The SELFI Study: Iodine Excess and Thyroid Dysfunction in Women Undergoing Oil-Soluble Contrast Hysterosalpingography.

CONTEXT: Hysterosalpingography (HSG) with oil-soluble contrast medium (OSCM) improves pregnancy rates. However, OSCM has high iodine content and long half-life, leading to potential iodine excess. OBJECTIVE: This work aimed to determine the pattern of iodine excess after OSCM HSG and the effect on thyroid function. METHODS: A prospective cohort study was conducted of 196 consecutive consenting eligible women without overt hypothyroidism or hyperthyroidism. All completed the study with compliance greater than 95%. Participants underwent OSCM HSG (Auckland, 2019-2021) with serial monitoring of thyrotropin (TSH), free thyroxine (FT4), and urine iodine concentration (UIC) for 24 weeks. The main outcome measure was the development of subclinical hypothyroidism (SCH), defined as a nonpregnant TSH greater than 4 mIU/L with normal FT4 (11-22 pmol/L) in those with normal baseline thyroid function. RESULTS: Iodine excess (UIC ≥ 300 µg/L) was almost universal (98%) with UIC peaking usually by 4 weeks. There was marked iodine excess, with 90% and 17% of participants having UIC greater than or equal to 1000 µg/L and greater than 10 000 µg/L, respectively. Iodine excess was prolonged with 67% having a UIC greater than or equal to 1000 µg/L for at least 3 months. SCH developed in 38%; the majority (96%) were mild (TSH 4-10 mIU/L) and most developed SCH by week 4 (75%). Three participants met the current treatment guidelines (TSH > 10 mIU/L). Thyroxine treatment of mild SCH tended to improve pregnancy success (P = .063). Hyperthyroidism (TSH < 0.3 mIU/L) occurred in 9 participants (5%). CONCLUSION: OSCM HSG resulted in marked and prolonged iodine excess. SCH occurred frequently with late-onset hyperthyroidism occasionally. Regular thyroid function tests are required for 6 months following this procedure.

Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind, studies (SPIRIT 1 and 2).

BACKGROUND: Endometriosis is a common cause of pelvic pain in women, for which current treatment options are suboptimal. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, combined with estradiol and a progestin, was evaluated for treatment of endometriosis-associated pain. METHODS: In these two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled trials at 219 community and hospital research centres in Africa, Australasia, Europe, North America, and South America, we randomly assigned women aged 18-50 years with surgically or directly visualised endometriosis with or without histological confirmation, or with histological diagnosis alone. Participants were eligible if they had moderate to severe endometriosis-associated pain and, during the 35-day run-in period, a dysmenorrhoea Numerical Rating Scale (NRS) score of 4·0 or higher on two or more days and a mean non-menstrual pelvic pain NRS score of 2·5 or higher, or a mean score of 1·25 or higher that included a score of 5 or more on 4 or more days. Women received (1:1:1) once-daily oral placebo, relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0·5 mg), or delayed relugolix combination therapy (relugolix 40 mg monotherapy followed by relugolix combination therapy, each for 12 weeks) for 24 weeks. During the double-blind randomised treatment and follow-up period, all patients, investigators, and sponsor staff or representatives involved in the conduct of the study were masked to treatment assignment. The co-primary endpoints were responder rates at week 24 for dysmenorrhoea and non-menstrual pelvic pain, both based on NRS scores and analgesic use. Efficacy and safety were analysed in the modified intent-to-treat population (randomised patients who received ≥1 study drug dose). The studies are registered at ClinicalTrials.gov (SPIRIT 1 [NCT03204318] and SPIRIT 2 [NCT03204331]) and EudraCT (SPIRIT 1 [2017-001588-19] and SPIRIT 2 [2017-001632-19]). Eligible patients who completed the SPIRIT studies could enrol in a currently ongoing 80-week open-label extension study (SPIRIT EXTENSION [NCT03654274, EudraCT 2017-004066-10]). Database lock for the on-treatment duration has occurred, and post-treatment follow-up for safety, specificially for bone mineral density and menses recovery, is ongoing at the time of publication. FINDINGS: 638 patients were enrolled into SPIRIT 1 and randomly assigned between Dec 7, 2017, and Dec 4, 2019, to receive relugolix combination therapy (212 [33%]), placebo (213 [33%]), or relugolix delayed combination therapy (213 [33%]). 623 patients were enrolled into SPIRIT 2 and were randomly assigned between Nov 1, 2017 and Oct 4, 2019, to receive relugolix combination therapy (208 [33%]), placebo (208 [33%]), or relugolix delayed combination therapy (207 [33%]). 98 (15%) patients terminated study participation early in SPIRIT 1 and 115 (18%) in SPIRIT 2. In SPIRIT 1, 158 (75%) of 212 patients in the relugolix combination therapy group met the dysmenorrhoea responder criteria compared with 57 (27%) of 212 patients in the placebo group (treatment difference 47·6% [95% CI 39·3-56·0]; p<0·0001). In SPIRIT 2, 155 (75%) of 206 patients in the relugolix combination therapy group were dysmenorrhoea responders compared with 62 (30%) of 204 patients in the placebo group (treatment difference 44·9% [95% CI 36·2-53·5]; p<0·0001). In SPIRIT 1, 124 (58%) of 212 patients in the relugolix combination therapy group met the non-menstrual pelvic pain responder criteria versus 84 (40%) patients in the placebo group (treatment difference 18·9% [9·5-28·2]; p<0·0001). In SPIRIT 2, 136 (66%) of 206 patients were non-menstrual pelvic pain responders in the relugolix combination therapy group compared with 87 (43%) of 204 patients in the placebo group (treatment difference 23·4% [95% CI 13·9-32·8]; p<0·0001). The most common adverse events were headache, nasopharyngitis, and hot flushes. There were nine reports of suicidal ideation across both studies (two in the placebo run-in, two in the placebo group, two in the relugolix combination therapy group, and three in the delayed relugolix combination therapy group). No deaths were reported. Least squares mean percentage change in lumbar spine bone mineral density in the relugolix combination therapy versus placebo groups was -0·70% versus 0·21% in SPIRIT 1 and -0·78% versus 0·02% in SPIRIT 2, and in the delayed relugolix combination group was -2·0% in SPIRIT 1 and -1·9% in SPIRIT 2. Decreases in opioid use were seen in treated patients as compared with placebo. INTERPRETATION: Once-daily relugolix combination therapy significantly improved endometriosis-associated pain and was well tolerated. This oral therapy has the potential to address the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment. FUNDING: Myovant Sciences.

Hysterosalpingography with Oil-Soluble Contrast Medium Does Not Increase Newborn Hypothyroidism.

OBJECTIVE: Hysterosalpingography (HSG) with oil-soluble contrast medium (OSCM) improves pregnancy rates in women with idiopathic infertility. However, OSCM has high iodine content and slow clearance resulting in potential iodine excess. If pregnancy occurs, this could impact fetal thyroid gland development and function. We aim to determine the effect of a preconceptional OSCM HSG on the thyroid function of the neonate. Design and Patients. This was a retrospective analysis of newborn TSH data for a cohort of neonates conceived within six months of an OSCM HSG in the Auckland region, New Zealand, from the years 2000 to 2019. Thyroid-stimulating hormone (TSH) levels of these newborns were obtained from newborn screening, which is routinely performed for all children at 48-72 hours of life. The primary outcome was the incidence of permanent or transient congenital hypothyroidism in this cohort. RESULTS: Of 146 babies included, all had normal TSH levels with values ranging from 1 to 7 mIU/L on the whole blood analysis of a capillary heel sample using the Perkin-Elmer AutoDelfia assay. Conception during the first 3 cycles following an OSCM HSG was 76%; however, TSH levels in this group were not higher than those conceived in later cycles. CONCLUSION: Preconceptional OSCM HSG did not increase the risk of congenital hypothyroidism in the New Zealand scenario.

Endometriosis Classification, Staging and Reporting Systems: A Review on the Road to a Universally Accepted Endometriosis Classification.

OBJECTIVE: In the field of endometriosis, several classification, staging and reporting systems have been developed. Which endometriosis classification, staging and reporting systems have been published and validated for use in clinical practice? DATA SOURCES: A systematic PUBMED literature search was performed. Data were extracted and summarized. METHODS OF STUDY SELECTION: na TABULATION, INTEGRATION AND RESULTS: Twenty-two endometriosis classification, staging and reporting systems have been published between 1973 and 2021, each developed for specific, and different, purposes. There still is no international agreement on how to describe the disease. Studies evaluating the different systems are summarized showing a discrepancy between the intended and the evaluated purpose, and a general lack of validation data confirming a correlation with pain symptoms or quality of life for any of the current systems. A few studies confirm the value of the ENZIAN system for surgical description of deep endometriosis. With regards to infertility, the endometriosis fertility index has been confirmed valid for its intended purpose. CONCLUSION: Of the 22 endometriosis classification, staging and reporting systems identified in this historical overview, only a few have been evaluated for the purpose for which they were developed. The literature search was limited to PUBMED. Unpublished classification, staging or reporting systems, or those published in books were not considered. It can be concluded that there is no international agreement on how to describe endometriosis or how to classify it, and that most classification/staging systems show no or very little correlation with patient outcomes. This overview of existing systems is a first step in working towards a universally accepted endometriosis classification.

Endometriosis classification, staging and reporting systems: a review on the road to a universally accepted endometriosis classification.

STUDY QUESTION: Which endometriosis classification, staging and reporting systems have been published and validated for use in clinical practice? SUMMARY ANSWER: Of the 22 endometriosis classification, staging and reporting systems identified in this historical overview, only a few have been evaluated, in 46 studies, for the purpose for which they were developed. WHAT IS KNOWN ALREADY: In the field of endometriosis, several classification, staging and reporting systems have been developed. PARTICIPANTS/MATERIALS SETTING METHODS: A systematic PUBMED literature search was performed. Data were extracted and summarized. MAIN RESULTS AND THE ROLE OF CHANCE: Twenty-two endometriosis classification, staging and reporting systems have been published between 1973 and 2021, each developed for specific, and different, purposes. There still is no international agreement on how to describe the disease. Studies evaluating the different systems are summarized showing a discrepancy between the intended and the evaluated purpose, and a general lack of validation data confirming a correlation with pain symptoms or quality of life for any of the current systems. A few studies confirm the value of the ENZIAN system for surgical description of deep endometriosis. With regards to infertility, the endometriosis fertility index has been confirmed valid for its intended purpose. LARGE SCALE DATA: NA. LIMITATIONS REASONS FOR CAUTION: The literature search was limited to PUBMED. Unpublished classification, staging or reporting systems, or those published in books were not considered. WIDER IMPLICATIONS OF THE FINDINGS: It can be concluded that there is no international agreement on how to describe endometriosis or how to classify it, and that most classification/staging systems show no or very little correlation with patient outcomes. This overview of existing systems is a first step in working toward a universally accepted endometriosis classification. STUDY FUNDING/COMPETING INTERESTS: The meetings and activities of the working group were funded by the American Association of Gynecologic Laparoscopists, European Society for Gynecological Endoscopy, European Society of Human Reproduction and Embryology and World Endometriosis Society. A.W.H. reports grant funding from the MRC, NIHR, CSO, Wellbeing of Women, Roche Diagnostics, Astra Zeneca, Ferring, Charles Wolfson Charitable Trust, Standard Life, Consultancy fees from Roche Diagnostics, AbbVie, Nordic Pharma and Ferring, outside the submitted work. In addition, A.W.H. has a patent Serum biomarker for endometriosis pending. N.P.J. reports personal fees from Abbott, Guerbet, Myovant Sciences, Vifor Pharma, Roche Diagnostics, outside the submitted work; he is also President of the World Endometriosis Society and chair of the trust board. S.M. reports grants and personal fees from AbbVie, and personal fees from Roche outside the submitted work. C.T. reports grants, non-financial support and other from Merck SA, non-financial support and other from Gedeon Richter, non-financial support from Ferring Pharmaceuticals, outside the submitted work and without private revenue. K.T.Z. reports grants from Bayer Healthcare, MDNA Life Sciences, Roche Diagnostics Inc, Volition Rx, outside the submitted work; she is also a Board member (Secretary) of the World Endometriosis Society and World Endometriosis Research Foundation, Research Advisory Board member of Wellbeing of Women, UK (research charity), and Chair, Research Directions Working Group, World Endometriosis Society. The other authors had nothing to disclose. TRIAL REGISTRATION NUMBER: NA.

Awareness and utilisation of advanced gynaecological ultrasound in the preoperative work-up of women planning surgery for endometriosis: A survey of RANZCOG fellows and trainees.

BACKGROUND: Endometriosis-specific (advanced gynaecological) ultrasound is recommended as part of preoperative work-up of women with suspected endometriosis. AIM: To evaluate the awareness and utilisation of advanced gynaecological ultrasound in the preoperative work-up of women with suspected endometriosis among active RANZCOG (Royal Australian and New Zealand College of Obstetricians and Gynaecologists) fellows and trainees. MATERIALS AND METHODS: Anonymous online survey invitations were emailed to all active RANZCOG fellows in Australia and New Zealand. Descriptive analysis of responses and multivariate analysis where appropriate were performed. P < 0.05 was considered statistically significant. RESULTS: A 17% (437/2567) survey response rate and 93% (409/437) completion rate were recorded; 59% (248/421) of respondents identified as generalists, whereas 15% (63/421) identified as advanced laparoscopic surgeons. Routine pelvic ultrasound (88.9%, 361/406) was the most common imaging modality requested by respondents; 32% (128/405) of respondents would also always request advanced gynaecology ultrasound. Respondents' self-reported practice type was significantly associated with utilisation of advanced gynaecological ultrasound (P = 0.03); 79.6% (348/437) agreed with our proposed definition of advanced gynaecological ultrasound for endometriosis. A major limitation to the utilisation of advanced gynaecological ultrasound for endometriosis was the lack of local expertise (63.8%, 233/356). CONCLUSION: The utilisation of advanced gynaecological ultrasound for endometriosis is significantly influenced by respondents' self-reported practice type and limited by the lack of local expertise.

Ignored Because It Is Benign - It Is Time to Treat Endometriosis as if It Were Cancer.

We are proposing a shift in mindset in the field of endometriosis, whereby care for patients with endometriosis mirrors that of patients with gynaecological cancer. To achieve this, we advocate for the recognition of complex benign gynaecology as a subspecialty. Since the establishment of gynaecological oncology as a subspecialty, outcomes for patients with ovarian cancer have improved, with their care managed by multidisciplinary teams in specialized units. Despite the marked difference in the primary treatment goal between these two conditions, they share common diagnostic and therapeutic challenges. We believe that care management by a multidisciplinary team of dedicated and specialized health care professionals will lead to improved outcomes, including improved quality of life, for people living with endometriosis.

When to Do Surgery and When Not to Do Surgery for Endometriosis: A Systematic Review and Meta-analysis.

OBJECTIVE: We performed a systematic review and meta-analysis with the aim to answer whether operative laparoscopy is an effective treatment in a woman with demonstrated endometriosis compared with alternative treatments. Moreover, we aimed to assess the risks of operative laparoscopy compared with those of alternatives. In addition, we aimed to systematically review the literature on the impact of patient preference on decision making around surgery. DATA SOURCES: We searched MEDLINE, Embase, PsycINFO, ClinicalTrials.gov, CINAHL, Scopus, OpenGrey, and Web of Science from inception through May 2019. In addition, a manual search of reference lists of relevant studies was conducted. METHODS OF STUDY SELECTION: Published and unpublished randomized controlled trials (RCTs) in any language describing a comparison between surgery and any other intervention were included, with particular reference to timing and its impact on pain and fertility. Studies reporting on keywords including, but not limited to, endometriosis, laparoscopy, pelvic pain, and infertility were included. In the anticipated absence of RCTs on patient preference, all original research on this topic was considered eligible. TABULATION, INTEGRATION, AND RESULTS: In total, 1990 studies were reviewed. Twelve studies were identified as being eligible for inclusion to assess outcomes of pain (n = 6), fertility (n = 7), quality of life (n = 1), and disease progression (n = 3). Seven studies of interest were identified to evaluate patient preferences. There is evidence that operative laparoscopy may improve overall pain levels at 6 months compared with diagnostic laparoscopy (risk ratio [RR], 2.65; 95% confidence interval [CI], 1.61-4.34; p <.001; 2 RCTs, 102 participants; low-quality evidence). Because the quality of the evidence was very low, it is uncertain if operative laparoscopy improves live birth rates. Operative laparoscopy probably yields little or no difference regarding clinical pregnancy rates compared with diagnostic laparoscopy (RR, 1.29; 95% CI, 0.99-1.92; p = .06; 4 RCTs, 624 participants; moderate-quality evidence). It is uncertain if operative laparoscopy yields a difference in adverse outcomes when compared with diagnostic laparoscopy (RR, 1.98; 95% CI, 0.84-4.65; p = .12; 5 RCTs, 554 participants; very-low-quality evidence). No studies reported on the progression of endometriosis to a symptomatic state or progression of extent of disease in terms of volume of lesions and locations in asymptomatic women with endometriosis. We found no studies that reported on the timing of surgery. No quantitative or qualitative studies specifically aimed at elucidating the factors informing a woman's choice for surgery were identified. CONCLUSION: Operative laparoscopy may improve overall pain levels but may have little or no difference with respect to fertility-related or adverse outcomes when compared with diagnostic laparoscopy. Additional high-quality RCTs, including comparing surgery to medical management, are needed, and these should report adverse events as an outcome. Studies on patient preference in surgical decision making are needed (International Prospective Register of Systematic Review registration number: CRD42019135167).

First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment-covariate interaction analyses and therefore offers an opportunity for personalised medicine. OBJECTIVE AND RATIONALE: We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics. SEARCH METHODS: We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs. OUTCOMES: IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17-1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23-1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38-2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01-1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00-1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00-1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87-1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01-1.06). WIDER IMPLICATIONS: In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS.

Long-Term Outcomes of Elagolix in Women With Endometriosis: Results From Two Extension Studies.

OBJECTIVE: To evaluate the efficacy and safety of elagolix, an oral, nonpeptide gonadotropin-releasing hormone antagonist, over 12 months in women with endometriosis-associated pain. METHODS: Elaris Endometriosis (EM)-III and -IV were extension studies that evaluated an additional 6 months of treatment after two 6-month, double-blind, placebo-controlled phase 3 trials (12 continuous treatment months) with two elagolix doses (150 mg once daily and 200 mg twice daily). Coprimary efficacy endpoints were the proportion of responders (clinically meaningful pain reduction and stable or decreased rescue analgesic use) based on average monthly dysmenorrhea and nonmenstrual pelvic pain scores. Safety assessments included adverse events, clinical laboratory tests, and endometrial and bone mineral density assessments. The power of Elaris EM-III and -IV was based on the comparison to placebo in Elaris EM-I and -II with an expected 25% dropout rate. RESULTS: Between December 28, 2012, and October 31, 2014 (Elaris EM-III), and between May 27, 2014, and January 6, 2016 (Elaris EM-IV), 569 participants were enrolled. After 12 months of treatment, Elaris EM-III responder rates for dysmenorrhea were 52.1% at 150 mg once daily (Elaris EM-IV 550.8%) and 78.2% at 200 mg twice daily (Elaris EMIV 575.9%). Elaris EM-III nonmenstrual pelvic pain responder rates were 67.5% at 150 mg once daily (Elaris EM-IV 566.4%) and 69.1% at 200 mg twice daily (Elaris EM-IV 567.2%)."After 12 months of treatment, Elaris EM-III dyspareunia responder rates were 45.2% at 150 mg once daily (Elaris EM-IV=45.9%) and 60.0% at 200 mg twice daily (Elaris EM-IV=58.1%). Hot flush was the most common adverse event. Decreases from baseline in bone mineral density and increases from baseline in lipids were observed after 12 months of treatment. There were no adverse endometrial findings. CONCLUSION: Long-term elagolix treatment provided sustained reductions in dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia. The safety was consistent with reduced estrogen levels and no new safety concerns were associated with long-term elagolix use. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01760954 and NCT02143713.

Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist.

BACKGROUND: Endometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to nearly full estrogen suppression in previous studies. METHODS: We performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) to evaluate the effects of two doses of elagolix - 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) - as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain. The two primary efficacy end points were the proportion of women who had a clinical response with respect to dysmenorrhea and the proportion who had a clinical response with respect to nonmenstrual pelvic pain at 3 months. Each of these end points was measured as a clinically meaningful reduction in the pain score and a decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary. RESULTS: A total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, a significantly greater proportion of women who received each elagolix dose met the clinical response criteria for the two primary end points than did those who received placebo. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P<0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to nonmenstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P<0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P=0.003 and P<0.001, respectively). The responses with respect to dysmenorrhea and nonmenstrual pelvic pain were sustained at 6 months. Women who received elagolix had higher rates of hot flushes (mostly mild or moderate), higher levels of serum lipids, and greater decreases from baseline in bone mineral density than did those who received placebo; there were no adverse endometrial findings. CONCLUSIONS: Both higher and lower doses of elagolix were effective in improving dysmenorrhea and nonmenstrual pelvic pain during a 6-month period in women with endometriosis-associated pain. The two doses of elagolix were associated with hypoestrogenic adverse effects. (Funded by AbbVie; Elaris EM-I and EM-II ClinicalTrials.gov numbers, NCT01620528 and NCT01931670 .).

World Endometriosis Society consensus on the classification of endometriosis.

STUDY QUESTION: What is the global consensus on the classification of endometriosis that considers the views of women with endometriosis? SUMMARY ANSWER: We have produced an international consensus statement on the classification of endometriosis through systematic appraisal of evidence and a consensus process that included representatives of national and international, medical and non-medical societies, patient organizations, and companies with an interest in endometriosis. WHAT IS KNOWN ALREADY: Classification systems of endometriosis, developed by several professional organizations, traditionally have been based on lesion appearance, pelvic adhesions, and anatomic location of disease. One system predicts fertility outcome and none predicts pelvic pain, response to medications, disease recurrence, risks for associated disorders, quality of life measures, and other endpoints important to women and health care providers for guiding appropriate therapeutic options and prognosis. STUDY DESIGN, SIZE, DURATION: A consensus meeting, in conjunction with pre- and post-meeting processes, was undertaken. PARTICIPANTS/MATERIALS, SETTING, METHODS: A consensus meeting was held on 30 April 2014 in conjunction with the World Endometriosis Society's 12th World Congress on Endometriosis. Rigorous pre- and post-meeting processes, involving 55 representatives of 29 national and international, medical and non-medical organizations from a range of disciplines, led to this consensus statement. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 28 consensus statements were made. Of all, 10 statements had unanimous consensus, however none of the statements was made without expression of a caveat about the strength of the statement or the statement itself. Two statements did not achieve majority consensus. The statements covered women's priorities, aspects of classification, impact of low resources, as well as all the major classification systems for endometriosis. Until better classification systems are developed, we propose a classification toolbox (that includes the revised American Society for Reproductive Medicine and, where appropriate, the Enzian and Endometriosis Fertility Index staging systems), that may be used by all surgeons in each case of surgery undertaken for women with endometriosis. We also propose wider use of the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project surgical and clinical data collection tools for research to improve classification of endometriosis in the future, of particular relevance when surgery is not undertaken. LIMITATIONS, REASONS FOR CAUTION: This consensus process differed from that of formal guideline development, although based on the same available evidence. A different group of international experts from those participating in this process may have yielded subtly different consensus statements. WIDER IMPLICATIONS OF THE FINDINGS: This is the first time that a large, global, consortium-representing 29 major stake-holding organizations, from 19 countries - has convened to systematically evaluate the best available evidence on the classification of endometriosis and reach consensus. In addition to 21 international medical organizations and companies, representatives from eight national endometriosis organizations were involved, including lay support groups, thus generating and including input from women who suffer from endometriosis in an endeavour to keep uppermost the goal of optimizing quality of life for women with endometriosis. STUDY FUNDING/COMPETING INTERESTS: The World Endometriosis Society convened and hosted the consensus meeting. Financial support for participants to attend the meeting was provided by the organizations that they represented. There was no other specific funding for this consensus process. Mauricio Abrao is an advisor to Bayer Pharma, and a consultant to AbbVie and AstraZeneca; G David Adamson is the Owner of Advanced Reproductive Care Inc and Ziva and a consultant to Bayer Pharma, Ferring, and AbbVie; Deborah Bush has received travel grants from Fisher & Paykel Healthcare and Bayer Pharmaceuticals; Linda Giudice is a consultant to AbbVie, Juniper Pharmaceutical, and NextGen Jane, holds research grant from the NIH, is site PI on a clinical trial sponsored by Bayer, and is a shareholder in Merck and Pfizer; Lone Hummelshoj is an unpaid consultant to AbbVie; Neil Johnson has received conference expenses from Bayer Pharma, Merck-Serono, and MSD, research funding from AbbVie, and is a consultant to Vifor Pharma and Guerbet; Jörg Keckstein has received a travel grant from AbbVie; Ludwig Kiesel is a consultant to Bayer Pharma, AbbVie, AstraZeneca, Gedeon Richter, and Shionogi, and holds a research grant from Bayer Pharma; Luk Rombauts is an advisor to MSD, Merck Serono, and Ferring, and a shareholder in Monash IVF. The following have declared that they have nothing to disclose: Kathy Sharpe Timms; Rulla Tamimi; Hugh Taylor. TRIAL REGISTRATION NUMBER: N/A.

Diagnostic laparoscopy in pre-surgical planning for higher stage endometriosis: Is it still relevant?

It has become necessary to re - examine the relevance of diagnostic laparoscopy in the two-stage approach to surgical management of symptomatic women with higher stage endometriosis following emerging evidence demonstrating acceptable diagnostic performance of alternative less invasive and less expensive imaging modalities. We highlight the relative merits of these presurgical diagnostic imaging modalities and propose strategies that address the challenge of transitioning to a new diagnostic paradigm in the management of symptomatic women with higher stage endometriosis.

Metformin use in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is an endocrinopathy characterised by increased resistance to insulin. Metformin is one of the longest established oral insulin sensitising agents. For decades its use was restricted to management of type 2 diabetes. However, in the past two decades, its properties as an insulin sensitising agent have been explored in relation to its applicability for women with PCOS. Metformin is an effective ovulation induction agent for non-obese women with PCOS and offers some advantages over other first line treatments for anovulatory infertility such as clomiphene. For clomiphene-resistant women, metformin alone or in combination with clomiphene is an effective next step. Women with PCOS undergoing in vitro fertilisation should be offered metformin to reduce their risk of ovarian hyperstimulation syndrome. Limited evidence suggests that metformin may be a suitable alternative to the oral contraceptive pill (OCP) for treating hyperandrogenic symptoms of PCOS including hirsutism and acne. More research is required to define whether metformin has a role in improving long term health outcomes for women with PCOS, including the prevention of diabetes, cardiovascular disease and endometrial cancer.

Ovarian biopsy has no role as a routine diagnostic test of ovarian reserve: a systematic review.

Ovarian reserve describes a woman's reproductive potential and there are a variety of tests for this. This reflects the lack of a gold standard and the lack of a single test that provides sufficient accuracy. Ovarian biopsy has been proposed as a potential tool for assessing the ovarian reserve and therefore the ability or inability for a woman to bear a child with or without treatment. The literature assessing the diagnostic accuracy of ovarian biopsy as a test of ovarian reserve for predicting fertility outcomes (live birth rate, ongoing pregnancy, clinical pregnancy, biochemical pregnancy, embryos available, oocytes retrieved or cancelled cycles) was systematically reviewed. There were no studies identified that assessed the diagnostic accuracy of ovarian biopsy for predicting fertility outcomes but a number of studies provided evidence that ovarian follicles are distributed unevenly and randomly throughout the ovarian cortex. This leads to sampling error when ovarian biopsy is used to sample the ovarian reserve. It is concluded that ovarian biopsy should not be used as a test of ovarian reserve. Every woman is born with a limited number of eggs, and as women age, their ability to have children eventually decreases to zero due to the loss of these eggs. Ovarian reserve is a term that describes the remaining pool of eggs. Testing for ovarian reserve enables one to predict the ability or inability of a woman to have a child and how long a woman may be able to defer having a child. This is of importance as social trends in developed countries are leading to increasing numbers of women who have children at later stages of their lives. One test of ovarian reserve is an ovarian biopsy, where a woman undergoes an operation to have a small piece of her ovary removed. The number of eggs in this removed piece is counted, and from this, the number of eggs in the whole ovary can be estimated and calculated. We reviewed the literature for all studies that examined the accuracy of ovarian biopsy to predict fertility outcomes but found no studies that answered this question. A number of studies have found that eggs are distributed unevenly and randomly in an ovary. As such, the number of eggs in an ovarian biopsy sample does not represent the actual number of eggs remaining in the ovary. Because of this and the risks inherent in the operation to perform this test, we believe that ovarian biopsy should not be used as a test of ovarian reserve.

Analysis of factors predicting success of metformin and clomiphene treatment for women with infertility owing to PCOS-related ovulation dysfunction in a randomised controlled trial.

BACKGROUND: Metformin has failed to gain wide acceptance as a first-line treatment option for women with anovulatory infertility related to polycystic ovary syndrome. This study aimed to ascertain factors that predict fertility success with treatment that included metformin compared to standard (non-metformin) treatment. METHODS: Randomised trial data analysis by logistic regression of factors likely to have a differential influence on the likelihood of success of metformin versus non-metformin treatment amongst women with ovulation dysfunction related to polycystic ovary syndrome. RESULTS: metformin versus those receiving placebo and those with lower BMI who received metformin were more likely to become pregnant than their lower BMI counterparts who received placebo (P=0.039). The subpopulation of women with BMI≤32 kg/m(2) had no factors showing a significantly different impact on the chance of pregnancy for women treated with metformin versus those receiving clomiphene treatment or combination metformin/clomiphene treatment versus clomiphene treatment. There were no significantly different effects of free testosterone, fasting insulin, duration of infertility or ultrasound appearance of polycystic ovaries in any treatment groups. CONCLUSION: This study provides preliminary evidence that BMI may be an important prognostic factor in response to metformin for women with ovulation dysfunction related to polycystic ovary syndrome, suggesting that women with a lower BMI may respond better to metformin treatment versus placebo amongst women with BMI>32 kg/m(2) . Individual patient data meta-analysis of existing randomised trials would clarify this further and would assess whether other factors might predict better response to metformin versus standard treatments.

Individual patient data meta-analysis of diagnostic and prognostic studies in obstetrics, gynaecology and reproductive medicine.

BACKGROUND: In clinical practice a diagnosis is based on a combination of clinical history, physical examination and additional diagnostic tests. At present, studies on diagnostic research often report the accuracy of tests without taking into account the information already known from history and examination. Due to this lack of information, together with variations in design and quality of studies, conventional meta-analyses based on these studies will not show the accuracy of the tests in real practice. By using individual patient data (IPD) to perform meta-analyses, the accuracy of tests can be assessed in relation to other patient characteristics and allows the development or evaluation of diagnostic algorithms for individual patients. In this study we will examine these potential benefits in four clinical diagnostic problems in the field of gynaecology, obstetrics and reproductive medicine. METHODS/DESIGN: Based on earlier systematic reviews for each of the four clinical problems, studies are considered for inclusion. The first authors of the included studies will be invited to participate and share their original data. After assessment of validity and completeness the acquired datasets are merged. Based on these data, a series of analyses will be performed, including a systematic comparison of the results of the IPD meta-analysis with those of a conventional meta-analysis, development of multivariable models for clinical history alone and for the combination of history, physical examination and relevant diagnostic tests and development of clinical prediction rules for the individual patients. These will be made accessible for clinicians. DISCUSSION: The use of IPD meta-analysis will allow evaluating accuracy of diagnostic tests in relation to other relevant information. Ultimately, this could increase the efficiency of the diagnostic work-up, e.g. by reducing the need for invasive tests and/or improving the accuracy of the diagnostic workup. This study will assess whether these benefits of IPD meta-analysis over conventional meta-analysis can be exploited and will provide a framework for future IPD meta-analyses in diagnostic and prognostic research.

Gynaecologic surgery from uncertainty to science: evolution of randomized control trials.

BACKGROUND: It is now accepted that both medical and surgical practice should be based on reliable and sound clinical evidence. However, randomized control trials comparing surgical interventions have been associated with many problems. The aim of this review is to assess if there has been progress made in establishing the evidence base for surgical interventions in gynaecology. METHODS: Relevant reviews were identified from Cochrane Database of Systematic Reviews (Issue , 2006) and data from individual randomized control trials extracted. Chi-squared test was used to compare quality pre- and post-Consolidated Standards of Reporting Trials (CONSORT) statement. Meta-regression analyses were performed to test the hypothesis that effect size decreased over time. Further multiple linear regression analyses were used to test the hypothesis that precision increased over time and finally a logistic regression model was used to estimate whether treatment effects differed between trials with and without allocation concealment. RESULTS: Twenty-three relevant reviews were identified, including 94 trials. The proportion of studies reporting allocation concealment significantly increased after the introduction of the CONSORT statement (P = 0.002). There was a trend towards improvement in precision over time. Similarly, there was a reduction in size of treatment effect over time (log of the ratio of odds ratios per year 0.96; 95% confidence interval 0.93-0.99, P = 0.04). CONCLUSIONS: Gynaecologic surgical practice appears to be benefiting from improvement in its research base in a subject where practitioners do not participate readily in randomized evaluation.