Single-cell analysis of endometriosis reveals a coordinated transcriptional programme driving immunotolerance and angiogenesis across eutopic and ectopic tissues.

Endometriosis is characterized by the growth of endometrial-like tissue outside the uterus. It affects many women during their reproductive age, causing years of pelvic pain and potential infertility. Its pathophysiology remains largely unknown, which limits early diagnosis and treatment. We characterized peritoneal and ovarian lesions at single-cell transcriptome resolution and compared them to matched eutopic endometrium, unaffected endometrium and organoids derived from these tissues, generating data on over 122,000 cells across 14 individuals. We spatially localized many of the cell types using imaging mass cytometry. We identify a perivascular mural cell specific to the peritoneal lesions, with dual roles in angiogenesis promotion and immune cell trafficking. We define an immunotolerant peritoneal niche, fundamental differences in eutopic endometrium and between lesion microenvironments and an unreported progenitor-like epithelial cell subpopulation. Altogether, this study provides a holistic view of the endometriosis microenvironment that represents a comprehensive cell atlas of the disease in individuals undergoing hormonal treatment, providing essential information for future therapeutics and diagnostics.

Medical management of endometriosis.

Endometriosis is a benign gynecologic disorder that is defined as functional endometrial tissue outside of the uterine cavity. It is an estrogen-dependent, inflammatory disease that leads to symptoms of pelvic pain, dysmenorrhea, dyspareunia, and infertility, occurring in 6-10% of reproductive aged women. The severity of the disease ranges from asymptomatic to debilitating symptoms that have a major impact on women's lives. It is a chronic, recurrent disease, frequently requiring long term management until menopause and beyond. It is considered a chronic disorder that is managed with surgery, medical treatment, and oftentimes, both. Current medical therapy for endometriosis is considered suppressive of the disease, rather than curative. Fortunately, many patients do experience improvement and control of their symptoms with medical therapy. However, long-term efficacy of the medical treatments is often limited by side effects and the cost of therapy, and symptoms do tend to recur after discontinuation of these medications. This review summarizes our understanding of the pathogenesis of endometriosis and provides more in-depth discussion of specific medical management options used to treat endometriosis, including mechanism of action and side effects. It also provides recommendations on strategy with a forward look to novel endometriosis treatments in the future. The authors emphasized that endometriosis is a chronic disorder requiring long term medical therapy. Early diagnosis of endometriosis is key in preventing severe, debilitating symptoms and progression of disease. By utilizing our current knowledge of the pathophysiology of endometriosis and by correctly implementing currently available medical and surgical therapies we can significantly reduce the physical, psychosocial and financial burden of this chronic, recurrent and indolent disease. Current available medications are suppressive therapies, but the authors are looking forward to future therapies that can effectively cure or at least control endometriosis with minimal side effects. Future research should continue to look for the genetic trigger for endometriosis which can lead us to its underlying pathogenesis and eventually a cure or prevention.

The impact of robotics on the mode of benign hysterectomy and clinical outcomes.

BACKGROUND: The impact of robotics on benign hysterectomy surgical approach, clinical outcomes, and learning curve is still unclear. METHODS: Review of abdominal, vaginal, laparoscopic, or robotic cases in 156 US hospitals in the Premier Research Database. RESULTS: Of 289 875 hysterectomies, abdominal cases decreased from 2005-2010 (60-33%) and minimally invasive approaches increased (40-67%). Conversion rates were: 0.04% for vaginal, 2.5% for robotic, and 7.2% for laparoscopy (P < 0.001). Robotic surgery time was longest (3.4 h vs. 2.2 vaginal, 2.5 abdominal, 2.7 laparoscopy, P < 0.001). Robotic complication rate was lowest (14.8% vs. 16.2% vaginal, 18.6% laparoscopy, 28.9% abdominal, P < 0.001). Hospital stay was longer following abdominal surgery (3.5 days vs. 1.8 robotic, 1.9 vaginal, 1.8 laparoscopy, P < 0.001). Robotic surgery times and conversion and complication rates improved with experience (2.8 h, 2%, and 13.9%, respectively), even with increasing complexity. CONCLUSIONS: Robotics was successfully incorporated without jeopardizing patient outcomes and increased the overall use of minimally invasive approaches.

Emerging therapy for endometriosis.

INTRODUCTION: Endometriosis is a chronic disease manifested by pain and infertility due to ectopic implantation of endometrial glands and stroma causing inflammation. Treatment of endometriosis utilizes a significant amount of health-care resources and requires chronic therapy. Management involves a combination of surgical and medical interventions and requires long-term treatment to avoid repeated surgeries. AREAS COVERED: Whereas medical therapies exist for management of endometriosis-related pain, each class has its limitations including side effects, cost, and known duration of relief of symptoms. Development of effective, well-tolerated medical therapies that are appropriate for long-term use is crucial to provide adequate treatment for this chronic disease. This review discusses the various medical therapies available, their limitations, and emerging therapies being developed to address many of these concerns. EXPERT OPINION: The authors recommend chronic suppressive therapy for management of endometriosis symptoms, particularly in the postoperative setting. Empiric treatment is appropriate for those patients without evidence of severe disease. Currently available option may not be effective for nor tolerated by all patients. Newer compounds, including gonadotropin-releasing antagonists and aromatase inhibitors combined with hormonal contraceptives, offer possible alternatives to currently available therapies.

Contrast ultrasonography for tubal patency.

Evaluation of tubal patency is an essential part of a fertility workup. Laparoscopy with chromopertubation in conjunction with hysteroscopy is the gold standard in evaluation of tubal patency and the uterine cavity. In this review article we describe a newer method for evaluation of the uterus and fallopian tubes, that is, hysterosalpingo-contrast sonography (HyCoSy). Accuracy of HyCoSy for tubal patency has been shown to be comparable to that with hysterosalpingography (HSG) when compared with laparoscopic chromopertubation. Sensitivity ranges from 75% to 96%, and specificity from 67% to 100%. HyCoSy is also accurate when compared with HSG in determining tubal occlusion after hysteroscopic sterilization, with 88% of patients stating they would prefer to undergo the tubal occlusion test in their gynecologist's office. Because HyCoSy also includes evaluation of the uterine cavity with saline solution-enhanced sonohysterography, accuracy in evaluating the uterine cavity is >90% when compared with hysteroscopy. HyCoSy enables the gynecologist to complete a fertility workup in the office in the most minimally invasive way. HyCoSy is well tolerated and has been suggested in the literature to replace HSG for evaluation of tubal disease in the subfertile population.

Three-dimensional ultrasound in diagnosis of adenomyosis: histologic correlation with ultrasound targeted biopsies of the uterus.

STUDY OBJECTIVE: To evaluate the accuracy of 3-dimensional transvaginal sonography (3D TVS) in the diagnosis of adenomyosis by correlating adenomyosis-induced morphologic alterations in the myometrium and the junctional zone (JZ) with histopathologic features of targeted biopsy specimens of the uterus. DESIGN: Prospective study (Canadian Task force classification II-2). SETTING: Private practice associated with a university program. PATIENTS: Symptomatic premenopausal women scheduled to undergo hysterectomy because of benign conditions. INTERVENTIONS: Patients underwent preoperative 3D TVS of the uterus to evaluate alterations to the JZ, to measure the smallest (JZ(min)) and largest (JZ(max)) JZ thickness, and to assess for the presence of myometrial heterogeneous and cystic areas, hyperechoic striations, and asymmetry of the myometrial wall. Localization and position of the lesions in the myometrial wall were accurately recorded. Results of the sonographic features were correlated with the histopathologic findings of the ultrasound-based targeted biopsy specimens of the uterus. MEASUREMENTS AND MAIN RESULTS: The study included 54 symptomatic premenopausal women with a mean age of 42.1 years. Of these, 12 had previously undergone endometrial ablation and 10 were receiving medical therapy, and these patients were considered separately for the statistical analysis. The prevalence of adenomyosis at histology was 66.6% (36/54). Of 32 patients who had received no previous treatment, 26 had adenomyosis on the targeted biopsy specimens of the myometrium. 3D TVS features of adenomyosis with the best specificity (83%) and positive predictive values were JZ(max) ≥8 mm, myometrial asymmetry, and hypoechoic striation. When we considered the presence of at least 2 of the described ultrasound features for the diagnosis of adenomyosis, accuracy was 90% (sensitivity, 92%; specificity, 83%; positive predictive value, 99%; and negative predictive value, 71%). Diagnostic accuracy was decreased to 50% in patients who had previously undergone endometrial ablation, and to 60% in patients receiving medical therapy. CONCLUSION: 3D TVS demonstrates high diagnostic accuracy in detection of site and position of adenomyosis in the uterine walls. Endometrial ablation and medical therapy alter the appearance of the JZ, compromising the accuracy of 3D US in enabling the diagnosis of adenomyosis.

Management of endometriosis-related pain: an update.

Endometriosis is a chronic and recurrent condition affecting 6-10% of women of a reproductive age. It results from implantation of endometrial tissue outside the uterine cavity. It is associated with pelvic pain and infertility. Treatment for endometriosis ranges from medical management, to conservative surgery, to definitive surgery with a hysterectomy and bilateral salpingo-oophorectomy, and should be based on patient's fertility desires and tolerance. Medical treatment involves hormonal manipulation to induce a hypoestrogenic or antiestrogenic state to induce regression and apoptosis of lesions. Endometriosis can have dire effects on women's lives and productivity; this article will focus on early diagnosis, treatment and prevention of recurrence of the disease.

Can hysterosalpingo-contrast sonography replace hysterosalpingography in confirming tubal blockage after hysteroscopic sterilization and in the evaluation of the uterus and tubes in infertile patients?

OBJECTIVE: The objective of the study was to assess the accuracy of hysterosalpingo-contrast sonography (HyCoSy) in establishing tubal patency or blockage and evaluating the uterine cavity by comparing it with hysteroscopy laparoscopy (HLC) or hysterosalpingography (HSG). STUDY DESIGN: This study was a chart review evaluating infertility patients and patients who had undergone hysteroscopic sterilization who underwent both HyCoSy and HLC or HyCoSy and HSG at private offices associated with university hospitals. Sensitivity, specificity, positive predictive value, and negative predictive value of HyCoSy were calculated. RESULTS: HyCoSy compared with HLC had a sensitivity of 97% and specificity of 82%, and HyCoSy compared with HSG was 100% concordant. Uterine cavities evaluated by sonohysterography and hysteroscopy were 100% concordant. CONCLUSION: HyCoSy is accurate in determining tubal patency and evaluating the uterine cavity, suggesting it could supplant HSG not only as the first-line diagnostic test in an infertility workup but also in confirming tubal blockage after hysteroscopic sterilization.

Adhesion reformation after laparoscopic adhesiolysis: where, what type, and in whom they are most likely to recur.

STUDY OBJECTIVE: To assess if the severity or extent of adhesions, the organs involved, or presence of endometriosis predict recurrence or de novo adhesion formation. DESIGN: Comparison of adhesion scores at initial operative laparoscopy and at second-look laparoscopy using the revised American Fertility Society adhesion classification system (Canadian Task Force classification I). SETTING: A university-affiliated reproductive endocrinology and infertility center. PATIENTS: In all, 38 women with moderate to severe adhesions who underwent laparoscopic adhesiolysis and second-look laparoscopy. INTERVENTIONS: Adhesion scores were assessed at 6 sites in the peritoneal cavity before initial laparoscopic adhesiolysis and compared with adhesion scores at second-look laparoscopy. Adhesions were evaluated by extent, severity, organ involvement, and presence or absence of endometriosis to evaluate potential determinants of recurrence and de novo adhesion formation. All adhesions were totally removed at initial laparoscopy, all patients received 1000 mL of Ringer's lactate solution intraperitoneally at the end of procedures, and the same surgeon treated all patients. MEASUREMENTS AND MAIN RESULTS: Adhesion scores decreased in extent [23.3% (p = .005)] and severity [26.3% (p = .001)]. Dense adhesions decreased 31% (p < .000) and filmy adhesions decreased 35% (p = .048). Extent of adhesions assessed at less than one-third, one-third to two-thirds, and more than two-thirds decreased by 33% (p = .002), 42% (p = .000), and 31% (p < .000), respectively. Severity and extent of adhesions of abdominal wall decreased by 45% (p = .003) and 40% (p = .016); of bowel by 33% (p = .002) and 31% (p = .012); and of posterior cul-de-sac by 14% (p = .040) and 9.5% (p = .091), respectively. Severity and extent of adhesions involving both adnexa decreased by 12% to 15%, respectively, which was not statistically significant. Presence of endometriosis did not affect adhesion recurrence. De novo adhesions developed at 48 (21%) of 228 potential sites occurring in 22 of 38 patients, and were most frequent and severe on the adnexa and least on the abdominal wall. CONCLUSION: Both extent and severity of adhesions are significantly reduced by laparoscopic adhesiolysis. Initial extent and severity of adhesions did not predict recurrence; however, the involved organ did, being most frequent on the adnexa and least frequent on the abdominal wall and bowel.

Pain associated with endometriosis: therapeutic options.

Defined as the presence of functional endometrial tissue outside the uterine cavity, endometriosis is a chronic and recurrent disease that affects 7-10% of reproductive-age women, causing pain, infertility or both, resulting in serious life disruption, emotional and physical suffering, and decreased productivity. The observation that endometriosis is more common in women with early ménarche, polymenorrhea, outflow genital tract obstruction or a family history of disease suggests that its development depends on the complex interaction of genetic, immunological, environmental and hormonal factors. Current therapies for the management of endometriosis are medical, surgical or both. Medical therapies induce a hypoestrogenic state to reduce menstrual flow and apoptosis of endometriotic lesions. They include androgenic or progestational compounds and gonadotropin-releasing hormone analogs, which are comparably effective but have very different adverse-effect profiles. Consequently, the choice of which medical treatment to prescribe may not be based on differences in efficacy but on differences in tolerability, safety and, when everything else is equal, cost. Although surgery to remove endometriosis is effective in relieving pain and restoring fertility, recurrence of symptoms is common and repeated medical and surgical interventions are often needed. The need for additional surgery may be reduced by the thorough excision of all lesions and disease at the initial surgery, followed by the postoperative administration of hormonal suppressive therapy with progestins to induce hypomenorrhea or amenorrhea. Definitive surgery with hysterectomy and removal of ovaries is frequently curative. Future therapies should be directed at identifying women at risk for the disease and implementing interventions that will prevent disease development altogether. Ultimately, the goal is to make endometriosis a disease of the past.

Outpatient vaginal hysterectomy is safe for patients and reduces institutional cost.

OBJECTIVE: To evaluate a management protocol based on scientific evidence in the care of patients undergoing vaginal hysterectomy. STUDY DESIGN: (Canadian Task Force classification II-2). SETTING: 110-bed community hospital. PATIENTS: Women with vaginal hysterectomy between 2000 and 2003. INTERVENTION: Data were collected on all vaginal hysterectomies performed by a single surgeon over a 4-year period. Demographics, surgical indications, procedural parameters, length of stay, and postoperative complications were evaluated. Hospital costs for all vaginal hysterectomies performed over a 2-year period at the same hospital also were examined. An analysis of the literature was performed to develop a protocol for optimizing patients' surgical experience. All patients were managed using the protocol. These patients were compared with a cohort at the same institution. MEASUREMENTS AND MAIN RESULTS: Four hundred twelve vaginal hysterectomies were performed by the lead author during the 4-year time period. Three hundred eighty-four patients (93%) were discharged within 12 hours of admission. There were no readmissions for bleeding, pain management, urinary retention, or nausea and vomiting. Four hundred nineteen vaginal hysterectomies were performed by 10 surgeons from 2002 through 2003 at the same institution, including 219 by the lead author. The average direct cost for outpatient vaginal hysterectomy was 21.3% lower than for inpatient vaginal hysterectomy. CONCLUSION: Incorporating a protocol based on scientific evidence into the management of surgical patients facilitated safe outpatient vaginal hysterectomy in a majority of patients. This optimized management may save up to 25% of the cost for these procedures.