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Cycles with progesterone elevation during controlled ovarian stimulation (COS) for IVF/ICSI are commonly managed with a \"freeze-all\" strategy, due to a well-recognized detrimental effect of high progesterone levels on endometrial receptivity. However, also a detrimental effect of elevated progesterone on day-3 embryo quality has recently been found with regards to top quality embryo formation rate. Because blastocyst culture and cryopreservation are largely adopted, we deemed relevant to determine whether this detrimental effect is also seen on blastocyst quality on day 5-6. This issue was investigated through a large two-center retrospective study including 986 GnRH antagonist IVF/ICSI cycles and using top quality blastocyst formation rate as the main outcome. Results showed that on multivariate analysis sperm motility (p<0.01) and progesterone levels at ovulation triggering (p = 0.01) were the only two variables that significantly predicted top quality blastocyst formation rate after adjusting for relevant factors including female age, BMI, basal AMH and total dose of FSH used for COS. More specifically, progesterone levels at induction showed an inverse relation with top quality blastocyst formation (correlation coefficient B = -1.08, 95% CI -1.9 to -0.02) and ROC curve analysis identified P level >1.49 ng/ml as the best cut-off for identification of patients at risk for the absence of top quality blastocysts (AUC 0.55, p<0.01). Our study is the first to investigate the top quality blastocyst formation rate in relation to progesterone levels in IVF/ICSI cycles, showing that increasing progesterone is associated with lower rates of top quality blastocyst. Hence, the advantages of prolonging COS to maximize the number of collected oocytes might eventually be hindered by a decrease in top quality blastocysts available for transfer, if increasing progesterone levels are observed. This observation extends the results of two recent studies focused on day-3 embryos and deserves further research.

Introduction/BackgroundUnilocular adnexal cysts are a common condition. The oncogenic potential of unilocular adenexal masses has often led to an overtreatment with high health care costs and psychological distress. We conducted a systematic review and meta-analysis to estimate the rate of malignancy in adnexal lesions described as echoic and anechoic unilocular cysts at pre-operative transvaginal ultrasound examination.MethodologyWe performed a Pubmed/MEDLINE search of papers published between January 1990–April 2019, using the terms ‘unilocular ovarian cysts’ or ‘simple ovarian cysts’ combined with ‘ovarian cancer’ or ‘surgery’ or ‘histology’ or ‘transvaginal ultrasound’. Only studies published as full-length in English and reporting original data were included. The present review and meta-analysis were performed according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) and MOOSE guidelines.ResultsFrom 35 selected studies, we extracted data on ovarian malignancy in the total series, and separately for premenopausal and postmenopausal women. Flowchart of the study selection process is shown in figure 1. Of the 2229 surgically removed lesions classified as unilocular cysts at pre-operative transvaginal ultrasound, 24 (1.1%; 95% CI: 0.73–1.60) were malignant (among these 12 had borderline malignancy: 0.5%). The rates were lower for premenopausal women (6/1034, 0.6%;95% CI: 0.27–1.26) than postmenopausal ones (12/377, 3.2%; 95% CI: 1.83–5.48). Of the 2296 surgically removed lesions classified as anechoic unilocular ovarian cysts on ultrasound, 20 (0.9%; 95% CI: 0.56–1.34) were malignant (among these 8 had borderline malignancy: 0.3%). The rates were lower for premenopausal women (3/907, 0.3%; 95% CI: 0.11–0.97) than postmenopausal ones (13/681, 1.9%; 95% CI: 1.56–3.96).Abstract EP807 Figure 1Flowchart of the study selection processConclusionThe malignancy rate in surgically removed unilocular adnexal cysts is low. The choice between surgery and expectant management should be individualized, and personalized counseling with the patient is advised to avoid the risk of overtreatment.DisclosureNothing to disclose.

The management of endometriosis-related infertility is still a challenging issue. Women can be managed with either surgery or in vitro fertilization (IVF). The decision is tailored to the patients considering pros and cons of both approaches. Surgery might increase the chances of natural conception and relieve symptoms. IVF may be more effective, but costs are higher and unoperated women face some peculiar additional risks during the procedure and pregnancy. The unavailability of randomized trials comparing the two strategies hampers the possibility to provide precise estimates. This Randomized Controlled Trial (RCT) aims at filling this gap. This is a multicenter, non-blinded, randomized controlled trial with parallel groups and allocation 1:1. Three Italian Academic Infertility Units will be involved. Main inclusion criteria are infertility for more than one year, age less than 40 years and a sonographic diagnosis of endometriosis (ovarian endometriomas or deep peritoneal lesions). Previous IVF and previous surgery for endometriosis are exclusion criteria. Women will be randomized to either surgery and then natural pregnancy seeking or a standard program of three IVF cycles. The primary aim is the comparison of live birth rate between the two groups (IVF versus surgery) within one year of randomization. The secondary aim is the evaluation of cost-effective profile of the two interventions. The present study can influence the clinical practice of infertility treatment in women with endometriosis. From a public health perspective, information on the more cost-effective clinical management strategy would consent a wiser allocation of resources. Trial registration: NCT04743167 , registered on 8 February 2021.

Background Vitamin D plays an important role in human physiology and pathology. The receptor for vitamin D regulates 0.5–5% of the human genome. Accordingly, vitamin D insufficiency has been shown to increase the risk of several diseases. In recent years, based on growing evidence, on a role of vitamin D has been also postulated in reproductive health both in animals and humans, especially in female fertility female fertility. In vitro fertilization success was shown to be higher in women with appropriate reserves of vitamin D. However a causal relation has not been demonstrated and randomized controlled trials testing the effectiveness of vitamin D supplementation in IVF are warranted. Methods This is a multicenter randomized double blinded placebo controlled study aimed at determining the benefits of vitamin D [25(OH)D] supplementation in improving clinical pregnancy rate in women undergoing IVF. Eligible women with a serum level of 25-hydroxyvitamin D [25(OH)D] < 30 ng/ml will be randomized. Recruited women will be given the drug (either 600,000 IU of 25(OH) D or placebo in a single oral administration) at the time of randomization. Two centres will participate and the sample size (700 women) is foreseen to be equally distributed between the two. Patients will be treated according to standard IVF protocols. Discussion The primary aim of the study is the cumulative clinical pregnancy rate per oocyte retrieval. Clinical pregnancy is defined as the presence of at least one intrauterine gestational sac with viable foetus at first ultrasound assessment (3 weeks after a positive human chorionic gonadotropin [hCG] assessment). Secondary outcomes include: 1) clinical and embryological variables; 2) oocyte and endometrium quality at a molecular level. To investigate this latter aspect, samples of cumulus cells, follicular and endometrial fluids will be obtained from a subgroup of 50 age-matched good-prognosis cases and controls. Trial registration The protocol was included in EudraCT on 22nd September 2015 with the registration number assigned ‘ 2015-004233-27 ’; it was submitted through the database of the Italian “Osservatorio Nazionale della Sperimentazione Clinica (OsSC)” - (National Monitoring Centre of Clinical Trials) to the National Competent Authority on 8th March 2016 and approved on 23rd June 2016.

PurposeTo investigate the impact of letrozole administration on follicular steroid hormones during controlled ovarian hyperstimulation for fertility preservation.MethodsOne hundred and nineteen women with cancer undergoing oocytes retrieval for fertility preservation were recruited. All women underwent ovarian hyperstimulation according to a random start protocol. Those with hormone-sensitive tumors also received letrozole, an aromatase inhibitor aimed at keeping peripheral estrogen levels low. At the time of oocytes retrieval, a sample of follicular fluid was collected and frozen. All samples were assayed concomitantly after thawing, by liquid chromatography tandem mass spectrometry. The concentration of 15 steroid hormones was determined and results were compared between women who did and did not receive letrozole.ResultsFifty-two women were treated with letrozole, while 67 were not. Statistically significant differences emerged for 12 of the 15 tested steroids. They were the following: cortisol, 11-deoxycortisol, 21-deoxycortisol, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), estradiol, androstenedione, testosterone, dihydrotestosterone (DHT), 17-hydroxyprogesterone, progesterone and corticosterone. The most striking differences were observed for testosterone that showed a more than 200-time increase in women receiving letrozole. Estradiol was conversely reduced to a third.ConclusionsThe endocrine microenvironment surrounding oocytes is markedly perturbed by the concomitant assumption of letrozole. Robust clinical evaluation is pressingly needed to rule out any detrimental effect on the chance of live birth with the use of these oocytes.

IntroductionRecent data suggest a higher clinical pregnancy rate performing assisted hatching (AH) on previously cryopreserved embryos but fail to demonstrate significant effects on live birth rate. However, current evidence is based on studies with a small sample size and may hide a type II error. Moreover, poor attention has been given to the specific effect of AH on frozen/thawed blastocysts. To shed light on this topic, we developed the present protocol for a randomised trial to investigate the benefits of the laser-mediated partial removal of the zona pellucida in vitrified/warmed blastocysts.Methods and analysisThe pArtiaL zonA pelluciDa removal by assisteD hatchINg of blastocysts (ALADDIN) study is a multicentric prospective comparative study with a parallel randomised controlled design aiming to investigate whether AH performed on warmed blastocysts before embryo transfer can improve live birth rate. Women allocated to the control group will undergo embryo transfer of blastocysts not previously subjected to AH. Two infertility units will be involved in the study. Enrolment of patients will last 18 months with quarterly monitoring and the entire study is foreseen to be closed in 36 months. Secondary outcomes include: proportion of transferred blastocysts/thawed blastocyst, morphological features of blastocysts before embryo transfer, implantation, biochemical pregnancy, clinical pregnancy (ultrasound visible gestational sac), miscarriage, multiple pregnancy, preterm birth (<37 weeks of gestation), obstetrical and neonatal complications and congenital anomaly rates.Ethics and disseminationThis protocol received a favourable ethical opinion from the Ethical Committee of IRCCS San Raffaele Scientific Institute and the Ethical Committee Area 2 Milan. Each participant will provide written consent to participate and remain encoded during the study. The trial results will be published in peer-reviewed journals and presented at conferences.Trial registration numberNCT03623659; Pre-results.

Abstract STUDY QUESTION Is oral Vitamin D supplementation able to modify the intrauterine milieu in terms of cytokine/chemokine pattern? SUMMARY ANSWER No significant differences were detected in cytokine and chemokine levels in endometrial secretions between patients undergoing ART with or without Vitamin D supplementation. WHAT IS KNOWN ALREADY Cytokines and chemokines secreted into the intrauterine environment are fundamental for the molecular crosstalk between the endometrium and the preimplantation embryo. Whether Vitamin D can regulate these mediators in the endometrial environment is still unclear. STUDY DESIGN, SIZE, DURATION This study was an analysis of a secondary outcome from the Supplementation of Vitamin D and Reproductive Outcomes—SUNDRO—clinical trial, a multicenter randomized double-blinded trial designed to explore the effects of Vitamin D replacement in women with Vitamin D levels below 30 ng/ml undergoing autologous ART cycles. Uterine fluid samples were collected from both patients supplemented with Vitamin D (n = 17) and from the placebo group (n = 32). PARTICIPANTS/MATERIALS, SETTING, METHODS Based on cutoff points for Vitamin D insufficiency (20–29.9 ng/ml) or deficiency (<20 ng/ml), 67% of patients in the study were insufficient, and 33% deficient, in Vitamin D, although they were considered together for the analysis. Women received a single dose of 600 000 IU 25-hydroxyvitamin D or placebo from 2 to 12 weeks before oocyte retrieval. Inclusion criteria were female age 18–39 years, with a BMI between 18 and 25 kg/m2. Serum 25-hydroxyvitamin D was assessed at the time of hCG administration. Uterine fluid samples were collected during the secretory phase of the menstrual cycle preceding oocyte retrieval. The quantitative determination of 27 cytokines in endometrial secretion samples was performed by using a multiplex immunoassay. MAIN RESULTS AND THE ROLE OF CHANCE Uterine fluid samples were collected after a median (range) of 21 (12–41) days after the oral Vitamin D supplementation. Both the supplemented and placebo groups had Vitamin D serum levels below 30 ng/ml at baseline/time of randomization ((median 23.4 ng/ml (interquartile range 19.5–28.4) and 23.4 ng/ml (17.8–25.9), respectively). At the time of hCG administration, serum Vitamin D in supplemented subjects was significantly raised compared to the placebo group ((median 52.9 ng/ml (interquartile range 40.7–64.1) and 24.6 ng/ml (19.3–29.2), respectively, P < 0.001). Our data revealed no significant differences in uterine fluid cytokine/chemokine composition of Vitamin D-supplemented women compared with the placebo group. This finding remained when the concentrations of all mediators studied were normalized to total protein. In a further analysis, no significant differences were found in the content of cytokines/chemokines in uterine fluid from women who conceived (n = 19) compared with the nonpregnant group (n = 30). LIMITATIONS, REASONS FOR CAUTION Using a randomized study design (a single dose of 600 000 IU 25-hydroxyvitamin D versus placebo), we found no significant differences between groups. However, we cannot exclude that any benefit of Vitamin D supplementation may be specific for some subgroups of patients, such as those with an imbalance of T-helper 1 and T-helper 2 cell populations. The uterine secretions were collected during the menstrual cycle that preceded oocyte retrieval; therefore, it is possible the uterine fluid collection and analysis in the same cycle of the embryo transfer might have resulted in different conclusions. Moreover, the small sample size could limit the power of the study. WIDER IMPLICATIONS OF THE FINDINGS Our analysis of the uterine secretome profiling failed to show any significant difference in endometrial cytokine/chemokine patterns between women with oral Vitamin D supplementation and the placebo group. Vitamin D may act on the uterine environment through a different mechanism. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by the Italian Ministry of Health following peer review in the competitive ‘Bando di Ricerca Finalizzata e Giovani Ricercatori 2013’ with reference code RF-2013-02358757. The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER EudraCT registration number: 2015-004233-27.

The aim of study was to analyse ventilation and perfusion (V/Q) lung scan findings in a series of Italian patients with Takayasu's arteritis. Eighteen consecutive patients underwent V/Q lung planar scintigraphy and single-photon emission tomography (SPET). Before perfusion scan acquisition was started, a first-pass study with ^sup 99m^Tc-macroaggregates of albumin was performed to assess the right ventricular ejection fraction (RVEF). All patients had normal chest X-rays and were symptom free at the time of the investigation. They also underwent echocardiography to evaluate pulmonary artery pressure and in 13 patients respiratory function tests were performed. In four patients, perfusion lung scan was repeated after 1 year. In 10/18 patients (55.5%), 43 unmatched lobar, segmental or subsegmental perfusion defects were found on planar images; ventilation scintigraphy was normal in all cases. On SPET images, 55 defects were found; no defects were found with SPET in the remaining patients who had normal planar images. All patients had normal RVEF and 5/13 patients had mild restrictive-obstructive lung disease. The pulmonary artery pressure was increased in two patients with perfusion defects. In the four patients who had repeat scintigraphy, all defects remained unchanged. The prevalence of lung perfusion abnormalities observed in Italian patients with Takayasu's arteritis is within the range of values reported in other countries, and V/Q planar scintigraphy is sufficient for the screening of patients.[PUBLICATION ABSTRACT]

A dosimetry study was performed on 26 patients with an autonomous thyroid nodule and suppressed serum thyroid-stimulating hormone, to determine the dose to extranodular tissue when the nodule receives 300 Gy for 131I therapy. Parameters of radioiodine turnover to be used in the dosimetry formula were separately obtained for the nodule and the contralateral lobe, as a measurable example of the extranodular tissue, using 55 MBq 123I and a computer-assisted gamma camera. The biologic half-life of 123I was then converted into the effective half-life of 131I, and the volumes of the nodule and the lobe were obtained by scintigraphy or sonography. The mean dose to the contralateral lobe from uptake and irradiation by the nodule was calculated to be 32 Gy, and that to the ipsilateral lobe was estimated to be 34 Gy. During radioiodine therapy for autonomous thyroid nodules, the extranodular tissue receives a higher dose than is generally assumed, which explains the relatively high rate of post-treatment hypothyroidism reported in the literature.