J Obstet Gynaecol Res. 2010 Feb;36(1):1-10. Mysteries of endometriosis pain: Chien-Tien Hsu Memorial Lecture 2009. Fraser IS. Department of Obstetrics and Gynaecology, University of Sydney, Sydney, New South Wales, Australia. The more that one looks at the condition endometriosis, the more one realises that it is a unique and complex condition exhibiting a bizarre range of deviations from normal endometrial and myometrial physiology, ...
Gynecol Endocrinol. 2017 Sep;33(9):712-715.
The association between progestins, nuclear receptors expression and inflammation in endometrial stromal cells from women with endometriosis.
Endometriosis is an inflammatory disease and nuclear receptors play a crucial role in mediating the inflammatory response. In endometrial stromal cells (ESC), nuclear receptors expression can be influenced by the local environment. Progestins are first-line, on-label treatments of endometriosis that may have direct effects on endometriotic lesions through these nuclear receptors. Therefore, we investigated whether there was an association between nuclear receptors expression and the influence of progestins on inflammatory cytokines production in a preliminary, in vitro study with primary cultures. ESC from endometrial biopsies of six subjects with histologically confirmed endometriosis were treated for 6 h with medium alone or with TNF-α (10 or 100 ng/ml) in the presence of dienogest (DNG), medroxyprogesterone acetate (MPA) and norethisterone acetate (NETA) 10-5 M. The progestin-mediated change in IL6, IL8 and MCP-1 mRNA transcription was measured, as was the PRA, PRB, GR, AR and MCR protein expression. The change (medium versus TNF-α 10 ng/ml and medium versus TNF-α 100 ng/ml) in IL6 mRNA transcription was positively associated with the change in PRB, but not PRA with both DNG and NETA treatment. The change in IL8 mRNA was negatively associated with AR expression in the presence of NETA. The change in MCP-1 mRNA expression was positively associated with GR expression and negatively associated with MCR after MPA treatment. The associations between the change in cytokines mRNA expression and nuclear receptors protein expression in response to progestins activity may indirectly suggest different activities of these compounds at a local level worthy of further investigations.
J Clin Ultrasound. 2017 Jul 8;45(6):313-318.
Transvaginal sonography in the diagnosis of deep infiltrating endometriosis: A review.
This review summarizes the current evidence regarding the diagnostic accuracy of sonography (US) in women with deep infiltrating endometriosis (DIE). It is well known that transvaginal ultrasound (TVUS) can detect ovarian endometriomas with a high degree of sensitivity. In recent years, US has also been used to detect DIE. In the hands of an experienced sonologist, the sensitivity and specificity of TVUS in the detection of DIE is comparable to those of MRI. TVUS can eliminate the need for an MRI in the majority of patients and reduce the need for diagnostic laparoscopy, proving to be an important tool in preoperative planning. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:313-318, 2017.
J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Jun 1;1054:20-26
Simultaneous determination of ten bioactive constituents of Sanjie Zhentong Capsule in rat plasma by ultra-high-performance liquid chromatography tandem mass spectrometry and its application to a pharmacokinetic study.
Sanjie Zhentong capsule, a well-known traditional Chinese medicine prescription, are used for the treatment of endometriosis-related diseases. In this study, a simple, rapid and sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed for the simultaneous determination of ten bioactive constituents, including peimine, peiminine, peimisine, loureirin A, loureirin B, 7,4′-dihydroxyflavone, pterostilbene, ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1 in rat plasma after oral administration of Sanjie Zhentong capsule. The sample preparations for protein removal was accomplished using a simple methanol precipitation method. The analytes were completely separated from the endogenous compounds on an Agilent Poroshell 120 SB-C18 column (4.6mm×150mm, 2.7μm) using an isocratic elution with methanol – 0.1% formic acid aqueous (4/1, v/v) as a mobile phase. The single-run analysis time was as short as 14.0min. The inter-day and intra-day precision of the quality control samples exhibited relative standard deviations (RSD) <9.5% and the accuracy values ranged from -8.6% to 15.0%. The lower limits of quantification (LLOQ) were 10, 10, 10, 10, 10, 10, 5, 10, 10 and 20ng/mL for peimine, peiminine, peimisine, loureirin A, loureirin B, 7,4′-dihydroxyflavone, pterostilbene, ginsenoside Rg1, ginsenoside Rb1, notoginsenoside R1, respectively. The analytical method was successfully applied to a pharmacokinetic study of the multi-components after oral administration of Sanjie Zhentong Capsule in rats.
Oncotarget. 2017 Jun 20;8(25):41679-41689.
Epithelial-to-mesenchymal transition in the development of endometriosis.
Endometriosis, an estrogen-dependent chronic gynecological disease, is common in reproductive-age women and profoundly affects their life quality. Although various pathogenic theories have been proposed, the origin of endometriosis remains unclear. Epithelial to mesenchymal transition (EMT) is a process that epithelial cells lose polarized organization of the cytoskeleton and cell-to-cell contacts, acquiring the high motility of mesenchymal cells. These changes are thought to be prerequisites for the original establishment of endometriotic lesions. However, no study exactly indicates which type of EMT occurs in endometriosis. In this review, we conclude that two different types of EMT may participate in this disease. Besides, two stimulating signals, hypoxia and estrogen, can through different pathways to activate the EMT process in endometriosis. Those pathways involve many cellular factors such as TGF-beta and Wnt, ultimately leading to cell proliferation and migration. As infertility is becoming a serious and intractable issue for women, EMT, during the implantation process, is gaining attention. In this review, we will describe the known functions of EMT in endometriosis, and suggest further studies that may aid in the development of medical therapy.
J Assist Reprod Genet. 2017 Jun;34(6):765-774
A higher prevalence of endometriosis among Asian women does not contribute to poorer IVF outcomes.
The purpose of the study was to determine whether diagnosis of endometriosis or endometriosis with endometrioma influences in vitro fertilization (IVF) outcomes in an ethnically diverse population.
Women undergoing a first IVF cycle (n = 717) between January 1, 2008 and December 31, 2009, at a university-affiliated infertility clinic, were retrospectively assessed for an endometriosis diagnosis. Differences in prevalence of endometriosis by ethnicity were determined, as well as differences in IVF success by ethnicity, with a focus on country of origin for Asian women. A multivariate model was generated to assess the relative contributions of country of origin and endometriosis to chance of clinical pregnancy with IVF.
Endometriosis was diagnosed in 9.5% of participants; 3.5% also received a diagnosis of endometrioma. Endometriosis prevalence in Asian women was significantly greater than in Caucasians (15.7 vs. 5.8%, p < 0.01). Women of Filipino (p < 0.01), Indian (p < 0.01), Japanese (p < 0.01), and Korean (p < 0.05) origin specifically were more likely to have endometriosis than Caucasian women, although there was no difference in endometrioma presence by race/ethnicity. Oocyte quantity, embryo quality, and fertilization rates did not relate to endometriosis. Clinical pregnancy rates were significantly lower for Asian women, specifically in Indian (p < 0.05), Japanese (p < 0.05), and Korean (p < 0.05) women, compared to Caucasian women, even after controlling for endometriosis status.
The prevalence of endometriosis appears to be higher in Filipino, Indian, Japanese, and Korean women presenting for IVF treatment than for Caucasian women; however, the discrepancy in IVF outcomes was conditionally independent of the presence of endometriosis. Future research should focus on improving pregnancy outcomes for Asian populations whether or not they are affected by endometriosis, specifically in the form of longitudinal studies where exposures can be captured prior to endometriosis diagnoses and infertility treatment.
Acta Obstet Gynecol Scand. 2017 Jun;96(6):688-693.
Does surgery for deep infiltrating bowel endometriosis improve fertility? A systematic review.
Reduced fertility is a major concern in women with endometriosis. The influence of surgery of deep infiltrating endometriosis (DIE) affecting the bowel wall on fertility is controversial and the literature on this field is heterogeneous. In this review we addressed whether surgery for bowel DIE improves the spontaneous pregnancy rate, and the results of in vitro fertilization (IVF), and the potential risk of such surgery.
MATERIAL AND METHODS:
We conducted a literature search including the terms “deep”, “deep infiltrating”, “bowel”, rectovaginal”, “endometriosis”, “fertility”, “infertility” and “IVF” in PubMed.
No randomized controlled studies were found. Other publications of relevance included four retrospective and three prospective observational studies. Moreover, one retrospective study compared results of IVF treatment with or without previous surgery for bowel DIE. All studies reported detailed data on surgical complications. The poor data quality precluded firm conclusions. The results indicate, however, the possibility that surgery for bowel DIE may improve the spontaneous pregnancy rate, and positive effects on IVF outcome cannot be excluded. Such surgery will be associated with risk of major complications.
The lack of proper data precludes conclusions on the potential role for bowel DIE surgery to improve the spontaneous pregnancy rate and results of IVF treatment. Positive effects cannot be excluded, but the definite risk of major complications must be taken into account.
Eur J Obstet Gynecol Reprod Biol. 2017 Jun;213:33-38.
Endometriosis doubles odds for miscarriage in patients undergoing IVF or ICSI.
To identify and estimate the importance of risk factors on pregnancy loss until the end of the second trimester after clinical pregnancy was achieved by either in vitro fertilisation (IVF) or intra-cytoplasmic sperm injection (ICSI).
Retrospective cohort study including 588 cycles with fresh embryo transfers and 150 cycles with frozen-thawed embryo transfers using logistic regression.
The rate of miscarriages subsequent to a fresh embryo transfer was significantly increased by a diagnosis of endometriosis (p=0.02), as well as significantly influenced by the age of the female patient at the time of oocyte retrieval (p<0.01) and the serum level of testosterone (p=0.02). The time between freezing and thawing of the pronuclear stages for a frozen-thawed embryo transfer revealed a trend to a higher rate of miscarriages (p=0.06).
Endometriosis significantly decreases the chance of having a baby even with IVF or ICSI.
Taiwan J Obstet Gynecol. 2017 Apr;56(2):181-183.
The clinical profile of young and adolescent women with laparoscopically diagnosed endometriosis in a Singapore tertiary hospital.
Endometriosis has been increasingly recognized as the cause of severe dysmenorrhea among younger women including adolescents, often with significant delay from time of presentation to diagnosis. Data on the South East Asian women is scarce. This study aims to describe the disease pattern in a group of young Asian women with histological diagnosis of endometriosis in our center.
MATERIALS AND METHODS:
A total of 709 laparoscopic operations were performed for endometriosis in our center between 2000 and 2007. Women aged 25 years old and below were included in this study. Details regarding clinical presentation and severity of disease were retrospectively reviewed and described.
A total of 45 women were included in this study, aged between 14 years and 25 years. Thirty seven patients (82.3%) were aged between 21 years and 25 years. Racial distribution was as follows: 57.8% Chinese, 26.7% Malay, and 15.6% Indian. Dysmenorrhea was the commonest symptom (84.4%); 44.4% of which were described as mild. Eleven patients (24.4%) presented with severe symptoms resulting in absence from school or work. Severity of endometriosis during laparoscopy was staged using the rAFS staging system, and was 11.1%, 17.8%, 28.9%, and 42.2% for disease Stage I, Stage II, Stage III, and Stage IV, respectively.
Endometriosis can cause severe disease even in adolescents and young females. Increased awareness among patients and healthcare providers would raise a higher index of suspicion for endometriosis in these women, with consequent early treatment which may result in better functional and fertility outcomes.
Taiwan J Obstet Gynecol. 2017 Apr;56(2):243-246.
Ileocecal endometriosis: diagnosis and management.
Ileocecal endometriosis is rare. Symptoms range from no symptoms, cramps, vomiting, to acute intestinal obstruction. Our objective was to review our cases, clarify, and resume its most appropriate management focusing on the factors to determine diagnosis. This is a retrospective study by revision of medical charts of all ileal endometriosis cases of our unit from 2006 to 2014.
Seven cases were found; three (43%) had previous endometriosis laparoscopic diagnosis, four (57%) had partial bowel obstruction episodes, three (43%) had chronic pelvic pain, and one developed acute intestinal obstruction in postoperative ileostomy closure. In three (43%), the diagnosis was made with magnetic resonance imaging (MRI) and double contrast barium enema, in one (14%) only with MRI, and the other three (43%) during surgery. All patients underwent resection of the ileum and evolved favorably.
Variability in symptoms hinders diagnosis. The gold standard for diagnosis is MRI, but clinical suspicion optimizes imaging test diagnosis. Segmental resection should be indicated in the majority of the cases.
Acta Obstet Gynecol Scand. 2017 Jun;96(6):727-735.
Surgery versus conservative management of endometriomas in subfertile women. A systematic review.
Endometriomas are present in up to 44% of all women with endometriosis and have a detrimental effect on fertility. However, it is controversial whether endometriomas should be surgically removed before assisted reproduction technology. Our purpose was to evaluate whether surgical stripping of endometriomas in subfertile women improves the chance of a live birth. Secondary outcomes were impact on ovarian reserve and pain.
MATERIAL AND METHODS:
We conducted a systematic review and meta-analysis with results reported in accordance to the PRISMA guidelines. A summary of findings table was developed using GRADE. We searched Medline and Embase. Two reviewers performed the screening.
Of 686 manuscripts, we included one randomized controlled trial and nine retrospective cohort studies, mostly of low quality. The odds ratio for live birth after surgery [compared with conservative management before in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI)] was 0.87 (95% CI 0.64-1.18, six studies, I2 = 3%; ⨁◯◯◯, VERY LOW quality). The mean difference of antral follicle count was -2.09 (95% CI -4.84 to 0.67, four studies). No difference was observed regarding antral follicle count between the two groups (MD -2.09, 95% CI -4.84 to 0.67, four studies, ⨁◯◯◯, VERY LOW quality). Pain outcome was not reported in the included studies.
The very low quality evidence suggests no difference in odds ratio of live birth between women who underwent surgery for endometriomas before IVF/ICSI compared with conservative management. Further high quality studies are needed, but due to a lack of convincing evidence favoring surgery, we recommend considering conservative treatment if the only indication is subfertility.
Acta Obstet Gynecol Scand. 2017 Jun;96(6):623-632.
Progesterone resistance in endometriosis: origins, consequences and interventions.
Endometriosis is a common cause of pelvic pain and affects up to 10% of women of reproductive age. Aberrant progesterone signaling in the endometrium plays a significant role in impaired decidualization and establishment of ectopic endometrial implants. Eutopic endometrial cells from women with endometriosis fail to downregulate genes needed for decidualization, such as those involved in cell cycle regulation, leading to unbridled proliferation. Several causes of progesterone resistance in the endometrium have been postulated, including congenital “preconditioning”, whereby the in utero environment renders infants susceptible to neonatal uterine bleeding and endometriosis. Progesterone action is crucial to decreasing inflammation in the endometrium, and deviant progesterone signaling results in a proinflammatory phenotype. Conversely, chronic inflammation can induce a progesterone-resistant state. Repetitive retrograde endometrial shedding begets chronic peritoneal inflammation, which further exacerbates progesterone resistance. Genetic causes of progesterone resistance include progesterone receptor gene polymorphisms, altered microRNA expression, and epigenetic modifications to progesterone receptors and their targets. Environmental toxins such as dioxin play a possible role in the genesis of endometriosis by permitting an inflammatory milieu. A consequence of impaired progesterone action is that hormonal therapy is rendered ineffective for a subset of women with endometriosis. Synthetic progestins, such as dienogest, may overcome this phenomenon by increasing progesterone receptor expression and decreasing proinflammatory cytokines. Other modalities include high dose depot formulations of progestins, medicated intrauterine devices and the likely advent of oral GnRH antagonists. Unearthing root causes of progesterone inaction in endometriosis will aid in the development of novel therapeutics geared toward prevention and treatment.
Clin Exp Reprod Med. 2017 Mar;44(1):28-32.
Cardiovascular risk may be increased in women with unexplained infertility.
Growing evidence suggests that increased cardiovascular disease (CVD) risk is associated with female infertility caused by conditions such as polycystic ovarian disease, obesity, thyroid dysfunction, and endometriosis. The aim of this study was to evaluate whether any relationship exists between CVD and unexplained infertility.
Sixty-five women with unexplained infertility and 65 fertile controls were enrolled in the study. CVD risk markers such as low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), triglycerides (TG), insulin resistance (defined by the homeostasis model assessment ratio), and high-sensitivity C-reactive protein (hs-CRP) were assessed.
TG, TC, LDL, and hs-CRP levels were higher and HDL levels were lower in patients with unexplained infertility than in fertile controls (p<0.05 for all). Positive associations were found between unexplained infertility and TG, TC, LDL, and hs-CRP levels, and a negative correlation was found for HDL (p<0.05 for all). Multivariate logistic regression analysis showed that TG, HDL, and hs-CRP were independent variables associated with unexplained infertility.
Our study showed that women with unexplained infertility had an atherogenic lipid profile and elevated hs-CRP levels, suggesting a higher risk of developing CVD in the future. Further studies with larger groups are needed to investigate the nature of this link.
Fundam Clin Pharmacol. 2017 Oct;31(5):506-512.
Effect of alpha-lipoic acid on endometrial implants in an experimental rat model.
To investigate the antioxidant and anti-inflammatory effects of alpha-lipoic acid (ALA) in the treatment of endometriosis in an experimental rat model by evaluating biochemical and histopathologic parameters. Experimental endometriosis was induced by the peritoneal implantation of autologous endometrial tissue. The rats were randomly divided into two groups with eight rats each. Group I was intraperitoneally administered ALA 100 mg/kg/day for 14 days. Group II was intraperitoneally administered saline solution at the same dosage and over the same period. Endometrial implant volume was measured in both groups both pre- and post-treatment. Tumor necrosis factor alpha (TNF-α) was measured in peritoneal fluid. Total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) were assessed in serum. The implants were histopathologically evaluated. In the ALA group, the serum TOS and OSI levels, the endometrial implant volumes, the TNF-α levels in serum and peritoneal fluid, and the histopathologic scores were significantly lower compared to the control group (P < 0.05). Alpha-lipoic acid may have a therapeutic potential in the treatment of endometriosis due to its antioxidant and anti-inflammatory effects.
Ann Ital Chir. 2017 Apr 13;6.
Malignant endometriosis of the abdominal wall.
Endometriosis is a disease represented by the presence of extra uterine endometrial tissue. It is a rare condition, and malignant transformation is seldom. We report a case with clear cell adenocarcinoma oncogenesis on abdominal wall scar that appeared after years of a caesarian section. After diagnosis, surgical treatment was performed twice, due to the fact that the margins were infiltrated with tumor cells, with replacement of the defect with a polypropylene mesh. The patient was cured and discharged with a favorable prognostic. To the best of our knowledge, there are few reported cases of clear cell adenocarcinoma arising from abdominal wall endometriosis. It is a rare condition that appears mostly after abdominal surgical interventions that clinicians must be aware.
Cytokine. 2017 Aug;96:166-172.
LIF endometrial expression is impaired in women with unexplained infertility while LIF-R expression in all infertility sub-groups.
The main objective of our study was to study LIF and LIF-R endometrial expression during the implantation window in the various sub-groups of infertile women according to infertility cause. A prospective observational case-control study was performed from March 2013 to February 2016. Infertile women consisted of the patients’ group (group 2) while fertile women were the control group (group 1). Infertile women were divided according to infertility cause in women with tubal factor (group 2a), poor ovarian reserve (group 2b), endometriosis (group 2c) and unexplained infertility (group 2d). Endometrial biopsy was performed on 7th-8th postovulatory menstrual day. Leukemia Inhibitory Factor (LIF) and LIF-Receptor (LIF-R) expression in epithelial and stromal cells were assessed with Immunohistochemistry (IHC). There were 20 infertile with poor ovarian reserve, 15 with tubal factor, 10 with endometriosis and 15 with unexplained infertility included in the analysis. LIF expression in patients with unexplained infertility was significantly compared with controls (P=0.006). No significant difference was observed between patients with tubal factor, poor ovarian reserve and endometriosis compared with control group (P=0.78, P=0.44 and P=0.56 respectively). Analysis of LIF-R expression in sub-categories of infertility indicated that expression was significantly decreased in all sub-groups of infertility. Our study indicated impaired LIF expression levels only in women with unexplained infertility, while LIF-R expression was impaired in all sub-groups of infertile women. Further multicenter prospective studies should be performed in order to assess the exact etiopathogenetic role of these cytokines in the molecular background of infertility.
Fertil Steril. 2017 May;107(5):1191-1199.
Peritoneal fluid cytokines related to endometriosis in patients evaluated for infertility.
Our aim was to characterize peritoneal cytokine profiles in patients with infertility, with and without endometriosis, to illuminate potential differences in immune profiles that may reflect mechanistic differences between these two patient populations.
University hospital and research center.
Women undergoing laparoscopy for infertility investigation (n = 107).
Peritoneal fluid was collected during surgery. Clinical characteristics were registered preoperatively.
MAIN OUTCOME MEASURE(S):
We determined the concentration of 48 different cytokines from the peritoneal fluid with multiplex immunoassays. Associations between cytokines and clinical findings were assessed with logistic regression and partial least squares discriminant analyses (PLS-DA).
Concentrations of SCGF-β, IL-8, HGF, and MCP-1 were significantly higher, while IL-13 was significantly lower in the endometriosis group compared with the group without endometriosis. Multiple stepwise logistic regression identified a combination of SCGF-β, IL-13, and G-CSF concentrations that predicted the presence of endometriosis with 86% sensitivity and 67% specificity. PLS-DA identified a class of 11 cytokines (SCGF-β, HGF, IL-13, MCP-1, CTACK, MCP-3, M-CSF, LIF, IL-5, IL-9, and IFN-a2) that were more characteristic of endometriosis than nonendometriosis patients.
By combining univariate and multivariate analyses, profiles of cytokines more likely to be enriched or depleted in infertility patients with endometriosis compared with those without endometriosis were identified. These findings may inform future analyses of pathophysiological mechanisms of endometriosis in infertile patients, including dysregulated Th1/Th2 response and mobilization and proliferation of hematopoietic stem cells.
J Minim Invasive Gynecol. 2017 Jul – Aug;24(5):815-821.
Randomized Trial on Fast Track Care in Colorectal Surgery for Deep Infiltrating Endometriosis.
To study the application of a fast-track care protocol in colorectal surgery for deep infiltrating endometriosis. Bowel endometriosis is an infrequent but not rare condition that often needs intestinal surgery and imposes a high economic burden on society.
Prospective randomized trial (Canadian Task Force classification I).
Tertiary referral center.
Two hundred twenty-seven patients with preoperative evidence of bowel endometriosis.
We randomly assigned 227 patients with preoperative evidence of bowel endometriosis to a fast-track protocol (no preoperative bowel preparation, early restoration of diet, no postoperative antibiotics, and early postoperative mobilization) or conventional care for laparoscopic intestinal surgery. Randomization was obtained on a double-blind, date-based schedule, and all procedures were performed by a homogenous group of expert surgeons. Surgical outcomes and a health economic evaluation were assessed.
MEASUREMENTS AND MAIN RESULTS:
The primary outcome was hospital stay. Patient’s well-being and intraoperative and postoperative complications up to 30 days after surgery were also assessed. Subsequently, direct medical costs were analyzed. Patients assigned to the fast-track protocol were discharged earlier (median 3 vs 7 days, p < .001) with no significant differences in subjective well-being (p = .55). Operative details, postoperative complications, and need of temporary ileostomy were similar (p = .89) between groups as well as readmission rates within 30 days (p = .69). The application of a fast-track protocol resulted in an overall significant reduction of costs (USD 6699 vs 8674, p < .01), and differences were more evident in cases of protective stoma (7652 vs 8793, p < .05) and surgery with postoperative complications (10 835 vs 14 005, p < .01).
The application of a fast-track care protocol for laparoscopy in cases of pelvic and intestinal endometriosis does not increase the risk of complications and ensures a reduction of medical costs.
Ultrasound Obstet Gynecol. 2018 Jan;51(1):145-146.
Transrectal High-Intensity Focused Ultrasound as focal therapy of posterior deep invasive endometriosis.
Posterior deep infiltrating endometriosis (DIE) is one of the most frequent locations of the disease.1 The rectosigmoid colon is often involved and can be associated with symptoms such as diarrhea, dyschezia and bowel cramping. As medical treatments are often not curative, surgical procedure are often mandatory.
Acta Obstet Gynecol Scand. 2017 Jun;96(6):707-714.
High intensity focused ultrasound for the treatment of adenomyosis: selection criteria, efficacy, safety and fertility.
Adenomyosis is a disorder of uterus in which endometrial glands and stroma are present within the uterine musculature. The main clinical manifestations are dysmenorrhea and menorrhagia. Adenomyosis has a great impact on both the quality of life and fertility of women. The treatment of adenomyosis remains an immense challenge. Relevant articles were searched through MEDLINE and PubMed between 2000 and March 2017. The search terms of adenomyosis, magnetic resonance imaging (MRI) features of adenomyosis, high intensity focused ultrasound (HIFU), ultrasound-guided HIFU and MRgFUS were used. There were no language restrictions. HIFU is a non-invasive local thermal ablation technique which has been used in the treatment of both focal and diffuse adenomyosis. Several case studies have demonstrated that HIFU presents low rate of minor and/or major complications and, at the same time, a long symptom-relief period. Multiple factors such as the enhancement type of the adenomyotic lesion, volume of the adenomyotic lesions, number of hyperintense foci on T2WI, location of the uterus, location of adenomyotic lesions, thickness of the abdominal wall and distance from the skin to the adenomyotic lesions contribute to the efficacy of HIFU. Consequently, based on these contributing factors, specific and strict selection criteria have been used to achieve higher efficacy. Thus, patients with pelvic endometriosis, adhesions between the bowel and the uterus, or an abdominal surgical scar wider than 10 mm, are not suitable for HIFU treatment. Moreover, HIFU-treated patients with adenomyosis, who wished to conceive, showed high conception and live birth rates. HIFU is a new and promising treatment option for patients with adenomyosis, but its efficacy, safety, cost-effectiveness and fertility outcome must be evaluated by randomized controlled trials.
Reprod Sci. 2018 Jan;25(1):102-109.
Reduced Expression of Eukaryotic Translation Initiation Factor 3 Subunit e and Its Possible Involvement in the Epithelial-Mesenchymal Transition in Endometriosis.
Epithelial-mesenchymal transition (EMT) is now well documented to be involved in the development of endometriosis through the promotion of invasion and fibrogenesis. To date, several factors have been reported to be involved in EMT in endometriosis. The eukaryotic translation initiation factor 3 subunit e (eIF3e) protein is a component of the multisubunit eIF3 complex essential for cap-dependent translation initiation. The aim of this study was to investigate whether eIF3e is involved in EMT in endometriosis. We recruited 40 premenopausal women (34.7 [6.8] years) with laparoscopically and histologically diagnosed ovarian endometriomas, and their ectopic endometrial tissue samples were collected after informed consent. As controls, endometrial tissue samples were obtained after informed consent from 40 premenopausal women, roughly age-matched (36.9 [6.4] years) and menstrual phase-matched with endometriosis group, who underwent surgery for benign gynecologic disorders or cervical intraepithelial neoplasia but without endometriosis, adenomyosis, or uterine fibroids. All tissue samples were subjected to immunohistochemistry analysis of eIF3e, transforming growth factor (TGF-β1), Snail, E-cadherin, vimentin, and proliferating cell nuclear antigen (PCNA). We found significantly reduced immunoreactivity against eIF3e and E-cadherin but elevated immunoreactivity against TGF-β1, Snail, vimentin, and PCNA in endometriotic epithelial cells when compared to that of control endometrium (all P values <.05). The eIF3e staining levels correlated negatively with that of TGF-β1 and Snail but positively with that of E-cadherin (all P values <.05). These data suggest that eIF3e downregulation may be involved in EMT in endometriosis, possibly through preferential translation of Snail. Future studies are warranted to confirm whether this is the mechanism.
Hum Pathol. 2017 Jun;64:156-163.
Expression of protease-activated receptor-2 (PAR-2) is related to advanced clinical stage and adverse prognosis in ovarian clear cell carcinoma.
Recent studies demonstrated that protease-activated receptor-2 (PAR-2) correlates with tumor progression in various tissues. On the other hand, oxidative stress arising from endometriosis has been considered a cause of carcinogenesis in ovarian clear cell carcinoma (OCCC). We previously demonstrated that oxidative stress up-regulates PAR-2 expression, and we conducted the present study to investigate the PAR-2 expression and its relation to clinicopathological factors and oxidative stress in OCCC. We performed an immunohistochemical evaluation in 95 cases of OCCC. For the evaluation of oxidative stress markers, 31 cases of ovarian endometrioid carcinoma (OEC) were also examined. No significant differences in the expression of cyclooxygenase-2 and inducible nitric oxide synthase were observed between OCCC and OEC. Sixty-two percent of the OCCC cases showed high 8-hydroxydeoxyguanosine expression, whereas all of the OEC cases showed almost negative immunoreactivities. The presence of endometriosis did not affect the expression of these oxidative stress markers or prognosis. High PAR-2 expression was observed in 20% (14/71) of the early International Federation of Gynecology and Obstetrics (FIGO) stage cases and 58% (14/24) of the advanced FIGO stage cases. High PAR-2 expression was significantly correlated with advanced FIGO stage and shorter overall survival. We found no correlations between PAR-2 expression and oxidative stress in OCCC. Our results suggest that PAR-2 plays an important role in the progression of OCCC. The expression of 8-hydroxydeoxyguanosine is a characteristic finding of OCCC, indicating that the injury of DNA by oxidative stress may be involved in the carcinogenesis of OCCC.
Am J Reprod Immunol. 2017 Oct;78(4).
Hypoxia-inhibited DUSP2 expression promotes IL-6/STAT3 signaling in endometriosis.
How does hypoxia-mediated downregulation of dual-specificity phosphatase-2 (DUSP2) promote the development of endometriotic lesions?
METHOD OF STUDY:
The levels of IL-6 and DUSP2 were assessed in eutopic stromal cells with DUSP2 knockdown or hypoxia treatment. Bromodeoxyuridine (BrdU) incorporation was applied for evaluating cell proliferation. The protein levels of DUSP2, cleaved caspase-3, phosphorylated STAT3, and STAT3 were analyzed using immunoblot.
The genomewide analysis of cells with DUSP2 overexpression indicated IL-6 regulates multiple pathways related to inflammation, proliferation, and apoptosis. DUSP2 overexpression significantly suppressed IL-6 expression, while DUSP2 knockdown promoted IL-6 expression. The hypoxia-treated eutopic stromal cells expressed higher levels of IL-6, recapitulating the elevated levels of IL-6 in ectopic stromal cells. The treatment with IL-6 elicited the phosphorylation of STAT3, mimicking the elevated levels of phosphorylated STAT3 in the ectopic stromal cells. The IL-6-treated eutopic stromal cells showed more BrdU incorporation and less cleaved caspase-3, which can be reversed by STAT3 inhibitor.
Hypoxia-induced IL-6 production in endometriotic lesions is mediated via downregulation of DUSP2, which causes aberrant activation of STAT3 signaling pathway and helps the endometriotic cells survive under the ectopic environment.
J Womens Health (Larchmt). 2017 Jul;26(7):788-797.
Factors Associated with Time to Endometriosis Diagnosis in the United States.
We aimed to quantify the time to diagnosis among women with endometriosis in the United States (US) and to identify patient- and physician-related factors affecting diagnostic delay.
PATIENTS AND METHODS:
An online cross-sectional survey was conducted from August 6, 2012, through November 14, 2012. Respondents aged 18-49 years who reported a physician’s diagnosis/suspicion of endometriosis within the previous 10 years were included. Endometriosis-related symptoms and diagnostic history were captured and summarized. Univariate analyses identified factors associated with time from symptom onset to first consultation and from first consultation to diagnosis.
Of 638 respondents included, most (56%) reported seeking care for at least one of the following symptoms: menstrual pain (31.6%), nonmenstrual pain (27.3%), and pain during sex (7.5%). Most diagnoses (84%) were made by obstetricians/gynecologists; 49% of diagnoses were surgical versus 51% nonsurgical. Mean time from symptom onset to diagnosis was 4.4 years. Mean time to first consultation was shorter among women aged 40-49 years versus those aged <18 years (14.2 vs. 43.5 months; p < 0.0001) and those consulting for symptoms versus routine/other care (27.9, 24.9, and 28.4 months for menstrual pain, nonmenstrual pain, and pain during sex, respectively, vs. 61.4 months; all p < 0.01). Mean time from first consultation to diagnosis was shorter among women aged 40-49 years versus those aged <18 years (12.4 vs. 34.5 months; p = 0.0009) and those diagnosed by obstetricians/gynecologists versus nonobstetricians/gynecologists (21.5 vs. 40.3 months; p = 0.041).
Time to endometriosis diagnosis appears to have shortened in the US. Better patient and physician education regarding symptomatology may contribute to further gains.
Zhonghua Fu Chan Ke Za Zhi. 2017 Apr 25;52(4):233-238
Evaluation of endometriosis fertility index in follow-up treatment of endometriosis combined with infertility patients after laparoscopic surgery.
Objective: To explore the application of endometriosis fertility index (EFI) in guidance after laparoscopic surgery of endometriosis patients combined with infertility and to explore methods to improve pregnancy rate in different EFI groups. Methods: A prospective research was done in endometriosis patients combined with infertility in Beijing Obstetrics and Gynecology Hospital from January 2010 to June 2011, after laparoscopic surgery, these 146 patients were divided into 3 groups by EFI score. Using different pregnancy guidance, these patients had 5 years follow-up. Results: (1) The 5 years overall pregnancy rate was 89.0% (130/146). The pregnancy rate was 95.7% (45/47) in EFI≥9 group, 92.8% (77/83) in EFI 5-8 group and 8/16 in EFI≤4 group, three groups were all reach satisfactory pregnancy rate; the rate of the first two groups had no statistically significance (P=0.498), but had significant difference with the last group (P<0.01). (2) In EFI≥5 patients, pregnancy rate was the highest in 6 months after operation; in EFI≥9 group, the pregnancy rate was 66.7% (30/45), and EFI 5-8 group was 50.6% (39/77). (3) EFI≥9 group had the highest natural pregnancy rate [83.6% (46/55)], natural pregnancy rate was significant statistical different in different EFI groups (P=0.001). Conclusions: EFI score is a useful evaluation in predicting and guiding pregnancy in endometriosis patients combined with infertility after laparoscopic surgery. EFI score guidance, strict post-operation management and positive pregnancy scheme could significantly improve the pregnancy rate of endometriosis patients with infertility.
Expert Opin Investig Drugs. 2017 Jun;26(6):661-667.
Investigational and experimental GnRH analogs and associated neurotransmitters.
The GnRH agonistic analogs enable for desensitizing the hypothalamo-pituitary-gonadal axis in malignant and benign conditions where minimizing the production of sex hormones, or blocking ovulation is necessary. The possible indications are prostate cancer, benign prostate hyperplasia, breast cancer, endometriosis, precocious puberty, uterine leiomyomata, assisted reproduction (ART)/in vitro fertilization (IVF), PCOS, minimizing the gonadotoxic effect of chemotherapy in young women, and possibly ovarian cancer. Areas covered: The aim of the current review is to summarize, giving a critical overview, of the investigational GnRH agonists, and shortly discuss the difference between the GnRH agonists, antagonists, Kisspeptin, and Neurokinin B analogs. Expert opinion: The broad armamentarium of agonists may make it possible, in the future, to expand the indications and uses of these analogs, choosing and specifically tailoring the analog to the required effect, while minimizing side effects.
Ann Clin Lab Sci. 2017 Mar;47(2):208-212.
Extrauterine Adenomyoma of the Liver in a 50 year old Female with Pelvic Endometriosis.
Extrauterine adenomyomas are defined as circumscribed tumor-like masses consisting of smooth muscle tissue, endometrioid glands and stroma. They are extremely rare tumors and similar to their uterine counterparts. We report case of a 50 year old female with an extrauterine adenomyoma of the liver associated with pelvic endometriosis. To the best of our knowledge, only fifteen cases of extrauterine adenomyomas have been reported with only one previous case in the liver. This is the first case of extrauterine adenomyoma of the liver associated with pelvic endometriosis.
Cancer Biol Med. 2017 Feb;14(1):9-32
Epidemiology of ovarian cancer: a review.
Ovarian cancer (OC) is the seventh most commonly diagnosed cancer among women in the world and the tenth most common in China. Epithelial OC is the most predominant pathologic subtype, with five major histotypes that differ in origination, pathogenesis, molecular alterations, risk factors, and prognosis. Genetic susceptibility is manifested by rare inherited mutations with high to moderate penetrance. Genome-wide association studies have additionally identified 29 common susceptibility alleles for OC, including 14 subtype-specific alleles. Several reproductive and hormonal factors may lower risk, including parity, oral contraceptive use, and lactation, while others such as older age at menopause and hormone replacement therapy confer increased risks. These associations differ by histotype, especially for mucinous OC, likely reflecting differences in etiology. Endometrioid and clear cell OC share a similar, unique pattern of associations with increased risks among women with endometriosis and decreased risks associated with tubal ligation. OC risks associated with other gynecological conditions and procedures, such as hysterectomy, pelvic inflammatory disease, and polycystic ovarian syndrome, are less clear. Other possible risk factors include environmental and lifestyle factors such as asbestos and talc powder exposures, and cigarette smoking. The epidemiology provides clues on etiology, primary prevention, early detection, and possibly even therapeutic strategies.
Reprod Sci. 2017 Nov;24(11):1493-1502.
Role of Oxidative Stress in Epigenetic Modification in Endometriosis.
Aberrant DNA methylation and histone modification are associated with an increased risk of reproductive disorders such as endometriosis. However, a cause-effect relationship between epigenetic mechanisms and endometriosis development has not been fully determined. This review provides current information based on oxidative stress in epigenetic modification in endometriosis. This article reviews the English-language literature on epigenetics, DNA methylation, histone modification, and oxidative stress associated with endometriosis in an effort to identify epigenetic modification that causes a predisposition to endometriosis. Oxidative stress, secondary to the influx of hemoglobin, heme, and iron during retrograde menstruation, is involved in the expression of CpG demethylases, ten-eleven translocation, and jumonji (JMJ). Ten-eleven translocation and JMJ recognize a wide range of endogenous DNA methyltransferases (DNMTs). The increased expression levels of DNMTs may be involved in the subsequent downregulation of the decidualization-related genes. This review supports the hypothesis that there are at least 2 distinct phases of epigenetic modification in endometriosis: the initial wave of iron-induced oxidative stress would be followed by the second big wave of epigenetic modulation of endometriosis susceptibility genes. We summarize the recent advances in our understanding of the underlying epigenetic mechanisms focusing on oxidative stress in endometriosis.
Einstein (Sao Paulo). 2017;15(1):65-70.
Patients with endometriosis using positive coping strategies have less depression, stress and pelvic pain.
To determine the correlations between coping strategies, depression, stress levels and pain perception in patients with endometriosis.
This prospective and exploratory study included 171 women undergoing treatment for endometriosisbetween April and August 2014. The questionnaires used were Brief COPE, Beck Depression Inventory, Lipp’s Stress Symptom Inventory for Adults and Visual Analogue Scale. Clinical data were collected from electronic medical records.
Patients with endometriosis who used positive coping strategies had better adaptation to stress (p<0.004) and less depression (p<0.004). The presence and intensity of depression, stress and acyclic pelvic pain were directly associated (p<0.05). The intensity of dysmenorrhea was associated with the degree of depression (p<0.001), whereas acyclic pelvic pain was associated with the degree of depression (p<0.001), stress level (p<0.001) and stress type (p<0.001).
We found a positive association between coping, depression levels, type and levels of stress and pain intensity in patients with endometriosis. The use of maladaptive coping strategies focused on emotion is correlated with increase in depression and stress.
Observar a correlação entre estratégias de enfrentamento, depressão, níveis de estresse e percepção de dor em pacientes com endometriose.
Estudo prospectivo e exploratório, que incluiu 171 mulheres em tratamento por endometriose entre abril e agosto de 2014. Foram utilizadas as escalas: COPE Breve, Inventário de Depressão de Beck, Inventário de Sintomas de Stress para Adultos de Lipp e a Escala Visual Analógica. Os dados clínicos foram coletados do prontuário eletrônico.
Pacientes com endometriose que utilizaram estratégias positivas de enfrentamento apresentaram melhor adaptação ao estresse (p<0,004) e menos depressão (p<0,004). A presença e a intensidade da depressão, do estresse e da dor pélvica estiveram diretamente associadas (p<0,05). A intensidade da dismenorreia foi associada com o grau de depressão (p<0,001), enquanto a intensidade da dor pélvica acíclica esteve associada com o grau de depressão (p<0,001), nível de estresse (p<0,001) e tipo de estresse (p<0,001).
Houve associação positiva entre coping, níveis de depressão, tipo e níveis de estresse e intensidade da dor nas pacientes com endometriose. A utilização de estratégias de coping desadaptativa focada na emoção está correlacionada com o aumento da depressão e do estresse.
Einstein (Sao Paulo). 2017 Jan-Mar;15(1):105-111.
Association of the protein tyrosine phosphatase non-receptor 22 polymorphism (PTPN22) with endometriosis: a meta-analysis.
To evaluate PTPN22 C1858T polymorphism and the risk of endometriosis.
A meta-analysis of 10 published case-control studies (from four articles), with a total sample of 971 cases and 1,181 controls, was performed. We estimated risk (odds ratio and 95% confidence intervals) of endometriosis associations with the C1858T polymorphism.
A significant increased risk in all genetic models of the variant T allele with endometriosis (odds ratio: 3.14-5.55; p<0.00001-0.002) was found. The analysis without the study whose controls deviated from the Hardy-Weinberg equilibrium exacerbated these effects in the homozygous and recessive models (odds ratio: 7.19-9.45; p<0.00001-0.0002). In the Italian subgroup, a significant risk association was found in the homozygous and recessive models (odds ratio: 8.72-11.12; p=0.002).
The associations observed between PTPN22 (C1858T) and the risk of endometriosis suggest this polymorphism might be a useful susceptibility marker for this disease.
Arch Gynecol Obstet. 2017 Jun;295(6):1459-1468.
Endometrial cancer arising in adenomyosis versus endometrial cancer coexisting with adenomyosis: are these two different entities?
While adenomyosis is one of the most common benign histologic findings in hysterectomy specimens of endometrial cancer, demographics of endometrial cancer arising in adenomyosis (EC-AIA) has not been well elucidated. The aim of this study is to evaluate histopathological findings and disease-free survival (DFS) of EC-AIA in comparison to endometrial cancer coexisting with adenomyosis (EC-A).
EC-AIA cases were identified via a systematic literature search (n = 46). EC-A cases were identified from a historical cohort that underwent hysterectomy-based surgical staging in two institutions (n = 350). Statistical comparisons of the two groups were based on univariate and multivariate analyses.
The EC-AIA group was significantly older than the EC-A group (58.9 versus 53.8, p = 0.002). As to tumor characteristics, 63.6% of EC-AIA cases reported tumor within the myometrium without endometrial extension. The EC-AIA group was significantly associated with more non-endometrioid histology (23.9 versus 14.8%; p = 0.002) and deep myometrial tumor invasion (51.6 versus 19.4%; p < 0.001) than EC-A. Tumor grade, stage, and nodal metastasis risk were similar (all, p > 0.05). In a univariate analysis, the EC-AIA group had a significantly decreased DFS compared to EC-A (5-year rates, 72.2 versus 85.5%, p = 0.001). After controlling for age, histology, tumor grade, and stage, EC-AIA remained an independent prognostic factor associated with decreased DFS compared to EC-A (adjusted-hazard ratio 2.87, 95% confidence interval 1.44-5.70, p = 0.031).
Our study demonstrated that EC-AIA has distinct tumor characteristics and a poorer survival outcome compared to EC-A. This suggests a benefit of recognition of this unique entity as an aggressive variant of endometrial cancer.
BJOG. 2018 Jan;125(1):55-62
Epidemiology of endometriosis: a large population-based database study from a healthcare provider with 2 million members.
Endometriosis constitutes a significant burden on the quality of life of women, their families and healthcare systems. The objective of this study is to describe the real-world epidemiology of endometriosis in an unselected low-risk population in Israel.
Retrospective population-based study.
SETTING AND SAMPLE:
The computerised databases of Maccabi Healthcare Services (MHS), a 2-million-member healthcare provider representing a quarter of the Israeli population.
The crude point prevalence (31 December 2015; diagnosed since 1998) and annual incidence (2000-2015) rates of diagnosed endometriosis (ICD-9-CM 617.xx) were assessed among women aged 15-55 years. Prevalent patients were characterised in terms of sociodemographic and clinical characteristics, including validated MHS infertility and chronic disease registries.
MAIN OUTCOME MEASURES:
Prevalence and incidence of diagnosed endometriosis in MHS.
The point prevalence of endometriosis [n = 6146, mean age 40.4 ± 8.0 years (SD)] was 10.8 per 1000 (95% CI 10.5-11.0). Women aged 40-44 years had the highest prevalence rate of 18.6 per 1000 (95% CI 17.7-19.5). Infertility was documented in 37% of patients. A total of 6045 patients were included in the cohort of newly-diagnosed endometriosis (mean age 34.0 ± 8.1 years), corresponding to an average annual incidence rate of 7.2 per 10 000 (95% CI 6.5-8.0).
We observed a substantially lower prevalence of diagnosed endometriosis compared with previous reports in high-risk populations, in line with population-based estimates from European databases (range 0.8-1.8%). Further characterisation of this cohort may help to understand what affects the prevalence of endometriosis in Israel, and to promote earlier diagnosis and improve management in clinical practice.
Endometriosis diagnosed in 1% of women, according to a large population-based study in a community setting.
J Minim Invasive Gynecol. 2017 Jul – Aug;24(5):822-826.
Five-Year Follow-Up After Laparoscopic Large Nerve Resection for Deep Infiltrating Sciatic Nerve Endometriosis.
To report neurologic follow-up of patients after laparoscopic large resection of deep infiltrating endometriosis of the sciatic nerve.
Prospective clinical case series.
Tertiary referral unit specializing in advanced gynecologic surgery and neuropelveology.
All data for patients who underwent laparoscopic surgery for endometriosis of the sciatic nerve between 2004 and 2016 (n = 259) were documented prospectively. In this study, patients who underwent a large resection of the sciatic nerve (>30% of the nerve) and were followed for at least 5 years were evaluated (n = 46). All patients presented preoperatively with incapacity for normal gait and foot drop. All were suffering from intractable and constant neuropathic sciatic pain (visual analog scale [VAS] score of 9 to 10 despite strong pain medicine), with sensorimotor disorders of the affected leg.
Laparoscopic large resection of endometriosis of the sciatic nerve.
MEASUREMENTS AND MAIN RESULTS:
All procedures were performed by laparoscopy. Postoperative management included medical treatment with neuroleptic agents and intensive physiotherapy. At the 5-year follow-up, all patients reported significant pain reduction, with a median VAS score of 2.1 (range, 0 to 3) and recovery of normal gait, including the ability to climb stairs.
In deep infiltrating intraneural endometriosis of the sciatic nerve, patients present with motor disorders before and after surgical resection. The average VAS score was reduced from 9.33 preoperatively to 1.25 at a 3-year follow-up. When full resection of endometriosis including nerve resection is completed, sciatic nerve function recover, but recovery of a normal gait may take at least 3 years and intensive physiotherapy.
Int J Surg Pathol. 2017 Oct;25(7):623-628.
Adenocarcinoma Ex-Goblet Cell Carcinoid of the Appendix With Metastatic Peritoneal Spread to Meckel’s Diverticulum and Endometriosis.
Adenocarcinoma ex-goblet cell carcinoid is a very rare and histologically unique appendiceal malignancy with dual glandular and neuroendocrine differentiation. There is a high incidence of this tumor among middle-aged women with metastasis to the gynecologic tract with the mode of metastasis following peritoneal spread rather than hematogenous distribution. Adenocarcinoma ex-goblet cell carcinoid can spread to any peritoneal site including ovaries or omentum. We report a 37-year-old healthy woman who initially presented with right lower quadrant abdominal pain and pseudomyxoma peritonei. Histopathology of the appendectomy specimen revealed an adenocarcinoma ex-goblet cell carcinoid, signet ring cell type. Follow-up right hemicolectomy, omentectomy, bilateral salpingo-oophorectomy, and regional peritoneal resections revealed metastatic involvement by adenocarcinoma ex-goblet cell carcinoid, signet ring cell type. In this report, we describe a case of appendiceal adenocarcinoma ex goblet cell carcinoid with metastases to Meckel’s diverticulum and areas of pelvic endometriosis, which have not been previously reported.
Gynecol Endocrinol. 2017 Dec;33(12):923-927.
Efficacy comparison of oral rosuvastatin versus oral progesterone and bevacizumab on regression of surgically endometriotic implants in rats.
This study hypothesizes that oral rosuvastatin, oral dienogest and intraperitoneal bevacizumab might improve endometriosis in randomly selected female Wistar albino rats with surgically endometriotic implants. Thirty female Wistar albino rats with surgically endometriotic implants were randomized into three treatment groups: oral rosuvastatin (20 mg kg/day; oral rosuvastatin group 1; n = 10), oral progesterone (dienogest group 2; n = 10) and intraperitoneal bevacizumab (2.5 mg/kg of single intraperitoneal injection of bevacizumab; bevacizumab group 3; n = 10), for 10 days. Post-treatment variables were compared. The oral rosuvastatin group showed higher reduction for the glandular epithelium and uterine vessels of histopathological scores values than the oral progesterone group (both, p < 0.017, respectively). The median glandular epithelium and uterine vessels and histopathological scores values did not show a statistically significant difference between group 1 and group 3 (p > 0.017). Endometrial thickness values and uterine volume values were more significantly reduced in the oral rosuvastatin group than the oral progesterone group (both, p < 0.017, respectively). Moreover, endometrial thickness and uterine volume values were not different in groups wecompared with group 3 (p > 0.017). In conclusion, oral rosuvastatin and intraperitoneal injection of bevacizumab may cause more significant regression of surgically endometriotic implants in rats than oral progesterone medications.
J Endocrinol. 2017 Jul;234(1):R53-R65.
Endocrine targets of hypoxia-inducible factors.
Endocrine is an important and tightly regulated system for maintaining body homeostasis. Endocrine glands produce hormones, which are released into blood stream to guide the target cells responding to all sorts of stimulations. For maintaining body homeostasis, the secretion and activity of a particular hormone needs to be adjusted in responding to environmental challenges such as changes in nutritional status or chronic stress. Hypoxia, a status caused by reduced oxygen availability or imbalance of oxygen consumption/supply in an organ or within a cell, is a stress that affects many physiological and pathological processes. Hypoxic stress in endocrine organs is especially critical because endocrine glands control body homeostasis. Local hypoxia affects not only the particular gland but also the downstream cells/organs regulated by hormones secreted from this gland. Hypoxia-inducible factors (HIFs) are transcription factors that function as master regulators of oxygen homeostasis. Recent studies report that aberrant expression of HIFs in endocrine organs may result in the development and/or progression of diseases including diabetes, endometriosis, infertility and cancers. In this article, we will review recent findings in HIF-mediated endocrine organ dysfunction and the systemic syndromes caused by these disorders.
J Minim Invasive Gynecol. 2017 Jul – Aug;24(5):747-756.
Laparoscopic Excision Versus Ablation for Endometriosis-associated Pain: An Updated Systematic Review and Meta-analysis.
The aim of this study was to update the evidence on the surgical management of endometriosis-associated pain. Does laparoscopic excision offer any benefits over laparoscopic ablation? This is a systematic review and meta-analysis in which we searched MEDLINE, Embase, Institute for Scientific Information conference proceedings, the International Standard Randomised Controlled Trial Number registry, the Register and Meta-register for randomized controlled trials, the World Health Organization trials search portal, the Cochrane Library, and the British Library of electronic theses. Three randomized controlled trials were included, which enrolled 335 participants with a sample size per study ranging from 24 to 178 participants. Of these 3 studies, data from 2 could be pooled for meta-analysis. The primary outcome measure was the reduction in the visual analog scale score for dysmenorrhea. The secondary outcome measures included the reduction in the visual analog scale score for dyspareunia, dyschezia, and chronic pelvic pain and the reduction in Endometriosis Health Profile-30 core pain scores. The meta-analysis showed that the excision group had a significantly greater reduction in symptoms of dysmenorrhea (mean difference [MD] = 0.99; 95% confidence interval [CI], -0.02 to 2.00; p = .05) and dyschezia (MD = 1.31; 95% CI, 0.33-2.29; p = .009) compared with ablation. The symptoms of dyspareunia showed a nonsignificant benefit with excision (MD = 0.96; 95% CI, -0.07 to 1.99; p = .07). Data from 1 study showed a significant reduction in chronic pelvic pain (MD = 2.57; 95% CI, 1.27-3.87; p = .0001) and Endometriosis Health Profile-30 core pain scores (MD = 13.20; 95% CI, 3.70-22.70; p = .006) with the excision group compared with the ablation group. The limited available evidence shows that at 12 months postsurgery, symptoms of dysmenorrhea, dyschezia, and chronic pelvic pain secondary to endometriosis showed a significantly greater improvement with laparoscopic excision compared with ablation.
Free Radic Biol Med. 2017 Sep;110:1-10.
Alteration of Nrf2 and Glutamate Cysteine Ligase expression contribute to lesions growth and fibrogenesis in ectopic endometriosis.
The redox-sensitive nuclear factor erythroid-derived 2-like 2 (NRF2) controls endogenous antioxidant enzymes’ transcription and protects against oxidative damage which is triggered by inflammation and known to favor progression of endometriosis. Glutamate Cysteine Ligase (GCL), a target gene of NRF2, is the first enzyme in the synthesis cascade of glutathione, an important endogenous antioxidant. Sixty-one patients, with thorough surgical examination of the abdominopelvic cavity, were recruited for the study: 31 with histologically-proven endometriosis and 30 disease-free women taken as controls. Expressions of NRF2 and GCL were investigated by quantitative RT-PCR and immunohistochemistry in eutopic and ectopic endometria from endometriosis-affected women and in endometrium of disease-free women. Ex vivo stromal and epithelial cells were extracted and purified from endometrial and endometriotic biopsies to explore expression of NRF2 and GCL in both stromal and epithelial compartments by western blot. Finally, in order to strengthen the role of NRF2 in endometriosispathogenesis, we evaluated the drop of NRF2 expression in a mouse model of endometriosis using NRF2 knockout (NRF2-/-) mice. The mRNA levels of NRF2 and GCL were significantly lower in ectopic endometria of endometriosis-affected women compared to eutopic endometria of disease-free women. The immunohistochemical analysis confirmed the decreased expression of both NRF2 and GCL in ectopic endometriotic tissues compared to eutopic endometria of endometriosis-affected and disease-free women. Immunoblotting revealed a significant decreased of NRF2 and GCL expression in epithelial and stroma cells from ectopic lesions of endometriosis-affected women compared to eutopic endometria from controls. Using a murine model of endometriosis, NRF2-/- implants were more fibrotic compared to wild-type with an increased weight and volume. These findings indicate that expression of the transcription factor NRF2 and its effector GCL are both profoundly deregulated in endometriotic lesions towards increased growth and fibrogenetic processes.
Biomed Pharmacother. 2017 Jul;91:220-228
Resveratrol and endometriosis: In vitro and animal studies and underlying mechanisms (Review).
Endometriosis is characterized by the existence of endometrial tissue and stroma exterior to the uterus. Despite the high prevalence, the etiology of endometriosis remains elusive. The search for the most promising compounds for treatment of endometriosis has led to the identification of resveratrol. Resveratrol, a plant-derived polyphenolic phytoalexin, demonstrates broad-spectrum health beneficial effects, including anti-proliferative, anti-inflammatory, antineoplastic and antioxidant. Because of these properties and its wide distribution in plants, resveratrol is proposed as a great potential to treat endometriosis. In animal models of endometriosis, resveratrol supplementation has displayed beneficial results as it decreased the number and volume of endometrial implants, suppressed proliferation, vascularization, inflammation, cell survival and increased apoptosis. On the other hand, resveratrol treatment in-vitro studies, reduced invasiveness of endometriotic stromal cells (ESCs) and suppressed their inflammatory responses. In this review, we will summarize the recent studies in in-vitro and animal studies on resveratrol and endometriosis.
Glob Qual Nurs Res. 2016 May 26
Practices and Attitudes Concerning Endometriosis Among Nurses Specializing in Gynecology.
Endometriosis is a chronic disease affecting approximately 10% of fertile women. These women often have negative health care experiences. This study adds new knowledge about endometriosis care in a hospital setting and nurses’ attitudes toward the disease. To explore how the personal attitudes of gynecological nurses, their specialized knowledge, and their clinical experiences influenced the way they conceptualized and cared for women with endometriosis, participant observations and semistructured interviews were conducted. Categorization of patients into certain kinds, with more or less legitimate needs, provided an important framework for practice. Specialized knowledge qualified the nurses’ views of their patients and seemed to be conducive to sustained patient involvement. However, the organization of care based solely on medical specialization restricted a holistic approach. An important goal is, therefore, to investigate patients’ perspectives of health and illness and to create participatory relationships with patients, regardless of their diagnosis.
Orv Hetil. 2017 Feb;158(7):264-269.
Prospective study to determine the diagnostic sensitivity of sigmoidoscopy in bowel endometriosis.
INTRODUCTION AND AIM:
In the treatment of colorectal endometriosis a multidisciplinary laparoscopic resection is suggested, for this reason the correct selection of bowel infiltration is essential before surgery.
PATIENTS AND METHOD:
Between 2009 and 2015, 383 sigmoidoscopies were performed in patients with endometriosis. Where mucosal invasion was absent secondary signs (wall rigidity, impression, kinking, pain during the examination, suffusion) were analysed. In endoscopically confirmed cases multidisciplinary surgery was performed, the remaining patients were operated by a gynecologic team only.
Endometriosis was endoscopically confirmed in 224 patients (58.49%), 108 of them underwent multidisciplinary operation, the negative 135 cases received gynaecological surgery. Bowel endometriosis was confirmed in 103 out of 108 cases intraoperatively, while in 8 cases of the sigmoidoscopically negative patients bowel infiltration was diagnosed intraoperatively by the gynaecological team. Complete sigmoidoscopy was performed in 43.47% of the cases. Intraluminal endometriosis was found in 4.91%, secondary signs as rigidity in 38.39%, impression in 45.54%, kinking in 57.14%, pain (in cases of examination without narcosis) in 26.06% and suffusion in 3.82% of the cases was found during sigmoidoscopy. Sigmoidoscopic examination has a 92.8% specificity and 96.2% sensitivity in cases of bowel endometriosis.
Sigmoidoscopy performed by an experienced gastroenterologist is a highly sensitive examination for the diagnosis of bowel endometriosis. Orv. Hetil., 2017, 158(7), 264-269.
J Reprod Immunol. 2017 Apr;120:48-55.
“What do we know about regulatory T cells and endometriosis? A systematic review”.
Endometriosis is a benign, chronic inflammatory disease that presents alterations in immune response that can be detected in eutopic endometrium, peritoneal fluid and peripheral blood of affected women. Regulatory T (TReg) cells are a subpopulation of T lymphocytes specialized in immune regulation that seem to participate in the development of endometriosis, by suppressing the immune response and favoring the establishment of lesions. Our aim was to review the scientific literature that evaluates TReg cell phenotypes in the context of endometriosis. PRISMA statement for systematic reviews was applied, using “regulatory T cells” and “endometriosis” as keywords in the following databases: PubMed, Cochrane, EMBASE and Lilacs. The initial search and abstract review yielded 41 papers relating to the subject. At the end, 12 studies, published between 2009 and 2016, were included. Most studies that analyzed TReg cells did not characterize these cells with current Bona Fide markers. In peritoneal fluid and endometriotic lesions, there was a higher concentration of TReg cell phenotype and/or TRegcell expression markers in patients with endometriosis when compared with controls. However, there is still not a consensus about TReg cells concentration in eutopic endometrium and peripheral blood between the revised studies. Taken together, this data collection suggests that endometriosis is related to TReg cells alterations, although further studies are necessary to reach more precise conclusions, especially regarding the percentage of these cells in eutopic endometrium and peripheral blood. This systematic review attempted to provide instructive and up-to-date collection of data that may help better design future studies.
Diagn Pathol. 2017 May 2;12(1):36.
Primary extragenital endometrial stromal sarcoma of the lung: first reported case and review of literature.
Endometrial stromal sarcomas arising in extrauterine and extraovarian sites, in the absence of a primary uterine lesion are quite rare, especially in the absence of endometriosis. They usually present as an abdominal or pelvic mass lesion.
In 2007, a 45-year-old woman underwent total hysterectomy for in situ squamous cell carcinoma of the cervix. In 2014, an upper left pulmonary lobectomy was performed for a mass, which was provisionally diagnosed as primary carcinosarcoma of the lung. A second histological revision of the lung surgical specimen was performed in the Pathology Unit of our Institute. After extensive immunohistochemical analyses, the preferred diagnosis was spindle-cell sarcoma, consistent with high-grade extragenital endometrial stromal sarcoma (EESS). A review of all slides of the hysterectomy specimen confirms the original diagnosis: no evidence of stromal tumor was found. Afterwards, the patient developed multiple and metachronous pulmonary lesions and a scapular soft tissue mass, which showed the same morphophenotypic features of the first lung mass. The patient was treated with antiblastic therapy, surgical resection and radioablation, when appropriate. To date, the patient has no signs or symptoms.
The authors present the first case of primary EESS arising in the lung with no association with endometriosis published to date. Detailed clinical history and follow-up are also described. Moreover, extensive literature review is reported, along with differential diagnoses, immunohistochemical and molecular findings, pathogenetic hypotheses and treatment options. The knowledge of EESS potential extrauterine location and of its peculiar morphophenotypic aspects are required for a correct diagnosis, and for choosing the most suitable treatment.
Rambam Maimonides Med J. 2017 Apr 28;8(2).
Impact of Endometrial Preparation Protocols for Frozen Embryo Transfer on Live Birth Rates.
It has been reported that a natural cycle (NC) is similar to or even better than hormone replacement therapy (HRT) in patients with regular cycles who undergo frozen embryo transfer (FET). Hundreds of FETs are managed yearly in our clinic. Scheduling these cycles is critical in a busy unit like ours. This is why we have to prove if a NC really shows a better outcome than other endometrium preparation protocols.
Hence we carried out a prospective study between June 2011 and June 2012, which included 530 patients (570 FET cycles) randomly allocated to two study groups: Group 1 (n=280 cycles), artificial cycle (HRT); or group 2 (n=290 cycles), natural cycle. Natural cycles were later divided into two groups: 169 patients scheduled with human chorionic gonadotropin (hCG) and 121 with endogenous luteinizing hormone (LH) surge. The inclusion criteria were: age <39 years, regular menstrual cycles (26-35 days), and previous IVF cycle with embryo cryopreservation. The exclusion criteria were polycystic ovarian syndrome and endometriosis stage III/IV.
No statistical differences were found in the baseline characteristics among groups, nor between implantation or ongoing pregnancy rates (30.8% HRT group; 32.7% hCG group; 34.5% LH surge group). However, a higher miscarriage rate was observed in the HRT group when compared to hCG or LH surge (21.2% versus 12.9% versus 11.1%, P<0.01). Live birth rates were similar among groups, as were perinatal outcomes, for rates of natural delivery and weight and length of newborns.
We conclude that scheduling FET with HRT on weekdays and avoiding work overload at weekends prove efficient and safe in cycle outcome terms. Another reason for the convenience of an HRT protocol is having fewer visits to the clinic compared to natural cycle protocols.
Transl Oncogenomics. 2017 Feb 24
ARID1A Expression is Down-Regulated by Oxidative Stress in Endometriosisand Endometriosis-Associated Ovarian Cancer.
Oxidative stress is considered an important factor in the development of endometriosis, including its malignant transformation. Previous studies have found that AT-rich interactive domain 1A (ARID1A), a tumor suppressor gene, is frequently mutated and inactivated in endometriosis-associated ovarian cancer (EAOC), and such a change in this gene is considered an early event in malignant transformation. We observed oxidative stress status by measuring the activity of the antioxidant enzyme manganese superoxide dismutase (MnSOD), malondialdehyde (MDA), and ARID1A gene expression in tissue samples from patients with endometriosis, EAOC, or non-endometriosis-associated ovarian cancer (non-EAOC). We also induced oxidative stress in the cultured cells from patients with primary endometriosis by adding H2O2 and tested for any alteration of ARID1Agene expression based on different H2O2 concentrations. The results showed that MnSOD activity in endometriosis and EAOC was lower than in non-EAOC, but MDA levels were higher. This study also showed that oxidative stress reduced ARID1A gene expression.
J Assist Reprod Genet. 2017 Jul;34(7):939-944.
CCDC22 gene polymorphism is associated with advanced stages of endometriosis in a sample of Brazilian women.
Based on the assumption that genetic factors are involved in the etiology of endometriosis, this study aimed to investigate the possibility of rs498679 (TLR4 gene), rs1799964 (TNF-α gene), rs3024496 (IL-10 gene), and rs2294021 (CCDC22 gene) polymorphisms being associated with the occurrence of this disease in a sample of Brazilian women.
We conducted a case-control study with 100 women with histological confirmation of endometriosis(endometriosis group) and 100 women submitted to laparoscopy for benign disorders, in which the absence of endometriosis was confirmed (control group). All samples were genotyped by real-time PCR technique for rs498679, rs1799964, rs3024496, and rs2294021 polymorphisms.
No significant difference was observed in genotypic or allelic frequencies between control and endometriosis groups for rs498679 (TLR4 gene), rs1799964 (TNF-α gene), rs3024496 (IL-10 gene), neither when comparing endometriosis subgroups (I-II versus III-IV). On the other hand, significant difference between stages I-II and III-IV of the disease was found in genotypic and allelic frequencies for the rs2294021 (CCDC22 gene) SNP (p = 0.048 and p = 0.017, respectively).
Our results suggest that the rs2294021 (CCDC22 gene) polymorphism could be associated with increased susceptibility to endometriosis in Brazilian women when the allele C is present. In order to clarify this result, further studies should be conducted on a larger population.