservative treatment. Relative risk (RR) for the associations, and sensitivity, specificity and area under the curve (AUC) on receiver operating characteristic curve for the predictive accuracy were calculated. RESULTS: Sixty-nine women, (47 AEH and 22 EEC) were included; deficient MMR expression was observed in 8.7% of cases. Resistance to conservative treatment was more common in MMR-deficient than MMR-proficient cases (33.3% vs 15.9%; RR = 2.1), but with no statistical significance (p = 0.2508). On the other hand, recurrence was significantly more common in MMR-deficient than MMR-proficient cases (100% vs 26.4%; RR = 3.8; p < 0.0001). In predicting recurrence, a deficient immunohistochemical expression of MMR showed sensitivity = 22.2%, specificity = 100%, and AUC = 0.61. CONCLUSION: Deficient MMR immunohistochemical expression does not imply resistance of AEH/EEC to conservative treatment. On the other hand, MMR-deficiency appears as a highly specific predictor of recurrence of AEH/EEC after initial regression.

The Invisible External Cervical Os. Tips and Tricks to Overcome this Challenge during In-Office Hysteroscopy.

OBJECTIVE: Hysteroscopy is considered the gold standard technique for the diagnosis and management of intrauterine pathology allowing to "see and treat" patients in 1 session if desired [1-3]. Pain and the inability to enter the uterine cavity are the most common limitations of hysteroscopy, especially when performed in an office setting [4-7]. Cervical stenosis is a common hysteroscopic finding frequently encountered in postmenopausal women, especially in patients with a history of cervical procedures such as cone biopsy [8]. It represents a challenge even for the most expert hysteroscopist. Overcoming the stenosis of the external cervical os is technically more demanding than facing the obliteration of the internal os. The aim of this video article is to illustrate the use of simple techniques that allow the hysteroscopist to safely identify the location of the external cervical os and to overcome the difficulties in entering the uterine cavity during in-office hysteroscopy in patients with severe cervical stenosis including those with complete obliteration of the external cervical os. These techniques are easy to adopt and can be used in different clinical situations in which the hysteroscopic evaluation of the uterine cavity is needed in women with severe cervical stenosis. DESIGN: A series of videos of challenging cases with severe cervical stenosis with complete obliteration of the external cervical os are presented that demonstrate maneuvers to properly identify and enter the cervical canal, unfolding key aspects of the procedure. Tips and tricks to facilitate the adoption of these useful maneuvers into clinical practice are highlighted. SETTING: In-office diagnostic hysteroscopy was performed using a 5-mm rigid continuous flow operative hysteroscope. Patients were placed in a dorsal lithotomy position. The vaginoscopy "no touch" technique was used [9]. No anesthesia or sedation was administered to any of the patients. Normal saline was used as distention media. INTERVENTIONS: Taking advantage of the magnification provided by the hysteroscope, the location of the external cervical os was determined. In cases in which the external cervical os was not clearly recognized, the cervix was gently probed with the use of the uterine palpator, grasper, or scissors (Fig. 1). Recognition of the landmarks of the cervical canal provides reassurance of the adequate identification of the external cervical os and facilitates the use of the correct plane of dissection that leads into the uterine cavity (Fig. 2). Additional maneuvers that are useful to navigate the endocervical canal to overcome stenosis of the internal cervical os are also illustrated. CONCLUSION: The combination of a delicate technique and operator experience aids in overcoming the challenge of cervical stenosis in an office setting. Adopting the presented tips and tricks to enter the uterine cavity in the presence of severe cervical stenosis will reduce the rate of failed hysteroscopic procedures, decreasing the need to take patients to the operating room and the use of general anesthesia.

Predictive Accuracy of Progesterone Receptor B in Young Women with Atypical Endometrial Hyperplasia and Early Endometrial Cancer Treated with Hysteroscopic Resection plus LNG-IUD Insertion.

STUDY OBJECTIVE: The immunohistochemical expression of isoform B of the progesterone receptor (PRB) has shown promising results in predicting the response of atypical endometrial hyperplasia (AEH) and early endometrial cancer (EEC) to conservative treatment. We aimed to calculate the accuracy of PRB as a predictive marker of conservative treatment outcome in AEH or EEC. DESIGN: Retrospective cohort study. SETTING: University of Naples Federico II, Naples, Italy. PATIENTS: Thirty-six consecutive premenopausal women <45 years of age with AEH (n = 29) or EEC (n = 7) conservatively treated from January 2007 to June 2018 were retrospectively assessed. INTERVENTIONS: All patients had been treated with hysteroscopic resection plus levonorgestrel-releasing intrauterine device insertion and followed for at least 1 year. The immunohistochemical expression of PRB was separately assessed in the glands and stroma of the lesion and dichotomized as "weak" or "normal." MEASUREMENT AND MAIN RESULTS: The treatment outcomes considered were (1) treatment failure (i.e., a combined outcome including no regression or recurrence); (2) no regression; and (3) recurrence. The predictive accuracy of PRB immunohistochemistry was assessed by calculating sensitivity (SE), specificity (SP), and area under the receiver operating characteristic curve (AUC). A weak glandular PRB expression showed SE = 70%, SP = 77%, and AUC = 0.74 for treatment failure; SE = 66.7%, SP = 70%, and AUC = 0.68 for no regression; and SE = 75%, SP = 68.8%, and AUC = 0.72 for recurrence. A weak stromal PRB expression showed SE = 100%, SP = 53.8%, and AUC = 0.77 for treatment failure; SE = 100%, SP = 46.7%, and AUC = 0.73 for no regression; and SE = 100%, SP = 43.8%, and AUC = 0.72 for recurrence. CONCLUSION: A weak stromal PRB expression is a highly sensitive predictive marker of both no response and recurrence of AEH and EEC conservatively treated.

Hysteroscopic endometrial biopsy: from indications to instrumentation and techniques. A call to action.

During the last twenty years, the diagnostic approach to endometrial pathology has radically evolved. For over a century, intrauterine blind biopsy techniques were considered the gold standard procedure for the histopathological diagnosis of intrauterine diseases. The advent of hysteroscopy, which made it possible to directly visualize the uterine cavity, and the subsequent miniaturization of the instruments allowing its use in the office setting without anesthesia are considered game-changers. To date, it is feasible to retrieve a targeted eye specimen of endometrial tissue with little or no discomfort for the patient in the office setting. To pursue this aim, several technological upgrades have improved the diagnostic accuracy of hysteroscopic endometrial biopsy. In this paper we provide an up-to-date review of the latest evidence regarding indications, instrumentations, and techniques for hysteroscopic endometrial biopsy, to help the operator in providing an adequate endometrial sampling for histopathological analysis.

Should endometrial biopsy under direct hysteroscopic visualization using the grasp technique become the new gold standard for the preoperative evaluation of the patient with endometrial cancer?

OBJECTIVE: To investigate the diagnostic accuracy of endometrial biopsy performed with hysteroscopic direct visualization using the "grasp technique" for the detection of endometrial carcinoma (EC) histology type and tumor grade. METHODS: A cross-sectional study including the clinical and pathology records of patients with confirmed EC who underwent definitive surgery at University of Naples was performed. The preoperative diagnosis of endometrial tumor type and grade obtained using the hysteroscopy grasp technique was correlated with the final pathology specimens. Those results were compared to the diagnostic accuracy of the biopsies collected in a cohort of patients who underwent preoperative diagnostic hysteroscopy followed by blind endometrial biopsy using the Novak curette with subsequent surgical definitive treatment at University of Pisa. Statistical analysis was based on frequency data and diagnostic agreement of the pathology results. RESULTS: A total of 129 patients were included in the final analysis. An agreement rate of 104/106 (98.1%) for endometrioid type and 15/23 (65.2%) for non-endometrioid type was obtained between preoperative hysteroscopic grasp endometrial biopsy specimens and the final pathology with a coefficient k for G1, G2 and G3 tumors of 0.928, 0.925 and 0.974, respectively. When compared to 121 patients undergoing preoperative blind Novak endometrial biopsy, the hysteroscopic grasp technique was superior in agreement rates for tumor histotype [diagnostic accuracy (0.922 vs 0.890); K value (0.705 vs 0.642)] and grade when in presence of endometrioid type EC (K Cohen 0.354 for G1, 0.263 for G2 and 0.488 for G3). CONCLUSIONS: Preoperative hysteroscopic guided "grasp" endometrial biopsy provides a more accurate diagnosis of EC histology type and tumor grade when in presence of endometrioid type tumor compared to blind endometrial biopsy obtained using the Novak curette.

Ulipristal acetate in symptomatic uterine fibroids. A real-world experience in a multicentric Italian study.

Surgery is the most frequent treatment in women with symptomatic uterine fibroids. A new medical approach with ulipristal acetate (UPA) has been suggested. The aim of this study was to provide data on effectiveness and safety of UPA in premenopausal women with symptomatic uterine fibroids. This was a multicenter retrospective cohort study. Data on all consecutive premenopausal women with symptomatic uterine fibroids referred to three Italian centers were included in a dedicated merged database. Women aged 18-55 years, who received pharmacologic therapy with UPA 5 mg orally once a day, were included in the study. The primary outcome was the percentage of women who underwent surgery after UPA treatment. One hundred and forty-two premenopausal women with uterine fibroids were included in this study. The mean age was 43.2 years. Eighty-one (57.0%) of 142 women treated with UPA had only medical treatment and did not undergo surgery. Surgical treatment occurred in 70, 23, 32, and 8% of the women who received one course, two courses, three courses, or four courses, of UPA treatment, respectively. The incidence of side effects was 10.6%. The effectiveness and safety of repeated UPA treatment courses in reducing number of women requiring surgery is confirmed by real-world data.

Long-Term Reproductive Outcomes after Hysteroscopic Treatment of Dysmorphic Uteri in Women with Reproductive Failure: An European Multicenter Study.

OBJECTIVE: To evaluate the long-term reproductive outcomes in patients with dysmorphic uterus treated by hysteroscopic metroplasty with miniaturized instruments. DESIGN: Retrospective multicenter cohort study. SETTING: Tertiary care university hospitals. PATIENTS: The study was conducted on 214 women with a dysmorphic uterus (T-shaped, infantilis, or other type of dysmorphic uterus according to the European Society of Human Reproduction and Embryology and the European Society for Gynaecological Endoscopy classification system) with history of primary unexplained infertility (group 1) or repeated (>2) early miscarriages (group 2). Dysmorphic uteri were diagnosed by office hysteroscopy and 3-dimensional transvaginal ultrasound (3D-TVS). INTERVENTIONS: All patients underwent in office hysteroscopic metroplasty using a continuous-flow hysteroscope with a 5 Fr operating channel introduced into the uterine cavity using the vaginoscopic approach. Longitudinal incisions were performed on the fibromuscular constriction rings in the isthmic area and in some cases on the other uterine walls with a 5 Fr bipolar electrode or scissors. At the end of the procedure, an antiadhesive gel was applied into the uterine cavity to minimize adhesion formation. Postsurgical assessment of the uterine cavity was carried out through office hysteroscopy and 3D-TVS. All patients were followed for at least 24 months. MEASUREMENTS AND MAIN RESULTS: The metroplasty was completed in all cases, resulting in a significant increase of uterine cavity volume (100%) and optimization of uterine morphology in 211 of 214 women (98.6%). After 60 months, the overall clinical pregnancy rate was 72.9% (n = 156/214), and the live birth rate was 80.1% (n = 125/156). Specifically, 74 of 156 women (47.4%) conceived spontaneously (with a median time to pregnancy of 5.5 months), of whom 32.4% had previously failed 1 or more attempts at in vitro fertilization/intracytoplasmic sperm injection. CONCLUSION: Our long-term follow-up data demonstrate that the hysteroscopic correction of dysmorphic uteri may result in a high live birth rate in women suffering from unexplained infertility or repeated miscarriages.