Gerard A.J. Dunselman

ESHRE guideline: management of women with endometriosis

STUDY QUESTION What is the optimal management of women with endometriosis based on the best available evidence in the literature? SUMMARY ANSWER Using the structured methodology of the Manual for ESHRE Guideline Development, 83 recommendations were formulated that answered the 22 key questions on optimal management of women with endometriosis. WHAT IS KNOWN ALREADY The European Society of Human Reproduction and Embryology (ESHRE) guideline for the diagnosis and treatment of endometriosis (2005) has been a reference point for best clinical care in endometriosis for years, but this guideline was in need of updating. STUDY DESIGN, SIZE, DURATION This guideline was produced by a group of experts in the field using the methodology of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included papers up to January 2012 and consensus within the guideline group on all recommendations. To ensure input from women with endometriosis, a patient representative was part of the guideline development group. In addition, patient and additional clinical input was collected during the scoping and review phase of the guideline. PARTICIPANTS/MATERIALS, SETTING, METHODS NA. MAIN RESULTS AND THE ROLE OF CHANCE The guideline provides 83 recommendations on diagnosis of endometriosis and on the treatment of endometriosis-associated pain and infertility, on the management of women in whom the disease is found incidentally (without pain or infertility), on prevention of recurrence of disease and/or painful symptoms, on treatment of menopausal symptoms in patients with a history of endometriosis and on the possible association of endometriosis and malignancy. LIMITATIONS, REASONS FOR CAUTION We identified several areas in care of women with endometriosis for which robust evidence is lacking. These areas were addressed by formulating good practice points (GPP), based on the expert opinion of the guideline group members. WIDER IMPLICATIONS OF THE FINDINGS Since 32 out of the 83 recommendations for the management of women with endometriosis could not be based on high level evidence and therefore were GPP, the guideline group formulated research recommendations to guide future research with the aim of increasing the body of evidence. STUDY FUNDING/COMPETING INTEREST(S) The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the implementation of the guideline. The guideline group members did not receive payment. All guideline group members disclosed any relevant conflicts of interest (see Conflicts of interest). TRIAL REGISTRATION NUMBER NA.

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, Crohns disease, rheumatoid arthritis). It arises predominantly from productivity loss, and is predicted by decreased quality of life.

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.

Early endometriosis invades the extracellular matrix.

OBJECTIVES To investigate whether the aminoterminal propeptides of type III procollagen are increased in patients with early endometriosis and to demonstrate that the subtle lesion of endometriosis is an active stage of the disease. DESIGN Aminoterminal propeptide of type III procollagen was determined in serum and peritoneal fluid (PF) of 100 consecutive patients undergoing laparoscopy. SETTING Academisch Ziekenhuis Maastricht, The Netherlands, a tertiary care center. RESULTS Aminoterminal propeptide PF levels were significantly higher in women with early lesions of endometriosis compared with levels in two groups of controls, i.e., fertile, cycling, women without the disease (P = 0.019) and women on oral contraceptives without the disease (P = 0.036). No difference was found in aminoterminal propeptide PF levels when comparing patients with early lesions of endometriosis and patients with unexplained infertility, the third control group. Aminoterminal propeptide PF levels of patients with endometriosis without early lesions were not different from PF levels in controls. CONCLUSION The early lesion is an active stage of endometriosis, invading the extracellular matrix. In women with unexplained infertility active, microscopic endometriosis may be present.

Expression of integrins E-cadherin in cells from menstrual effluent, endometrium, peritoneal fluid, peritoneum, endometriosis

Objective To detect the expression of integrins and E-cadherin in cells from peritoneal fluid (PF), endometrium, menstrual effluent, peritoneum, and endometriotic lesions during the early follicular phase of the menstrual cycle. Design An immunohistochemical study. Setting Tertiary care university medical center. Patients Sixteen patients undergoing a diagnostic laparoscopy as part of a subfertility work-up. All patients had regular and ovulatory cycles. Interventions A laparoscopy was performed in the early follicular phase (days 2 to 5). Simultaneously, samples were taken from endometrium, menstrual effluent, and PF, and a representative biopsy of an endometriotic lesion was obtained. If endometriosis was not noted, a peritoneal biopsy was obtained instead. Main Outcome Measures The expression of cell adhesion molecules, including the integrin α 2 β 1, α 3 β 1, α 4 β 1, α 5 β 1, and α 6 β 1 and E-cadherin, as determined by immunohistochemistry on frozen sections. Results All integrins tested could be detected in the endometrium samples and in endometriotic lesions. In menstrual effluent samples, positive staining for the integrins α 2 β 1 and α 3 β 1 was found in epithelial cells in 13 of 16 cases. Integrin α 5 β 1 was detected in 11 of 16 samples, and integrins α 4 β 1 and α 6 β 1 were detected in 5 of 16 samples. In PF, integrin α 3 β 1 was found in epithelial cells in 12 of 16 samples, integrin α 5 β 1 in 5 of 16, and integrins α 4 β 1 and α 6 β 1 in 2 of 16. The antibody for E-cadherin showed positive staining of epithelial cells in 6 of 16 menstrual effluent samples. All endometrial tissue samples showed positive staining for E-cadherin. In PF, E-cadherin was detected in the epithelial cells of one sample. One peritoneum biopsy revealed positive staining for E-cadherin. Conclusion Integrins α 2 β 1, α 3 β 1, α 4 β 1, α 5 β 1, and α 6 β 1, and E-cadherin, important cell adhesion molecules, are expressed in endometriotic lesions and in cells and tissues that are potentially involved in the development of endometriosis. These cell adhesion molecules could be involved in the shedding of endometrial tissue during menstruation and the attachment of endometrial tissue fragments to the peritoneum.

Endometrial wavelike movements during the menstrual cycle

OBJECTIVE To qualify and quantify endometrial waves in regularly cycling women. DESIGN A prospective transvaginal ultrasound study was performed throughout 23 cycles of 16 healthy women. Wave type and wave frequency were evaluated. SETTING Normal human volunteers in an academic research environment. PATIENTS Sixteen healthy regularly cycling women. RESULTS Of 23 cycles, 19 proved to be ovulatory. Five types of endometrial waves could be distinguished. Waves from cervix to fundus and opposing waves were seen predominantly periovulatorily. Waves from fundus to cervix were absent in the postovulatory phase. Endometrial wavelike activity was most pronounced in the periovulatory phase. CONCLUSIONS Standardized qualification and quantification of endometrial waves, as described in this study, might shed new light on the underlying mechanisms in selected cases of hitherto unexplained subfertility.

The significant effect of endometriosis on physical, mental and social wellbeing: results from an international cross-sectional survey

STUDY QUESTION To what extent do the management of endometriosis and the symptoms that remain after treatment affect the quality of life in women with the disease? SUMMARY ANSWER Many women with endometriosis had impaired quality of life and continued to suffer from endometriosis-associated symptoms even though their endometriosis has been managed in tertiary care centres. WHAT IS KNOWN ALREADY The existing literature indicates that quality of life and work productivity is reduced in women with endometriosis. However, most studies have small sample sizes, are treatment related or examine newly diagnosed patients only. STUDY DESIGN, SIZE, DURATION A cross-sectional questionnaire-based survey among 931 women with endometriosis treated in 12 tertiary care centres in 10 countries. PARTICIPANTS/MATERIALS, SETTING, METHODS Women diagnosed with endometriosis who had at least one contact related to endometriosis-associated symptoms during 2008 with a participating centre were enrolled into the study. The study investigated the effect of endometriosis on education, work and social wellbeing, endometriosis-associated symptoms and health-related quality of life, by using questions obtained from the World Endometriosis Research Foundation (WERF) GSWH instrument (designed and validated for the WERF Global Study on Womens Health) and the Short Form 36 version 2 (SF-36v2). MAIN RESULTS AND THE ROLE OF CHANCE Of 3216 women invited to participate in the study, 1450 (45%) provided informed consent and out of these, 931 (931/3216 = 29%) returned the questionnaires. Endometriosis had affected work in 51% of the women and affected relationships in 50% of the women at some time during their life. Dysmenorrhoea was reported by 59%, dyspareunia by 56% and chronic pelvic pain by 60% of women. Quality of life was decreased in all eight dimensions of the SF-36v2 compared with norm-based scores from a general US population (all P < 0.01). Multivariate regression analysis showed that number of co-morbidities, chronic pain and dyspareunia had an independent negative effect on both the physical and mental component of the SF-36v2. LIMITATIONS, REASONS FOR CAUTION The fact that women were enrolled in tertiary care centres could lead to a possible over-representation of women with moderate-to-severe endometriosis, because the participating centres typically treat more complex and referred cases of endometriosis. The response rate was relatively low. Since there was no Institute Review Board approval to do a non-responder investigation on basic characteristics, some uncertainty remains regarding the representativeness of the investigated population. WIDER IMPLICATIONS OF THE FINDINGS This international multicentre survey represents a large group of women with endometriosis, in all phases of the disease, which increases the generalizability of the data. Women still suffer from frequent symptoms, despite tertiary care management, in particular chronic pain and dyspareunia. As a result their quality of life is significantly decreased. A patient-centred approach with extensive collaboration across disciplines, such as pain specialists, psychologists, sexologists and social workers, may be a valuable strategy to improve the long-term care of women with endometriosis. STUDY FUNDING/COMPETING INTEREST(S) The WERF EndoCost study is funded by the World Endometriosis Research Foundation (WERF) through grants received from Bayer Schering Pharma AG, Takeda Italia Farmaceutici SpA, Pfizer Ltd and the European Society of Human Reproduction and Embryology. The sponsors did not have a role in the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript. L.H. is the chief executive and T.D. was a board member of WERF at the time of funding. T.D. holds the Merck-Serono Chair in Reproductive Medicine and Surgery, and the Ferring Chair in Reproductive Medicine at the Katholieke Universiteit Leuven in Belgium and has served as consultant/research collaborator for Merck-Serono, Schering-Plough, Astellas and Arresto.

Relation between endometrial wavelike activity and fecundability in spontaneous cycles

OBJECTIVE To determine whether endometrial activity is related to the occurrence of pregnancy in spontaneous menstrual cycles. DESIGN Prospective observational ultrasound evaluation of endometrial activity during fertility screening cycles. SETTING University hospital-based infertility clinic. PATIENT(S) Fifty-nine fertility screening cycles (ultrasound monitoring of follicle growth and ovulation, postcoital test, semen analysis, midluteal P, Chlamydia antibody determination, and tubal patency testing) were performed in 47 couples complaining of infertility. In 33 couples (37 cycles), no fertility impairing factors were found. Endometrial activity was analyzed in these cycles. INTERVENTION(S) Ultrasound examination was performed transvaginally throughout the cycle. MAIN OUTCOME MEASURE(S) Endometrial activity, wave pattern, pregnancy. RESULTS(S) Nine women conceived within the cycle studied. Conception cycles showed less-activity compared with nonconception cycles. Endometrial wavelike activity increased throughout the follicular phase and decreased after ovulation in conception and nonconception cycles. CONCLUSION(S) Endometrial activity is related to fecundability in a spontaneous cycle.

Elevated Levels of Basal Estradiol-17β Predict Poor Response in Patients with Normal Basal Levels of Follicle-Stimulating Hormone Undergoing In Vitro Fertilization

OBJECTIVE To evaluate whether the predictive ability of a normal FSH level on cycle day 3 can be enhanced by levels of estradiol-17beta (E2) on cycle day 3. DESIGN Prospective cohort study. SETTING University hospital-based, tertiary care infertility center. PATIENT(S) Two hundred thirty-one consecutively seen patients who attended the center for their first IVF attempt. INTERVENTION(S) Blood samples were collected on day 3 of the cycle preceding IVF; IVF was performed in all patients. MAIN OUTCOME MEASURE(S) Patients age, number of ampules of hMG, cancellation rate, number of oocytes, fertilization rate, and clinical pregnancy rate. RESULT(S) In patients with elevated FSH levels on cycle day 3, a low oocyte yield was achieved (7 versus 11) and a high number of ampules of hMG was necessary (56 versus 33). Their cancellation rate was high (67% versus 16%). In patients with normal basal FSH levels, high E2 levels predicted a high cancellation rate (56%, versus 13% in patients with low E2 levels) and a low oocyte yield (9, versus 11 in patients with low E2 levels). Patients with both normal FSH levels and low E2 levels on cycle day 3 fared best. CONCLUSION(S) The basal E2 level on cycle day 3 is a useful prognosticator of response to stimulation in IVF patients with normal basal FSH levels.

Increased Production of 17β-Estradiol in Endometriosis Lesions Is the Result of Impaired Metabolism

CONTEXT substantial evidence suggests that the expression of steroid metabolizing enzymes in endometriosis is altered, turning the ectopic endometrium into a source of 17beta-estradiol. However, whether these differences result in a net increase in local 17beta-estradiol production/activity has not been shown. SUBJECTS AND METHODS The activities of the most important steroidogenic enzymes synthesizing and inactivating 17beta-estradiol were determined by HPLC in matched eutopic and ectopic tissue from patients with endometriosis (n = 14) and in endometrium from controls (n = 20). RESULTS Aromatase activity is negligible in the ectopic endometrium, whereas the activity of estrogen sulfatase is high though not different between ectopic, eutopic and control endometrium. The activity of 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) converting estrone into 17beta-estradiol is higher in the ectopic compared to the eutopic endometrium in patients. The activity of 17beta-HSDs converting 17beta-estradiol back to estrone is significantly lower in the ectopic compared to the eutopic endometrium of both patients and controls. To evaluate the net metabolic capacity of tissues to synthesize 17beta-estradiol, we calculated the activity ratio between 17beta-HSDs synthesizing versus 17beta-HSDs inactivating 17beta-estradiol. This ratio is significantly higher in the ectopic compared to the eutopic endometrium of patients and controls, indicating a high synthesis of 17beta-estradiol in the ectopic locations. This is further supported by the elevated mRNA levels of the estrogen-responsive gene TFF1 in all ectopic compared to eutopic endometria. CONCLUSION Endometriotic lesions have higher production of 17beta-estradiol than the eutopic endometrium of patients and controls. This is mostly the result of impaired metabolism.