Clinical evaluation of the oral gonadotropin-releasing hormone-antagonist elagolix for the management of endometriosis-associated pain.

Endometriosis is an estrogen-dependent chronic inflammatory disease associated with pelvic pain symptoms that are often severe, mainly dysmenorrhea, nonmenstrual pelvic pain and dyspareunia. This condition is also associated with peripheral and central sensitization. The current medical treatment options for endometriosis-associated pain are limited. Recently, the US FDA approved the novel, oral, nonpeptide gonadotropin-releasing hormone antagonist elagolix for the management of moderate to severe endometriosis-associated pain. Elagolix produces dose-dependent estrogen suppression, from partial suppression at lower doses to nearly full suppression at higher doses. This review article summarizes the current understanding of the pathophysiology of endometriosis, with a focus on the role of estrogen and the mechanisms of pain symptoms, and reviews the clinical development of elagolix in women with endometriosis-associated pain.

Recurrent massive ascites due to mossy endometriosis.

OBJECTIVE: To report the medical and surgical management of a rare case of recurrent moss-like endometriosis and associated hemorrhagic ascites. DESIGN: Video description of the case, demonstration of the surgical technique, discussion of the histology, and review of endometriosis-associated ascites. SETTING: Tertiary referral center. PATIENT(S): A 26-year-old nulliparous woman of Nigerian heritage with recurrent hemorrhagic ascites due to endometriosis. Three years previously she underwent an exploratory laparotomy for similar symptoms, and 7 L of hemorrhagic ascites were evacuated from her abdomen. Friable lesions covering the peritoneum of the uterus, bladder, and pouch of Douglas were biopsied and consistent with endometriosis. After her initial surgery, the patient was hormonally suppressed with goserelin for 3 months and oral medroxyprogesterone for 1 year. She then stopped the medications to attempt pregnancy but was unsuccessful. She used clomiphene for 3 months, and the ascites reaccumulated. The patient was started on depot leuprolide and oral norethindrone, but the ascites persisted. INTERVENTION(S): The patient underwent small-diameter laparoscopy using a multipuncture technique, evacuation of 7.8 L of hemorrhagic ascites, enterolysis, appendectomy, chromopertubation, and treatment of the endometriosis. MAIN OUTCOME MEASURE(S): Diffuse olive-green "mossy" endometriosis lesions blanketed the pelvic and abdominal peritoneum. The endometriosis was surgically resected with a combination of peritoneal stripping, excision with carbon dioxide laser, and ablation with neutral argon plasma. Examination of the ascites showed scattered hemosiderin-laden macrophages in a background of red blood cells. Histology of the olive-green mossy lesions revealed dense sheets of hemosiderin-laden macrophages and rare foci of endometriosis. Surgical reports in deidentified patients are exempted from Institutional Review Board approval. The patient gave consent to use photography and images for the video article. RESULT(S): No postoperative hormone suppression was given to the patient because she desired pregnancy. At 6 months after her second surgery, the patient had not achieved pregnancy, but the ascites had not reaccumulated. She was referred for further infertility care. CONCLUSION(S): This rare form of mossy endometriosis often mimics ovarian cancer, pelvic tuberculosis, and other gynecologic conditions, but when identified, the endometriosis can be treated and symptoms can subside with drainage of the ascites, thorough ablation of the diffuse, superficial lesions, and restoration of anatomy.

Excision of an epidermal inclusion cyst: Correction of a long-term complication of female genital circumcision.

Epidermal inclusion cysts are a late complication of female genital circumcision, which is a practice that affects 125 million women primarily from Africa and the Middle East. A 30-year-old woman, gravida 4, para 1, presented to our clinic with an 8-year history of a slowly enlarging periclitoral mass. The patient had undergone female genital circumcision at the age of 5 years. We describe and video-illustrate the surgical technique of excising the 8-cm epidermal inclusion cyst. Using this technique, the entire cyst was resected intact, excess vulvar skin removed, and defect repaired. Postoperatively, she had minimal pain, no dyspareunia, and good cosmesis. Restoration of anatomy for this late complication of female genital circumcision is achievable with knowledge of anatomy, adherence to basic surgical principles that include tension-free closure, and close postoperative follow up.

Endometriosis in adolescents.

BACKGROUND AND OBJECTIVES: Women with endometriosis often report onset of symptoms during adolescence; however, the diagnosis of endometriosis is often delayed. The aim of this study was to describe the experience of adolescents who underwent laparoscopy for pelvic pain and were diagnosed with endometriosis: specifically, the symptoms, time from onset of symptoms to correct diagnosis, number and type of medical professionals seen, diagnosis, treatment, and postoperative outcomes. METHODS: We reviewed a series of 25 females ≤21 years of age with endometriosis diagnosed during laparoscopy for pelvic pain over an 8-year period. These patients were followed up for 1 year after surgery. RESULTS: The mean age at the time of surgery was 17.2 (2.4) years (range, 10-21). The most common complaints were dysmenorrhea (64%), menorrhagia (44%), abnormal/irregular uterine bleeding (60%), ≥1 gastrointestinal symptoms (56%), and ≥1 genitourinary symptoms (52%). The mean time from the onset of symptoms until diagnosis was 22.8 (31.0) months (range, 1-132). The median number of physicians who evaluated their pain was 3 (2.3) (range, 1-12). The adolescents had stage I (68%), stage II (20%), and stage III (12%) disease. Atypical endometriosis lesions were most commonly observed during laparoscopy. At 1 year, 64% reported resolved pain, 16% improved pain, 12% continued pain, and 8% recurrent pain. CONCLUSIONS: Timely referral to a gynecologist experienced with laparoscopic diagnosis and treatment of endometriosis is critical to expedite care for adolescents with pelvic pain. Once the disease is diagnosed and treated, these patients have favorable outcomes with hormonal and nonhormonal therapy.

Novel port placement and 5-mm instrumentation for robotic-assisted hysterectomy.

BACKGROUND AND OBJECTIVES: The value of robotic surgery for gynecologic procedures has been critically evaluated over the past few years. Its drawbacks have been noted as larger port size, location of port placement, limited instrumentation, and cost. In this study, we describe a novel technique for robotic-assisted laparoscopic hysterectomy (RALH) with 3 important improvements: (1) more aesthetic triangular laparoscopic port configuration, (2) use of 5-mm robotic cannulas and instruments, and (3) improved access around the robotic arms for the bedside assistant with the use of pediatric-length laparoscopic instruments. METHODS: We reviewed a series of 44 women who underwent a novel RALH technique and concomitant procedures for benign hysterectomy between January 2008 and September 2011. RESULTS: The novel RALH technique and concomitant procedures were completed in all of the cases without conversion to larger ports, laparotomy, or video-assisted laparoscopy. Mean age was 49.9 years (SD 8.8, range 33-70), mean body mass index was 26.1 (SD 5.1, range 18.9-40.3), mean uterine weight was 168.2 g (SD 212.7, range 60-1405), mean estimated blood loss was 69.7 mL (SD 146.9, range 20-1000), and median length of stay was <1 day (SD 0.6, range 0-2.5). There were no major and 3 minor peri- and postoperative complications, including 2 urinary tract infections and 1 case of intravenous site thrombophlebitis. Mean follow-up time was 40.0 months (SD 13.6, range 15-59). CONCLUSION: Use of the triangular gynecology laparoscopic port placement and 5-mm robotic instruments for RALH is safe and feasible and does not impede the surgeon's ability to perform the procedures or affect patient outcomes.

Office visceral slide test compared with two perioperative tests for predicting periumbilical adhesions.

OBJECTIVE: To determine whether the office visceral slide test is an effective screening test for predicting obliterating periumbilical adhesions compared with two ultrasound tests performed in the operating room. METHODS: Women undergoing benign laparoscopic gynecologic surgery between July 2012 and August 2013 were invited to participate. All participants had an office-based ultrasound test at their preoperative visit (the office visceral slide test), two operating room ultrasound tests (the preoperative examination with visceral slide and the periumbilical ultrasound-guided saline infusion test), and then their scheduled laparoscopic procedure. We measured the ability of the three screening tests to detect obliterating periumbilical adhesions. RESULTS: Eighty-two women completed the study; 12 women were excluded because they had no history of surgery and 70 women with a history of abdominal and pelvic surgery were analyzed in the study group. The study group (n=70) had a median of two (range, 1-6) previous abdominal surgeries. The median number of previous laparotomies was 0 (range, 0-5). The median number of previous laparoscopies was 1 (range, 0-6). At laparoscopy, 6 of 70 women (8.6%) had periumbilical adhesions diagnosed; 18 of 70 women (25.7%) had any adhesions located in the abdomen or pelvis. The office visceral slide test had a sensitivity of 83.3%, specificity of 100%, positive predictive value of 100%, negative predictive value of 98.5% and diagnostic accuracy of 98.6%. CONCLUSION: The office visceral slide test is a simple and reliable test for detecting obliterating periumbilical adhesions in the outpatient setting. LEVEL OF EVIDENCE: II.

Laparoscopically-assisted, hysteroscopic removal of an interstitial pregnancy with a fertility-preserving technique.

Described is a novel surgical management of an unruptured interstitial pregnancy with preservation of the ipsilateral fallopian tube and uterine cornua. The patient was a 34-year-old woman, gravida 3, para 1, with an unruptured left interstitial pregnancy at 9 weeks' gestation, who desired preservation of fertility. The ectopic pregnancy was entirely removed via laparoscopically assisted hysteroscopy with a fertility-preserving surgical technique, with minimal blood loss, preservation of reproductive organs, restoration of anatomy, a patent ipsilateral fallopian tube, and expedient return to normal reproductive function. After the procedure, serial human chorionic gonadotropin levels were obtained until they were <5 mIU/mL. A hysterosalpingogram obtained 2 months after the procedure showed normal uterine and fallopian tube contour and bilateral tubal patency. We conclude that this laparoscopically assisted hysteroscopic technique is a safe and efficient fertility-preserving approach to management of an unruptured interstitial pregnancy.

Hematoureter due to endometriosis.

OBJECTIVE: To report the laparoscopic management of a rare case of hematoureter due to endometriosis in a young woman with multiple genitourinary anomalies. DESIGN: Video demonstration of a surgical technique and review of genitourinary endometriosis. SETTING: Hospital. PATIENT(S): A 17-year-old nulliparous woman with multiple genitourinary anomalies presented with pelvic pain and unilateral retroperitoneal mass. The patient had uterine didelphys, a history of left nephrectomy, and partial ureter resection as an infant. She had a partial resection of a left transverse vaginal septum due to hematocolpos at age 12. A preoperative magnetic resonance imaging (MRI) scan revealed a left retroperitoneal mass with extension to the paravesical region, reaccumulation of the hematocolpos behind the partially resected left transverse vaginal septum, and a dilated left uterine horn with hematometra. INTERVENTION(S): Laparoscopic management of hematoureter due to intrinsic endometriosis. MAIN OUTCOME MEASURE(S): Intraoperative findings showed uterus didelphys with dilated left horn, normal right horn, and normal right and left fallopian tubes and ovaries. The left transverse vaginal septum was resected vaginally, and the hematocolpos and hematometra drained. The left uterine horn and cervix were laparoscopically resected. The left-side serpiginous retroperitoneal mass was dissected from the pelvic sidewall, ligated, and transected, with spillage of thick, brown liquid. The pathology of the mass wall was smooth muscle and transitional epithelium consistent with ureter, in addition to hemorrhage and glandular structures consistent with endometriosis. Endometriosis was also present in the serosa of the left uterine horn. Thus, the left retroperitoneal mass was the left ureter remnant, which acquired endometriosis and collected menstrual debris, resulting in hematoureter. CONCLUSION(S): Two major pathologic types of ureteral endometriosis have been described: intrinsic, as occurred in this patient, and extrinsic. Women with müllerian anomalies, vaginal obstruction, or imperforate hymen are at higher risk of endometriosis. Prior urogenital surgery can further complicate and distort the anatomy. Thus, a preoperative understanding of the patient's urogenital anomalies is important to consider the differential diagnoses and anticipate surgical needs.

Infiltration of tumor-associated macrophages is increased in the epithelial and stromal compartments of endometrial carcinomas.

Tumor-associated macrophages (TAMs) are derived from monocytes and recruited to the tumor microenvironment, where they play an important role in the progression of cancer. There is strong evidence for an inverse relationship between TAM density and clinical prognosis in solid tumors of the breast, prostate, ovary, and cervix. However, the role of TAMs in endometrial cancer is not well described. The objectives of this study were to determine whether macrophage distribution or density differed among normal endometrial tissue, hyperplasia, Type I, and II endometrial adenocarcinomas. In addition, we looked for a correlation among TAM density, known histopathologic prognostic indicators, and endometrial cancer progression. The pathologic specimens of women who underwent hysterectomy for benign disorders, endometrial hyperplasia, Type I, or Type II cancers were sectioned and stained with anti-CD68 antibody. The density of CD68 macrophages was quantified and stratified according to their epithelial or stromal location. Type I and II endometrial carcinomas had significantly higher macrophage density in both epithelial and stromal compartments than benign endometrium. In both benign and neoplastic specimens, the numbers of macrophages were significantly higher in the stroma compared with the epithelium. Although there were important trends in the density of TAMs with regard to several histopathologic prognostic indicators of endometrial cancer, none were statistically significant and the patients' cancer progression did not correlate significantly with the number of TAMs.

A cyclic pain: the pathophysiology and treatment of menstrual migraine.

UNLABELLED: Catamenial migraine is a headache disorder occurring in reproductive-aged women relevant to menstrual cycles. Catamenial migraine is defined as attacks of migraine that occurs regularly in at least 2 of 3 consecutive menstrual cycles and occurs exclusively on day 1 to 2 of menstruation, but may range from 2 days before (defined as -2) to 3 days after (defined as +3 with the first day of menstruation as day +1). There are 2 subtypes: the pure menstrual migraine and menstrually related migraine. In pure menstrual migraine, there are no aura and no migraine occurring during any other time of the menstrual cycle. In contrast, menstrually related migraine also occurs in 2 of 3 consecutive menstrual cycles, mostly on days 1 and 2 of menstruation, but it may occur outside the menstrual cycle. Catamenial migraine significantly interferes with the quality of life and causes functional disability in most sufferers. The fluctuation of estrogen levels is believed to play a role in the pathogenesis of catamenial migraine. In this review, we discuss estrogen and its direct and indirect pathophysiologic roles in menstrual-related migraine headaches and the available treatment for women. TARGET AUDIENCE: Obstetricians and gynecologists, family physicians. LEARNING OBJECTIVES: After completing this CME activity, physicians should be better able to discuss the pathophysiology of catamenial migraine, identify the risk factors for catamenial migraine among women, and list the prophylactic and abortive treatments for migraines.

A rare case of primary extranodal marginal zone B-cell lymphoma of the ovary, fallopian tube, and appendix in the setting of endometriosis.

Extranodal marginal zone B-cell lymphomas are uncommon. Most occur in the gastrointestinal tract. Marginal zone B-cell lymphomas of the female genital tract are rare, and few cases exist of marginal zone B-cell lymphomas of the uterus, cervix, and fallopian tubes. We report the first marginal zone B-cell lymphoma of the ovary, fallopian tube, and appendix arising in endometriosis.

Tubal factor infertility: diagnosis and management in the era of assisted reproductive technology.

Tubal factor infertility accounts for a large portion of female factor infertility. The most prevalent cause of tubal factor infertility is pelvic inflammatory disease and acute salpingitis. The diagnosis of tubal occlusion can be established by a combination of clinical suspicion based on patient history and diagnostic tests, such as hysterosalpingogram, sonohysterosalpingography, and laparoscopy with chromopertubation. Depending on several patient factors, tubal microsurgery or more commonly in vitro fertilization with its improving success rates are the recommended treatment options.

G protein-coupled estrogen receptor 1-mediated effects in the rat myometrium.

G protein-coupled estrogen receptor 1 (GPER), also named GPR30, has been previously identified in the female reproductive system. In this study, GPER expression was found in the female rat myometrium by reverse transcriptase-polymerase chain reaction and immunocytochemistry. Using GPER-selective ligands, we assessed the effects of the GPER activation on resting membrane potential and cytosolic Ca(2+) concentration ([Ca(2+)](i)) in rat myometrial cells, as well as on contractility of rat uterine strips. G-1, a specific GPER agonist, induced a concentration-dependent depolarization and increase in [Ca(2+)](i) in myometrial cells. The depolarization was abolished in Na(+)-free saline. G-1-induced [Ca(2+)](i) increase was markedly decreased by nifedipine, a L-type Ca(2+) channel blocker, by Ca(2+)-free or Na(+)-free saline. Intracellular administration of G-1 produced a faster and transitory increase in [Ca(2+)](i), with a higher amplitude than that induced by extracellular application, supporting an intracellular localization of the functional GPER in myometrial cells. Depletion of internal Ca(2+) stores with thapsigargin produced a robust store-activated Ca(2+) entry; the Ca(2+) response to G-1 was similar to the constitutive Ca(2+) entry and did not seem to involve store-operated Ca(2+) entry. In rat uterine strips, administration of G-1 increased the frequency and amplitude of contractions and the area under the contractility curve. The effects of G-1 on membrane potential, [Ca(2+)](i), and uterine contractility were prevented by pretreatment with G-15, a GPER antagonist, further supporting the involvement of GPER in these responses. Taken together, our results indicate that GPER is expressed and functional in rat myometrium. GPER activation produces depolarization, elevates [Ca(2+)](i) and increases contractility in myometrial cells.

Advances in the genetics of endometriosis.

Endometriosis is a gynecological disease characterized by implantation of endometrial tissue outside of the uterus. Early familial aggregation and twin studies noted a higher risk of endometriosis among relatives. Studies on the roles of the environment, genetics and aberrant regulation in the endometrium and endometriotic lesions of women with endometriosis suggest that endometriosis arises from the interplay between genetic variants and environmental factors. Elucidating the hereditary component has proven difficult because multiple genes seem to produce a susceptibility to developing endometriosis. Molecular techniques, including linkage and genome-wide analysis, have identified candidate genes located near known loci related to development and regulation of the female reproductive tract. As new candidate genes are discovered and hereditary pathways identified using technologies such as genome-wide analysis, the possibility of prevention and treatment becomes more tangible for millions of women affected by endometriosis. Here, we discuss the advances of genetic research in endometriosis and describe technologies that have contributed to the current understanding of the genetic variability in endometriosis, variability that includes regulatory polymorphisms in key genes.