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.

Incidence of Septate Uterus in Reproductive-Aged Women With and Without Endometriosis.

STUDY OBJECTIVE: To compare the incidence of a uterine septum in women with and without endometriosis and if such incidence correlates with the stage of endometriosis Although a correlation between obstructive Mullerian anomalies and endometriosis has been well established, its link with non-obstructive anomalies remains controversial. To elucidate whether there is a correlation between endometriosis and non-obstructive Mullerian anomalies, we conducted this prospective study on all patients admitted to our Reproductive Endocrinology and Infertility surgical service from February 1, 2010 through June 30, 2012. All patients underwent both hysteroscopy and laparoscopy. Surgical indications included: infertility, pain, and/or menorrhagia. The presence or absence of endometriosis and uterine anomalies were recorded immediately after each surgery and subsequently analyzed. Endometriosis was staged according to the r-ASRM Classification and treated by resection and ablation of deep and superficial lesions, respectively. Since uterine septum is the most common Mullerian anomaly, we considered only this anomaly to test the hypothesis that uterine septum may be associated with an increased incidence of endometriosis. DESIGN: Prospective Study. Evidence from a well-designed case-control study (Canadian Task Force classification II-2). SETTING: University-affiliated tertiary care center. PATIENTS: Reproductive aged women admitted to our service for treatment of pelvic pain, abnormal uterine bleeding, and/or infertility. INTERVENTION: All patients underwent both hysteroscopy and laparoscopy as part of their evaluation and treatment of pelvic pain, abnormal uterine bleeding, and/or infertility. MEASUREMENTS AND MAIN RESULTS: 343 patients were included in the study. The diagnosis of each patient included infertility - 52, pain - 215, both - 30 and other - 46. The diagnosis of septate uterus was made at hysteroscopy when the endometrial cavity was separated by an avascular septum that obscured visualization of both cornua when the hysteroscope was advanced to the mid-uterine segment. The septum was lysed sharply from cornua to cornua restoring normal fundal configuration. In all cases, the septolysis was bloodless, confirming its avascular nature. The overall incidence of uterine septum was 33% in our patient population. In patients with a histologically confirmed diagnosis of endometriosis, the incidence of septum was 37% versus 27% in patients without endometriosis (P = .046). In patients with advanced endometriosis, Stage IV disease, the incidence of septate uterus was 41% (P = .022). The odds ratio of Stage IV endometriosis with a uterine septum was 1.94 (CI 1.09-3.44). CONCLUSION: The incidence of septate uterus in our population of women with infertility and/or pelvic pain ranges from 27% to 37%, being significantly higher in women with endometriosis and mores so with Stage IV disease. Our data suggests that the presence of a uterine septum may predispose to more advanced disease.

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.

Effect of surgery for endometrioma on ovarian function: a different point of view.

Recent evidence in the literature suggests that surgical excision of the endometrioma wall may reduce ovarian reserve, which may have a negative effect on subsequent reproductive function. However, because of inconsistent results and methodologic flaws of anti-müllerian hormone (AMH) as a marker of ovarian reserve, antral follicle count may be a more accurate noninvasive marker than AMH. Evaluating ovarian reserve using antral follicle count rather than AMH may yield different conclusions insofar as postsurgical damage to the ovary. Surgery should be performed only by experienced surgeons, and the stripping technique currently is still the only one supported by strong scientific evidence. The dual function of surgery, that is, to improve fertility and reduce pain, cannot be minimized or undervalued.

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.

The uterine junctional zone: a 3-dimensional ultrasound study of patients with endometriosis.

OBJECTIVE: The uterine junctional zone (JZ) alterations are correlated with adenomyosis. An accurate evaluation of the JZ may be obtained by 3-dimensional transvaginal sonography (TVS). The aim of the present prospective study was to assess the value of detectable alterations by 3-dimensional TVS of the JZ in patients with pelvic endometriosis (diagnosed by laparoscopy and histologic condition) and to compare these findings with those of women without pelvic endometriosis. STUDY DESIGN: Eighty-two patients who were scheduled for laparoscopy had undergone previous surgery and 2- and 3-dimensional TVS. Uterine multiplanar sections that were obtained by 3-dimensional TVS were used to evaluate JZ features. During laparoscopy, an accurate staging of pelvic endometriosis was performed. JZ thickness and JZ alterations were correlated with stage of endometriosis. RESULTS: Of the 82 patients, 59 patients had endometriosis at laparoscopy and histology. The maximum thickness of JZ in patients with endometriosis was significantly greater than in patients without endometriosis (6.5 ± 1.9 mm vs 4.8 ± 1.0 mm; P < .001). The features of JZ appeared similar at different stages, whereas they are statistically different if correlated with patients without endometriosis. CONCLUSION: JZ thickness and its alterations are different in patients with endometriosis compared with those women without endometriosis and are not correlated with American Society of Reproductive Medicine staging methods. Because these JZ ultrasound features are associated mostly with adenomyosis, a correlation between endometriosis and JZ hyperplasia and adenomyosis could be hypothesized. Noninvasive evaluation of the JZ may be useful in the identification of those women who are affected by endometriosis also in early stage of the disease when there are no other sonographic signs of pelvic endometriosis.

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.

Sex allocation in haplodiploids is mediated by egg size: evidence in the spider mite Tetranychus urticae Koch.

Haplodiploid species display extraordinary sex ratios. However, a differential investment in male and female offspring might also be achieved by a differential provisioning of eggs, as observed in birds and lizards. We investigated this hypothesis in the haplodiploid spider mite Tetranychus urticae, which displays highly female-biased sex ratios. We show that egg size significantly determines not only larval size, juvenile survival and adult size, but also fertilization probability, as in marine invertebrates with external fertilization, so that female (fertilized) eggs are significantly larger than male (unfertilized) eggs. Moreover, females with on average larger eggs before fertilization produce a more female-biased sex ratio afterwards. Egg size thus mediates sex-specific egg provisioning, sex and offspring sex ratio. Finally, sex-specific egg provisioning has another major consequence: male eggs produced by mated mothers are smaller than male eggs produced by virgins, and this size difference persists in adults. Virgin females might thus have a (male) fitness advantage over mated females.

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.

Myomectomy.

Uterine leiomyomas are common, monoclonal tumors affecting 25% to 45% of reproductive age women. Although frequently asymptomatic, leiomyomas may cause heavy menstrual bleeding, pelvic pressure or pain, and infertility. Myomectomy, which is indicated in symptomatic women who wish to preserve their reproductive function, may be performed by hysteroscopy, laparoscopy, or laparotomy, according to their size, location, number, and the experience of the surgeon. The latter is the most important determinant, as the completeness of the myomectomy and the adequacy of the myometrial closure will determine the subsequent function of the organ in relieving the symptoms and restoring reproductive potential.

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.

Adept (icodextrin 4% solution) reduces adhesions after laparoscopic surgery for adhesiolysis: a double-blind, randomized, controlled study.

OBJECTIVE: To evaluate the efficacy and safety of Adept (4% icodextrin solution) in reducing adhesions after laparoscopic gynecological surgery involving adhesiolysis. DESIGN: Multicenter, prospective, randomized, double-blind study comparing Adept with lactated Ringer's solution (LRS). PATIENT(S): Four hundred two patients randomized intraoperatively to Adept (n = 203) or LRS (n = 199) returned for second laparoscopy within 4-8 weeks. Incidence, severity, and extent of adhesions were determined on both occasions. MAIN OUTCOME MEASURE(S): The primary efficacy measure defined by the Food and Drug Administration was the number of patients achieving clinical success with adhesion treatment. Other measures included incidence and American Fertility Society (AFS) scores. RESULT(S): Significantly more Adept patients achieved clinical success than did LRS patients (49% vs. 38%). In infertility patients, Adept demonstrated particular clinical success compared with LRS (55% vs. 33%). This was reflected in the number of patients with a reduced AFS score (53% vs. 30%) and in fewer patients with a moderate/severe AFS category score (43% vs. 14%). Safety was comparable in both groups. Most events were related to the surgery, with an increase in transient labial edema in the Adept group. CONCLUSION(S): This is the first randomized, double-blind trial of an adhesion reduction agent. It demonstrated that Adept is a safe and effective adhesion reduction agent in laparoscopy.

Subcutaneous injection of depot medroxyprogesterone acetate compared with leuprolide acetate in the treatment of endometriosis-associated pain.

OBJECTIVE: To compare the efficacy and safety of SC depot medroxyprogesterone acetate (DMPA-SC 104) with that of leuprolide acetate in treatment of endometriosis. DESIGN: Phase 3, multicenter, randomized, evaluator-blinded, comparator-controlled trial. SETTING: Clinical trial sites in Canada and United States. PATIENT(S): Two hundred seventy-four women with surgically diagnosed endometriosis. INTERVENTION(S): Intramuscular injections of DMPA-SC (104 mg) or leuprolide acetate (11.25 mg), given every 3 months for 6 months, with 12 months of posttreatment follow-up. MAIN OUTCOME MEASURE(S): Reduction in five endometriosis symptoms or signs (dysmenorrhea, dyspareunia, pelvic pain, pelvic tenderness, pelvic induration); change in bone mineral density (BMD), hypoestrogenic symptoms, bleeding, and weight. RESULT(S): The depot medroxyprogesterone acetate given SC was statistically equivalent to leuprolide in reducing four of five endometriosis symptoms or signs at the end of treatment (month 6) and in reducing all five symptoms after 12 months' follow-up (month 18). Patients in the DMPA-SC 104 group showed significantly less BMD loss than did leuprolide patients at month 6, with scores returning to baseline at 12 months' follow-up. No statistically significant differences in median weight changes were observed between groups. Compared with leuprolide, DMPA-SC 104 was associated with fewer hypoestrogenic symptoms but more irregular bleeding. CONCLUSION(S): Efficacy of DMPA-SC 104 was equivalent to that of leuprolide for reducing endometriosis-associated pain, with less impact on BMD and fewer hypoestrogenic side effects but more bleeding.

Advances in the management of endometriosis: an update for clinicians.

Endometriosis is a chronic and recurrent disease characterized by the presence and proliferation of endometrial tissue outside the uterine cavity, which occurs in approximately 10% of women of reproductive age. In this estrogen-dependent disorder, lesions become inactive and gradually undergo regression during states of ovarian down-regulation, such as amenorrhoea or menopause. The impact of endometriosis includes impaired fertility potential, as well as symptoms of dysmenorrhoea, dyspareunia and chronic non-menstrual pain, all of which adversely affect quality of life. Management of endometriosis focuses on pain relief and includes medical and surgical treatment. Pharmacologic therapies currently in use include combination oral contraceptives (COCs), danazol, GnRH analogues and progestins. Although some agents show efficacy in relieving pain, all differ in their side effects, making it difficult to achieve a balance between efficacy and safety. Efficacy has been demonstrated with danazol or GnRH analogues; however, treatment is limited to 6 months because of significant metabolic side effects. Alternatives for longer-term management of symptoms include add-back therapy with GnRH analogues, COCs or progestins. Newer options for treatment of endometriosis include depot medroxyprogesterone acetate subcutaneous injection, as well as several agents under investigation that may prove to have therapeutic potential.