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RESEARCH QUESTION: Does additional supplementation with oral dydrogesterone improve reproductive outcomes in patients with low serum progesterone concentrations on the day of frozen embryo transfer (FET) after artificial (HRT) endometrial preparation? DESIGN: Retrospective, single-centre cohort study including 694 unique patients performing single blastocyst transfer in an HRT cycle. For luteal phase support, intravaginal micronized vaginal progesterone (MVP, 400 mg twice daily) was administered. Serum progesterone concentrations were assessed prior to FET and outco-mes were compared among patients with normal serum progesterone (≥8.8 ng/ml) continuing the routine protocol and patients with low serum progesterone (

A high ovarian response to conventional ovarian stimulation (OS) is characterized by an increased number of follicles and/or oocytes compared with a normal response (10-15 oocytes retrieved). According to current definitions, a high response can be diagnosed before oocyte pick-up when >18-20 follicles ≥11-12 mm are observed on the day of ovulation triggering; high response can be diagnosed after oocyte pick-up when >18-20 oocytes have been retrieved. Women with a high response are also at high risk of early ovarian hyper-stimulation syndrome (OHSS)/or late OHSS after fresh embryo transfers. Women at risk of high response can be diagnosed before stimulation based on several indices, including ovarian reserve markers (anti-Müllerian hormone [AMH] and antral follicle count [AFC], with cutoff values indicative of a high response in patients with PCOS of >3.4 ng/mL for AMH and >24 for AFC). Owing to the high proportion of high responders who are at the risk of developing OHSS (up to 30%), this educational article provides a framework for the identification and management of patients who fall into this category. The risk of high response can be greatly reduced through appropriate management, such as individualized choice of the gonadotropin starting dose, dose adjustment based on hormonal and ultrasound monitoring during OS, the choice of down-regulation protocol and ovulation trigger, and the choice between fresh or elective frozen embryo transfer. Appropriate management strategies still need to be defined for women who are predicted to have a high response and those who have an unexpected high response after starting treatment. ispartof: BEST PRACTICE & RESEARCH CLINICAL OBSTETRICS & GYNAECOLOGY vol:86 ispartof: location:Netherlands status: published

PURPOSE: Sperm DNA fragmentation (SDF) has been associated with male infertility and poor outcomes of assisted reproductive technology (ART). The purpose of this study was to investigate global practices related to the management of elevated SDF in infertile men, summarize the relevant professional society recommendations, and provide expert recommendations for managing this condition. MATERIALS AND METHODS: An online global survey on clinical practices related to SDF was disseminated to reproductive clinicians, according to the CHERRIES checklist criteria. Management protocols for various conditions associated with SDF were captured and compared to the relevant recommendations in professional society guidelines and the appropriate available evidence. Expert recommendations and consensus on the management of infertile men with elevated SDF were then formulated and adapted using the Delphi method. RESULTS: A total of 436 experts from 55 different countries submitted responses. As an initial approach, 79.1% of reproductive experts recommend lifestyle modifications for infertile men with elevated SDF, and 76.9% prescribe empiric antioxidants. Regarding antioxidant duration, 39.3% recommend 4-6 months and 38.1% recommend 3 months. For men with unexplained or idiopathic infertility, and couples experiencing recurrent miscarriages associated with elevated SDF, most respondents refer to ART 6 months after failure of conservative and empiric medical management. Infertile men with clinical varicocele, normal conventional semen parameters, and elevated SDF are offered varicocele repair immediately after diagnosis by 31.4%, and after failure of antioxidants and conservative measures by 40.9%. Sperm selection techniques and testicular sperm extraction are also management options for couples undergoing ART. For most questions, heterogenous practices were demonstrated. CONCLUSIONS: This paper presents the results of a large global survey on the management of infertile men with elevated SDF and reveals a lack of consensus among clinicians. Furthermore, it demonstrates the scarcity of professional society guidelines in this regard and attempts to highlight the relevant evidence. Expert recommendations are proposed to help guide clinicians.

RESEARCH QUESTION: Does ageing affect endometrial stromal cell function and gene expression involved in decidualization? DESIGN: Stromal cells were isolated and cultured (98% purity) from pipelle endometrial biopsies obtained from female donors, at the proliferative phase of the menstrual cycle. Initially, 28 samples were collected (age range 25-46 years). These samples were divided into two groups: 25-35 years and 36-46 years. Cell proliferation assays were carried out to determine changes in stromal cell proliferation, in vitro, between the two groups. In addition, mRNA and protein expression of decidualization factors, BMP2 and STAT3, were analysed for the same age groups and samples using real-time polymerase chain reaction and western blot analysis, respectively. Finally, another 12 pipelle endometrial biopsies (age range 25-46 years) were used in separate in-vitro decidualization experiments. The mRNA expression of decidualization markers, prolactin and IGFBP-1 were analysed in cultured stromal cells after adding 8-bromo-cAMP. RESULTS: A statistically significant decrease was observed in stromal cell proliferation with increasing age (P = 0.0006). Messenger RNA expression of BMP2 and STAT3 were found to decrease (P = 0.0167; P = 0.0037, respectively) in the older age group. In addition, BMP2 and STAT3 protein expression between the samples analysed changed significantly (P = 0.0085; P = 0.0463, respectively) with increasing age. In-vitro induced decidualization experiments showed significant changes in stromal cell mRNA expression of decidualization markers (IGFBP1 and prolactin) between different age groups. CONCLUSION: Ageing affected endometrial cell function and gene expression. Changes in cell function and expression of associated molecules that differ in the ageing endometrium can help understand the causes of infertility.

Summarization: Input methods for interaction in smartphone-based virtual and mixed reality (VR/MR) are currently based on uncomfortable head tracking controlling a pointer on the screen. User fixations are a fast and natural input method for VR/MR interaction. Previously, eye tracking in mobile VR suffered from low accuracy, long processing time, and the need for hardware add-ons such as anti-reflective lens coating and infrared emitters. We present an innovative mobile VR eye tracking methodology utilizing only the eye images from the front-facing (selfie) camera through the headset’s lens, without any modifications. Our system first enhances the low-contrast, poorly lit eye images by applying a pipeline of customised low-level image enhancements suppressing obtrusive lens reflections. We then propose an iris region-of-interest detection algorithm that is run only once. This increases the iris tracking speed by reducing the iris search space in mobile devices. We iteratively fit a customised geometric model to the iris to refine its coordinates. We display a thin bezel of light at the top edge of the screen for constant illumination. A confidence metric calculates the probability of successful iris detection. Calibration and linear gaze mapping between the estimated iris centroid and physical pixels on the screen results in low latency, real-time iris tracking. A formal study confirmed that our system’s accuracy is similar to eye trackers in commercial VR headsets in the central part of the headset’s field-of-view. In a VR game, gaze-driven user completion time was as fast as with head-tracked interaction, without the need for consecutive head motions. In a VR panorama viewer, users could successfully switch between panoramas using gaze. Presented on: ACM Transactions on Applied Perception

Over 80 species are recognized in the commercially important genus Morchella, many of them endemic to specific regions or continents. Among them, M. anatolica and M. rufobrunnea are the earliest diverging lineages and are key in decoding the evolutionary history, global biogeography, and ecological trends within this iconic genus. Early ancestral area reconstruction (AAR) tests postulated a western North American origin of morels but had not included in the analyses M. anatolica, whose phylogenetic identity remained at the time unresolved. Following new collections of M. anatolica and M. rufobrunnea from the Mediterranean islands of Cyprus, Kefalonia, Lesvos, Malta, and Zakynthos, we performed revised AAR tests to update the historical biogeography of the genus. Our results, inferred from multilocus analysis of an expanded data set of 79 phylospecies, challenge previous reconstructions and designate the Mediterranean basin as the most likely place of origin for morels. Detailed morphoanatomical analyses demonstrate that ascocarp rufescence, the nondarkening apothecial ridges, the absence of a sinus, and the stipe pruinescence are all stable synapomorphic features of sect. Rufobrunnea, which could be interpreted as ancestral for the genus. The saprotrophic mode of nutrition, suggested by the prolific in vitro growth of M. anatolica, might also be an ancestral trait. Emended descriptions, including extensive imagery and scanning electron microscopy, are provided, and a new evolutionary hypothesis of the genus is proposed.

Research question Is there an association between ovarian response and perinatal outcomes? Design A retrospective, single-centre cohort study including all women undergoing their first ovarian stimulation cycle in a gonadotrophin releasing hormone antagonist protocol, with a fresh embryo transfer that resulted in a singleton live birth from January 2009 to December 2015. Patients were categorized into four groups according to the number of oocytes retrieved: one to three (category 1), four to nine (category 2), 10–15 (category 3), or over 15 oocytes (category 4). Results The overall number of patients analysed was 964. No relevant statistical difference was found among neonatal outcomes across the four ovarian response categories. Neonatal weight (in grams) was comparable between all groups (3222 ± 607 versus 3254 ± 537 versus 3235 ± 575 versus 3200 ± 622; P = 0.85, in categories 1, 2, 3 and 4, respectively). No statistically significant differences were found among the ovarian response categories for birth weight z-scores (taking into account neonatal sex and delivery term). The incidence of pre-term birth and low birth weight was comparable across the different ovarian response groups (P = 0.127 and P = 0.19, respectively). Finally, the occurrence of adverse obstetric outcomes did not differ among the ovarian response categories. Multivariate regression analysis revealed that the number of oocytes was not associated with neonatal birth weight. Conclusions No association was found between ovarian response and adverse perinatal outcomes in antagonist IVF and intracytoplasmic sperm injection cycles. Future, larger scale and prospectively designed investigations are needed to validate these results.

Introduction: 36.9% of men worldwide use tobacco. Previous studies suggest a negative effect of cigarette smoking on semen quality, but the results are contradictory. We have studied the effects of smoking on the semen characteristics such as sperm concentration, semen volume, sperm motility, sperm vitality and sperm morphology in a large group of infertile men.Methods: This retrospective study was conducted on a total of 5146 infertile men with at least one year of idiopathic infertility, who admitted to the Centre for Reproductive medicine (CRG) at the Brussels University Hospital, Belgium between 2010 and 2017. The smokers were classified as mild (1-10 cigarettes/d), moderate (11-20 cigarettes/d) or heavy smokers (> 20 cigarettes/d). Semen analysis was performed for all patients. Statistical analysis was performed using the R software package and t-test or Mann-Whitney U tests were used, group comparisons were performed using ANOVA, ANCOVA or Kruskal-Wallis tests as appropriate. A p-value

Research question: Do live birth rates (LBRs) differ in frozen cycles of women who received single versus double embryo transfer? Design: Retrospective cohort study including women who underwent their first frozen embryo transfer (FET) in a tertiary referral University Hospital between 2009–2014. Results: 3601 patients were included in the analysis with 1936 (53.8%) having a single embryo transfer (SET) and 1665 (46.2%) having a double embryo transfer (DET). Overall, 657/3601 (18.24%) had a live birth. LBR were similar between SET and DET either for cleavage [100/757 (13.1%) versus 153/1032 (14.8%), p =.33] or blastocyst stage FET [256/1179 (21.7%) versus 148/633 (23.4%), p =.4). Ongoing pregnancy rates were comparable between DET and SET [316/1665 (18.9%) versus 359/1936 (18.5%)]. Multiple delivery rates were significantly higher in women with DET compared to SET [53/316 (16.7%) versus 7/359 (1.9%), p

Monitoring the riverine output of Suspended Particulate Matter (SPM) distribution in marine embayment is a crucial factor for the water quality of neighbouring coastal regions. This study p...

To investigate whether there is an association between androgens and ovarian reserve, expressed through anti-Mullerian hormone. This is a retrospective cross-sectional analysis of all consecutive women attending a tertiary fertility center, who presented with regular menstrual cycles. Patients had their AMH values measured with the same AMH assay (Immunotech (IOT) Beckmann Coulter assay), the same day in which androgens sampling was performed. Women with PCOS or other forms of androgen excess or untreated endocrine or metabolic disorders were excluded. A total of 942 women were included. Significant correlation was observed between total testosterone/free androgens index (FAI)/DHEAS and AMH (Spearman's r = 0.20/0.14/0.13, P value < 0.001, P value < 0.001, and P value < 0.001, respectively). After multiple linear regression analysis adjusting for confounders (age, BMI, cause of infertility, day of the menstrual cycle when the blood sample was performed), the regression slope in all participants for total testosterone predicting logAMH was 0.20 (P value < 0.001). Similarly, FAI was significantly associated with logAMH (regression coefficient = 0.04, P value = 0.04). In contrast, DHEAS was not significantly associated with logAMH. There was a significant, but weak relation between testosterone and AMH, while no significant association was observed between DHEAS and AMH. Future research is needed to elucidate whether testosterone supplementation may have any effect on ovarian function.

STUDY QUESTION Is late follicular elevated progesterone (LFEP) in the fresh cycle hindering cumulative live birth rates (CLBRs) when a freeze only strategy is applied? SUMMARY ANSWER LFEP in the fresh cycle does not affect the CLBR of the frozen transfers in a freeze only approach, nor the embryo freezing rate. WHAT IS KNOWN ALREADY Ovarian stimulation promotes the production of progesterone (P) which has been demonstrated to have a deleterious effect on IVF outcomes. While there is robust evidence that this elevation produces impaired endometrial receptivity, the impact on embryo quality remains a matter of debate. In particular, previous studies have shown that LFEP is associated with a hindered CLBR. However, most clinical insight on the effect of progesterone on embryo quality in terms of CLBRs have focused on embryo transfers performed after the fresh transfer, thus excluding the first embryo of the cohort. To be really informative on the possible detrimental effects of LFEP, evidence should be derived from freeze-all cycles where no fresh embryo transfer is performed in the presence of progesterone elevation, and the entire cohort of embryos is cryopreserved. STUDY DESIGN, SIZE, DURATION This was a matched case-control, multicentre (three centres), retrospective analysis including all GnRH antagonist ICSI cycles in which a freeze all (FA) policy of embryos on day 3/5/6 of embryonic development was applied between 2012 and 2018. A total of 942 patients (471 cases with elevated P and 471 matched controls with normal P values) were included in the analysis. Each patient was included only once. PARTICIPANTS/MATERIALS, SETTING, METHODS The sample was divided according to the following P levels on the day of ovulation triggering: MAIN RESULTS AND THE ROLE OF CHANCE The baseline characteristics of the two groups were similar. Estradiol levels on the day of trigger were significantly higher in the elevated P group. There was no significant difference in terms of fertilisation rate between the two groups. The elevated P group had significantly more cleavage stage frozen embryos compared to the normal P group while the total number of cryopreserved blastocyst stage embryos was the same. The CLBR did not differ between the two study groups (29.3% and 28.2% in the normal versus LFEP respectively, P = 0.773), also following confounder adjustment using multivariable GEE regression analysis (accounting for age at oocyte retrieval, total dose of FSH, progesterone levels on the day of ovulation trigger, day of freezing, at least one top-quality embryo transferred and number of previous IVF cycles, as the independent variables). LIMITATIONS, REASONS FOR CAUTION This is a multicentre observational study based on a retrospective data analysis. Better extrapolation of the results could be validated by performing a prospective analysis. WIDER IMPLICATIONS OF THE FINDINGS This is the first study demonstrating that LFEP in the fresh cycle does not hinder CLBR of the subsequent frozen cycles in a FA approach. Thus, a FA strategy circumvents the issue of elevated P in the late follicular phase. STUDY FUNDING/COMPETING INTEREST(S) No funding was received for this study. Throughout the study period and manuscript preparation, authors were supported by departmental funds from: Centre for Reproductive Medicine, Brussels, Belgium; Infertility Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Centro Scienze Natalità, San Raffaele Scientific Institute, Milan, Italy; and IVI-RMA, Lisbon, Portugal. E.S. has competing interests with Ferring, Merck-Serono, Theramex and Gedeon-Richter outside the submitted work. E.P. reports grants from Ferring, grants and personal fees from Merck-Serono, grants and personal fees from MSD and grants from IBSA outside the submitted work. All the other authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A.

Since the publication of the first edition of the WHO (World Health Organization) Laboratory Manual for the examination of Human Semen in 1980, the reference values of sperm parameters have been updated on four occasions. Currently and globally, most of the laboratories analyzing semen samples use the latest, 5th edition of the manual that recommends ejaculatory abstinence from two to seven days before producing the sample for examination. While this standardized interval of time facilitates the interpretation of the results and research, no solid evidence exists to support the WHO-recommended abstinence time for a semen analysis in order to optimize clinical outcomes after assisted reproduction. Most of the studies refer to different clinical outcomes, different groups of patients and different editions of the WHO Laboratory Manual, including heterogeneous intervals of abstinence or sperm parameters. The aim of the current systematic review was to evaluate available evidence correlating ejaculatory abstinence time with clinical outcomes and sperm parameters analyzed according to the last edition of the World Health Organization Laboratory Manual reference values in different male populations. The results from the included studies indicate that WHO abstinence recommendations may need revision, given that a shorter ejaculatory abstinence interval appears to be associated with improved sperm parameters, such as sperm DNA fragmentation, progressive motility or morphology, while evidence suggests a potential increase in embryo euploidy rates and pregnancy outcomes.

Study question Does a 3-day pretreatment course with a GnRH antagonist in the early follicular phase increase the number of oocytes in a GnRH antagonist stimulation protocol? Summary answer The administration of 3 days of GnRH antagonist before starting ovarian stimulation in a GnRH antagonist protocol increases the number of COCs (Cumulus-Oocyte-Complexes). What is known already The GnRH antagonist protocol is characterized by higher gonadotropin and E2 serum levels at the start of ovarian stimulation (OS), compared with a long pituitary down regulation protocol. The unsuppressed FSH level at the start of a GnRH antagonist cycle allows the initial growth of follicles before addition of exogenous FSH, which may result in asynchrony of the follicular cohort. Menstrual administration of a GnRH antagonist can inhibit follicle growth and improve homogeneity of recruitable follicles. Previous studies showed a trend toward higher numbers of COCs and improved maturation and fertilization rates of retrieved oocytes. Study design, size, duration Retrospective single center crossover study, including consecutive women enrolled in an IVF program in a university hospital from January 2011 to December 2020. All women underwent one standard GnRH antagonist stimulation cycle (“standard cycle”) and one GnRH antagonist stimulation cycle preceded by early administration of GnRH antagonist for 3 days (“pretreatment cycle”). Women with basal progesterone levels >1.5ng/ml, and women undergoing oocyte freezing, oocyte donation or PGT were excluded. In total, 427 patients were included. Participants/materials, setting, methods Women were included when the pretreatment cycle occurred within a time interval of Main results and the role of chance The average female age was 35.1 ± 4.7 years. Indications for fertility treatment included unexplained infertility (34.3%), male-factor infertility (33.3%), age (16.9%), PCOS (8.2%) and endometriosis (2.6%). All cycles were divided into two groups: group 1 (standard, 427 cycles) and group 2 (pretreatment, 427 cycles). The mean duration of stimulation was similar in both groups (10.3 vs 10.3 days, p = 0.2). The starting dose of gonadotropin (196.8 vs 234.9IU, p Limitations, reasons for caution Despite the large dataset, the presence of biases related to the retrospective study design cannot be excluded. Besides, the impact of GnRH pretreatment on pregnancy rate cannot be assessed because of the crossover design. Wider implications of the findings: A 3-day course of GnRH antagonist pretreatment increases the number of COCs obtained after OS. Furthermore, since the initiation of OS in a GnRH antagonist protocol relies on the occurrence of spontaneous menses, addition of three days of GnRH antagonist pretreatment may enhance scheduling flexibility without reducing efficacy. Trial registration number Not applicable

Study question Does the dose or type of gonadotropin affect the reproductive outcomes of poor responders undergoing MNC-IVF? Summary answer Neither the type nor the dose of gonadotropins affects the reproductive outcomes of poor responders undergoing MNC-IVF. What is known already Poor ovarian response (POR) to ovarian stimulation remains a major therapeutic challenge in routine IVF practice, because of the association with low live birth rates and high cancellation rates. Although high doses of gonadotropins are traditionally used to stimulate the ovaries in women with predicted POR, MNC-IVF has been proposed as a mild-approach alternative in this population. Typically, the MNC protocol includes GnRH-antagonists to avoid premature ovulation and gonadotropin add-back stimulation at the late follicular phase. However, evidence is sparse, and there is no consensus regarding a specific dose or type of gonadotropins in this mild stimulation protocol. Study design, size, duration This is a retrospective cohort study including patients attending a tertiary referral University Hospital from 1st January 2017 until 1st March 2020. Participants/materials, setting, methods All women who underwent MNC-IVF in our center were included. Gonadotropins [recombinant FSH (rFSH), urinary FSH (uFSH) or highly purified human menopausal gonadotrophin (hp-hMG)] were started when a follicle with a mean diameter of 12–14 mm was observed on ultrasound scan, followed by GnRH antagonists (0.25mg/day) from the next day onwards. Mature oocytes were inseminated using ICSI. Main results and the role of chance In total, 484 patients undergoing 1398 cycles were included. Mean (SD) age and serum AMH were 38.2 (3.7) years and 0.46 (0.78) ng/ml, respectively. The daily dose of gonadotropins was either Limitations, reasons for caution The main limitation is the retrospective design of our study, with an inherent risk of bias. Wider implications of the findings: This is the first and largest study evaluating MNC-IVF protocol modalities. Our data demonstrate that any type of gonadotropin can be used and there is no benefit from daily doses beyond 75IU. Trial registration number N/A

OBJECTIVE: The aim of this study is to analyze post-cesarean morphine consumption using continuous ropivacaine subfascial wound infusion. METHODS: After standardized spinal anesthesia (0.5% hyperbaric bupivacaine 8-10 mg combined with sufentanil 2-2.5 μg), women undergoing cesarean section (n = 69) were randomly allocated to receive either ropivacaine 0.2% (n = 35) or NaCl 0.9% (n = 34) infused through a subfascial wound catheter during 48 h in a multimodal analgesic approach. As primary outcome, opioid use by intravenous patient-controlled analgesia was analyzed. Secondary outcomes were intensity of pain on visual analog scale at rest and at mobilization, postoperative nausea/vomiting, pruritus and time of first ambulation. Independent t test or Mann-Whitney U test, and Pearson's χ2 test or Fisher's exact test were used as appropriate. RESULTS: Morphine consumption was significantly lower in the ropivacaine group (21.52 ± 21.56 mg) compared with the placebo group (29.57 ± 22.38 mg; 95% confidence interval -18.8 to 2.76; p = 0.047). No significant differences were observed in pain evaluated by visual analog scale, except for pain at mobilization 6 h after surgery (ropivacaine versus placebo: 3.90 ± 2.66 versus 5.36 ± 2.55; p = 0.030). No significant differences were observed in the incidence of postoperative nausea/vomiting, pruritus, and time of first ambulation. CONCLUSION: Continuous ropivacaine subfascial wound infusion results in less post-cesarean morphine consumption. EudraCT trail registration number: 2017-004797-33. EudraCT link: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-004797-33/BE#A.

Study question Do cumulative live birth rates (CLBR) differ between PCOS phenotypes when a freeze-all strategy is used to prevent OHSS after ovarian stimulation (OS)? Summary answer When conventional-dose OS resulted in high response, a CLBR of ∼ 70% was observed after “freeze-all” in women with PCOS, irrespective of their phenotype. What is known already Previous observational studies have shown that CLBR in women with PCOS who undergo assisted reproductive technologies (ART) may depend on their phenotype. When OS was performed with caution to avoid ovarian hyperresponse, CLBR was lower in women with a hyperandrogenic PCOS phenotype. However, when women with PCOS do exhibit hyperresponse and a freeze-all strategy is used, the impact of the PCOS phenotype on the clinical outcome of the ART cycle is unclear. Study design, size, duration This is a single-centre, retrospective cohort study including 422 women with polycystic ovary syndrome (PCOS) as defined by Rotterdam criteria or PCO-like ovarian morphology-only (PCOM) in whom a freeze-all strategy was applied after GnRH agonist triggering in the context of hyperresponse defined as ³19 follicles of ³11mm in their first or second IVF-ICSI cycle between January 2015 and December 2019 in a tertiary referral hospital. Participants/materials, setting, methods PCOS phenotype was based on hyperandrogenism (H), ovulatory dysfunction (O) and PCO-like ovarian morphology (P). Ovarian stimulation was performed with rFSH or HPhMG, adjusted to BMI. The primary outcome was cumulative live birth rate (CLBR) resulting from the transfer of all cryopreserved embryos from the same IVF-ICSI cycle. Patient and cycle characteristics and laboratory and clinical data were analysed. Data were analysed by multivariate logistic regression adjusting for covariates. Main results and the role of chance In total, 91/422 (21.6%) patients had PCOS phenotype A (HOP); 33 (7.8%) had phenotype C (HP), 161/422 (38.2%) had phenotype D (OP) and 137/422 (32.5%) had PCOM (n = 137). BMI, AMH and AFC were significantly different between phenotype groups (p Limitations, reasons for caution These data should be interpreted with caution as the retrospective nature of the study holds the possibility of unmeasured confounding factors. The results cannot be generalised to all ART cycles in women with polycystic ovaries as they pertain to those cycles where OS leads to hyperresponse. Wider implications of the findings In subfertile women with PCOS eligible for ART, hyperresponse after OS confers excellent cumulative live birth rates when a freeze-all strategy is used, eliminating unfavourable clinical outcomes that had previously been observed in hyperandrogenic PCOS women after mild OS targeting normal ovarian response and fresh embryo transfer. Trial registration number not applicable

Study question When repeated cycles of OS for planned oocyte cryopreservation using a standard GnRH antagonist protocol are required, can OS protocol modifications improve oocyte yield? Summary answer Compared to repeating a standard GnRH antagonist protocol, switching to a long GnRH agonist protocol for POC results in a higher number of cryopreserved oocytes. What is known already The total number of cryopreserved oocytes is a key parameter of POC programs because of its association with livebirth. A substantial proportion of women embarking on POC will undergo repeated cycles of OS to reach their desired target number of vitrified oocytes. According to recent guidelines, the GnRH antagonist protocol with GnRH agonist triggering is considered the first choice protocol for POC, because of its safety profile and convenience. However, in women with normal ovarian reserve, the long GnRH agonist protocol results in a higher number of oocytes retrieved. Evidence regarding the optimal protocol for POC is limited. Study design, size, duration This is a single-centre, retrospective cohort study including 283 women who had a first cycle for POC using a standard GnRH antagonist protocol and who requested a second OS cycle to increase their total number of vitrified oocytes for later use. The choice of protocol for the second cycle was left at the discretion of the reproductive medicine specialist. All OS cycles took place between January 2009 and December 2019 in a tertiary referral hospital. Participants/materials, setting, methods After ovarian reserve testing, the first cycle OS was performed using rFSH or HPhMG in a GnRH antagonist protocol. For the second cycle, a GnRH antagonist protocol with or without antagonist pretreatment, or a long GnRH agonist protocol was prescribed. The primary outcome was the number of mature oocytes (MII) vitrified per cycle. Cycle characteristics were compared. Data were assessed by generalized estimating equation (GEE) regression analysis adjusting for covariates. Main results and the role of chance In total, 226 (79.9%) women had a GnRH antagonist protocol and 57 (20.1%) had a long GnRH agonist protocol in their second OS cycle for POC. Overall, mean age was 36.6±2.4 years. The median (CI) number of mature oocytes vitrified after the second OS cycle was significantly higher than that after the first cycle [8 (5–11) vs. 7 (4–10), p Similarly, of 174 women who underwent their first OS cycle with a standard GnRH antagonist protocol, 133 women (76.4%) had the same protocol for their second cycle and 41 women (23.6%) an additional three-day course of GnRH antagonist pretreatment. According to GEE multivariate regression, this protocol modification did not result in more mature oocytes available for vitrification (coefficient –0.25, CI –1.86–1.36, p-value = 0.76). Limitations, reasons for caution These data should be interpreted with caution because of the retrospective design and limited sample. Although more oocytes were obtained with a long GnRH agonist protocol we have no data on livebirth in women returning to use their oocytes to support the choice for a specific OS protocol for POC. Wider implications of the findings: Although oocyte yield in the context of POC is an important parameter that may be modulated by the choice of OS protocol, the ultimate outcome measure of a successful POC program is livebirth after oocyte vitrification. Future research of oocyte parameters reflecting oocyte quality is paramount. Trial registration number Not applicable

Teriparatide belongs to osteo-anabolic compounds and has been used in recent years to treat patients with osteoporosis, with the benefits of increased bone density. Its osteo-anabolic action has led to the investigation of the use of teriparatide for the improvement of bone quality. Apart from the enhancement of fracture union, teriparatide has been extensively studied in the promotion of fusion rate after spinal fusion. This study summarizes the preclinical and clinical results of the off-label use of teriparatide in the spine, and specifically its intermittent administration after instrumented spinal arthrodesis along with its impact on the spinal bone quality and spinal bone mineral density.

STUDY QUESTION Does the presence of single nucleotide polymorphisms (SNPs) in the FSH receptor gene (FSHR) and/or FSH beta subunit-encoding gene (FSHB) influence ovarian response in predicted normal responders treated with rFSH? SUMMARY ANSWER The presence of FSHR SNPs (rs6165, rs6166, rs1394205) has a statistically significant impact in ovarian response, although this effect is of minimal clinical relevance in predicted normal responders treated with a fixed dose of 150 IU rFSH. WHAT IS KNOWN ALREADY Ovarian reserve markers have been a breakthrough in response prediction following ovarian stimulation. However, a significant percentage of patients show a disproportionate lower ovarian response, as compared with their actual ovarian reserve. Studies on pharmacogenetics have demonstrated a relationship between FSHR or FSHB genotyping and drug response, suggesting a potential effect of individual genetic variability on ovarian stimulation. However, evidence from these studies is inconsistent, due to the inclusion of patients with variable ovarian reserve, use of different starting gonadotropin doses, and allowance for dose adjustments during treatment. This highlights the necessity of a well-controlled prospective study in a homogenous population treated with the same fixed protocol. STUDY DESIGN, SIZE, DURATION We conducted a multicenter multinational prospective study, including 368 patients from Vietnam, Belgium, and Spain (168 from Europe and 200 from Asia), from November 2016 until June 2019. All patients underwent ovarian stimulation followed by oocyte retrieval in an antagonist protocol with a fixed daily dose of 150 IU rFSH until triggering. Blood sampling and DNA extraction was performed prior to oocyte retrieval, followed by genotyping of four SNPs from FSHR (rs6165, rs6166, rs1394205) and FSHB (rs10835638). PARTICIPANTS/MATERIALS, SETTING, METHODS Eligible were predicted normal responder women MAIN RESULTS AND THE ROLE OF CHANCE The prevalence of derived allele homozygous SNPs in the FSHR was rs6166 (genotype G/G) 15.8%, rs6165 (genotype G/G) 34.8%, and rs1394205 (genotype A/A) 14.1%, with significant differences between Caucasian and Asian women (P T) was very rare (0.5%). Genetic model analysis revealed that the presence of the G allele in FSHR variant rs6166 resulted in less oocytes retrieved when compared to the AA genotype (13.54 ± 0.46 vs 14.81 ± 0.61, estimated mean difference (EMD) −1.47 (95% CI −2.82 to −0.11)). In FSHR variant rs1394205, a significantly lower number of oocytes was retrieved in patients with an A allele when compared to G/G (13.33 ± 0.41 vs 15.06 ± 0.68, EMD −1.69 (95% CI −3.06 to −0.31)). A significantly higher prevalence of hypo-responders was found in patients with the genotype A/G for FSHR variant rs6166 (55.9%, n = 57) when compared to A/A (28.4%, n = 29), ORadj 1.87 (95% CI 1.08–3.24). No significant differences were found regarding the FORT across the genotypes for FSHR variants rs6166, rs6165, or rs1394205. Regarding the FOI, the presence of the G allele for FSHR variant rs6166 resulted in a lower FOI when compared to the A/A genotype, EMD −13.47 (95% CI −22.69 to −4.24). Regarding FSHR variant rs6165, a lower FOI was reported for genotype A/G (79.75 ± 3.35) when compared to genotype A/A (92.08 ± 6.23), EMD −13.81 (95% CI −25.41 to −2.21). LIMITATIONS, REASONS FOR CAUTION The study was performed in relatively young women with normal ovarian reserve to eliminate biases related to age-related fertility decline; thus, caution is needed when extrapolating results to older populations. In addition, no analysis was performed for FSHB variant rs10835638 due to the very low prevalence of the genotype T/T (n = 2). WIDER IMPLICATIONS OF THE FINDINGS Based on our results, genotyping FSHR SNPs rs6165, rs6166, rs1394205, and FSHB SNP rs10835638 prior to initiating an ovarian stimulation with rFSH in predicted normal responders should not be recommended, taking into account the minimal clinical impact of such information in this population. Future research may focus on other populations and other genes related to folliculogenesis or steroidogenesis. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by an unrestricted grant by Merck Sharp & Dohme (MSD). N.P.P. reports grants and/or personal fees from MSD, Merck Serono, Roche Diagnostics, Ferring International, Besins Healthcare, Gedeon Richter, Theramex, and Institut Biochimique SA (IBSA). N.L.V. and M.T.H. report consultancy and conference fees from Merck, Ferring, and MSD, outside the submitted work. P.D. has received honoraria for lecturing and/or research grants from MSD, Ferring International, and Merck. D.S. reports grants and/or personal fees from MSD, Ferring International, Merck Serono, Cook, and Gedeon Richter. A.R.N., B.A.M., C.S., J.M., L.H.L., P.Q.M.M., H.T., and S.G. report no conflict of interests. TRIAL REGISTRATION NUMBER NCT03007043

Research question Does the levonorgestrel-releasing intrauterine device (LNG-IUD) influence cumulative live birth rate (CLBR) in oocyte donor cycles? Design Retrospective cohort study based on prospectively collected data from 1 May 2009 to 31 December 2017, without attrition, consisting of 491 consecutive cycles of vitrified oocyte donation, none lost to follow-up (unique donor–recipient pairs). All donors underwent ovarian stimulation using gonadotrophin releasing hormone (GnRH) antagonist co-treatment and GnRH agonist trigger. CLBR was chosen as primary outcome measure. Results In total, 103 (21.0%) cycles were carried out in donors carrying a LNG-IUD. In 388 (79.0%) cycles, no LNG-IUD was present. After confounder-adjustment, the use of an LNG-IUD did not have a statistically significant influence on CLBR. Conclusions The LNG-IUD does not negatively affect CLBR.

STUDY QUESTION Are the LH levels at the start of ovarian stimulation predictive of suboptimal oocyte yield from GnRH agonist triggering in GnRH antagonist down-regulated cycles? SUMMARY ANSWER LH levels at the start of ovarian stimulation are an independent predictor of suboptimal oocyte yield following a GnRH agonist trigger. WHAT IS KNOWN ALREADY A GnRH agonist ovulation trigger may result in an inadequate oocyte yield in a small subset of patients. This failure can range from empty follicle syndrome to the retrieval of much fewer oocytes than expected. Suboptimal response to a GnRH agonist trigger has been defined as the presence of circulating LH levels STUDY DESIGN, SIZE, DURATION In this retrospective cohort study, all patients (n = 3334) who received GnRH agonist triggering (using Triptoreline 0.2 mg) for final oocyte maturation undergoing a GnRH antagonist cycle in our centre from 2011 to 2017 were included. The primary outcome of the study was oocyte yield, defined as the ratio between the total number of collected oocytes and the number of follicles with a mean diameter >10 mm prior to GnRH agonist trigger. PARTICIPANTS/MATERIALS, SETTING, METHODS The endocrine profile of all patients was studied at initiation as well as at the end of ovarian stimulation. In order to evaluate whether LH levels, not only at the end but also at the start, of ovarian stimulation predicted oocyte yield, we performed multivariable regression analysis adjusting for the following confounding factors: female age, body mass index, oral contraceptives before treatment, basal and trigger day estradiol levels, starting FSH levels, use of highly purified human menopausal gonadotrophin and total gonadotropin dose. Suboptimal response to GnRH agonist trigger was defined as MAIN RESULTS AND THE ROLE OF CHANCE The average age was 31.9 years, and the mean oocyte yield was 89%. The suboptimal response to GnRH agonist trigger cut-off ( LIMITATIONS, REASONS FOR CAUTION The main limitation of the study is its retrospective design. WIDER IMPLICATIONS OF THE FINDINGS This is the largest study of GnRH agonist trigger cycles only, since most of the previous research on the predictive value of basal LH levels was performed in dual trigger cycles. LH values should be measured prior to start of ovarian stimulation. In cases where they are immeasurable, suboptimal response to GnRH agonist trigger can be anticipated, and an individualized approach is warranted. STUDY FUNDING/COMPETING INTEREST(S) There was no funding and no competing interests. TRIAL REGISTRATION NUMBER Not applicable.

Clinical outcomes of fresh embryo transfer in non-hCG triggered in vitro maturation (IVM) cycles are inferior compared to vitrified-warmed embryo transfer. This is a prospective observational pilot study in a consecutive cohort of 31 polycystic ovary syndrome (PCOS) patients and 37 normo-ovulatory egg donors who underwent IVM without fresh embryo transfer between July 2009 and June 2014. All subjects received 150 IU of highly purified menotropin (HP-hMG) daily for three days. On cycle day 6, all patients started transdermal oestradiol (E2) at a daily dose of 9 mg. There was no human chorionic gonadotropin (hCG) trigger before oocyte retrieval (OR). Vaginal micronized progesterone was commenced on the evening after OR, at a daily dose of 600 mg. Additional luteal phase support (LPS) was administered as follows: Group A: no additional LPS; Group B: 1500 IU of hCG administered 4 h after OR and Group C: 5000 IU of hCG administered 4 h after OR + an additional injection of 5000 IU of hCG 1 day before endometrial biopsy. Endometrial biopsy for histology and immunohistochemistry (IHC) was performed on day 5 or 6 after OR. Instead of being downregulated, both PR-B and ERα in endometrial glands and stroma were moderately to strongly expressed in all three protocols, suggesting that the mid-luteal histological signature of endometrial receptivity is deficient in a non-hCG-triggered IVM cycle. Poor clinical outcomes after fresh embryo transfer following IVM are probably related to inappropriate endometrial development which may be linked to the short follicular phase of IVM cycles.

Objective: To ascertain the increase in detection rate of sentinel lymph node (SLN) associated with the use of indocyanine green (ICG) in comparison with methylene blue dye in women with endometrial cancer. Methods: For this randomized controlled trial, all patients underwent SLN mapping after injection of blue dye on one side of the cervix and ICG on the other side. Randomization was for the side (right vs. left) on which ICG was used so that each patient's contralateral hemipelvis (HP) served as a control to her ipsilateral HP. We performed a two-tailed, normal-approximate McNemar test for paired-matched data. The primary endpoint was the difference in SLN detection rate for each HP according to the dye used. Results: This trial included 132 patients, and 46 patients underwent robotic-assisted surgery while 86 had standard laparoscopic surgery. Successful detection of SLN was 90.9% using ICG and 64.4% using blue dye (p < 0.0001). There were no differences in the duration of the SLN procedure (median 10 min per HP) and number of SLN per HP (mean 1.2) according to the dye used. The SLN detection rates for either dye were very similar whether the surgical approach was robotic (mean BMI 45) or laparoscopic (mean BMI 29). Crossover of dye to the contralateral HP was present in 3% of cases. Conclusion: The use of ICG instead of blue dye results in a 26.5% (95% CI 17.4%–35.6%) increase of SLN detection rates per HP in women with endometrial cancer.

Over 80 species are recognized in the commercially important genus