Four-dimensional ultrasound guided embryo transfers improve live birth rates when compared to the clinical touch technique: a randomised controlled trial.

Most aspects of in-vitro fertilisation (IVF) have changed dramatically since introduction, but embryo transfer (ET) technique remains largely unaltered. We aimed to determine whether four-dimensional ultrasound guided embryo transfers (4D UGET) could improve pregnancy rates when compared with clinical touch technique (CTT). This was a single centre open labelled randomised controlled trial in a tertiary fertility centre in the UK. 320 women were randomised on the day of single ET. The primary outcome was clinical pregnancy rate (CPR), secondary outcomes included live birth rate (LBR), biochemical pregnancy rate (BPR), miscarriage, pregnancy of unknown location (PUL) and ectopic pregnancy. 4D-UGET resulted in significantly higher CPR [50% vs 36% p = 0.02, OR 1.78 (1.12-2.84)] and LBR [41% vs 28%, p = 0.02, OR 1.77 (1.09-2.87)] when compared to CTT technique. Miscarriage (p = 0.49), PUL (p = 0.14) and ectopic pregnancy (p = 0.96) were similar between the two groups. LBR, from this trial, are significantly higher than the current UK average (41% vs 24%). 4D UGET allows for superior imaging of the uterine cavity, whilst tailoring the embryo deposition point specifically to the patient. Further RCTs are required to determine if these results can be replicated in other units and whether 4D UGET is superior to 2D UGET.

Evidence-based guideline: unexplained infertility†.

STUDY QUESTION: What is the recommended management for couples presenting with unexplained infertility (UI), based on the best available evidence in the literature? SUMMARY ANSWER: The evidence-based guideline on UI makes 52 recommendations on the definition, diagnosis, and treatment of UI. WHAT IS KNOWN ALREADY: UI is diagnosed in the absence of any abnormalities of the female and male reproductive systems after 'standard' investigations. However, a consensual standardization of the diagnostic work-up is still lacking. The management of UI is traditionally empirical. The efficacy, safety, costs, and risks of treatment options have not been subjected to robust evaluation. STUDY DESIGN, SIZE, DURATION: The guideline was developed according to the structured methodology for ESHRE guidelines. Following formulation of key questions by a group of experts, literature searches, and assessments were undertaken. Papers written in English and published up to 24 October 2022 were evaluated. PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on the available evidence, recommendations were formulated and discussed until consensus was reached within the guideline development group (GDG). Following stakeholder review of an initial draft, the final version was approved by the GDG and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: This guideline aims to help clinicians provide the best care for couples with UI. As UI is a diagnosis of exclusion, the guideline outlined the basic diagnostic procedures that couples should/could undergo during an infertility work-up, and explored the need for additional tests. The first-line treatment for couples with UI was deemed to be IUI in combination with ovarian stimulation. The place of additional and alternative options for treatment of UI was also evaluated. The GDG made 52 recommendations on diagnosis and treatment for couples with UI. The GDG formulated 40 evidence-based recommendations-of which 29 were formulated as strong recommendations and 11 as weak-10 good practice points and two research only recommendations. Of the evidence-based recommendations, none were supported by high-quality evidence, one by moderate-quality evidence, nine by low-quality evidence, and 31 by very low-quality evidence. To support future research in UI, a list of research recommendations was provided. LIMITATIONS, REASONS FOR CAUTION: Most additional diagnostic tests and interventions in couples with UI have not been subjected to robust evaluation. For a large proportion of these tests and treatments, evidence was very limited and of very low quality. More evidence is required, and the results of future studies may result in the current recommendations being revised. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides clinicians with clear advice on best practice in the care of couples with UI, based on the best evidence currently available. In addition, a list of research recommendations is provided to stimulate further studies in the field. The full guideline and a patient leaflet are available in www.eshre.eu/guideline/UI. STUDY FUNDING/COMPETING INTEREST(S): The guideline was developed by ESHRE, who funded the guideline meetings, literature searches, and dissemination of the guideline in collaboration with the Monash University led Australian NHMRC Centre of Research Excellence in Women's Health in Reproductive Life (CREWHIRL). The guideline group members did not receive any financial incentives; all work was provided voluntarily. D.R. reports honoraria from IBSA and Novo Nordisk. B.A. reports speakers' fees from Merck, Gedeon Richter, Organon and Intas Pharma; is part of the advisory board for Organon Turkey and president of the Turkish Society of Reproductive Medicine. S.B. reports speakers' fees from Merck, Organon, Ferring, the Ostetric and Gynaecological Society of Singapore and the Taiwanese Society for Reproductive Medicine; editor and contributing author, Reproductive Medicine for the MRCOG, Cambridge University Press; is part of the METAFOR and CAPE trials data monitoring committee. E.B. reports research grants from Roche diagnostics, Gedeon Richter and IBSA; speaker's fees from Merck, Ferring, MSD, Roche Diagnostics, Gedeon Richter, IBSA; E.B. is also a part of an Advisory Board of Ferring Pharmaceuticals, MSD, Roche Diagnostics, IBSA, Merck, Abbott and Gedeon Richter. M.M. reports consulting fees from Mojo Fertility Ltd. R.J.N. reports research grant from Australian National Health and Medical Research Council (NHMRC); consulting fees from Flinders Fertility Adelaide, VinMec Hospital Hanoi Vietnam; speaker's fees from Merck Australia, Cadilla Pharma India, Ferring Australia; chair clinical advisory committee Westmead Fertility and research institute MyDuc Hospital Vietnam. T.P. is a part of the Research Council of Finland and reports research grants from Roche Diagnostics, Novo Nordics and Sigrid Juselius foundation; consulting fees from Roche Diagnostics and organon; speaker's fees from Gedeon Richter, Roche, Exeltis, Organon, Ferring and Korento patient organization; is a part of NFOG, AE-PCOS society and several Finnish associations. S.S.R. reports research grants from Roche Diagnostics, Organon, Theramex; consulting fees from Ferring Pharmaceuticals, MSD and Organon; speaker's fees from Ferring Pharmaceuticals, MSD/Organon, Besins, Theramex, Gedeon Richter; travel support from Gedeon Richter; S.S.R. is part of the Data Safety Monitoring Board of TTRANSPORT and deputy of the ESHRE Special Interest Group on Safety and Quality in ART; stock or stock options from IVI Lisboa, Clínica de Reprodução assistida Lda; equipment/medical writing/gifts from Roche Diagnostics and Ferring Pharmaceuticals. S.K.S. reports speakers' fees from Merck, Ferring, MSD, Pharmasure. HRV reports consulting and travel fees from Ferring Pharmaceuticals. The other authors have nothing to disclose. DISCLAIMER: This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.).

Fertility Preservation in Female Patients with Cancer.

Advances in cancer treatment with resultant dramatic improvements in long-term survival have led to increasing awareness of the wide range of medical and social issues faced by survivors of malignancy. The potential deleterious effects on fertility are a significant worry of women and trans gender men, and the rising trend in delaying childbearing and the higher proportion of patients who have not completed their family at the time of diagnosis increases the demand for an optimised fertility-preservation service. Fertility preservation for this group following a diagnosis of cancer is a rapidly expanding area of reproductive medicine, although provision for such treatment often varies by region. In the past, there were few treatment options, but with dramatic improvements in oocyte cryopreservation and, more recently, ovarian tissue cryopreservation, this area of fertility care has broadened substantially. This review will be exploring areas that apply to all cisgender women, but not necessarily all trans men and non-binary individuals. There are specific considerations in fertility preservation for trans people, which are beyond the scope of this paper. All individuals with female reproductive organs should be offered the opportunity to discuss fertility preservation prior to starting potential gonadotoxic treatment. Failure to do this may negatively influence their anticancer treatment choices and adherence to treatment regimens. There are currently few networks streamlined around offering this service and as demand for these treatment options increases, it is recognised that these complex patients require specialist management within recognised care pathways. Here we are looking to describe some of the unique challenges associated with providing a state-of-the-art service, particularly in a financially unpredictable climate in the midst of the COVID-19 pandemic.

Retrospective observational RT-PCR analyses on 688 babies born to 843 SARS-CoV-2 positive mothers, placental analyses and diagnostic analyses limitations suggest vertical transmission is possible.

RESEARCH QUESTION: Is there vertical transmission (from mother to baby antenatally or intrapartum) after SARS-CoV-2 (COVID-19) infected pregnancy? STUDY DESIGN: A systematic search related to SARS-CoV-2 (COVID-19), pregnancy, neonatal complications, viral and vertical transmission. The duration was from December 2019 to May 2020. RESULTS: A total of 84 studies with 862 COVID positive women were included. Two studies had ongoing pregnancies while 82 studies included 705 babies, 1 miscarriage and 1 medical termination of pregnancy (MTOP). Most publications (50/84, 59.5%), reported small numbers (<5) of positive babies. From 75 studies, 18 babies were COVID-19 positive. The first reverse transcription polymerase chain reaction (RT-PCR) diagnostic test was done in 449 babies and 2 losses, 2nd RT-PCR was done in 82 babies, IgM tests were done in 28 babies, and IgG tests were done in 28 babies. On the first RT-PCR, 47 studies reported time of testing while 28 studies did not. Positive results in the first RT-PCR were seen in 14 babies. Earliest tested at birth and the average time of the result was 22 hours. Three babies with negative first RT-PCR became positive on the second RT-PCR at day 6, day 7 and at 24 hours which continued to be positive at 1 week.Four studies with a total of 4 placental swabs were positive demonstrating SARS-CoV-2 localised in the placenta. In 2 studies, 10 tests for amniotic fluid were positive for SARS-CoV-2. These 2 babies were found to be positive on RT-PCR on serial testing. CONCLUSION: Diagnostic testing combined with incubation period and placental pathology indicate a strong likelihood that intrapartum vertical transmission of SARS-CoV-2 (COVID-19) from mother to baby is possible.

Elective oocyte cryopreservation for age-related fertility decline.

PURPOSE: Women who pursue fertility at an advanced age are increasingly common. Family planning and sexual education have traditionally focused on contraception and prevention of sexually transmitted diseases. A focus should now also be placed on fertility awareness and fertility preservation. This manuscript aims to give an update on the existing evidence around elective oocyte cryopreservation, also highlighting the need for fertility education and evidence-based, individualized counselling. METHODS: A thorough electronic search was performed from the start of databases to March 2020 aiming to summarize the existing evidence around elective egg freezing, the logic behind its use, patient counselling and education, success rates and risks involved, regulation, cost-effectiveness, current status and future perspectives. RESULTS: Clinician-led counselling regarding reproductive aging and fertility preservation is often overlooked. Elective oocyte cryopreservation is not a guarantee of live birth, and the answer regarding cost-effectiveness needs to be individualized. The existing studies on obstetric and perinatal outcomes following the use of egg freezing are, until now, reassuring. Constant monitoring of short-term and long-term outcomes, uniform regulation and evidence-based, individualized counselling is of paramount importance. CONCLUSIONS: Elective oocyte cryopreservation is one of the most controversial aspects of the world of assisted reproduction, and a lot of questions remain unanswered. However, women today do have this option which was not available in the past. Elective oocyte cryopreservation for age-related fertility decline should be incorporated in women's reproductive options to ensure informed decisions and reproductive autonomy.

Automated anti-Mullerian hormone measurement: data review to provide insights and interpretation.

RESULTS: AMH results were pooled and a table with 2.5 and 97.5 percentiles for each age group constructed. Based on Youden index, the optimal cut off for low responders (0-3 eggs), was 5.5 pmol/l (87% sensitivity, 55% specificity) and for high responders (>15 eggs) 15.6 pmol/l (78% sensitivity, 57% specificity). AMH correlated with number of eggs collected (r = 0.48) and clinical pregnancies (r = 0.14), (p < .0001). CONCLUSIONS: The table of AMH levels measured using the Access 2 fully automated immunoassay system according to age may be used as a reference and cutoff levels for high and poor responders are clearly defined to help tailor controlled ovarian stimulation, maximizing efficiency and ensuring patient safety. The use of a random access automated immunoassay system means that blood sampled on arrival can produce an AMH result in 40 mins by the time the subject enters the doctor's clinic together with other relevant endocrine markers.

Adverse outcomes in SAR-CoV-2 (COVID-19) and SARS virus related pregnancies with probable vertical transmission

The global severe acute respiratory syndrome-related coronavirus SARS-CoV-2 (COVID-19) pandemic has had an unprecedented impact on all aspects of daily life and healthcare. Information on the infection risks for pregnant women and their offspring have so far been limited to small case series, until a large UK report on 427 SARS-CoV-2 infected pregnant women was published. Previous SARS epidemic experiences were drawn upon. Diagnostic use of real time polymerase chain reaction (RT-PCR) and IgG and IgM antibody tests are fraught with concerns of non-validation and false negative results, as are sampling methodologies. Virtually no information on controls accompany these reports. Infection of the mother and baby has serious implications for obstetric and neonatal care. Information on early and late stage pregnancy infection and the relationship to severity of infection on fetal development is both useful and clearly warranted. An increasing number of reports centre around mildly infected women showing no evidence of fetal infection while a few reports suggesting vertical transmission require further validation. Vertical transmission from mother to baby however small would have profound health implications for obstetric and neonatal care and fetal abnormalities. Some data suggesting intrapartum vertical transmission from mother to baby cannot be dismissed given the lack of controls and limitations of diagnostic viral tests. This analysis covers some key early reports addressing pregnancy outcomes following SARS-CoV-2 infection. (AU)

Reappraisal of clinical data supports double IUI for improved pregnancy outcomes.

Optimising pregnancy and live birth outcomes for fertility procedures is highly desirable and involves disentangling numerous potentially contributing factors. In IUI procedures would double inseminations within a cycle be beneficial? Despite mistaken belief amongst the fertility practitioners the available evidence including Cochrane review has suggested, there would be beneficial effects of utilising double IUI within a cycle. Here we examine new evidence attempting to clarify the role of double versus single IUI.

GnRH antagonist versus long agonist protocols in IVF: a systematic review and meta-analysis accounting for patient type.

BACKGROUND: Most reviews of IVF ovarian stimulation protocols have insufficiently accounted for various patient populations, such as ovulatory women, women with polycystic ovary syndrome (PCOS) or women with poor ovarian response, and have included studies in which the agonist or antagonist was not the only variable between the compared study arms. OBJECTIVE AND RATIONALE: The aim of the current study was to compare GnRH antagonist protocols versus standard long agonist protocols in couples undergoing IVF or ICSI, while accounting for various patient populations and treatment schedules. SEARCH METHODS: The Cochrane Menstrual Disorders and Subfertility Review Group specialized register of controlled trials and Pubmed and Embase databases were searched from inception until June 2016. Eligible trials were those that compared GnRH antagonist protocols and standard long GnRH agonist protocols in couples undergoing IVF or ICSI. The primary outcome was ongoing pregnancy rate. Secondary outcomes were: live birth rate, clinical pregnancy rate, number of oocytes retrieved and safety with regard to ovarian hyperstimulation syndrome (OHSS). Separate comparisons were performed for the general IVF population, women with PCOS and women with poor ovarian response. Pre-planned subgroup analyses were performed for various antagonist treatment schedules. OUTCOMES: We included 50 studies. Of these, 34 studies reported on general IVF patients, 10 studies reported on PCOS patients and 6 studies reported on poor responders. In general IVF patients, ongoing pregnancy rate was significantly lower in the antagonist group compared with the agonist group (RR 0.89, 95% CI 0.82-0.96). In women with PCOS and in women with poor ovarian response, there was no evidence of a difference in ongoing pregnancy between the antagonist and agonist groups (RR 0.97, 95% CI 0.84-1.11 and RR 0.87, 95% CI 0.65-1.17, respectively). Subgroup analyses for various antagonist treatment schedules compared to the long protocol GnRH agonist showed a significantly lower ongoing pregnancy rate when the oral hormonal programming pill (OHP) pretreatment was combined with a flexible protocol (RR 0.74, 95% CI 0.59-0.91) while without OHP, the RR was 0.84, 95% CI 0.71-1.0. Subgroup analysis for the fixed antagonist schedule demonstrated no evidence of a significant difference with or without OHP (RR 0.94, 95% CI 0.79-1.12 and RR 0.94, 95% CI 0.83-1.05, respectively). Antagonists resulted in significantly lower OHSS rates both in the general IVF patients and in women with PCOS (RR 0.63, 95% CI 0.50-0.81 and RR 0.53, 95% CI 0.30-0.95, respectively). No data on OHSS was available from trials in poor responders. WIDER IMPLICATIONS: In a general IVF population, GnRH antagonists are associated with lower ongoing pregnancy rates when compared to long protocol agonists, but also with lower OHSS rates. Within this population, antagonist treatment prevents one case of OHSS in 40 patients but results in one less ongoing pregnancy out of every 28 women treated. Thus standard use of the long GnRH agonist treatment is perhaps still the approach of choice for prevention of premature luteinization. In couples with PCOS and poor responders, GnRH antagonists do not seem to compromise ongoing pregnancy rates and are associated with less OHSS and therefore could be considered as standard treatment.

Anti-Mullerian hormone (AMH) and embryo quality assessed by time-lapse imaging (TLI): a cross-sectional observational study.

PURPOSE: Serum anti-Mullerian hormone shows a strong positive correlation to the quantitative ovarian reserve but its correlation to embryo quality is unclear. This study assessed the association between serum AMH as a marker of ovarian reserve and embryo quality, using the technology of time-lapse imaging of the embryos in women undergoing in vitro fertilisation (IVF) treatment. METHODS: 304 embryos from 198 women undergoing IVF were included in the study. Serum AMH was assessed for all women. Embryo quality was assessed with the known implantation data (KID) score generated by the time-lapse imaging system. RESULTS: There was no statistically significant difference in mean serum AMH among different KID score categories (p = 0.135). This remained non-significant after controlling for confounding variables (p = 0.305). CONCLUSIONS: The results of our study show no significant association between serum AMH and embryo quality in women undergoing IVF treatment when embryo quality was assessed using the KID scores generated by time-lapse imaging which is a better method of embryo assessment rather than conventional morphological assessment.

First line fertility treatment strategies regarding IUI and IVF require clinical evidence.

The advent of intracytoplasmic sperm injection (ICSI) has contributed to a significant growth in the delivery of assisted conception technique, such that IVF/ICSI procedures are now recommended over other interventions. Even the UK National Institute for Health Care Excellence (NICE) guidelines controversially recommends against intrauterine insemination (IUI) procedures in favour of IVF. We reflect on some of the clinical, economic, financial and ethical realities that have been used to selectively promote IVF over IUI, which is less intrusive and more patient friendly, obviates the need for embryo storage and has a global application. The evidence strongly favours IUI over IVF in selected couples and national funding strategies should include IUI treatment options. IUI, practised optimally as a first line treatment in up to six cycles, would also ease the pressures on public funds to allow the provision of up to three IVF cycles for couple who need it. Fertility clinics should also strive towards ISO15189 accreditation standards for basic semen diagnosis for male infertility used to triage ICSI treatment, to reduce the over-diagnosis of severe male factor infertility. Importantly, there is a need to develop global guidelines on inclusion policies for IVF/ICSI procedures. These suggestions are an ethically sound basis for constructing the provision of publicly funded fertility treatments.

Serum anti-Mullerian hormone levels across different ethnic groups: a cross-sectional study.

OBJECTIVE: To assess whether ethnic differences in serum anti-Mullerian hormone (AMH) exist in a population of subfertile women presenting to a fertility clinic. DESIGN: Observational cross-sectional study. SETTING: Homerton University Hospital Fertility Centre, London, UK. POPULATION: A total of 865 women attending the fertility clinic for their first consultation appointment between September 2012 and September 2013. METHODS: Serum AMH was compared amongst women from five different ethnic groups. MAIN OUTCOME MEASURES: Serum AMH and ethnicity were the primary outcome variables. RESULTS: Although initial comparison showed South Asian women to have a higher serum AMH, compared with white European and Afro-Caribbean women (F = 3.817; P < 0.005), South Asian women attending the clinic were significantly younger and less likely to be smokers than women from other ethnic groups. The prevalence of polycystic ovary syndrome (PCOS) was significantly higher in South Asian and South East Asian women than in other ethnic groups. Differences in serum AMH were no longer significant after controlling for confounding factors: age, body mass index (BMI), and smoking status with (P = 0.869) and without (P = 0.215) controlling for PCOS. CONCLUSION: The results from our study show that there was no independent association of ethnicity and serum AMH levels in an unselected population of women attending the fertility clinic.

Short-term changes in hormonal profiles after laparoscopic ovarian laser evaporation compared with diagnostic laparoscopy for PCOS.

STUDY QUESTION: Which reproductive endocrine changes are attributed exclusively to laparoscopic ovarian drilling in polycystic ovarian syndrome (PCOS)? SUMMARY ANSWER: Laser evaporation-specific endocrine effects were the prevention of an immediate increase in inhibin B and a sustained decrease in testosterone, androstenedione and anti-Müllarian hormone (AMH). WHAT IS KNOWN ALREADY: All ovarian drilling procedures result in reproductive endocrine changes. It is not known which of these changes are the result of ovarian drilling and which are related to the surgery per se. STUDY DESIGN, SIZE, DURATION: This prospective controlled study was performed at an outpatient academic fertility clinic. Between 2007 and 2010, a total of 21 oligo- or amenorrheic PCOS patients were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Included were oligo- or amenorrheic PCOS patients with all three of the Rotterdam criteria and luteinizing hormone (LH) >6.5 U/l. All PCOS patients had an indication for diagnostic surgery due to subfertility. There were 12 PCOS patients who chose to undergo ovarian laser evaporation (CO2 laser, 25 W, 20 times/ovary) and 9 PCOS who chose a diagnostic laparoscopy only (controls). Reproductive endocrinology was measured before, and until 5 days after, surgery, and four gonadotrophin-releasing hormone (GnRH) 'double pulse' tests were included. The main outcome measures were changes in reproductive endocrinology and pituitary sensitivity/priming to GnRH after laser evaporation compared with diagnostic laparoscopy only. MAIN RESULTS AND THE ROLE OF CHANCE: In the first hours after surgery, both groups showed an increase in LH, follicle stimulating hormone, estrogen and a decrease in testosterone, androstenedione, AMH and insulin growth factor-1 (P < 0.05). Inhibin B increased in the laparoscopy only group (P < 0.05). In the first days after surgery, testosterone, androstenedione and AMH remained at lower than baseline levels exclusively in the laser group (P < 0.05). Pituitary sensitivity/priming to GnRH was not altered after either laser evaporation or laparoscopy only. LIMITATIONS, REASONS FOR CAUTION: The limitations of this study are the short follow-up period and the relatively small groups. WIDER IMPLICATIONS OF THE FINDINGS: The strength of this study is the integrally measured endocrine profiles in combination with an optimal control group of PCOS patients undergoing diagnostic laparoscopy only. Interestingly, most of the immediate endocrine changes after laser evaporation could be related to the surgical context and not to the ovarian drilling procedure itself. STUDY FUNDING/COMPETING INTERESTS: The study was funded by the Foundation of Scientific Research in Obstetrics and Gynaecology and the study medication, Lutrelef, was donated by Ferring, The Netherlands, Hoofdorphe There were no conflicts of interests mentioned by the authors.

Acupuncture in IVF: A review of current literature.

Women's choice to delay fertility due to various reasons is making subfertility a growing problem and increased use of IVF as a last resort. Despite advances in the technology, IVF success remains low, especially in older women. Hence, many of these women need to undergo several cycles of IVF and are faced with unprecedented anxiety and frustration. In desperation, they resort to anything that might increase the success of their IVF treatment. Acupuncture has gained popularity among the various complementary medicines available and many go privately to have acupuncture while undergoing IVF. Since 1999, in spite of multiple trials and systematic reviews, the beneficial effect of acupuncture in improving the success of IVF remains unproven and debatable. As clinicians, we face the dilemma of what to suggest to our patients when asked about having acupuncture during IVF, given that different meta-analyses have come to different conclusions. Hence, this review is conducted with the aim to summarise the available literature and provide a better insight into this complex and controversial topic.

Influence of ovarian manipulation on reproductive endocrinology in polycystic ovarian syndrome and regularly cycling women.

OBJECTIVE: Little is known about the function of the ovarian neuronal network in humans. In many species, copulation influences endocrinology through this network. As a first step, the possible influence of ovarian mechanical manipulation on pituitary and ovarian hormones was evaluated in polycystic ovarian syndrome (PCOS) and regularly cycling women. DESIGN: Prospective case-control study (2008-2010). METHODS: Ten PCOS women (Rotterdam criteria) undergoing ovulation induction with recombinant-FSH and ten normal ovulatory controls were included in an academic fertility clinic. In the late follicular phase blood was drawn every 10 min for 6 h. After 3 h the ovaries were mechanically manipulated by moving a transvaginal ultrasound probe firmly over each ovary ten times. Main outcome measures were LH and FSH pulsatility and ovarian hormones before and after ovarian manipulation. RESULTS: All PCOS patients showed an LH decline after the ovarian manipulation (before 13.0 U/l and after 10.4 U/l, P<0.01), probably based on a combination of a longer LH pulse interval and smaller amplitude (P=0.07). The controls showed no LH change (before 9.6 U/l and after 9.3 U/l, P=0.67). None of the ovarian hormones (estradiol, progesterone, anti-Müllerian hormone, inhibin B, androstenedione and testosterone) changed in either group. CONCLUSIONS: Ovarian mechanical manipulation lowers LH secretion immediately and typically only in preovulatory PCOS patients. The immediate LH change after the ovarian manipulation without any accompanying ovarian hormonal changes point to nonhormonal communication from the ovaries to the pituitary. A neuronal pathway from the ovaries communicating to the hypothalamic-pituitary system is the most reasonable explanation.

Recombinant LH supplementation to a standard GnRH antagonist protocol in women of 35 years or older undergoing IVF/ICSI: a randomized controlled multicentre study.

STUDY QUESTION: Does the addition of exogenous LH to an IVF/ICSI stimulation protocol with recombinant FSH (r-FSH) and a GnRH antagonist improve the ovarian response and pregnancy rates in women of 35 years and older? SUMMARY ANSWER: Supplementation of LH during the second half of the follicular phase has no effect on pregnancy rates, implantation rates or on ovarian response in women of 35 years and older undergoing GnRH antagonist IVF/ICSI cycles. WHAT IS KNOWN ALREADY: In IVF/ICSI stimulation protocols GnRH agonists or antagonists are administered to prevent a premature pituitary LH surge, which can have a detrimental effect on the IVF/ICSI procedure. In effect, GnRH analogues cause the levels of both gonadotrophins to drop. In order to allow follicle growth FSH is administered exogenously, whereas LH is usually not supplemented. Although GnRH analogues prevent LH surges, there is evidence that, particularly in older women, administration of GnRH analogues may cause endogenous LH levels to decrease excessively. Several studies have been performed to investigate whether the addition of recombinant LH (r-LH) to r-FSH improves cycle outcome. Only a few studies have analysed this issue in the GnRH antagonist protocol and the results of these trials obtained in older women (>35 years old) are conflicting. STUDY DESIGN, SIZE, DURATION: A multicentre RCT was performed between 2004 and 2010 in 253 couples who were undergoing IVF or ICSI. Women were 35 years or older and received ovarian stimulation in a protocol with r-FSH (Gonal-F 225 IU/day) starting from cycle day 3 and GnRH antagonist (Cetrotide 0.25 mg/day) from stimulation day 6. Randomization took place on stimulation day 6 to receive both r-FSH and r-LH (Luveris 150 IU/day) or continue with FSH alone. Randomization for r-LH supplementation was performed centrally by serially numbered, opaque, sealed envelopes, stratified by centre. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of 253 subjects randomized, 125 received both r-FSH and r-LH and 128 received r-FSH only. Patients were recruited from the Division of Reproductive Medicine of the Obstetrics and Gynaecology department of four hospitals in the Netherlands. MAIN RESULTS AND THE ROLE OF CHANCE: There were no demographic or clinical differences between the groups. The intention-to-treat analysis revealed that of those receiving both r-FSH and r-LH, 35 (28.0%) had a clinical pregnancy, compared with 38 (29.7%) receiving only r-FSH (mean difference -1.5%; 95% confidence interval (CI) -9.4 to 12.7, P = 0.9). Ongoing pregnancy rates were 25 (20%) versus 28 (21.9%) (mean difference -1.9%; 95% CI -8.2 to 11.9, P = 0.9) and implantation rates 18.8 versus 20.7% (mean difference -1.9%; 95% CI -8.0 to 11.7, P = 0.6) in the 'r-FSH and r-LH' and 'r-FSH only' groups respectively. LIMITATIONS, REASONS FOR CAUTION: A limitation of our study is its early closure. This was done because the interim analysis after randomization of 250 patients indicated no benefit in any aspect of the experiment. WIDER IMPLICATIONS OF THE FINDINGS: Given previous data, including a Cochrane review, and our own results the evidence indicates that LH supplementation has no benefit on ongoing pregnancy rates in women of 35 years or older. STUDY FUNDING/COMPETING INTEREST(S): Merck Serono Netherlands, an affiliate of Merck Serono SA- Geneva, an affiliate of Merck KGaA, Darmstadt, Germany has donated the r-LH (Luveris(®)). No conflict of interest to declare. TRIAL REGISTRATION NUMBER: The trial was registered in the Dutch trial register (ISRCTN10841210).

The relationship of serum anti-Mullerian hormone with polycystic ovarian morphology and polycystic ovary syndrome: a prospective cohort study.

STUDY QUESTION: What is the relationship of serum anti-Mullerian hormone (AMH) with polycystic ovarian morphology (PCOM) and polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Serum AMH concentrations are capable of differentiating between normal ovaries, PCOM and PCOS. WHAT IS KNOWN ALREADY: Serum AMH levels are high in PCOS reflecting the number of small antral follicles and an intrinsic defect of individual granulosa cells. STUDY DESIGN, SIZE, DURATION: Data were collected prospectively and analysed from three groups of women: those with PCOS according to Rotterdam criteria, those with PCOM but no symptoms and those with normal ovaries. PARTICIPANTS/MATERIAL, SETTING, METHODS: Women with PCOS (n = 90), with PCOM (n = 35) and with normal ovaries (controls, n = 90), matched for age and body mass index, were all being treated for infertility at Homerton University Hospital, a tertiary referral centre. MAIN RESULTS AND THE ROLE OF CHANCE: Using adequate numbers and statistical methods for demographically similar groups, there were significant differences in the mean serum AMH concentrations between women with PCOS [77.6 pmol/l (95% CI 64.8-90.3)], those with PCOM [52.2 pmol/l (95% CI 40.1-64.2)] and controls [23.6 pmol/l (95% CI 20.5-26.7)] (P < 0.001). The combination of AMH >48 pmol/l and LH > 6 IU/l diagnosed 82.6% of women with PCOS. The mean serum FSH was lower in both PCOS and PCOM compared with controls, whereas LH was higher in PCOS compared with PCOM and controls and correlated positively with AMH (r = 0.321, P < 0.01). LIMITATIONS, REASONS FOR CAUTION: Further research is needed to determine the relationship of AMH, PCOS and PCOM. The study was restricted to women who sought out treatment for infertility. WIDER IMPLICATIONS OF THE FINDINGS: The study suggests that the severity of symptoms of PCOS is positively related to the number of small follicles and that AMH may play an important part in the pathophysiology of anovulation. STUDY FUNDING/COMPETING INTEREST: None.