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Key content Lynch syndrome is an autosomal dominant condition closely associated with colorectal, endometrial and ovarian cancer.Women with Lynch syndrome are at increased risk of both endometrial and ovarian cancer and should be offered personalised counselling regarding family planning, red flag symptoms and risk-reducing strategies.Surveillance for gynaecological cancer in women with Lynch syndrome remains controversial; more robust data are needed to determine its effectiveness.Universal testing for Lynch syndrome in endometrial cancer is being adopted by centres across Europe and is now recommended by the National Institute for Health and Care Excellence; thus, gynaecologists must become familiar with testing strategies and their results.Testing strategies involve risk stratification of cancers based on phenotypical features and definitive germline testing. Learning objectives To define the pathogenesis of Lynch syndrome and its associated gynaecological cancers.To understand the testing strategies for Lynch syndrome in women with gynaecological cancer.To learn how best to counsel women with Lynch syndrome regarding gynaecological cancer and risk-reducing strategies to enable informed decision-making. Ethical issues Offering gynaecological surveillance despite a lack of robust evidence for its clinical effectiveness may falsely reassure women and delay risk-reducing hysterectomy.Genetic testing may yield variants of unknown significance with ill-defined clinical implications, which can lead to confusion and anxiety.Genetic testing has implications not only for the individual, but also for the whole family, so expert counselling is crucial.

BACKGROUND/AIM To investigate tumor suppression as an indicator of malignization potential within endometrial polyps in asymptomatic postmenopausal women. MATERIALS AND METHODS Immunohistochemical studies of the phosphatase and tensin homolog (PTEN) were performed. Cases included 52 benign postmenopausal polyps, 19 endometrioid carcinomas with coexisting benign polyps, and 12 polyps with foci of carcinoma. Controls included 31 atrophic endometria and 32 benign premenopausal polyps. PTEN was scored by quantitative methods according to staining intensity. RESULTS The mean epithelial and stromal PTEN H-score in postmenopausal benign endometrial polyps (193.8 and 123.2, respectively) was significantly higher than that in the atrophic endometrium (135.5 and 90.2, p=0.008), and premenopausal benign endometrial polyps (100.7 and 198.7, p

Ovarian cancer is most commonly diagnosed at an advanced stage (3 or 4) and remains the deadliest gynecologic malignancy. When diagnosed at stage 1, a survival rate of greater than 90% has been demonstrated, compared with a 5-year survival rate of 27% and 13% for stage 3 and stage 4 disease, respectively. Despite international efforts to identify robust screening methods and increase early-stage detection, to date no evidence that screening saves lives has been presented. The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomized controlled trial that demonstrated no evidence associated with screening for ovarian cancer and reduction in ovarian cancer-related deaths at primary analysis but requires further follow-up. This secondary analysis of the UKCTOCS randomized controlled trial aimed to provide a follow-up and report on the long-term mortality effects of ovarian cancer screening. The UKCTOCS is a multicenter randomized trial of 202,638 women aged 50 to 74 years assigned to 2 annual screening groups (multimodal screening [MMS] vs ultrasound screening [USS]). Women in the United Kingdom were recruited from 13 National Health Service (NHS) centers and randomized to MMS, USS, or no screening in a 1:1:2 ratio. Annual screening in the MMS group involved serum CA125 measurements used in conjunction with the risk of ovarian cancer (ROCA) calculation to guide follow-up involving either no additional screening, repeat CA125 ROCA in 3 months, or transvaginal USS as a second test. Annual screening in the USS group involved transvaginal ultrasound with follow-up involving either continuation of annual screening, repeat in 3 months, or requiring a scan with a senior ultrasonographer within 6 weeks. The primary study outcome was death due to ovarian cancer or tubal cancer. A total of 202,638 women were randomized between April 2001 and September 2005, with screening concluding in December 2011 and follow-up continuing until June 2020. The final analysis cohort consisted of 202,562 women, 50,625 in the MMS group, 50,623 in the USS group, and 101,314 in the no screening group. Compliance with screening was 81% in the MMS group versus 78% in the USS group, with a median of 8 annual screens per participant. The median follow-up was 16.3 years (interquartile range, 15.1–17.3). A total of 2055 participants were diagnosed with ovarian or tubal cancer. At 9.5 years after screening, there was a 47.2% (95% confidence interval, 19.7–81.1) greater incidence of stage 1 disease and a 24.5% (-41.8 to -2.0) lower incidence of stage IV disease in the MMS group compared with the no screening group. Overall, a 39.2% (95% confidence interval, 16.1–66.9) greater incidence of stage I or II disease and a 10.2% (-21.3 to 2.4) lower incidence of stage III or IV disease was observed in the MMS group compared with the no screening group. At follow-up conclusion, 1206 women had died of ovarian cancer (296/50,625 [0.6%] in the MMS group, 291/50,623 [0.6%] in the USS group, 619/101,314 [0.6%] in the no screening group) with no significant difference between the MMS (P = 0.58) and USS (P = 0.36) groups compared with the no screening group. The results of this large-scale ovarian cancer screening trial demonstrate that, on long-term follow-up, while the screening strategies defined here resulted in a greater likelihood of diagnosing early stage disease, neither MMS nor USS resulted in a significant reduction in deaths from ovarian or tubal cancer.

STUDY QUESTION Is the innate immunity system active in early human embryo development? SUMMARY ANSWER The pattern recognition receptors and innate immunity Toll-like receptor (TLR) genes are widely expressed in preimplantation human embryos and the pathway appears to be active in response to TLR ligands. WHAT IS KNOWN ALREADY Early human embryos are highly sensitive to their local environment, however relatively little is known about how embryos detect and respond to specific environmental cues. While the maternal immune response is known to be key to the establishment of pregnancy at implantation, the ability of human embryos to detect and signal the presence of pathogens is unknown. STUDY DESIGN, SIZE, DURATION Expression of TLR family and related genes in human embryos was assessed by analysis of published transcriptome data (n = 40). Day 5 (D-5) human embryos (n = 25) were cultured in the presence of known TLR ligands and gene expression and cytokine production measured compared to controls. PARTICIPANTS/MATERIALS, SETTING, METHODS Human embryos surplus to treatment requirements were donated with informed consent from several ART centres. Embryos were cultured to Day 6 (D-6) in the presence of the TLR3 and TLR5 ligands Poly (I: C) and flagellin, with gene expression measured by quantitative PCR and cytokine release into medium measured using cytometric bead arrays. MAIN RESULTS AND THE ROLE OF CHANCE TLR and related genes, including downstream signalling molecules, were expressed variably at all human embryo developmental stages. Results showed the strongest expression in the blastocyst for TLRs 9 and 5, and throughout development for TLRs 9, 5, 2, 6 and 7. Stimulation of Day 5 blastocysts with TLR3 and TLR5 ligands Poly (I: C) and flagellin produced changes in mRNA expression levels of TLR genes, including the hyaluronan-mediated motility receptor (HMMR), TLR5, TLR7, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and monocyte chemoattractant Protein-1 (MCP-1) (P LIMITATIONS, REASONS FOR CAUTION This was a descriptive and experimental study which suggests that the TLR system is active in human embryos and capable of function, but does not confirm any particular role. Although we identified embryonic transcripts for a range of TLR genes, the expression patterns were not always consistent across published studies and expression levels of some genes were low, leaving open the possibility that these were expressed from the maternal rather than embryonic genome. WIDER IMPLICATIONS OF THE FINDINGS This is the first report of the expression and activity of a number of components of the innate immunity TLR system in human embryos. Understanding the role of TLRs during preimplantation human development may be important to reveal immunological mechanisms and potential clinical markers of embryo quality and pregnancy initiation during natural conception and in ART. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by the Ministry of Higher Education, The State of Libya, the UK Medical Research Council, and the NIHR Local Comprehensive Research Network and NIHR Manchester Clinical Research Facility and the European Union’s Horizon 2020 Research and Innovation Programmes under the Marie Skłodowska-Curie Grant Agreement No. 812660 (DohART-NET). In accordance with H2020 rules, no new human embryos were sacrificed for research activities performed from the EU funding, which concerned only in silico analyses of recorded time-lapse and transcriptomics datasets. None of the authors has any conflict of interest to declare. TRIAL REGISTRATION NUMBER n/a.

Background and objectives: Endometrial polyps in asymptomatic postmenopausal women are often incidentally found, yet only 1.51% of them are malignant. Their potential for malignant transformation has not been adequately addressed. The aim of this study was to investigate the proliferation within endometrial polyps as one of the indicators of their malignization potential in asymptomatic postmenopausal women. Materials and Methods: Immunohistochemical studies of Ki-67 were performed. Cases included 52 benign postmenopausal polyps, 19 endometrioid carcinoma with coexisting benign polyps, 12 polyps with foci of carcinoma and 4 cases of polyps, which later developed carcinoma. The control group included 31 atrophic endometria and 32 benign premenopausal polyps. Ki-67 was scored in either 10 or 20 &ldquo, hot spot&rdquo, fields, as percentage of positively stained cells. Results: The median epithelial Ki-67 score in postmenopausal benign polyps (4.7%) was significantly higher than in atrophic endometria (2.41%, p &lt, 0.0001) and significantly lower than in premenopausal benign polyps (11.4%, p = 0.003) and endometrial cancer (8.3%, p &lt, 0.0001). Where endometrial polyps were found in association with endometrial carcinoma, Ki-67 was significantly higher in cancer (p &lt, 0.0001). No significant difference was found between Ki-67 scores of cancer focus and of the polyps tissue itself, respectively 2.8% and 4.55%, p = 0.37. Ki-67 expression, where polyps were resected and women later developed cancer, was not significantly different (p = 0.199). Conclusion: Polyps from asymptomatic postmenopausal women showed significantly more proliferation in both epithelial and stromal components than inactive atrophic endometria but less than premenopausal benign polyps and/or endometrial cancer. Benign postmenopausal endometrial polyps exhibit low proliferative activity, suggesting low malignant potential and may not require resection in asymptomatic women.

Purpose\ud \ud There are no internationally agreed upon clinical guidelines as to which women with gynecological cancer would benefit from Lynch syndrome screening or how best to manage the risk of gynecological cancer in women with Lynch syndrome. The Manchester International Consensus Group was convened in April 2017 to address this unmet need. The aim of the Group was to develop clear and comprehensive clinical guidance regarding the management of the gynecological sequelae of Lynch syndrome based on existing evidence and expert opinion from medical professionals and patients.\ud \ud Methods\ud \ud Stakeholders from Europe and North America worked together over a two-day workshop to achieve consensus on best practice.\ud \ud Results\ud \ud Guidance was developed in four key areas: (1) whether women with gynecological cancer should be screened for Lynch syndrome and (2) how this should be done, (3) whether there was a role for gynecological surveillance in women at risk of Lynch syndrome, and (4) what preventive measures should be recommended for women with Lynch syndrome to reduce their risk of gynecological cancer.\ud \ud Conclusion\ud \ud This document provides comprehensive clinical guidance that can be referenced by both patients and clinicians so that women with Lynch syndrome can expect and receive appropriate standards of care.

Objective Pelvic vein incompetence (PVI) affects 15–20% of all women, yet we know little about how it affects sufferers. The aim of this prospective pilot study was to explore symptoms experienced by women with PVI, and determine its impact on quality of life and NHS costs. Study design Case-control study at a UK University teaching hospital conducted over an eight-month period. Cases were 40 premenopausal women aged 18–49 years with PVI and varicose veins (VV). There were two age-matched controls groups: (i) 40 healthy women with no PVI but with VV, and (ii) 40 healthy women with no PVI and no VV. Subjects were asked to complete a structured questionnaire on disease specific outcomes, health status and use of healthcare resources. Results Mean age (range) was 39.8 (24–47) years for cases, 39.1 (24–49) for VV controls and 38 (25–49) for healthy controls. Pelvic pain was reported by 38 of 40 (95%) PVI cases, compared with 25 of 40 (62%) VV controls, and 26 of 40 (65%) healthy controls ( p = 0.001). The median (range) EQ-5D utility score for PVI cases was 0.80 (0.29–1.0) compared with 0.80 (0.09–1.0) for VV controls and 1.0 (0.62–1.0) for healthy controls ( p = 0.002). Of the 40 PVI cases, 35 (88%) visited a consultant in the previous 12 months compared with 12 of 40 (30%) VV controls, and 14 of 40 (35%) healthy controls ( p Conclusions Women with PVI report a greater frequency of pelvic pain with reduced health status and increased use of healthcare resources compared with matched controls.

Chronic pelvic pain (CPP) affects 24% of women worldwide; the cause cannot be identified in 40% despite invasive investigations. Dilated, refluxing pelvic veins may be a cause of CPP and treatment by trans-venous occlusion is increasingly performed when gynecological causes are excluded, but is it effective? A systematic review of the literature published between 1966 and July 2014 was conducted. Two authors independently reviewed potential studies according to a set of eligibility criteria, with a third assessor available as an arbiter. Thirteen studies including 866 women undergoing trans-venous occlusion of pelvic veins for CPP were identified (Level of evidence: one study grade 2b, 12 studies grade four). Statistical significant improvements in pelvic pain were reported in nine of the 13 studies. Technical success was reported in 865 of 866 (99.8%) with low complication rates: coil migration in 14 women (1.6%), abdominal pain in ten women (1.2%) and vein perforation in five (0.6%). In a study on varicose veins of the legs, recurrence was seen in 13% of 179 women 5-years following coil embolization. Subjective improvements in pain were seen in all 13 studies after treatment by trans-venous occlusion. All 13 studies were of poor methodological quality. Complication rates were low and no fatalities occurred. Well-designed studies are essential to determine whether pelvic vein incompetence (PVI) is associated with CPP, and to explore whether trans-venous occlusion of PVI improves quality of life for these women.

BACKGROUND: Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer mortality. METHODS: In this randomised controlled trial, we recruited postmenopausal women aged 50-74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer-generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032. FINDINGS: Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202,638 women: 50,640 (25·0%) to MMS, 50,639 (25·0%) to USS, and 101,359 (50·0%) to no screening. 202,546 (>99·9%) women were eligible for analysis: 50,624 (>99·9%) women in the MMS group, 50,623 (>99·9%) in the USS group, and 101,299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345,570 MMS and 327,775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0-12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0-14 of 15% (95% CI -3 to 30; p=0·10) with MMS and 11% (-7 to 27; p=0·21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (-20 to 31) in years 0-7 and 23% (1-46) in years 7-14, and in the USS group, of 2% (-27 to 26) in years 0-7 and 21% (-2 to 42) in years 7-14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0·021), with an overall average mortality reduction of 20% (-2 to 40) and a reduction of 8% (-27 to 43) in years 0-7 and 28% (-3 to 49) in years 7-14 in favour of MMS. INTERPRETATION: Although the mortality reduction was not significant in the primary analysis, we noted a significant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7-14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening. FUNDING: Medical Research Council, Cancer Research UK, Department of Health, The Eve Appeal.

Objective: To evaluate the malignant potential of ultrasound-detected ovarian inclusion cysts in the development of ovarian cancer (OC) in postmenopausal women. Design: Prospective cohort study. Setting: UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Population: Postmenopausal women. Methods: In UKCTOCS, women in the ultrasound group have annual scans. Women with inclusion cysts (single/multiple anechoic £10-mm ovarian cysts) and normal ovaries (both uniform hypoechogenicity) on their first scan were identified and followed up through cancer registry/questionnaires. Main outcome measures: Relative risk (RR) of developing OC, invasive epithelial ovarian cancer (iEOC), breast cancer (BC) and endometrial cancer (EC) in women with inclusion cysts relative to those with normal ovaries. The incidence was compared with UK age-adjusted expected rates (Office for National Statistics, 2005). Results: Postmenopausal women (n = 48 230) attended the year 1(11 June 2001–6 December 2006) screen; 1234 (2.5%) had inclusion cysts alone and 22 914 had normal scans. By 1 November 2009 (median follow-up, 6.13 years; interquartile range,4.96–6.98 years), four, three (one Type II), seven and 22 women with inclusion cysts and 32, 29 (20 Type II), 90 and 397 women with normal ovaries were diagnosed with OC, iEOC, EC and BC,respectively. The RR values for the respective cancers (OC [RR,2.32; confidence interval [CI], 0.86–6.28], iEOC [RR, 1.92; CI,0.62–5.92], EC [RR, 1.44; CI, 0.68–3.05], BC [RR, 1.12; CI,0.73–1.73]) were not increased. There was no difference between the observed versus expected incidence rates for these cancers in women with inclusion cysts. Conclusions: Postmenopausal women with ultrasound-detected inclusion cysts do not seem to be at increased risk of ovarian or breast/endometrial (hormone-dependent) cancers.

Summary Background The increase in the worldwide incidence of endometrial cancer relates to rising obesity, falling fertility, and the ageing of the population. Transvaginal ultrasound (TVS) is a possible screening test, but there have been no large-scale studies. We report the performance of TVS screening in a large cohort. Methods We did a nested case-control study of postmenopausal women who underwent TVS in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) following recruitment between April 17, 2001, and Sept 29, 2005. Endometrial thickness and endometrial abnormalities were recorded, and follow-up, through national registries and a postal questionnaire, documented the diagnosis of endometrial cancer. Our primary outcome measure was endometrial cancer and atypical endometrial hyperplasia (AEH). Performance characteristics of endometrial thickness and abnormalities for detection of endometrial cancer within 1 year of TVS were calculated. Epidemiological variables were used to develop a logistic regression model and assess a screening strategy for women at higher risk. Our study is registered with ClinicalTrials.gov, number NCT00058032, and with the International Standard Randomised Controlled Trial register, number ISRCTN22488978. Findings 48 230 women underwent TVS in the UKCTOCS prevalence screen. 9078 women were ineligible because they had undergone a hysterectomy and 2271 because their endometrial thickness had not been recorded; however, 157 of these women had an endometrial abnormality on TVS and were included in the analysis. Median follow-up was 5·11 years (IQR 4·05–5·95). 136 women with endometrial cancer or AEH within 1 year of TVS were included in our primary analysis. The optimum endometrial thickness cutoff for endometrial cancer or AEH was 5·15 mm, with sensitivity of 80·5% (95% CI 72·7–86·8) and specificity of 86·2% (85·8–86·6). Sensitivity and specificity at a 5 mm or greater cutoff were 80·5% (72·7–86·8) and 85·7% (85·4–86·2); for women with a 5 mm or greater cutoff plus endometrial abnormalities, the sensitivity and specificity were 85·3% (78·2–90·8) and 80·4% (80·0–80·8), respectively. For a cutoff of 10 mm or greater, sensitivity and specificity were 54·1% (45·3–62·8) and 97·2% (97·0–97·4). When our analysis was restricted to the 96 women with endometrial cancer or AEH who reported no symptoms of postmenopausal bleeding at the UKCTOCS scan before diagnosis and had an endometrial thickness measurement available, a cutoff of 5 mm achieved a sensitivity of 77·1% (67·8–84·3) and specificity of 85·8% (85·7–85·9). The logistic regression model identified 25% of the population as at high risk and 39·5% of endometrial cancer or AEH cases were identified within this high risk group. In this high-risk population, a cutoff at 6·75 mm achieved sensitivity of 84·3% (71·4–93·0) and specificity of 89·9% (89·3–90·5). Interpretation Our findings show that TVS screening for endometrial cancer has good sensitivity in postmenopausal women. The burden of diagnostic procedures and false-positive results can be reduced by limiting screening to a higher-risk group. The role of population screening for endometrial cancer remains uncertain, but our findings are of immediate value in the management of increased endometrial thickness in postmenopausal women undergoing pelvic scans for reasons other than vaginal bleeding. Funding Cancer Research UK, Medical Research Council, NHS Research and Development, and The Eve Appeal.

Background: We report on a unique audit of seven sonographers self-reporting high visualization rates of normal postmenopausal ovaries in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). This audit was ordered by the trial’s Ultrasound Management Subcommittee after an initiative taken in 2008 to improve the quality of scanning and the subsequent increase in the number of sonographers claiming very high ovary visualisation rates. Methods: Seven sonographers reporting high rates (>89%) of visualizing normal postmenopausal ovaries in examinations performed between 1st January and 31st December 2008 were identified. Eight experts in gynaecological scanning reviewed a random selection of exams performed by these sonographers and assessed whether visualization of both ovaries could be confirmed (cVR-Both) in the examinations. A random effects bivariate probit model was fitted to analyse the results. Results: The eight experts reviewed images from 357 examinations performed on 349 postmenopausal women (mean age 60.0 years, range 50.2-73.3) by the seven sonographers. The mean cVR-Both obtained from the model for these sonographers was 67.2% with a range of 47.6-86.5% (95%CI 63.9-70.5%). The range of cVR-Both between the experts was 47.3-88.3% and the intra-class correlation coefficient (ICC) for left and right ovary confirmation was 0.39. Conclusions: The audit suggests that self-reported visualization of postmenopausal ovaries is unreliable, as visualisation of both ovaries could not be confirmed in almost a third of examinations. The agreement for visualization of both ovaries based on review of a static image between experts and sonographers and between expert reviewers alone was only moderate. Further research is needed to develop reliable Quality Control metrics for transvaginal ultrasound.

There are significant variations in the legalisation, restrictions and legal abortion rates worldwide. This undoubtedly influences the provision and accessibility to abortion services. Although there have been changes to the laws in several countries over the last decade, this has not yet been translated into practice in the provision of safe abortion in these countries. In countries where abortions are permitted without restriction; the majority of abortions are carried out by trained practitioners in approved facilities. In contrast, in countries where restrictions are imposed, the majority of abortions performed are considered to be unsafe and therefore associated with significant morbidity and mortality. This article discusses the most recent data available regarding worldwide legal abortion rates, trends over the last ten years and issues related to specific regions which may influence the provision of safe abortion services in the future.

To summarize current knowledge about premature ovarian failure (POF) with an emphasis on recent developments regarding its management.The incidence of POF is increasing largely due to improved survival rates of cancer patients treated with radiation and chemotherapy. Delayed diagnosis and management of POF leads to suboptimal outcomes. Anticipation and early detection of this condition in high-risk women by means of ovarian function testing, followed by early institution of appropriate management could improve outcomes. Choice of strategies should vary depending on the age of onset, associated symptoms and fertility aspirations of the individual, and should change with the patient's advancing age.Early assessment of the individual's risk of developing POF, development of a strategic management plan, and timely commencement of infertility and hormone deficiency treatment, together with counselling in an integrated management plan should improve both the short and long-term health of those with POF.

Summary Background Results of observational studies suggest that hormone replacement therapy (HRT) could reduce the risk of coronary heart disease (CHD), but those of randomised trials do not indicate a lower risk in women who use oestrogen plus progestagen. The aim of this study was to ascertain whether or not unopposed oestrogen reduces the risk of further cardiac events in postmenopausal women who survive a first myocardial infarction. Methods The study was a randomised, blinded, placebo controlled, secondary prevention trial of postmenopausal women, age 50–69 years (n=1017) who had survived a first myocardial infarction. Individuals were recruited from 35 hospitals in England and Wales. Women received either one tablet of oestradiol valerate (2 mg; n=513) or placebo (n=504), daily for 2 years. Primary outcomes were reinfarction or cardiac death, and all-cause mortality. Analyses were by intention-to-treat. Secondary outcomes were uterine bleeding, endometrial cancer, stroke or other embolic events, and fractures. Findings Frequency of reinfarction or cardiac death did not differ between treatment groups at 24 months (rate ratio 0·99, 95% CI 0·70–1·41, p=0·97). Similarly, the reduction in all-cause mortality between those who took oestrogen and those on placebo was not significant (0·79, 0·50–1·27, p=0·34). The relative risk of any death (0·56, 0·23–1·33) and cardiac death (0·33, 0·11–1·01) was lowest at 3 months post-recruitment. Interpretation Oestradiol valerate does not reduce the overall risk of further cardiac events in postmenopausal women who have survived a myocardial infarction.

Specific terminal carbohydrate structures and mucin-associated glycans increase in expression within the human endometrial epithelium during the secretory phase of the menstrual cycle but exhibit wide intercellular variation. We postulated that variation in glycosylation between cells would produce differences in the glycocalyx and result in complex mixtures of cells bearing different combinations of glycans. MUC-1 mucin, keratan sulphate and fucosylated lactosaminoglycans were examined in epithelial gland fragment cultures with antibodies (HMFG1, 5D4) and a lectin (Dolichos biflorus agglutinin). The glycocalyx was examined by transmission and high resolution scanning electron microscopy. The data were related to patterns of expression seen in vivo. The MUC-1 mucin was expressed relatively uniformly in culture, but heterogeneity was evident in mucin sialylation within the epithelial cell population. Double labelling of gland explant cultures for combinations of fucosylated lactosaminoglycans, keratan sulphate and MUC-1 demonstrated cells expressing all combinations of these markers. Ultrastructural examination confirmed remarkable intercellular variation in the glycocalyx. Though the human endometrial epithelium is relatively morphologically homogeneous, these observations reveal complex variations of cell surface glycosylation between neighbouring cells and suggest that secretory function might vary in a similar fashion.

Ectopic pregnancy is a leading cause of maternal mortality. Its incidence has progressively increased in recent years. Assisted conception techniques are associated with a significantly higher rate of ectopic pregnancies. Cervical ectopic pregnancies are very rare, accounting for1% of all ectopic pregnancies.A 41-year-old, Caucasian woman presented for routine transvaginal scan at 6 weeks' gestation following a single embryo transfer as part of in vitro fertilization (IVF) follow-up. This revealed a monochorionic diamniotic twin pregnancy within the cervix. Serum beta-hCG concentration was 18,470 IU/L, and she reported only a mild brown-stained vaginal discharge. She was counseled regarding the risks of this pregnancy and was managed medically, receiving oral mifepristone and systemic methotrexate. She was subsequently monitored with serial serum beta-hCG measurements and transvaginal ultrasonography. After 6 weeks, due to the slow serum beta-hCG decline and lack of spontaneous menstruation, she was counseled regarding the potential risks of the persistent pregnancy and underwent suction evacuation.This case is an example of a complication of LVF. To the best of our knowledge and following a search of the Medline database, this is the only case of monochorionic twin pregnancy located within the cervical canal.

Obesity in childhood and adolescence is a modern global epidemic with adverse health impacts, including cardiovascular, respiratory, orthopedic, endocrinological, metabolic, and psychological effects. Polycystic ovarian syndrome (PCOS) is associated with obesity and may be present in adolescence, although the diagnosis may not be straightforward in this age group, as recognized criteria may not be applicable. The cornerstones of management of obesity and PCOS in adolescence are prevention and lifestyle interventions, although medical and surgical managements have a role to play. In particular, the evidence for management of PCOS in adolescence continues to emerge; however, large trials in this age group are awaited.

We have used subunit-specific monoclonal antibodies (MAbs) and immunohistochemistry to examine the distribution of integrin alpha 6 beta 4 in normal ectocervical epithelium and various grades of cervical intraepithelial neoplasia (CIN). Antibodies were first characterised by immunoprecipitation from two surface-labelled tumour cell lines. Monoclonal antibody G71 was found to precipitate integrin beta 4 from BeWo but not T47D cells, while other anti-beta 4 antibodies precipitated beta 4 from both cell lines. Both G71 and an antiserum to the C-terminal peptide of beta 4 precipitated free beta 4 from surface-iodinated BeWo cells. Neither antibody recognised truncated beta 4 chains observed at approximately 160 kDa. These data suggest that different isoforms of beta 4 are expressed in different tumour cell lines, and that there may be a pool of beta 4 at the cell surface that is not complexed to alpha 6. In normal cervix, both the alpha 6 and beta 4 subunits occur at the basal surface of the basal cell layer. In CIN, the distribution is markedly altered, with strong expression of alpha 6 and beta 4 in the upper cell layers of the ectocervical epithelium. All 40 cases of CIN that were studied exhibited this alteration. Furthermore, the extent of extrabasal staining appeared to correspond with the grade of CIN. The form of integrin beta 4 recognised by antibody G71 also appears in the upper cell layers in CIN, but it shows a more restricted distribution than the normal isoform. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5

The presence of cell adhesion molecules on human oocytes, early embryos, and pre-hatched blastocysts was examined by indirect immunofluorescence and compared to the distribution found on first trimester villous placenta with the same antibodies. Six integrin subunits (alpha 3, alpha V, beta 1, beta 3, beta 4, beta 5) were observed consistently throughout preimplantation development. Evidence was also obtained for the presence of integrin subunits alpha 2, alpha 4, alpha L, beta 2, and beta 7 on a small number of oocytes. A more restricted developmental analysis of E-cadherin, ICAM-1, NCAM, and VCAM-1 demonstrated that these cell adhesion molecules are also present on oocytes and early embryos. L-selectin was detected on oocytes but was not found on 8-cell embryos. The oocyte and early blastomeres have complex surfaces in which the integrin and CAM families are represented.

The cell surface glycoprotein CD44 has been demonstrated in a variety of cell types in embryonic and adult tissues. We have established that CD44 is present on human oocytes, cumulus cells, early embryos and pre-hatched blastocysts by indirect immunofluorescence. We have also shown that CD44 is present on 8-11 week placental stroma cells, but not on the trophoblast. These findings demonstrate that CD44 is present throughout preimplantation development, and that down-regulation occurs on the embryonic surface after implantation.

The presence of cell adhesion molecules on human oocytes, early embryos, and pre-hatched blastocysts was examined by indirect immunofluorescence and compared to the distribution found on first trimester villous placenta with the same antibodies. Six integrin subunits (alpha 3, alpha V, beta 1, beta 3, beta 4, beta 5) were observed consistently throughout preimplantation development. Evidence was also obtained for the presence of integrin subunits alpha 2, alpha 4, alpha L, beta 2, and beta 7 on a small number of oocytes. A more restricted developmental analysis of E-cadherin, ICAM-1, NCAM, and VCAM-1 demonstrated that these cell adhesion molecules are also present on oocytes and early embryos. L-selectin was detected on oocytes but was not found on 8-cell embryos. The oocyte and early blastomeres have complex surfaces in which the integrin and CAM families are represented.

The distribution of the cell-surface adhesion glycoprotein CD44 in human endometrium was examined by immunofluorescence using six monoclonal antibodies to epitopes common to all forms of the molecule, and by reverse transcription-polymerase chain reaction (RT-PCR). Immunoreactivity was observed throughout the menstrual cycle in stroma, vessels, glandular, and luminal epithelium. Variations in staining intensity were observed, especially in the epithelial compartment. CD44 was also expressed strongly by decidualized stromal cells of first-trimester pregnancy. No systematic variation of immunoreactivity was observed with stages of the normal cycle, but a fraction (25%) of the specimens lacked reactivity in the epithelium. To determine the molecular size of the epithelial isoform, an immunoprecipitation technique was developed using surface-radioiodinated, detergent-extracted glands. This indicated the presence at the cell surface of a single dominant CD44E species with an approximate molecular mass of 130 kDa. RT-PCR was used to investigate the isoforms present in whole endometrial tissue, isolated gland fragments, and Ishikawa endometrial carcinoma cells. Complementary DNA produced from total endometrial mRNA was PCR-amplified across the splice junction between exons 5 and 15. Transcripts corresponding to the hyaluronate receptor CD44H as well as a larger isoform were identified. CD44H was absent, or very scarce, in cDNA from purified gland epithelium. In contrast, Ishikawa cells expressed this form abundantly. The glands and Ishikawa cells also expressed CD44E containing sequences encoded by exons 12, 13, and 14. These data demonstrate the presence of CD44 in human endometrium and decidua, and show that different isoforms of CD44 are associated with tissue compartments in which different functional roles can be anticipated.

The cell surface mucin MUC-1 is present in endometrial epithelial cells and their associated apical glycocalyx and is also released into gland lumens as a secretory product. MUC-1 mRNA and core protein are found at low levels in the proliferative phase of the cycle, but their abundance increases after ovulation. Endometrial MUC-1 has been found to carry sialokeratan sulphate chains and these show a dramatically increased abundance in cells and secretions in the post-ovulatory phase of the cycle, reaching a maximum in secretions 6-7 days after the LH peak. The apical epithelium also contains adhesion receptor molecules of the integrin and CD44 families. MUC-1 is large and highly glycosylated and probably extends farther from the cell surface than these 'conventional' glycoprotein receptors. It has the potential to inhibit sterically receptor-mediated cell-cell adhesion. However, it is also possible that MUC-1 displays specific (e.g., glycan) recognition structures for the initial attachment of the blastocyst or that the embryo may create a specialised microenvironment in which to implant.

Background Participants in trials evaluating preventive interventions such as screening are on average healthier than the general population. To decrease this 'healthy volunteer effect' (HVE) women were randomly invited from population registers to participate in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and not allowed to self refer. This report assesses the extent of the HVE still prevalent in UKCTOCS and considers how certain shortfalls in mortality and incidence can be related to differences in socioeconomic status. Methods Between 2001 and 2005, 202 638 postmenopausal women joined the trial out of 1 243 312 women randomly invited from local health authority registers. The cohort was flagged for deaths and cancer registrations and mean follow up at censoring was 5.55 years for mortality, and 2.58 years for cancer incidence. Overall and cause-specific Standardised Mortality Ratios (SMRs) and Standardised Incidence Ratios (SIRs) were calculated based on national mortality (2005) and cancer incidence (2006) statistics. The Index of Multiple Deprivation (IMD 2007) was used to assess the link between socioeconomic status and mortality/cancer incidence, and differences between the invited and recruited populations. Results The SMR for all trial participants was 37%. By subgroup, the SMRs were higher for: younger age groups, extremes of BMI distribution and with each increasing year in trial. There was a clear trend between lower socioeconomic status and increased mortality but less pronounced with incidence. While the invited population had higher mean IMD scores (more deprived) than the national average, those who joined the trial were less deprived. Conclusions Recruitment to screening trials through invitation from population registers does not prevent a pronounced HVE on mortality. The impact on cancer incidence is much smaller. Similar shortfalls can be expected in other screening RCTs and it maybe prudent to use the various mortality and incidence rates presented as guides for calculating event rates and power in RCTs involving women. Trial Registration This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978. Medical Research Council (grant no. G990102), Cancer Research UK (grant no. C1479/A2884) and Department of Health

Secretory differentiation of endometrium after multiple follicular stimulation using gonadotrophin releasing hormone and human menopausal gonadotrophin has been studied both histologically and immunohistochemically in 30 women undergoing in-vitro fertilization treatment. None had embryo transfer. Patients were randomly allocated to receive luteal phase support with a single dose of human chorionic gonadotrophin. The latter failed to produce any significant enhancement of endometrial structure or secretions. Appropriate glandular morphology was present in a greater proportion of those who were successfully stimulated than those who responded poorly. However, defective secretion of the cycle-dependent component studied, using monoclonal antibody D9B1, was demonstrated in two-thirds of cases regardless of the ovarian response. Early vascular maturation in the stroma was a common finding, and was thus considered as a feature of structural modulation of these endometria.

OBJECTIVE: To describe the factors that contributed to successful recruitment of more than 200,000 women to the UK Collaborative Trial of Ovarian Cancer Screening, one of the largest ever randomised controlled trials. DESIGN: Descriptive study. SETTING: 13 NHS trusts in England, Wales, and Northern Ireland. PARTICIPANTS: Postmenopausal women aged 50-74; exclusion criteria included ovarian malignancy, bilateral oophorectomy, increased risk of familial ovarian cancer, active non-ovarian malignancy, and participation in other ovarian cancer screening trials. MAIN OUTCOME MEASURES: Achievement of target recruitment, acceptance rates of invitation, and recruitment rates. RESULTS: The trial was set up in 13 centres with 27 adjoining local health authorities. The coordinating centre team was led by one of the senior investigators, who was closely involved in planning and day to day trial management. Of 1 243,282 women invited, 23.2% (288 955) replied that they were eligible and would like to participate. Of those sent appointments, 73.6% (205 090) attended for recruitment. The acceptance rate varied from 19% to 33% between trial centres. Measures to ensure target recruitment included named coordinating centre staff supporting and monitoring each centre, prompt identification and resolution of logistic problems, varying the volume of invitations by centre, using local non-attendance rates to determine the size of recruitment clinics, and organising large ad hoc clinics supported by coordinating centre staff. The trial randomised 202,638 women in 4.3 years. CONCLUSIONS: Planning and trial management are as important as trial design and require equal attention from senior investigators. Successful recruitment needs constant monitoring by a committed proactive management team that is willing to explore individual solutions for different centres and use central resources to improve local recruitment. Automation of trial processes with web based trial management systems is crucial in large multicentre randomised controlled trials. Recruitment can be further enhanced by using information videos and group discussions. Trial registration Current Controlled Trials ISRCTN22488978. See also Erratum in: BMJ. 2008;337:a2976.

Teenage pregnancy occurs during a time when the maternal skeleton may still be accruing mineral. We hypothesized that teenage mothers would have reduced amounts of bone mineral and altered bone geometry compared with controls. This cross-sectional, observational compared teenage mothers (n=18) to age- and ethnicity-matched controls (n=52). The main outcomes were peripheral quantitative computed tomography and dual-energy X-ray absorptiometry to measure bone geometry, bone mineral density (BMD) at radius, lumbar spine and hip, and whole body bone mineral content (WBBMC). In teenage mothers, cortical BMD was reduced at the radial diaphysis (mean difference: -1.3%; p=0.03). Size-adjusted WBBMC was reduced (mean difference: -4.0%; p=0.004) and was lower for a given amount of lean mass (mean difference: -5.8%; p=0.02). No other significant differences between groups were found. The recruitment and retention of participants to this study were extremely difficult and disappointing. Teenage mothers had lower BMD at cortical sites compared with age-matched controls. These data suggest that pregnancy might have a detrimental effect on teenage mothers' future skeletal health. The results of this study require confirmation and provide pilot data for further investigations.

OBJECTIVE--To study a group of women with unexplained infertility to see whether they have a defect that is intrinsic to the endometrium. DESIGN--Evaluation of the functional response of the endometrium by examining endometrial biopsy specimens using immunohistochemical methods in a group of women with unexplained infertility and in a control group of women with normal fertility. PATIENTS--27 Women with unexplained infertility (average age 33.2); median duration of infertility five years. A control group of 44 women with normal fertility (average age 33.8) who were requesting sterilisation or reversal of sterilisation. SETTING--Infertility clinic, Jessop Hospital for Women, Sheffield. INTERVENTION--Secretory phase endometrial biopsy specimens were taken, with informed consent, as an outpatient procedure. MAIN OUTCOME MEASURES--Immunohistochemistry with monoclonal antibody D9B1, was used to assess the production and secretion of an oligosaccharide epitope produced by endometrial gland cells between two and seven days after the luteinising hormone surge. A reflected light measuring system was used to assess the amount of epitope within the gland cells, and in the gland lumen. RESULTS--In the control group of women, mean reflected light measurements at the cell base and cell apex peaked at three and five days after the luteinising hormone surge respectively, and in the gland lumen the epitope accumulated rapidly from three days, reaching a peak at seven days. In the women with infertility the peaks of epitope at the cell base and cell apex were lower, broader, and delayed in onset, and the build up of epitope in the gland lumen was retarded. The synthesis and secretion of the epitope in the women with infertility was therefore significantly reduced and delayed, even in the presence of normal concentrations of circulating progesterone. CONCLUSIONS--The results suggest that a primary dysfunction of the endometrium might be associated with hitherto unexplained infertility.

Tubal disease is the cause of subfertility in approximately 30% of women, and 10-25% of these are due to proximal tubal obstruction. False-positive diagnosis of proximal tubal obstruction can be as high as 50%. A decrease in expertise in tubal microsurgery has resulted largely from the use of IVF as the treatment option for most causes of infertility and more specifically for tubal factor infertility. Selective salpingography and tubal cannulation have a unique role in the management of tubal infertility and should be offered to selected candidates prior to IVF. Tubal cannulation can be used effectively to restore patency in a proportion of cases of proximal tubal obstruction thus avoiding the need for expensive assisted reproductive techniques. This review examines the evidence supporting the effectiveness of tubal cannulation and aims to enhance awareness of the procedure as an option for the management of female subfertility secondary to isolated proximal tubal obstruction.

Objective To characterize endometrial development in unexplained and tubal factor infertility. Design Prospective study of 20 women with unexplained infertility, 22 with tubal factor infertility, and 21 fertile controls in the midproliferative, periovulatory, and midluteal phases of the menstrual cycle. Setting Reproductive Medicine Department of St. Mary's Hospital, Manchester, United Kingdom. Patient(s) Women awaiting assisted conception. Investigation(s) Serum hormone assays, transvaginal ultrasound, Doppler, and midluteal endometrial biopsies. Main outcome measure(s) Serum levels of E2, P, and LH, endometrial ultrasound morphometry, uterine and subendometrial artery Doppler, and endometrial histology and biochemistry. Result(s) Women with unexplained infertility demonstrated significantly reduced uterine artery flow velocity in all phases, significantly elevated uterine and subendometrial artery impedance in the periovulatory and midluteal phases, and significantly reduced endometrial texture in the midproliferative phase. Women with tubal factor infertility demonstrated significantly reduced uterine artery flow velocity, without a concomitant increase in impedance, and significantly greater expression of endometrial glandular and luminal keratan sulphate. Conclusion(s) Unexplained infertility is associated with a profound impairment of endometrial perfusion that might be amenable to treatment by perfusion enhancers. Tubal factor infertility is associated with endometrial developmental defects that might be corrected by salpingectomy. Endometrial ultrasound and Doppler studies are likely to become a vital tool in the investigation of infertility.

BACKGROUND: During the past decade in the UK, only one in six cycles of assisted conception has resulted successfully in a live birth. Assisted hatching (AH) has been proposed to improve outcome. This systematic review of randomized controlled trials addresses primary outcomes of live birth, clinical pregnancy and embryo implantation. METHODS: Trials on post-fertilization disruption of the zona pellucida were identified from the Cochrane Controlled Trials Register, MEDLINE, EMBASE and published bibliographies. Outcomes were analysed using random effects meta-analysis, sensitivity analysis, sub-grouping and meta-regression. RESULTS: Of 23 included trials recruiting 2572 women, only six reported live birth data. AH had no significant effect on live birth (OR 1.21, 95% CI 0.82-1.78). There was a significant benefit of AH on clinical pregnancy (OR 1.63, 95% CI 1.27-2.09), especially in the sub-group of women with previous failure of assisted conception (OR 2.33, 95% CI 1.63-3.34). Meta-regression suggested that AH might be more useful in older women. Implantation data were not considered valid for statistical analysis. The methodological quality of included trials was sub-optimal. CONCLUSIONS: AH probably enhances clinical pregnancy, especially in women with previous failure of assisted conception treatment and in older women; however, trials were of poor quality and so may be biased. Better quality trials reporting live birth are required to confirm any positive effects on the 'take-home-baby rate'.

Diagnosis of ovarian cancer at early stages increases the likelihood for effective treatment and long-term survival. Preliminary data from a randomized controlled trial suggested a survival benefit of routine screening for ovarian cancer sequentially with the CA-125 blood test and ultrasound (multimodal screening). This randomized controlled trial ― the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) - assessed the effect of screening with CA-125 and transvaginal ultrasound on mortality. Between 2001 and 2005, a total of 202,638 postmenopausal women aged 50 to 74 years were randomly assigned to 3 groups: (1) a no treatment control group receiving no ovarian screening (n = 101,359); (2) an annual CA-125 screening group with transvaginal ultrasound scan as a second-line test (multimodal screening [MMS] [n = 50,640]); or (3) an annual screening transvaginal ultrasound group (USS) (n = 50, 639). The serum CA-125 tumor marker was measured from blood samples.

Objective To demonstrate the effect of superovulation using a GnRH agonist (GnRH-a) and hMG and hCG on endometrial structure. Design Prospective, case-controlled study. Setting Tertiary referral assisted reproduction unit in an academic department. Patients Eleven women undergoing GIFT or IVF, without ET. Interventions All women were treated with a long stimulation regimen using the depot GnRH-a Goserelin (ICI, Macclesfield, United Kingdom) and hMG and hCG. Main Outcome Measures Comparison of endometrial biopsy specimens taken 4days after ovulation in an unstimulated cycle with specimens taken 4days after oocyte recovery, using standard dating criteria and morphometric analysis. Results There was no difference in endometrial glandular development as assessed by either standard criteria or morphometric analysis. Conclusions Superovulation preceded by pituitary down regulation is not associated with abnormal endometrial glandular development, even though supraphysiological levels of E 2 and P are induced.

After ovulation, progesterone stimulates a temporally regulated secretory transformation in human endometrial epithelium. Using a combination of immunohistochemistry, and Western and Northern blotting, we demonstrate that 1) the polymorphic epithelial mucin MUC1 is secreted by human endometrial epithelium; 2) low levels of both mRNA and core protein are present in the preovulatory phase of the menstrual cycle; 3) mRNA levels increase several-fold after ovulation, consistent with transcriptional regulation by progesterone; 4) there is an increase in translation product in postovulatory endometrium; and 5) the tandem repeat domain of the MUC-1 polypeptide is glycosylated in endometrium.

To examine the effects of progesterone (P) receptor blockade by RU486 (Mifepristone; Roussel-Uclaf, Paris, France) on a secretory endometrial glycan recognized by monoclonal antibody D9B1.Retrospective comparison of endometrial biopsies from treated and untreated women from 2 to 8 days after the luteinizing peak (LH) peak.Infertility clinic, Jessop Hospital for Women, Sheffield.Twenty-two normal fertile women received the RU486. A control group of 44 normal fertile women were also assessed.RU486 was administered to 22 normal women during the first half of the luteal phase and an endometrial biopsy examined 3 days later.Immunohistochemistry was used to assess the production and secretion of the D9B1 epitope.When the drug was given 2 days after the LH peak, it prevented appearance of the epitope. When RU486 was administered 5 days after the LH peak, epitope already present in gland cells was subsequently secreted.These data suggest that production of the sialo-oligosaccharide is P-dependent, but secretion through established intracellular pathways is P-independent.This study examined the effects of progesterone (P) receptor blockade by RU486 (Mifepristone; Roussel-Uclaf, Paris, France) on a secretory endometrial glycan recognized by monoclonal antibody D9B1. 22 normal fertile women participated in this retrospective comparison of endometrial biopsies at the infertility clinic, Jessop Hospital for Women, in Sheffield. RU486 was administered to this group and a control group of 44 normal fertile women was also assessed; endometrial biopsies were taken from both groups from 2-8 days after the luteinizing hormone (LH) peak. Immunohistochemistry was used to assess the production and secretion of the D9B1 epitope. When the drug was given 2 days after LH peak, it prevented the appearance of the epitope; when administered 5 days after, the epitope was already present in the gland cells and was subsequently secreted. These data suggest that production of the sialo-oligosaccharide is P-dependent, but secretion through established intracellular pathways in P-independent.

During the preimplantation phase, the endometrium undergoes a variety of histological (Dallenbach-Hellweg, 1981) and compositional (Bell, 1986; Aplin, 1989) alterations. These are believed to create an appropriate milieu for the implanting blastocyst. The changes include the production of secretory material for the implanting blastocyst; the alteration of cell surface composition at the luminal epithelium; and changes in the stromal environment. We (Seif et al., 1989) and others (Bell, 1986) have reported previously studies of hormonally regulated secretory components of human endometrium and decidua. Here we describe an approach to the characterization of endometrial cell surfaces during the menstrual cycle which may be useful both in furthering understanding of reproductive function and in diagnosis of reproductive failure. We have focused on endometrial epithelium since this forms the site of initial interaction of maternal and fetal cells.

This paper reports the pattern of production and secretion of a secretory phase epitope in the endometrium of 44 normal fertile women. Peroxidase immunochemistry was used to detect the monoclonal antibody D9B1, which binds to a peptide-associated sialylated oligosaccharide, in endometrial biopsies all chronologically dated from the luteinizing hormone (LH) peak. During the proliferative phase, the epitope was shown to be absent from tissue sections. It first made its appearance within gland cells 2 days after the LH peak. By LH+3 a rapid accumulation of the D9B1 epitope was noted in the base of the cell, below the nucleus. On subsequent days, increasing amounts of the antigen were detected in the apical cytoplasm, apparently in a more concentrated form than in the basal cell zone. On day LH+6, around the time of implantation, secretory vesicles in the cell apex were discharged into the gland lumen where the glycoconjugate finally accumulated. This immunohistochemical approach introduces a new parameter for evaluation of endometrial function and could be used to improve the accuracy of histological assessment of the endometrial cycle.

Monoclonal antibody D9B1 has been shown to bind to a carbohydrate epitope associated with high molecular weight secretory sialoglycoprotein(s) of human endometrium. The authors demonstrate that, in a group of 28 patients diagnosed on the basis of histopathologic assessment as exhibiting luteal phase defect, 68% reveal significantly diminished expression of the epitope. Furthermore, histologic assessment of the secretory activity in single glands does not correlate simply with the level of expression of the epitope. Of specimens from patients complaining of infertility, 92% showed defective production of the D9B1 epitope. Thus, D9B1 immunohistochemistry provides a new molecular criterion for defective endometrial function.

Background: Ovarian cancer has a high case–fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS. Methods: Between 2001 and 2005, a total of 202 638 post-menopausal women aged 50–74 years were randomly assigned to no treatment (control; n=101 359); annual CA125 screening (interpreted using a risk of ovarian cancer algorithm) with transvaginal ultrasound scan as a second-line test (multimodal screening [MMS]; n=50 640); or annual screening with transvaginal ultrasound (USS; n=50 639) alone in a 2:1:1 ratio using a computer-generated random number algorithm. All women provided a blood sample at recruitment. Women randomised to the MMS group had their blood tested for CA125 and those randomised to the USS group were sent an appointment to attend for a transvaginal scan. Women with abnormal screens had repeat tests. Women with persistent abnormality on repeat screens underwent clinical evaluation and, where appropriate, surgery. This trial is registered as ISRCTN22488978 and with ClinicalTrials.gov, number NCT00058032. Findings: In the prevalence screen, 50 078 (98·9%) women underwent MMS, and 48 230 (95·2%) underwent USS. The main reasons for withdrawal were death (two MMS, 28 USS), non-ovarian cancer or other disease (none MMS, 66 USS), removal of ovaries (five MMS, 29 USS), relocation (none MMS, 39 USS), failure to attend three appointments for the screen (72 MMS, 757 USS), and participant changing their mind (483 MMS, 1490 USS). Overall, 4355 of 50 078 (8.7%) women in the MMS group and 5779 of 48 230 (12·0%) women in the USS group required a repeat test, and 167 (0·3%) women in the MMS group and 1894 (3·9%) women in the USS group required clinical evaluation. 97 of 50 078 (0·2%) women from the MMS group and 845 of 48 230 (1·8%) from the USS group underwent surgery. 42 (MMS) and 45 (USS) primary ovarian and tubal cancers were detected, including 28 borderline tumours (eight MMS, 20 USS). 28 (16 MMS, 12 USS) of 58 (48·3%; 95% CI 35·0–61·8) of the invasive cancers were stage I/II, with no difference (p=0·396) in stage distribution between the groups. A further 13 (five MMS, eight USS) women developed primary ovarian cancer during the year after the screen. The sensitivity, specificity, and positive-predictive values for all primary ovarian and tubal cancers were 89·4%, 99·8%, and 43·3% for MMS, and 84·9%, 98·2%, and 5·3% for USS, respectively. For primary invasive epithelial ovarian and tubal cancers, the sensitivity, specificity, and positive-predictive values were 89·5%, 99·8%, and 35·1% for MMS, and 75·0%, 98·2%, and 2·8% for USS, respectively. There was a significant difference in specificity (p

The effect of the intrauterine contraceptive device (IUD) on the composition of endometrial secretion has been studied using the monoclonal antibody D9B1. The antibody binds to a polypeptide-associated oligosaccharide epitope that is secreted by endometrial epithelium in the secretory phase with a maximum around the time of implantation. In endometria affected by the IUD in situ, a significant reduction in epitope expression has been observed using immunohistochemistry. This defect can occur against a background of normal secretory differentiation and in the expectation of normal ovarian stimulus. The data provide new insight into the contraceptive mechanisms of action of the IUD.The effect of the presence of a copper-containing IUD in situ on endometrial tissue was studied in 38 women, only 2 of which were nulliparous. The study showed that changes in the components of endometrial secretions correlate to a decrease in secretory activity when an IUD is present. At the actual sight, a decrease in epitope was noticeable. In epithelial intracellular locations, the absence of epitope in bulk secretion in glandular lumens leads to the conclusion that there has been an impairment in the biosynthesis process. The IUD also inhibits secretory activity of endometrium. Increased copper ion concentration, although the effect on enzymes is unknown, does effect enzymatic activities such as betaglucuronidase and alkaline phosphatase. Many theories have been proposed to explain the contraceptive process of an IUD; however, the only plausible theory is one that identifies the many reactions caused by an IUD at the early reproductive stage rather than any one specific reaction. The study focuses on the endometrial response in female contraception and use of the IUD.

Tubular aggregates of glandular epithelial cells (gland fragments) were isolated from human endometrium by collagenase digestion of surrounding stroma, thus exposing the basal surfaces of the cells. Using these aggregates as immunogen, monoclonal antibodies could be derived that recognized basally located antigens. One such antibody, G71, is described, that binds to a basal epithelial cell antigen present in a variety of human epithelia. Epitope-bearing molecules in the range Mr 60 000–180 000 are present in two of the tissues studied, amnion and endometrium. The epitope is associated with areas of epithelial cell-extracellular matrix contact.