Intraoperative enhanced imaging for detection of endometriosis: A systematic review of the literature.

The diagnosis of peritoneal endometriosis during laparoscopy may be difficult due to the polymorphic aspects of the lesions. Enhanced imaging using contrast agents has potential to provide a better identification of peritoneal endometriosis. The aim of this systematic review is to provide an overview of the literature on what is known about the intraoperative laparoscopic visual enhancement of peritoneal endometriosis using contrast agents. A systematic review was done of studies about enhanced imaging during laparoscopy for endometriosis using contrast agents. Clinical studies which contained a description of imaging with a contrast agent and also reported visual findings of endometriosis during laparoscopy, were included. Nine suitable studies were identified. Intraoperative visualization of endometriosis was analyzed with or without histologic confirmation. Four studies evaluated 5-aminolevulinic acid-induced fluorescence (5-ALA), 1 study evaluated indigo carmine, 2 studies evaluated methylene blue (MB), 1 study evaluated indocyanine green (ICG) and 1 study evaluated so-called bloody peritoneal fluid painting. All studies, with a combined total of 171 included patients, showed potential of enhanced visibility of endometriosis using contrast agents. A combined total of 7 complications, all related to the use of 5-ALA, were reported. We conclude that the use of contrast-based enhanced imaging during laparoscopy is promising and that it can provide a better visualization of peritoneal endometriosis. However, based on the limited data no technique of preference can yet be identified.

Research Priorities for Endometriosis.

The 3rd International Consensus Workshop on Research Priorities in Endometriosis was held in São Paulo on May 4, 2014, following the 12th World Congress on Endometriosis. The workshop was attended by 60 participants from 19 countries and was divided into 5 main sessions covering pathogenesis/pathophysiology, symptoms, diagnosis/classification/prognosis, disease/symptom management, and research policy. This research priorities consensus statement builds on earlier efforts to develop research directions for endometriosis. Of the 56 research recommendations from the 2011 meeting in Montpellier, a total of 41 remained unchanged, 13 were updated, and 2 were deemed to be completed. Fifty-three new research recommendations were made at the 2014 meeting in Sao Paulo, which in addition to the 13 updated recommendations resulted in a total of 66 new recommendations for research. The research recommendations published herein, as well as those from the 2 previous papers from international consensus workshops, are an attempt to promote high-quality research in endometriosis by identifying and agreeing on key issues that require investigation. New areas included in the 2014 recommendations include infertility, patient stratification, and research in emerging nations, in addition to an increased focus on translational research. A revised and updated set of research priorities that builds on this document will be developed at the 13th World Congress on Endometriosis to be held on May 17-20, 2017, in Vancouver, British Columbia, Canada.

Influence of endometriosis on assisted reproductive technology outcomes: a systematic review and meta-analysis.

OBJECTIVE: To investigate the association of endometriosis on assisted reproductive technology (ART) outcomes and to review if surgical treatment of endometriosis before ART affects the outcomes. DATA SOURCES: We searched studies published between 1980 and 2014 on endometriosis and ART outcome. We searched MEDLINE, PubMed, ClinicalTrials.gov, and Cochrane databases and performed a manual search. METHODS OF STUDY SELECTION: A total of 1,346 articles were identified, and 36 studies were eligible to be included for data synthesis. We included published cohort studies and randomized controlled trials. TABULATION, INTEGRATION, AND RESULTS: Compared with women without endometriosis, women with endometriosis undertaking in vitro fertilization and intracytoplasmic sperm injection have a similar live birth rate per woman (odds ratio [OR] 0.94, 95% confidence interval [CI] 0.84-1.06, 13 studies, 12,682 patients, I=35%), a lower clinical pregnancy rate per woman (OR 0.78, 95% CI 0.65-0.94), 24 studies, 20,757 patients, I=66%), a lower mean number of oocyte retrieved per cycle (mean difference -1.98, 95% CI -2.87 to -1.09, 17 studies, 17,593 cycles, I=97%), and a similar miscarriage rate per woman (OR 1.26, 95% CI (0.92-1.70, nine studies, 1,259 patients, I=0%). Women with more severe disease (American Society for Reproductive Medicine III-IV) have a lower live birth rate, clinical pregnancy rate, and mean number of oocytes retrieved when compared with women with no endometriosis. CONCLUSION: Women with and without endometriosis have comparable ART outcomes in terms of live births, whereas those with severe endometriosis have inferior outcomes. There is insufficient evidence to recommend surgery routinely before undergoing ART.

Inhibition of type 1 17ß-hydroxysteroid dehydrogenase impairs the synthesis of 17ß-estradiol in endometriosis lesions.

CONTEXT: Endometriosis affects 10% of the women before menopause and has important personal, professional, and societal economic burdens. Because current medical treatments are aimed at reducing the symptoms only, novel therapeutic targets should be identified. Endometriosis is estrogen dependent and in some patients the endometriosis tissue is able to produce estrogens in an autocrine/paracrine manner. In a number of patients, this is the consequence of the high local activity of the 17ß-hydroxysteroid-dehydrogenases (17ß-HSDs), enzymes able to generate active estrogens from precursors with low activity. OBJECTIVE: The objective of the study was to identify the 17ß-HSD(s) responsible for the high local generation of estrogens in endometriosis and test the possibility to inhibit these enzymes for therapeutic purposes. DESIGN: The expression of different 17ß-HSDs involved in the estrogen metabolism was assessed by real-time PCR in eutopic and ectopic tissue from endometriosis patients (n=14). These biopsies had previously confirmed unbalanced local 17ß-HSD activity, which caused high estrogen generation. The possibility to block the synthesis of estrogens by one inhibitor specific for type 1 17ß-HSD was assessed by HPLC in tissue lysates from endometriosis tissues (n=27). RESULTS: In all but one of the patients, a high type 1 17ß-HSD level is associated with the unbalanced metabolism of estrogens, leading to higher estrogen synthesis in endometriosis than in the endometrium inside the uterus. Inhibition of type 1 17ß-HSD restores to various extents, depending on the patient, the correct metabolism. In 19 of 27 patients analyzed (70%), the 17ß-HSD type 1 inhibitor decreased the generation of 17ß-estradiol by greater than 85%. CONCLUSIONS: Inhibition of 17ß-HSD type 1 can be a potential future treatment option aimed at restoring the correct metabolic balance of estrogens in endometriosis patients with increased local 17ß-HSD type 1 enzyme activity.

What is the societal burden of endometriosis-associated symptoms? a prospective Belgian study.

Endometriosis is a complex disease that affects a large number of women of reproductive age and imposes a significant burden on patients and society. The aim of this study was to evaluate diagnosis, comorbidities, healthcare resource use, treatment patterns, costs and quality of life of women with endometriosis seen in a Belgian tertiary care centre. A total of 134 patients were included in a prospective questionnaire-based cost-of-illness study. Patients were diagnosed after a median delay of 2 years after onset of symptoms. Almost all patients reported having at least one comorbidity. Total annual costs per patient were €9872 (95% confidence interval €7930­11,870), with costs of productivity loss representing 75% of total costs. Hospitalizations, surgeries, infertility treatments, pain and anxiety increased total costs significantly (P 0.001). Patients generated an average of 0.82 QaLY over a 1-year time horizon. This study showed that direct and indirect costs attributable to endometriosis-associated symptoms are substantial. Earlier diagnosis and cost-effective treatment of endometriosis may decrease productivity loss, quality of life impairment and healthcare consumption and consequently reduce total costs to patients and society.

Fertility preservation in female classic galactosemia patients.

Almost every female classic galactosemia patient develops primary ovarian insufficiency (POI) as a diet-independent complication of the disease. This is a major concern for patients and their parents, and physicians are often asked about possible options to preserve fertility. Unfortunately, there are no recommendations on fertility preservation in this group. The unique pathophysiology of classic galactosemia with a severely reduced follicle pool at an early age requires an adjusted approach. In this article recommendations for physicians based on current knowledge concerning galactosemia and fertility preservation are made. Fertility preservation is only likely to be successful in very young prepubertal patients. In this group, cryopreservation of ovarian tissue is currently the only available technique. However, this technique is not ready for clinical application, it is considered experimental and reduces the ovarian reserve. Fertility preservation at an early age also raises ethical questions that should be taken into account. In addition, spontaneous conception despite POI is well described in classic galactosemia. The uncertainty surrounding fertility preservation and the significant chance of spontaneous pregnancy warrant counseling towards conservative application of these techniques. We propose that fertility preservation should only be offered with appropriate institutional research ethics approval to classic galactosemia girls at a young prepubertal age.

The male reproductive system in classic galactosemia: cryptorchidism and low semen volume.

Previous studies examining reproductive parameters in men with galactosemia have inconsistently demonstrated abnormalities. We hypothesized that men with galactosemia may demonstrate evidence of reproductive dysfunction. Pubertal history, physical examination, hormone levels and semen analyses were examined in 26 males with galactosemia and compared to those in 46 controls. The prevalence of cryptorchidism was higher in men with galactosemia than in the general population [11.6% vs. 1.0% (95%CI: 0.75-1.26; p <0.001)]. Testosterone (461±125 vs. 532± 33 ng%; p=0.04), inhibin B (144±66 vs. 183±52 pg/mL; p=0.002) and sperm concentration (46±36 vs. 112±75×10(6) spermatozoa/mL; p=0.01) were lower and SHBG was higher (40.7±21.5 vs 26.7±14.6; p=0.002) in men with galactosemia compared to controls. Semen volume was below normal in seven out of 12 men with galactosemia. Men with galactosemia have a higher than expected prevalence of cryptorchidism and low semen volumes. The subtle decrease in testosterone and inhibin B levels and sperm count may indicate mild defects in Sertoli and Leydig cell function, but does not point towards severe infertility causing reproductive impairment. Follow-up studies are needed to further determine the clinical consequences of these abnormalities.

The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres.

BACKGROUND: This study aimed to calculate costs and health-related quality of life of women with endometriosis-associated symptoms treated in referral centres. METHODS: A prospective, multi-centre, questionnaire-based survey measured costs and quality of life in ambulatory care and in 12 tertiary care centres in 10 countries. The study enrolled women with a diagnosis of endometriosis and with at least one centre-specific contact related to endometriosis-associated symptoms in 2008. The main outcome measures were health care costs, costs of productivity loss, total costs and quality-adjusted life years. Predictors of costs were identified using regression analysis. RESULTS: Data analysis of 909 women demonstrated that the average annual total cost per woman was €9579 (95% confidence interval €8559-€10 599). Costs of productivity loss of €6298 per woman were double the health care costs of €3113 per woman. Health care costs were mainly due to surgery (29%), monitoring tests (19%) and hospitalization (18%) and physician visits (16%). Endometriosis-associated symptoms generated 0.809 quality-adjusted life years per woman. Decreased quality of life was the most important predictor of direct health care and total costs. Costs were greater with increasing severity of endometriosis, presence of pelvic pain, presence of infertility and a higher number of years since diagnosis. CONCLUSIONS: Our study invited women to report resource use based on endometriosis-associated symptoms only, rather than drawing on a control population of women without endometriosis. Our study showed that the economic burden associated with endometriosis treated in referral centres is high and is similar to other chronic diseases (diabetes, Crohn's disease, rheumatoid arthritis). It arises predominantly from productivity loss, and is predicted by decreased quality of life.

Towards endometriosis diagnosis by gadofosveset-trisodium enhanced magnetic resonance imaging.

Endometriosis is defined as the presence of endometrial tissue outside the uterus. It affects 10-15% of women during reproductive age and has a big personal and social impact due to chronic pelvic pain, subfertility, loss of work-hours and medical costs. Such conditions are exacerbated by the fact that the correct diagnosis is made as late as 8-11 years after symptom presentation. This is due to the lack of a reliable non-invasive diagnostic test and the fact that the reference diagnostic standard is laparoscopy (invasive, expensive and not without risks). High-molecular weight gadofosveset-trisodium is used as contrast agent in Magnetic Resonance Imaging (MRI). Since it extravasates from hyperpermeable vessels more easily than from mature blood vessels, this contrast agent detects angiogenesis efficiently. Endometriosis has high angiogenic activity. Therefore, we have tested the possibility to detect endometriosis non-invasively using Dynamic Contrast-Enhanced MRI (DCE-MRI) and gadofosveset-trisodium as a contrast agent in a mouse model. Endometriotic lesions were surgically induced in nine mice by autologous transplantation. Three weeks after lesion induction, mice were scanned by DCE-MRI. Dynamic image analysis showed that the rates of uptake (inwash), persistence and outwash of the contrast agent were different between endometriosis and control tissues (large blood vessels and back muscle). Due to the extensive angiogenesis in induced lesions, the contrast agent persisted longer in endometriotic than control tissues, thus enhancing the MRI signal intensity. DCE-MRI was repeated five weeks after lesion induction, and contrast enhancement was similar to that observed three weeks after endometriosis induction. The endothelial-cell marker CD31 and the pericyte marker α-smooth-muscle-actin (mature vessels) were detected with immunohistochemistry and confirmed that endometriotic lesions had significantly higher prevalence of new vessels (CD31 only positive) than the uterus and control tissues. The diagnostic value of gadofosveset-trisodium to detect endometriosis should be tested in human settings.

Overexpression of 17ß-hydroxysteroid dehydrogenase type 1 increases the exposure of endometrial cancer to 17ß-estradiol.

CONTEXT: The local interconversions between estrone (low activity) and 17ß-estradiol (potent compound) by 17ß-hydroxysteroid dehydrogenases (17ß-HSDs) can lead to high 17ß-estradiol generation in endometrial cancer (EC). OBJECTIVE: Examine the balance between the 17ß-HSDs reducing estrone to 17ß-estradiol (types 1, 5, 12, and 7) and those oxidizing 17ß-estradiol to estrone (2, 4, and 8), in EC. PATIENTS AND METHODS: Reducing and oxidizing 17ß-HSD activities (HPLC) and mRNA level (RT-PCR) were assessed in normal post-menopausal (n = 16), peritumoral endometrium (normal tissue beside cancer, n = 13), and 58 EC (29 grade 1, 18 grade 2, 11 grade 3). RESULTS: Grade 1 EC displayed a shifted estrone reduction/17ß-estradiol oxidation balance in favor of 17ß-estradiol compared with controls. This was more pronounced among estrogen receptor-α (ER-α)-positive biopsies. Type 1 17ß-HSD mRNA (HSD17B1 gene expression, real time PCR) and protein levels (immunohistochemistry) were higher in ER-α-positive grade 1 EC than controls. The mRNA coding for types 4, 5, 7, 8, and 12 17ß-HSD did not vary, whereas that coding for type 2 17ß-HSD was increased in high-grade lesions compared with controls. Three-dimensional ex vivo EC explant cultures demonstrated that 17ß-HSD type 1 generated 17ß-estradiol from estrone and increased tumor cell proliferation. Additional in vitro studies using EC cells confirmed that in the presence of 17ß-HSD type 1, estrone induced estrogen signaling activation similarly to 17ß-estradiol. Therefore, estrone was reduced to 17ß-estradiol. CONCLUSIONS: Type 1 17ß-HSD increases 17ß-estradiol exposure in grade 1 EC, thus supporting tumor growth. This enzyme represents a potential therapeutic target.

Deoxyribonucleic acid methyltransferases and methyl-CpG-binding domain proteins in human endometrium and endometriosis.

OBJECTIVE: To determine [1] expression levels of both DNA methyltransferases (DNMTs) and methyl-CpG-binding domain proteins (MBDs) in human endometrium throughout the menstrual cycle and in eutopic and ectopic endometrium of patients with endometriosis and [2] hormone responsiveness of DNMT and MBD expression in explant cultures of proliferative phase endometrium. DESIGN: In vitro study. SETTING: Academic medical center. PATIENT(S): Premenopausal women with and without endometriosis. INTERVENTION(S): Explant cultures of proliferative phase endometrium were treated with vehicle, 17ß-E(2), or a combination of E(2) and P (E(2) + P) for 24 hours. MAIN OUTCOME MEASURE(S): Expression levels of DNMT1, DNMT2, and DNMT3B and MBD1, MBD2, and MeCP2 with use of real-time quantitative polymerase chain reaction. RESULT(S): Expression levels of DNMT1 and MBD2 were significantly higher in secretory-phase endometrium compared with proliferative endometrium and menstrual endometrium. In explant cultures, treatment with E(2) + P resulted in significant up-regulation of DNMT1 and MBD2. Expression levels of several DNMTs and MBDs were significantly lower in endometriotic lesions compared with eutopic endometrium of women with endometriosis and disease-free controls. CONCLUSION(S): These findings suggest a role for DNMTs and MBDs in the growth and differentiation of the human endometrium and support the notion that endometriosis may be an epigenetic disease.

The European Society of Human Reproduction and Embryology guideline for the diagnosis and treatment of endometriosis: an electronic guideline implementability appraisal.

BACKGROUND: Clinical guidelines are intended to improve healthcare. However, even if guidelines are excellent, their implementation is not assured. In subfertility care, the European Society of Human Reproduction and Embryology (ESHRE) guidelines have been inventoried, and their methodological quality has been assessed. To improve the impact of the ESHRE guidelines and to improve European subfertility care, it is important to optimise the implementability of guidelines. We therefore investigated the implementation barriers of the ESHRE guideline with the best methodological quality and evaluated the used instrument for usability and feasibility. METHODS: We reviewed the ESHRE guideline for the diagnosis and treatment of endometriosis to assess its implementability. We used an electronic version of the guideline implementability appraisal (eGLIA) instrument. This eGLIA tool consists of 31 questions grouped into 10 dimensions. Seven items address the guideline as a whole, and 24 items assess the individual recommendations in the guideline. The eGLIA instrument identifies factors that influence the implementability of the guideline recommendations. These factors can be divided into facilitators that promote implementation and barriers that oppose implementation. A panel of 10 experts from three European countries appraised all 36 recommendations of the guideline. They discussed discrepancies in a teleconference and completed a questionnaire to evaluate the ease of use and overall utility of the eGLIA instrument. RESULTS: Two of the 36 guideline recommendations were straightforward to implement. Five recommendations were considered simply statements because they contained no actions. The remaining 29 recommendations were implementable with some adjustments. We found facilitators of the guideline implementability in the quality of decidability, presentation and formatting, apparent validity, and novelty or innovation of the recommendations. Vaguely defined actions, lack of facilities, immeasurable outcomes, and inflexibility within the recommendations formed barriers to implementation. The eGLIA instrument was generally useful and easy to use. However, assessment with the eGLIA instrument is very time-consuming. CONCLUSIONS: The ESHRE guideline for the diagnosis and treatment of endometriosis could be improved to facilitate its implementation in daily practice. The eGLIA instrument is a helpful tool for identifying obstacles to implementation of a guideline. However, we recommend a concise version of this instrument.

Neoplastic transformation of endocervicosis into an extraovarian mucinous cystadenocarcinoma.

Although extraovarian mucinous cystadenocarcinomas resemble primary ovarian carcinomas, both histologically and clinically, their specific etiology is not clear. This is the first report to show neoplastic transformation of endocervicosis into an extraovarian mucinous cystadenocarcinoma. The histologic spectrum and specific KRAS mutational analysis for this tumor were the same as for their ovarian counterparts. This supports a müllerian origin and the current approach to extrapolate the results from ovarian mucinous cystadenocarcinoma trials in prescribing treatment for patients with extraovarian mucinous cystadenocarcinomas.

Endometriosis cost assessment (the EndoCost study): a cost-of-illness study protocol.

AIMS: The EndoCost study aims to calculate the costs of endometriosis from a societal perspective. METHODS: This multicentre, prevalence-based cost-of-illness analysis aggregates data on endometriosis costs and quality of life from a prospective hospital questionnaire and from both retrospective and prospective patient questionnaires. The EndoCost study comprises 12 representative tertiary care centres involved in the care of women with endometriosis in 10 countries. The sample includes patients with a laparoscopic and/or histological diagnosis of endometriosis and with at least 1 patient contact related to endometriosis during 2008. The EndoCost study measures direct healthcare costs (e.g. costs of medication, physician visits), direct non-healthcare costs (e.g. transportation costs), and indirect costs of productivity loss. Cost questions are developed specifically for the purpose of the EndoCost study. Quality of life is measured using the EuroQol-5D and relevant parts of the Global Study of Women's Health instruments. Both aggregate analyses and country-specific analyses are planned for total costs per patient. Costs are broken down into cost drivers and into the various payers that incur costs. CONCLUSIONS: The cost estimates provided by the EndoCost cost-of-illness analysis may be used to justify the prioritisation of future research in endometriosis.

Olfactomedin-4 regulation by estrogen in the human endometrium requires epidermal growth factor signaling.

Olfactomedin-4 (OLFM-4) is an extracellular matrix protein that is highly expressed in human endometrium. We have examined the regulation and function of OLFM-4 in normal endometrium and in cases of endometriosis and endometrial cancer. OLFM-4 expression levels are highest in proliferative-phase endometrium, and 17ß-estradiol up-regulates OLFM-4 mRNA in endometrial explant cultures. Using the luciferase reporter under control of the OLFM-4 promoter, it was shown that both 17ß-estradiol and OH-tamoxifen induce luciferase activity, and epidermal growth factor receptor-1 is required for this estrogenic response. In turn, EGF activates the OLFM-4 promoter, and estrogen receptor-α is needed for the complete EGF response. The cellular functions of OLFM-4 were examined by its expression in OLFM-4-negative HEK-293 cells, which resulted in decreased vimentin expression and cell adherence as well as increased apoptosis resistance. In cases of endometriosis and endometrial cancer, OLFM-4 expression correlated with the presence of epidermal growth factor receptor-1 and estrogen receptor-α (or estrogen signaling). An increase of OLFM-4 mRNA was observed in the endometrium of endometriosis patients. No change in OLFM-4 expression levels were observed in patients with endometrial cancer relative with controls. In conclusion, cross-talk between estrogen and EGF signaling regulates OLFM-4 expression. The role of OLFM-4 in endometrial tissue remodeling before the secretory phase and during the predisposition and early events in endometriosis can be postulated but requires additional investigation.

Effect of in vitro culture of human embryos on birthweight of newborns.

BACKGROUND: In animal models, in vitro culture of preimplantation embryos has been shown to be a risk factor for abnormal fetal outcome, including high and low birthweight. In the human, mean birthweight of singletons after in vitro fertilization (IVF) is considerably lower than after natural conception, but it is not known whether culture conditions play a role in this. METHODS: We compared pregnancy rates and perinatal outcomes from singleton pregnancies resulting from a total of 826 first IVF treatment cycles in which oocytes and embryos were randomly allocated to culture in either of two commercially available sequential media systems. RESULTS: When the 110 live born singletons in the Vitrolife group were compared with the 78 singletons in the Cook group, birthweight +/- SEM (3453 +/- 53 versus 3208 +/- 61 g, P = 0.003), and birthweight adjusted for gestational age and gender (mean z-score +/- SEM: 0.13 +/- 0.09 versus -0.31 +/- 0.10, P = 0.001) were both significantly higher in the Vitrolife group. When analyzed by multiple linear regression together with several other variables that could possibly affect birthweight as covariates, the type of culture medium was significantly (P = 0.01) associated with birthweight. CONCLUSIONS: In vitro culture of human embryos can affect birthweight of live born singletons.

Identification of novel ER-alpha target genes in breast cancer cells: gene- and cell-selective co-regulator recruitment at target promoters determines the response to 17beta-estradiol and tamoxifen.

Tamoxifen and 17beta-estradiol are capable of up-regulating the expression of some genes and down-regulate the expression of others simultaneously in the same cell. In addition, tamoxifen shows distinct transcriptional activities in different target tissues. To elucidate whether these events are determined by differences in the recruitment of co-regulators by activated estrogen receptor-alpha (ER-alpha) at target promoters, we applied chromatin immunoprecipitation (ChIP) with promoter microarray hybridisation in breast cancer T47D cells and identified 904 ER-alpha targets genome-wide. On a selection of newly identified targets, we show that 17beta-estradiol and tamoxifen stimulated up- or down-regulation of transcription correlates with the selective recruitment of co-activators or co-repressors, respectively. This is shown for both breast (T47D) and endometrial carcinoma cells (ECC1). Moreover, differential co-regulator recruitment also explains that tamoxifen regulates a number of genes in opposite direction in breast and endometrial cancer cells. Over-expression of co-activator SRC-1 or co-repressor SMRT is sufficient to alter the transcriptional action of tamoxifen on a number of targets. Our findings support the notion that recruitment of co-regulator at target gene promoters and their expression levels determine the effect of ER-alpha on gene expression to a large extent.