Top 10 priorities for future infertility research: an international consensus development study.

STUDY QUESTION: Can the priorities for future research in infertility be identified? SUMMARY ANSWER: The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction, and ethics, access, and organization of care for people with fertility problems were identified. WHAT IS KNOWN ALREADY: Many fundamental questions regarding the prevention, management, and consequences of infertility remain unanswered. This is a barrier to improving the care received by those people with fertility problems. STUDY DESIGN, SIZE, DURATION: Potential research questions were collated from an initial international survey, a systematic review of clinical practice guidelines, and Cochrane systematic reviews. A rationalized list of confirmed research uncertainties was prioritized in an interim international survey. Prioritized research uncertainties were discussed during a consensus development meeting. Using a formal consensus development method, the modified nominal group technique, diverse stakeholders identified the top 10 research priorities for each of the categories male infertility, female and unexplained infertility, medically assisted reproduction, and ethics, access, and organization of care. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, people with fertility problems, and others (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process using formal consensus methods advocated by the James Lind Alliance. MAIN RESULTS AND THE ROLE OF CHANCE: The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions. A rationalized list of 231 confirmed research uncertainties were entered into an interim prioritization survey completed by 317 respondents from 43 countries. The top 10 research priorities for each of the four categories male infertility, female and unexplained infertility (including age-related infertility, ovarian cysts, uterine cavity abnormalities, and tubal factor infertility), medically assisted reproduction (including ovarian stimulation, IUI, and IVF), and ethics, access, and organization of care, were identified during a consensus development meeting involving 41 participants from 11 countries. These research priorities were diverse and seek answers to questions regarding prevention, treatment, and the longer-term impact of infertility. They highlight the importance of pursuing research which has often been overlooked, including addressing the emotional and psychological impact of infertility, improving access to fertility treatment, particularly in lower resource settings, and securing appropriate regulation. Addressing these priorities will require diverse research methodologies, including laboratory-based science, qualitative and quantitative research, and population science. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods, which have inherent limitations, including the representativeness of the participant sample, methodological decisions informed by professional judgement, and arbitrary consensus definitions. WIDER IMPLICATIONS OF THE FINDINGS: We anticipate that identified research priorities, developed to specifically highlight the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems, and others, will help research funding organizations and researchers to develop their future research agenda. STUDY FUNDING/ COMPETING INTEREST(S): The study was funded by the Auckland Medical Research Foundation, Catalyst Fund, Royal Society of New Zealand, and Maurice and Phyllis Paykel Trust. Geoffrey Adamson reports research sponsorship from Abbott, personal fees from Abbott and LabCorp, a financial interest in Advanced Reproductive Care, committee membership of the FIGO Committee on Reproductive Medicine, International Committee for Monitoring Assisted Reproductive Technologies, International Federation of Fertility Societies, and World Endometriosis Research Foundation, and research sponsorship of the International Committee for Monitoring Assisted Reproductive Technologies from Abbott and Ferring. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and editor for the Cochrane Gynaecology and Fertility Group. Hans Evers reports being the Editor Emeritus of Human Reproduction. Andrew Horne reports research sponsorship from the Chief Scientist's Office, Ferring, Medical Research Council, National Institute for Health Research, and Wellbeing of Women and consultancy fees from Abbvie, Ferring, Nordic Pharma, and Roche Diagnostics. M. Louise Hull reports grants from Merck, grants from Myovant, grants from Bayer, outside the submitted work and ownership in Embrace Fertility, a private fertility company. Neil Johnson reports research sponsorship from Abb-Vie and Myovant Sciences and consultancy fees from Guerbet, Myovant Sciences, Roche Diagnostics, and Vifor Pharma. José Knijnenburg reports research sponsorship from Ferring and Theramex. Richard Legro reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. Ben Mol reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. Ernest Ng reports research sponsorship from Merck. Craig Niederberger reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. Jane Stewart reports being employed by a National Health Service fertility clinic, consultancy fees from Merck for educational events, sponsorship to attend a fertility conference from Ferring, and being a clinical subeditor of Human Fertility. Annika Strandell reports consultancy fees from Guerbet. Jack Wilkinson reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. Andy Vail reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and of the journal Reproduction. His employing institution has received payment from HFEA for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. Lan Vuong reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the present work. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: Not applicable.

Top 10 priorities for future infertility research: an international consensus development study† ‡.

STUDY QUESTION: Can the priorities for future research in infertility be identified? SUMMARY ANSWER: The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care for people with fertility problems were identified. WHAT IS KNOWN ALREADY: Many fundamental questions regarding the prevention, management and consequences of infertility remain unanswered. This is a barrier to improving the care received by those people with fertility problems. STUDY DESIGN, SIZE, DURATION: Potential research questions were collated from an initial international survey, a systematic review of clinical practice guidelines and Cochrane systematic reviews. A rationalized list of confirmed research uncertainties was prioritized in an interim international survey. Prioritized research uncertainties were discussed during a consensus development meeting. Using a formal consensus development method, the modified nominal group technique, diverse stakeholders identified the top 10 research priorities for each of the categories male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, people with fertility problems and others (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process using formal consensus methods advocated by the James Lind Alliance. MAIN RESULTS AND THE ROLE OF CHANCE: The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions. A rationalized list of 231 confirmed research uncertainties was entered into an interim prioritization survey completed by 317 respondents from 43 countries. The top 10 research priorities for each of the four categories male infertility, female and unexplained infertility (including age-related infertility, ovarian cysts, uterine cavity abnormalities and tubal factor infertility), medically assisted reproduction (including ovarian stimulation, IUI and IVF) and ethics, access and organization of care were identified during a consensus development meeting involving 41 participants from 11 countries. These research priorities were diverse and seek answers to questions regarding prevention, treatment and the longer-term impact of infertility. They highlight the importance of pursuing research which has often been overlooked, including addressing the emotional and psychological impact of infertility, improving access to fertility treatment, particularly in lower resource settings and securing appropriate regulation. Addressing these priorities will require diverse research methodologies, including laboratory-based science, qualitative and quantitative research and population science. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods, which have inherent limitations, including the representativeness of the participant sample, methodological decisions informed by professional judgment and arbitrary consensus definitions. WIDER IMPLICATIONS OF THE FINDINGS: We anticipate that identified research priorities, developed to specifically highlight the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems and others, will help research funding organizations and researchers to develop their future research agenda. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Auckland Medical Research Foundation, Catalyst Fund, Royal Society of New Zealand and Maurice and Phyllis Paykel Trust. G.D.A. reports research sponsorship from Abbott, personal fees from Abbott and LabCorp, a financial interest in Advanced Reproductive Care, committee membership of the FIGO Committee on Reproductive Medicine, International Committee for Monitoring Assisted Reproductive Technologies, International Federation of Fertility Societies and World Endometriosis Research Foundation, and research sponsorship of the International Committee for Monitoring Assisted Reproductive Technologies from Abbott and Ferring. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and editor for the Cochrane Gynaecology and Fertility Group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. A.W.H. reports research sponsorship from the Chief Scientist's Office, Ferring, Medical Research Council, National Institute for Health Research and Wellbeing of Women and consultancy fees from AbbVie, Ferring, Nordic Pharma and Roche Diagnostics. M.L.H. reports grants from Merck, grants from Myovant, grants from Bayer, outside the submitted work and ownership in Embrace Fertility, a private fertility company. N.P.J. reports research sponsorship from AbbVie and Myovant Sciences and consultancy fees from Guerbet, Myovant Sciences, Roche Diagnostics and Vifor Pharma. J.M.L.K. reports research sponsorship from Ferring and Theramex. R.S.L. reports consultancy fees from AbbVie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. E.H.Y.N. reports research sponsorship from Merck. C.N. reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring and retains a financial interest in NexHand. J.S. reports being employed by a National Health Service fertility clinic, consultancy fees from Merck for educational events, sponsorship to attend a fertility conference from Ferring and being a clinical subeditor of Human Fertility. A.S. reports consultancy fees from Guerbet. J.W. reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. A.V. reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and the journal Reproduction. His employing institution has received payment from Human Fertilisation and Embryology Authority for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the present work. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: N/A.

Individual patient data meta-analysis of randomized evidence to assess the effectiveness of laparoscopic uterosacral nerve ablation in chronic pelvic pain.

BACKGROUND: There have been conflicting results in randomized trials of the effects of laparoscopic uterosacral nerve ablation (LUNA) in chronic pelvic pain. Our objective was to perform a meta-analysis using individual patient data (IPD) to provide the most comprehensive and reliable assessment of the effectiveness of LUNA. METHODS: Electronic searches were conducted in the Medline, Embase, PsycInfo and Cochrane Library databases from database inception to August 2009. The reference lists of known relevant papers were searched for any further articles. Randomized trials comparing LUNA with no additional intervention were selected and authors contacted for IPD. Raw data were available from 862 women randomized into five trials. Pain scores were calibrated to a 10-point scale and were analysed using a multilevel model allowing for repeated measures. RESULTS: There was no significant difference between LUNA and No LUNA for the worst pain recorded over a 12 month time period (mean difference 0.25 points in favour of No LUNA on a 0-10 point scale, 95% confidence interval: -0.08 to 0.58; P = 0.1). CONCLUSIONS: LUNA does not result in improved chronic pelvic pain.

PCOSMIC: a multi-centre randomized trial in women with PolyCystic Ovary Syndrome evaluating Metformin for Infertility with Clomiphene.

BACKGROUND: Ovulation induction treatment with metformin, either alone or in combination with clomiphene citrate (CC), remains controversial even though previous randomized trials have examined this. METHODS: A double blinded multi-centre randomized trial was undertaken including 171 women with anovulatory or oligo-ovulatory polycystic ovary syndrome. Women with high body mass index (BMI) > 32 kg/m(2) received placebo ('standard care') or metformin; women with BMI < or = 32 kg/m(2) received CC ('standard care'), metformin or both. Treatment continued for 6 months or until pregnancy was confirmed. Primary outcomes were clinical pregnancy and live birth. RESULTS: For women with BMI > 32 kg/m(2), clinical pregnancy and live birth rates were 22% (7/32) and 16% (5/32) with metformin, 15% (5/33) and 6% (2/33) with placebo. For women with BMI < or = 32 kg/m(2), clinical pregnancy and live birth rates were 40% (14/35) and 29% (10/35) with metformin, 39% (14/36) and 36% (13/36) with CC, 54% (19/35) and 43% (15/35) with combination metformin plus CC. CONCLUSIONS: There is no evidence that adding metformin to 'standard care' is beneficial. Pregnancy and live birth rates are low in women with BMI > 32 kg/m(2) whatever treatment is used, with no evidence of benefit of metformin over placebo. For women with BMI < or = 32 kg/m(2) there is no evidence of significant differences in outcomes whether treated with metformin, CC or both. ClinicalTrials.gov number NCT00795808; trial protocol accepted for publication November 2005: Johnson, Aust N Z Journal Obstet Gynaecol 2006;46:141-145.

Dynamic tests of ovarian reserve: a systematic review of diagnostic accuracy.

Despite a plethora of tests of ovarian reserve, there is no perfect test to predict pregnancy. Recent evidence points that anti-Müllerian hormone and antral follicle count may be better than other tests, although other tests continue to be used and form the basis of exclusion of women from fertility treatments. This systematic review concentrated on dynamic tests of ovarian reserve [clomifene citrate challenge test (CCCT), gonadotrophin-releasing hormone agonist stimulation test (GAST) and exogenous FSH ovarian reserve test (EFORT)] and assessed their predictability in terms of fertility outcomes. The study did not restrict itself to women undergoing IVF. The diagnostic odds of abnormal CCCT for non-pregnancy were 2.11 (95% confidence interval, 1.04-4.29) at FSH >10 IU/l (day 3 or 10). The diagnostic accuracy of GAST and EFORT could not be determined due to inconsistencies in the way these tests were conducted. This systematic review and meta-analysis was limited by heterogeneity in terms of the population sampled and the index and reference tests. There is an urgent need for consensus on the performance of these tests and the definition of normality, if their use is to be continued. However, given the present level of evidence, these tests should be completely abandoned.

Gynaecologic surgery from uncertainty to science: evidence-based surgery is no passing fad.

BACKGROUND: The randomized controlled trial (RCT) is the least biased measure of the effectiveness of interventions, including surgical interventions. The aim was to review the available evidence base in gynaecologic surgery, to assess what progress has been made and to determine gaps in the evidence for clinical decision-making. METHODS: Systematic reviews involving gynaecological surgery interventions were extracted from the Cochrane Database of Systematic Reviews (Issue 2, 2007) and data were extracted for key primary outcomes from each of the randomized trials in the reviews. The reviews were categorized as to whether they had provided evidence of effectiveness for pre-defined outcomes of most relevance to patients. RESULTS: Of 371 reviews or protocols published on the Cochrane Database of Systematic Reviews (Issue 2, 2007), only 30 were completed reviews assessing surgical interventions. Seven reviews concluded there was evidence of a significant effect (whether beneficial or harmful) of the interventions studied for pre-defined primary outcomes; 11 reviews concluded there was some evidence of significant effects for primary outcomes along with some gaps for primary outcomes; 12 reviews concluded insufficient evidence of effectiveness. Common themes of unique methodological challenges and pitfalls with trials of surgical interventions were apparent. CONCLUSIONS: Cochrane reviews have gone a long way to establishing a sound evidence base in gynaecologic surgery: some gaps in the evidence have been eliminated and others highlighted. In general, gynaecology has been a specialty where surgical interventions have been well exposed to the scrutiny of RCTs compared with other surgical specialties.

Ovarian reserve tests for predicting fertility outcomes for assisted reproductive technology: the International Systematic Collaboration of Ovarian Reserve Evaluation protocol for a systematic review of ovarian reserve test accuracy.

BACKGROUND: The presence of a wide range of tests of ovarian reserve suggests that no single test provides a sufficiently accurate result. Many tests are used without reference to an evidence base. So far, individual studies conducted on these tests are too small to give precise estimates of prognostic accuracy. OBJECTIVES: To systematically assess the accuracy of the available tests of ovarian reserve in terms of prediction of fertility outcomes. SEARCH STRATEGY: The search will be conducted using the name of the respective index test being studied (as listed on the MESH database), if more than 2000 citations are listed, 'ovary' and or 'ovarian', 'fertility' and or 'reserve' will be combined with the original search term as required. Studies of the accuracy of tests of ovarian reserve will be obtained without language restrictions from 1980 to 2005 using the following electronic databases and Ovid software: MEDLINE, EMBASE, PUBmed, Biological extracts, Pascal, Cochrane Library (CDSR, DARE, CCTR, HTA), Best Evidence databases, SCISEARCH, Conference Proceedings (ISI Proceedings, Healthstar, Current Contents, Science Citation Index, Cancerlit and Econlit and NHS Economic Evaluation database. The National Research Register, the Medical Research Council's Clinical Trials Register, MEDION, DARE, and the US Clinical Trials register. SELECTION CRITERIA: Studies will be selected if accuracy of tests are compared with a reference standard and include data that can be abstracted into a two-by-two table to calculate sensitivity and specificity. The studies to be included in this review will examine one of the following index 'tests' within a study population of women undergoing assisted reproductive technology: * Clinical variables--age, history of cancelled cycles. * Basal blood tests--follicle-stimulating hormone (FSH), lutenising hormone (LH), FSH:LH ratios, estradiol (E(2)), inhibin A and B, progesterone (P(4)), P(4):E(2) ratios, antimullerian hormone, testosterone, vascular endothelial growth factor, insulin-like growth factor-1:insulin-like growth factor binding protein-1 ratios. * Dynamic tests--clomiphene citrate challenge test, gonadotropin analogue stimulating test, exogenous FSH ovarian reserve test. * Ultrasound tests-antral follicle count, ovarian volume, ovarian stromal peak systolic velocity, including waveform and pulsatility index, ovarian follicular vascularity. * Histology--ovarian biopsy. Data collection and analysis Two independent reviewers will perform quality assessment and data extraction. Prognostic accuracy will be determined by calculating positive and negative likelihood ratios for the following outcomes or reference standards: live birth, ongoing pregnancy, clinical pregnancy, biochemical pregnancy, embryos available for transfer, eggs obtained at oocyte retrieval, cycles cancelled prior to oocyte retrieval. Main results and conclusions N/A.

Total versus subtotal hysterectomy for benign gynaecological conditions.

BACKGROUND: Hysterectomy using an abdominal approach removes either the uterus alone (subtotal hysterectomy) or both the uterus and the cervix (total hysterectomy). The latter is more common but outcomes have not been systematically compared. OBJECTIVES: To assess and compare outcomes with subtotal hysterectomy versus total abdominal hysterectomy for benign gynaecological conditions. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group's specialised register of controlled trials (December 2005), Central (December 2005), Medline (1966 to December 2005), EmBase (1980 to December 2005), Biological Abstracts (1980 to December 2005), the National Research Register and relevant citation lists. SELECTION CRITERIA: Only randomised controlled trials of women undergoing either total or subtotal hysterectomy for benign gynaecological conditions were included. DATA COLLECTION AND ANALYSIS: Three trials that included 733 participants were included. Independent selection of trials and data extraction were undertaken by 2 reviewers and results compared. MAIN RESULTS: There was no evidence of a difference in the rates of incontinence, constipation or measures of sexual function. In one unblinded trial, a significantly greater proportion of women indicated that they had frequent episodes of urinary incontinence after subtotal hysterectomy when compared with total hysterectomy (OR=2.1, 1.02 to 4.3), but these results were not confirmed by the other two trials that measured both stress and urge incontinence and urinary frequency. . Length of surgery and amount of blood lost during surgery were significantly reduced during subtotal hysterectomy when compared with total hysterectomy, but there was no evidence of a difference in the odds of transfusion. Febrile morbidity was less likely (OR=0.43, 0.25 to 0.75) and ongoing cyclical vaginal bleeding one year after surgery was more likely (OR=11.3, 4.1 to 31.2) after subtotal when compared with total hysterectomy. There was no evidence of a difference in the rates of other complications, recovery from surgery or readmission rates. AUTHORS' CONCLUSIONS: This review has not confirmed the perception that subtotal hysterectomy offers improved outcomes for sexual, urinary or bowel function when compared with total abdominal hysterectomy. Surgery is shorter and intraoperative blood loss and fever are reduced but women are more likely to experience ongoing cyclical bleeding up to a year after surgery with subtotal hysterectomy compared to total hysterectomy.

Surgical interruption of pelvic nerve pathways for primary and secondary dysmenorrhoea.

BACKGROUND: Dysmenorrhoea is the occurrence of painful menstrual cramps of uterine origin and is a very common gynaecological complaint with negative effect on a sufferer's quality of life. Medical therapy for dysmenorrhoea includes oral contraceptive pills (OCP) and nonsteroidal anti-inflammatory drugs (NSAIDs) which both act by suppressing prostaglandin levels. While these treatments are very successful there is still a 20 to 25% failure rate and surgery has been an option for such cases. Uterine nerve ablation (UNA) and presacral neurectomy (PSN) are two surgical treatments that have become increasingly utilised in recent years due to advances in laparoscopic procedures. These procedures both interrupt the majority of the cervical sensory pain nerve fibres. Observational studies have supported the use of these procedures for primary dysmenorrhoea. However, both operations only partially interrupt the cervical sensory nerve fibres in the pelvic area and, therefore, this type of surgery may not always benefit women with dysmenorrhoea. OBJECTIVES: To assess the effectiveness of surgical interruption of pelvic nerve pathways as treatment for primary and secondary dysmenorrhoea, and to determine the most effective surgical treatment. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched 9 June 2004), CENTRAL (The Cochrane Library Issue 2, 2004), MEDLINE (1966 to Nov 2003), EMBASE (1980 to Nov 2003), and CINAHL (1982 to Oct 2003). Attempts were also made to identify trials from the metaRegister of Controlled Trials and the citation lists of review articles and included trials. In most cases the first or corresponding author of each included trial was contacted for additional information. SELECTION CRITERIA: The inclusion criteria were randomised comparisons of surgical techniques of interruption of the pelvic nerve pathways (using both open and laparoscopic procedures) for the treatment of primary and secondary dysmenorrhoea. The main outcome measures were pain relief and adverse effects. DATA COLLECTION AND ANALYSIS: Eleven randomised controlled trials (RCTs) were identified that initially appeared to fulfil the inclusion criteria for this review. Two trials were subsequently excluded (Garcia Leon 2003; Sutton 1991). Of the remaining nine trials, eight were included in the meta-analysis. The results of one trial were included in the text of the review for discussion because the data were not available in a form that allowed them to be combined in the meta-analysis. Five trials investigated laparoscopic uterine nerve ablation (LUNA), two trials laparoscopic presacral neurectomy (LPSN) and two open presacral neurectomy (PSN). MAIN RESULTS: For the treatment of primary dysmenorrhoea there was some evidence of the effectiveness of laparoscopic uterine nerve ablation (LUNA) when compared to a control or no treatment. The comparison between LUNA and laparoscopic presacral neurectomy (LPSN) for primary dysmenorrhoea showed no significant difference in pain relief in the short term; however, long-term LPSN was shown to be significantly more effective than LUNA. For the treatment of secondary dysmenorrhoea six identified RCTs addressed endometriosis and one included women with uterine myomas. The treatment of LUNA combined with surgical treatment of endometrial implants versus surgical treatment of endometriosis alone showed that the addition of LUNA did not aid pain relief. For PSN combined with endometriosis treatment versus endometriosis treatment alone there was an overall difference in pain relief although the data suggests this may be specific to laparoscopy and for midline abdominal pain only. Adverse events were significantly more common for presacral neurectomy; however, the majority were complications such as constipation, which may spontaneously improve. AUTHORS' CONCLUSIONS: There is insufficient evidence to recommend the use of nerve interruption in the management of dysmenorrhoea, regardless of cause. Future methodologically sound and sufficiently powered RCTs should be undertaken.

A double-blind randomised controlled trial of laparoscopic uterine nerve ablation for women with chronic pelvic pain.

OBJECTIVE: To determine the effectiveness of laparoscopic uterine nerve ablation (LUNA) for chronic pelvic pain in women with endometriosis and women with no laparoscopic evidence of endometriosis. DESIGN: A prospective double-blind randomised controlled trial (RCT). SETTING: Single-centre, secondary-level gynaecology outpatient service and tertiary-level pelvic pain and endometriosis outpatient service in Auckland, New Zealand. POPULATION: One hundred and twenty-three women undergoing laparoscopy for investigation and management of chronic pelvic pain, 56 with no laparoscopic evidence of endometriosis and 67 with endometriosis. METHODS: Women were randomised from the two populations, firstly those with no evidence of endometriosis and secondly those undergoing laparoscopic surgical treatment for endometriosis, to receive LUNA or no LUNA. Participant and assessor blinding was employed. Follow up for pain outcomes was undertaken at 24 hours, 3 months and 12 months. MAIN OUTCOME MEASURES: Changes in non-menstrual pelvic pain, dysmenorrhoea, deep dyspareunia and dyschezia were assessed primarily by whether there was a decrease in visual analogue score for these types of pain of 50% or more from baseline and additionally whether there was a significantly different change in median visual analogue score. The numbers requiring further surgery or starting a new medical treatment for pelvic pain and complications were also measured. RESULTS: There was a significant reduction in dysmenorrhoea at 12 month follow up in women with chronic pelvic pain in the absence of endometriosis who underwent LUNA (median change in visual analogue scale (VAS) from baseline -4.8 versus-0.8 (P= 0.039), 42.1%versus 14.3% experiencing a successful treatment defined as a 50% or greater reduction in visual analogue pain scale for dysmenorrhoea (P= 0.045). There was no significant difference in non-menstrual pelvic pain, deep dyspareunia or dyschezia in women with no endometriosis undergoing LUNA versus no LUNA. The addition of LUNA to laparoscopic surgical treatment of endometriosis was not associated with a significant difference in any pain outcomes. CONCLUSIONS: LUNA is effective for dysmenorrhoea in the absence of endometriosis, although there is no evidence of effectiveness of LUNA for non-dysmenorrhoeic chronic pelvic pain or for any type of chronic pelvic pain related to endometriosis.

Surgical treatment for tubal disease in women due to undergo in vitro fertilisation.

BACKGROUND: Tubal disease, and particularly hydrosalpinx, has a detrimental effect on the outcome of in-vitro fertilisation (IVF). It has been less clear whether surgical intervention for tubal disease prior to IVF is effective in improving the likelihood of successful outcome. Most data are retrospective or poorly controlled. To date no single prospective randomised trial has shown a significant benefit from such surgical treatment prior to IVF. OBJECTIVES: To assess the value of surgical treatment for tubal disease prior to IVF. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group trials register (10 March 2004), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2004), MEDLINE (January 1966 to February 2004), EMBASE (January 1985 to February 2004), reference lists of articles and contacted researchers in the field. SELECTION CRITERIA: All trials comparing a surgical treatment for tubal disease with a control group generated by randomisation were considered for inclusion in the review. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. The studied outcomes were live birth (and ongoing pregnancy), pregnancy, ectopic pregnancy, miscarriage, multiple pregnancy and complications. MAIN RESULTS: Three randomised controlled trials involving 295 (or couples) were included in this review. The odds of ongoing pregnancy and live birth (Peto odds ratio (OR) 2.13, 95% confidence interval (CI) 1.24 to 3.65) were increased with laparoscopic salpingectomy for hydrosalpinges prior to IVF. The odds of pregnancy were also increased (Peto odds ratio (OR )1.75, 95%CI 1.07 to 2.86). There was no significant difference in the odds of ectopic pregnancy (Peto OR 0.42, 95%CI 0.08 to 2.14), miscarriage (Peto OR 0.49, 95%CI 0.16 to 1.52) or treatment complications (Peto OR 5.80, 95%CI 0.35 to 96.79). No data were available concerning the odds of multiple pregnancy. REVIEWERS' CONCLUSIONS: Laparoscopic salpingectomy should be considered for all women with hydrosalpinges prior to IVF treatment. Currently unilateral salpingectomy for a unilateral hydrosalpinx (bilateral salpingectomy for bilateral hydrosalpinges) should be recommended, although this requires further evaluation. Further randomised trials are required to assess other surgical treatments for hydrosalpinx, such as salpingostomy, tubal occlusion or needle drainage of a hydrosalpinx at oocyte retrieval. The role of surgery for tubal disease in the absence of a hydrosalpinx is unclear and merits further evaluation.

Is ovarian surgery effective for androgenic symptoms of polycystic ovarian syndrome?

The effectiveness of laparoscopic ovarian drilling for treatment of anovulation in polycystic ovarian syndrome (PCOS) has been proved. The role of ovarian surgery in the treatment of symptoms related to hyperandrogenaemia, such as hirsutism and acne, has been less clear. This review sought to evaluate the effectiveness of ovarian surgery in the treatment of non-infertility symptoms related to PCOS. A systematic literature review was undertaken, by searching the Medline database for the years 1966-2002 inclusive. The search yielded 19 studies recording the outcomes of hirsutism, acne or androgen levels from surgical treatment for women with PCOS: three assessed unilateral oophorectomy; two ovarian wedge resection; and 14 ovarian drilling. There was no consensus of a clear improvement in hirsutism or acne in women undergoing surgery. There was a trend towards a decrease in serum androgen levels in most studies. We conclude that, while there is evidence that ovarian surgery may decrease androgen levels in some women with PCOS, the evidence that this translates into a clear improvement in hirsutism and acne is less clear. Further high quality clinical research, including data from randomisation, would be required to answer this question.

Laparoscopic salpingectomy for women with hydrosalpinges enhances the success of IVF: a Cochrane review.

BACKGROUND: The aim of this study was to determine whether surgical intervention is effective for women with tubal disease who are due to undergo treatment with IVF. METHODS: A systematic review employing the principles of the Cochrane Menstrual Disorders and Subfertility Group was undertaken. Three randomized controlled trials were included, the population of women in all three studies having hydrosalpinges. RESULTS: The odds of pregnancy [odds ratio (OR) = 1.75, 95% confidence interval (CI) 1.07-2.86] and of ongoing pregnancy and live birth (OR = 2.13, 95% CI 1.24-3.65) were increased with laparoscopic salpingectomy for hydrosalpinges prior to IVF. There were no significant differences in the odds of embryo implantation (OR = 1.34, 95% CI 0.87-2.05), ectopic pregnancy (OR = 0.42, 95% CI 0.08-2.14), miscarriage (OR = 0.49, 95% CI 0.16-1.52) or treatment complications (OR = 5.80, 95% CI 0.35-96.79). No data were available concerning the odds of multiple pregnancy or the proportion of IVF cycles resulting in embryo transfer. CONCLUSION: Laparoscopic salpingectomy should be considered for all women with hydrosalpinges due to undergo IVF; further research is required to assess other pre-IVF surgical interventions (such as needle aspiration of hydrosalpinx fluid, laparoscopic proximal tubal occlusion and laparoscopic salpingostomy) for women with hydrosalpinges.

Surgical treatment for tubal disease in women due to undergo in vitro fertilisation.

BACKGROUND: Tubal disease, and particularly hydrosalpinx, has a detrimental effect on the outcome of in-vitro fertilisation (IVF). It has been less clear whether surgical intervention for tubal disease prior to IVF is effective in improving the likelihood of successful outcome. Most data are retrospective or poorly controlled. To date no single prospective randomised trial has shown a significant benefit from such surgical treatment prior to IVF. OBJECTIVES: To assess the value of surgical treatment for tubal disease prior to IVF. SEARCH STRATEGY: The search strategy of the Menstrual Disorders and Subfertility Group was used for the identification of relevant randomised controlled trials. SELECTION CRITERIA: All trials where a surgical treatment for tubal disease was compared with a control group generated by randomisation were considered for inclusion in the review. DATA COLLECTION AND ANALYSIS: Three randomised controlled trials were identified and included in this review, after an attempt to obtain further information from the authors of all three trials. All trials were assessed for quality criteria. The studied outcomes were live birth (and ongoing pregnancy), pregnancy, ectopic pregnancy, miscarriage, multiple pregnancy, complications, implantation rate and the proportion of IVF cycles resulting in embryo transfer. MAIN RESULTS: The odds of pregnancy (OR 1.75, 95%CI 1.07, 2.86) and of ongoing pregnancy and live birth (OR 2.13, 95%CI 1.24, 3.65) were increased with laparoscopic salpingectomy for hydrosalpinges prior to IVF. There was no significant difference in the odds of ectopic pregnancy (OR 0.42, 95%CI 0.08, 2.14), miscarriage (OR 0.49, 95%CI 0.16, 1.52), treatment complications (OR 5.80, 95%CI 0.35, 96.79) or implantation rate (OR 1.34, 95%CI 0.87, 2.05). No data were available concerning the odds of multiple pregnancy or the proportion of IVF cycles resulting in embryo transfer. REVIEWER'S CONCLUSIONS: Laparoscopic salpingectomy should be considered for all women with hydrosalpinges prior to IVF treatment. Currently unilateral salpingectomy for a unilateral hydrosalpinx (bilateral salpingectomy for bilateral hydrosalpinges) should be recommended, although this requires further evaluation. Further randomised trials are required to assess other surgical treatments for hydrosalpinx, such as salpingostomy, tubal occlusion or needle drainage of a hydrosalpinx at oocyte retrieval. The role of surgery for tubal disease in the absence of a hydrosalpinx is unclear and merits further evaluation.

Equilibrium binding of single-stranded DNA to the secondary DNA binding site of the bacterial recombinase RecA.

The bacterial recombinase RecA forms a nucleoprotein filament in vitro with single-stranded DNA (ssDNA) at its primary DNA binding site, site I. This filament has a second site, site II, which binds ssDNA and double-stranded DNA. We have investigated the binding of ssDNA to the RecA protein in the presence of adenosine 5'-O-(thiotriphosphate) cofactor using fluorescence anisotropy. The RecA protein carried out DNA strand exchange with a 5'-fluorescein-labeled 32-mer oligonucleotide. The anisotropy signal was shown to measure oligonucleotide binding to RecA, and the relationship between signal and binding density was determined. Binding of ssDNA to site I of RecA was stable at high NaCl concentrations. Binding to site II could be described by a simple two-state equilibrium, K = 4.5 +/- 1.5 x 10(5) m(-1) (37 degrees C, 150 mm NaCl, pH 7.4). The reaction was enthalpy-driven and entropy-opposed. It depended on salt concentration and was sensitive to the type of monovalent anion, suggesting that anion-dependent protein conformations contribute to ssDNA binding at site II.

Cochrane review: post-operative procedures for improving fertility following pelvic reproductive surgery.

The objectives of the study was to determine the effectiveness of post-operative procedures following female pelvic reproductive surgery. A systematic review employing the principles of the Cochrane Menstrual Disorders and Subfertility Group was used. Five randomized controlled trials were included. Participants were women undergoing pelvic reproductive surgery; interventions were any post-operative procedure designed to improve fertility; outcomes were pregnancy, live birth, ectopic pregnancy and miscarriage rates and the rates of tubal patency and procedure-related complications. Summary statistics were expressed as odds ratios. The results showed that the odds of pregnancy, live birth, ectopic pregnancy and miscarriage were not significantly altered by post-operative hydrotubation nor second-look laparoscopy with adhesiolysis. Whether hydrotubation was early or late and whether hydrotubation fluid contained steroid or not had no significant impact on the odds of pregnancy, live birth, ectopic pregnancy or miscarriage. The odds of pregnancy and live birth were significantly increased and infective complications significantly decreased by hydrotubation with fluid containing antibiotic compared with hydrotubation with fluid containing no antibiotic, in late hydrotubation following tubal stent removal 6 weeks after tubal surgery. The odds of at least one patent Fallopian tube were significantly increased with late hydrotubation following tubal stent removal compared with early hydrotubation in women who had no tubal stenting, but this intervention had no significant impact on the odds of pregnancy, live birth, ectopic pregnancy or miscarriage. In conclusion, there is insufficient evidence to support the routine practice of hydrotubation or second-look laparoscopy following female pelvic reproductive surgery. The studies on which this conclusion is based were either poor quality or underpowered. Post-operative hydrotubation with fluid containing antibiotic following tubal surgery may offer benefit over hydrotubation fluid without antibiotic. A randomized controlled trial of post-operative hydrotubation with antibiotic-containing fluid versus no hydrotubation for improving fertility following tubal surgery is justified.

Surgical interruption of pelvic nerve pathways for primary and secondary dysmenorrhoea.

BACKGROUND: Dysmenorrhoea is the occurrence of painful menstrual cramps of uterine origin and is a very common gynaecological complaint. Medical therapy for dysmenorrhoea includes oral contraceptive pills (OCP) and nonsteroidal anti-inflammatory drugs (NSAIDS) which both act by suppressing prostaglandin levels. While these treatments are very successful there is still a 20-25% failure rate and surgery has been an option for cases of dysmenorrhoea that fail to respond to medical therapy. Uterine nerve ablation (UNA) and presacral neurectomy (PSN) are two surgical treatments that have become increasingly utilised in recent years. These procedures both interrupt the majority of the cervical sensory nerve fibres, thus diminishing uterine pain. Uncontrolled studies have supported the use of these procedures for primary dysmenorrhoea however both operations only partially interrupt some of the cervical sensory nerve fibres in the pelvic area; therefore dysmenorrhoea associated with additional pelvic pathology may not always benefit from this type of surgery. OBJECTIVES: To assess the effectiveness of surgical interruption of pelvic nerve pathways as treatment for primary and secondary dysmenorrhoea, and to determine the most effective surgical treatment. SEARCH STRATEGY: Electronic searches of the Cochrane Menstrual Disorders and Subfertility Group Register of controlled trials, MEDLINE, and EMBASE were performed to identify relevant randomised controlled trials (RCTs). Attempts were also made to identify trials from citation lists of review articles and handsearching. In most cases, the first or corresponding author of each included trial was contacted for additional information. SELECTION CRITERIA: The inclusion criteria were randomised comparisons of surgical techniques of interruption of the pelvic nerve pathways (both open and laparoscopic procedures) for the treatment of primary and secondary dysmenorrhoea. The main outcome measures were pain relief and adverse effects. DATA COLLECTION AND ANALYSIS: Seven RCTs were identified that fulfilled the inclusion criteria for this review. One trial (Sutton 1994) was excluded because another treatment was given in combination with destruction of pelvic nerve pathways and the effects of these two treatments could not be separated. Of the remaining six trials, three were included in the meta-analysis (Chen 1996, Candiani 1992, Lichten 1987). The results of the other three trials (Dover 1999, Tjaden 1990, Vercellini 1997) were included in the text of the review for discussion because the data were not available in a form that allowed them to be combined in a meta-analysis. MAIN RESULTS: For the treatment of primary dysmenorrhoea there is some evidence of the effectiveness of uterine nerve ablation (UNA) when compared to a control of no treatment. The comparison between UNA with presacral neurectomy (PSN) for primary dysmenorrhoea showed no significant difference in pain relief in the short term, however long term PSN was shown to be significantly more effective. For the treatment of secondary dysmenorrhoea the identified RCTs addressed only endometriosis. The treatment of UNA combined with surgical treatment of endometrial implants versus surgical treatment of endometriosis alone showed that the addition of UNA did not aid pain relief. For PSN combined with endometriosis treatment versus endometriosis treatment alone there was also no overall difference in pain relief, although the data suggests a significant difference in relief of midline abdominal pain. Adverse events were significantly more common for presacral neurectomy, however the majority were complications such as constipation, which may spontaneously improve. REVIEWER'S CONCLUSIONS: There is insufficient evidence to recommend the use of nerve interruption in the management of dysmenorrhoea, regardless of cause. Future RCTs should be undertaken.

Postoperative procedures for improving fertility following pelvic reproductive surgery.

BACKGROUND: Hydrotubation with oil-soluble contrast media for unexplained infertility and adhesiolysis for infertility due to peritubal adhesions are primary procedures of recognised benefit. It is less clear whether postoperative procedures such as hydrotubation or second-look laparoscopy with adhesiolysis are beneficial following pelvic reproductive surgery. OBJECTIVES: To assess the value of postoperative hydrotubation and second-look laparoscopy with adhesiolysis following female pelvic reproductive surgery. SEARCH STRATEGY: The search strategy of the Menstrual Disorders and Subfertility Group was used for the identification of all relevant randomised controlled trials. SELECTION CRITERIA: All trials where a postoperative procedure following pelvic reproductive surgery was compared with a control group generated by randomisation were considered for inclusion in the review. DATA COLLECTION AND ANALYSIS: Five randomised controlled trials were identified and included in this review, after an attempt to obtain further information from authors of all five trials. All trials were assessed for quality criteria. The studied outcomes were pregnancy, live birth, ectopic pregnancy and miscarriage rates and the rates of tubal patency and procedure-related complications. Reviewers extracted the data independently and odds ratios for these dichotomous outcomes were estimated from the data. MAIN RESULTS: The odds of pregnancy, live birth, ectopic pregnancy and miscarriage were not significantly different with postoperative hydrotubation versus no hydrotubation nor with second-look laparoscopy and adhesiolysis versus no second-look laparoscopy. Whether hydrotubation was early or late and whether hydrotubation fluid contained steroid or not had no significant impact on the odds of pregnancy, live birth, ectopic pregnancy or miscarriage. The odds of pregnancy and live birth were significantly increased and infective complications significantly decreased by hydrotubation with fluid containing antibiotic versus hydrotubation with fluid containing no antibiotic, in late hydrotubation following tubal stent removal six weeks after tubal surgery. The odds of at least one patent fallopian tube were significantly increased with late hydrotubation following tubal stent removal versus early hydrotubation in women who had no tubal stenting, but this intervention had no significant impact on the odds of pregnancy, live birth, ectopic pregnancy or miscarriage. REVIEWER'S CONCLUSIONS: There is insufficient evidence to support the routine practice of hydrotubation or second-look laparoscopy following female pelvic reproductive surgery. The studies on which this conclusion is based were either poor quality or underpowered. These interventions should be performed in the context of a good quality, adequately powered randomised controlled trial. Postoperative hydrotubation with fluid containing antibiotic following tubal surgery may offer benefit over hydrotubation fluid without antibiotic. A randomised controlled trial of postoperative hydrotubation with antibiotic-containing fluid versus no hydrotubation for improving fertility following tubal surgery is justified.

Can diagnostic laparoscopy be avoided in routine investigation for infertility?

OBJECTIVE: To determine whether routine testing for serum Chlamydia trachomatis antibodies, considered in combination with a woman's clinical features, may avoid the need for diagnostic laparoscopy in routine investigation for infertility. DESIGN: Retrospective case notes analysis. SETTING: Secondary level care infertility clinic. POPULATION: Eighty women who had undergone both laparoscopy and serum Chlamydia trachomatis antibody testing. METHODS: Ascertainment of any history of suspected pelvic inflammatory disease, pelvic pain, cervical intraepithelial neoplasia, pelvic surgery or appendicectomy; any abnormality on clinical pelvic examination; the findings at laparoscopy; the result of serum Chlamydia trachomatis antibody testing by enzyme-linked immunosorbent assay (ELISA) screening with microimmunofluorescence (MIF) confirmatory diagnostic testing. The usefulness of clinical features, the serum Chlamydia trachomatis antibody test and these two variables combined in the detection of tubal disease and pelvic pathology of relevance to infertility were measured statistically. MAIN OUTCOME MEASURES: Specificity, sensitivity, positive predictive value, negative predictive value and likelihood ratio for each of the tests. RESULTS: The combination of any positive clinical feature with a positive test for serum Chlamydia trachomatis antibodies detects tubal disease with sensitivity 92%, specificity 70%, positive predictive value 72%, negative predictive value 91% and likelihood ratio 3 x 1; it detects bilateral tubal obstruction with sensitivity 84%, specificity 51%, positive predictive value 35%, negative predictive value 91% and likelihood ratio 1 x 7; it detects pelvic pathology relevant to infertility with sensitivity 76%, specificity 71%, positive predictive value 80%, negative predictive value 65% and likelihood ratio 2 x 6. The negative predictive value for pelvic pathology from the use of clinical features in addition to the chlamydia antibody test is not significantly higher than that from the chlamydia antibody test alone (53%). CONCLUSIONS: A policy of selective laparoscopy in routine investigation for infertility, based on the result of the test for serum Chlamydia trachomatis antibodies and a woman's clinical features, is not supported.

Do men undergoing sterilizing cancer treatments have a fertile future?

This study was designed to assess the effect of cancer treatments on the natural and assisted reproductive potential of men. A cohort of men with cancer, in whom radiotherapy and/or chemotherapy was planned, were invited to participate. Twenty-two pre- and post-treatment semen samples were analysed. The reproductive potential of participants was assessed with respect to the current range of fertility treatment options available. Abnormal sperm concentrations were found in 27% of patients pre-treatment compared to 68% post-treatment following a mean latency of 20 months from treatment. Fifty-nine percent of patients experienced a clinically significant decrease in sperm, concentration following radiotherapy and/or chemotherapy; 23% developed azoospermia following treatment. Eighty-two percent of patients with testicular malignancy had oligo- or azoospermia post-treatment. Only one patient had a clinically significant reduction in the percentage of motile spermatozoa post-treatment. Cryopreservation of semen prior to treatment improved the fertility prospects of 55% of patients. Intracytoplasmic sperm injection (ICSI) enhanced the fertility prospects of a further 14%. In the absence of, or after depletion of, cryopreserved semen, ICSI could enhance the fertility prospects of 45% of patients. Fertilization has been achieved by ICSI using spermatozoa retrieved by testicular biopsy from an azoospermic testicular cancer survivor 8 years after chemotherapy. It was concluded that chemotherapy and/or radiotherapy may depress semen concentration to the extent of rendering a man infertile. The severity of the reduction in sperm concentration following treatment is unpredictable but likely to be most severe in those with testicular malignancy and those treated with radiotherapy or alkylating chemotherapy agents. Not all men are keen to undergo an appraisal of their post-treatment fertility potential, for reasons which are unclear. Improving awareness and education of patients concerning the effects of both cancer and cancer treatments on reproductive potential is essential. With the advent of ICSI, it is possible to offer a very reasonable chance of conception in all men with cancer who present for cryopreservation of semen prior to treatment in whom spermatozoa (even in very low concentrations) are present in the ejaculate.