Increased Vasoactive Intestinal Peptide (VIP) in polycystic ovary syndrome patients undergoing IVF.

Introduction: Polycystic ovary syndrome (PCOS) is a common multifactorial and polygenic disorder of the endocrine system, affecting up to 20% of women in reproductive age with a still unknown etiology. Follicular fluid (FF) represents an environment for the normal development of follicles rich in metabolites, hormones and neurotransmitters, but in some instances of PCOS the composition can be different. Vasoactive intestinal peptide (VIP) is an endogenous autonomic neuropeptide involved in follicular atresia, granulosa cell physiology and steroidogenesis. Methods: ELISA assays were performed to measure VIP and estradiol levels in human follicular fluids, while AMH, FSH, LH, estradiol and progesterone in the plasma were quantified by chemiluminescence. UHPLC/QTOF was used to perform the untargeted metabolomic analysis. Results: Our ELISA and metabolomic results show: i) an increased concentration of VIP in follicular fluid of PCOS patients (n=9) of about 30% with respect to control group (n=10) (132 ± 28 pg/ml versus 103 ± 26 pg/ml, p=0,03) in women undergoing in vitro fertilization (IVF), ii) a linear positive correlation (p=0.05, r=0.45) between VIP concentration and serum Anti-Müllerian Hormone (AMH) concentration and iii) a linear negative correlation between VIP and noradrenaline metabolism. No correlation between VIP and estradiol (E2) concentration in follicular fluid was found. A negative correlation was found between VIP and noradrenaline metabolite 3,4-dihydroxyphenylglycolaldehyde (DOPGAL) in follicular fluids. Conclusion: VIP concentration in follicular fluids was increased in PCOS patients and a correlation was found with noradrenaline metabolism indicating a possible dysregulation of the sympathetic reflex in the ovarian follicles. The functional role of VIP as noradrenergic modulator in ovarian physiology and PCOS pathophysiology was discussed.

Assessing ovarian stimulation with letrozole and levonorgestrel intrauterine system after combined fertility-sparing approach for atypical endometrial lesions: a retrospective case-control study.

RESEARCH QUESTION: Is ovarian stimulation with levonorgestrel intrauterine system (LNG-IUS) in situ and co-treatment with letrozole safe and effective in patients undergoing fertility-sparing combined treatment for atypical endometrial hyperplasia (AEH) or early endometrial cancer limited to the endometrium? DESIGN: Retrospective case-control study recruiting women who had undergone fertility-sparing 'combined' treatment and ovarian stimulation with letrozole and LNG-IUS in situ. The 'three steps' hysteroscopic technique was used. Once complete response was achieved, the ovaries were stimulated, and mature oocytes cryopreserved. The LNG-IUS was removed, and embryos transferred. A comparative analysis was conducted between the two control groups of the initial outcomes of ART (number of oocytes and MII oocytes retrieved): healthy infertile women undergoing ovarian stimulation for IVF/ICSI (control group A); and patients diagnosed with breast cancer who underwent ovarian stimulation with letrozole (control group B). RESULTS: Of the 75 patients analysed, 15 underwent oocyte cryopreservation after achieving a complete response to fertility-sparing treatment (study group); 30 patients in control group A and B, respectively. No statistically significant differences were observed in retrieved oocytes and mature oocytes between the study and control groups. In the nine patients who underwent embryo transfer, clinical pregnancy (55.6%), cumulative live birth (44.4%) and miscarriage (20%) rates were reported. In three patients with AEH, recurrence occurred (12%) at 3, 6 and 16 months after removing the LNG-IUS to attempt embryo transfer, respectively. CONCLUSION: Fertility-sparing hysteroscopic combined treatment and subsequent ovarian stimulation with letrozole and LNG-IUS in situ could be suggested to women with AEH or early endometrial cancer who ask for future fertility preservation.

Oocyte competence is comparable between progestin primed ovarian stimulation with Norethisterone acetate (NETA-PPOS) and GnRH-antagonist protocols: A matched case-control study in PGT-A cycles.

OBJECTIVE: To outline oocyte competence after progestin primed ovarian stimulation with Norethisterone acetate (NETA-PPOS) compared to conventional GnRH-antagonist protocol. STUDY DESIGN: Retrospective matched case-control study involving advanced-maternal-age women undergoing ICSI with PGT-A. 89 NETA-PPOS were matched with 178 control patients based on maternal age and ovarian reserve biomarkers. Both groups underwent recombinant-FSH OS with GnRH-agonist ovulation trigger and collected ≥1 MII. In the study group, NETA (10 mg/day) was administered orally starting from day2 of the menstrual cycle. Euploid blastocyst rate per cohort of metaphase-II oocytes (EBR per MII) was the primary outcome. All other embryological and clinical outcomes were reported. Gestational age, birthweight and length were also assessed. RESULTS: The EBR per MII was comparable among PPOS and control (13.9 % ± 19.3 % versus 13.3 % ± 17.9 %; the sample size allowed to exclude up to a 10 % difference). Blastocysts morphology and developmental rate were similar. No difference was reported for all clinical outcomes among the 61 and 107 vitrified-warmed euploid single blastocyst transfers respectively conducted. The cumulative live birth delivery rate per concluded cycles was also comparable (24.7 % versus 21.9 %). Neonatal outcomes were analogous. CONCLUSIONS: Oocyte competence after NETA-PPOS and standard OS is comparable. This evidence is reassuring and, because of its lower cost and possibly higher patients' compliance, supports PPOS administration whenever the patients are indicated to freeze-all (e.g., fertility preservation, PGT-A, oocyte donation). More data are required about follicle recruitment, oocyte yield, gestational and perinatal outcomes. Randomized-controlled-trials are advisable to confirm our evidence.

Assisted Reproductive Technology and Disease Management in Infertile Women with Multiple Sclerosis.

Multiple sclerosis (MS) predominantly affects women of fertile age. Various aspects of MS could impact on fertility, such as sexual dysfunction, endocrine alterations, autoimmune imbalances, and disease-modifying therapies (DMTs). The proportion of women with MS (wMS) requesting infertility management and assisted reproductive technology (ART) is increasing over time. In this review, we report on data regarding ART in wMS and address safety issues. We also discuss the clinical aspects to consider when planning a course of treatment for infertility, and provide updated recommendations to guide neurologists in the management of wMS undergoing ART, with the goal of reducing the risk of disease activation after this procedure. According to most studies, there is an increase in relapse rate and magnetic resonance imaging activity after ART. Therefore, to reduce the risk of relapse, ART should be considered in wMS with stable disease. In wMS, especially those with high disease activity, fertility issues should be discussed early as the choice of DMT, and fertility preservation strategies might be proposed in selected cases to ensure both disease control and a safe pregnancy. For patients with stable disease taking DMTs compatible with pregnancy, treatment should not be interrupted before ART. If the ongoing therapy is contraindicated in pregnancy, then it should be switched to a compatible therapy. Prior to beginning fertility treatments in wMS, it would be reasonable to assess vitamin D serum levels, thyroid function and its antibody serum levels; start folic acid supplementation; and ensure smoking and alcohol cessation, adequate sleep, and food hygiene. Cervico-vaginal swabs for Ureaplasma urealyticum, Mycoplasma hominis, and Chlamydia trachomatis, as well as serology for viral hepatitis, HIV, syphilis, and cytomegalovirus, should be performed. Steroids could be administered under specific indications. Although the available data do not clearly show a definite raised relapse risk associated with a specific ART protocol, it seems reasonably safe to prefer the use of gonadotropin-releasing hormone (GnRH) antagonists for ovarian stimulation. Close clinical and radiological monitoring is reasonably recommended, particularly after hormonal stimulation and in case of pregnancy failure.

Laparoscopic oocyte retrieval for fertility preservation in a patient with squamous cell carcinoma of the vagina.

OBJECTIVE: To describe a feasible fertility preservation strategy in a woman with vaginal carcinoma. DESIGN: Video case report demonstrating the diagnostic work-up and laparoscopic oocyte retrieval performed under regional anesthesia. SETTING: University tertiary care hospital. PATIENT(S): A 35-year-old nulliparous woman presented with vaginal bleeding and foul-smelling vaginal discharge. After a comprehensive diagnostic work-up, a final diagnosis of squamous cell carcinoma of the vagina stage II (Federation International Obstetrics and Gynecology classification) was made. As per the patient's desire, before undergoing chemoradiotherapy, the patient underwent oocyte cryopreservation. Transvaginal retrieval of oocytes was not feasible because of stenosis of the vaginal introitus and the potential risk of intracavitary tumor cell spillage. Transabdominal ultrasound-guided oocyte retrieval was not possible because of the body's habitus. INTERVENTION(S): The patient underwent ovarian stimulation for in vitro fertilization. To minimize estrogen levels, letrozole was used during controlled ovarian stimulation. Laparoscopic oocyte retrieval was performed under spinal anesthesia. MAIN OUTCOME MEASURE(S): Successful laparoscopic egg retrieval and cryopreservation in a woman with squamous cell carcinoma of the vagina. RESULT(S): A total follicular count of nine was estimated before the oocyte retrieval. Eight oocytes were retrieved at laparoscopy, and eight mature oocytes were successfully cryopreserved. No complications were encountered, and the patient was discharged on the same day of surgery. CONCLUSION(S): To our knowledge, this is the first published case of fertility preservation using the laparoscopic approach in a patient with vaginal cancer. Letrozole is a valuable strategy to reduce high estrogen in patients with gynecological cancer undergoing controlled ovarian stimulation. Laparoscopy oocyte retrieval, performed under regional anesthesia, can be performed in an ambulatory setting and should be considered an effective fertility preservation strategy in patients with large vaginal tumors.

Immunobiology of pregnancy: from basic science to translational medicine.

Embryo implantation failure and spontaneous abortions represent the main causes of infertility in developed countries. Unfortunately, incomplete knowledge of the multiple factors involved in implantation and fetal development keeps the success rate of medically assisted procreation techniques relatively low. According to recent literature, cellular and molecular mechanisms of 'immunogenic tolerance' towards the embryo are crucial to establish an 'anti-inflammatory' state permissive of a healthy pregnancy. In this review we dissect the role played by the immune system in the endometrial-embryo crosstalk, with a particular emphasis towards the fork-head-box-p3 (Foxp3+) CD4+CD25+ regulatory T (Treg) cells and discuss the most recent therapeutic advances in the context of early immune-mediated pregnancy loss.

Opening the black box: why do euploid blastocysts fail to implant? A systematic review and meta-analysis.

BACKGROUND: A normal chromosomal constitution defined through PGT-A assessing all chromosomes on trophectoderm (TE) biopsies represents the strongest predictor of embryo implantation. Yet, its positive predictive value is not higher than 50-60%. This gap of knowledge on the causes of euploid blastocysts' reproductive failure is known as 'the black box of implantation'. OBJECTIVE AND RATIONALE: Several embryonic, maternal, paternal, clinical, and IVF laboratory features were scrutinized for their putative association with reproductive success or implantation failure of euploid blastocysts. SEARCH METHODS: A systematic bibliographical search was conducted without temporal limits up to August 2021. The keywords were '(blastocyst OR day5 embryo OR day6 embryo OR day7 embryo) AND (euploid OR chromosomally normal OR preimplantation genetic testing) AND (implantation OR implantation failure OR miscarriage OR abortion OR live birth OR biochemical pregnancy OR recurrent implantation failure)'. Overall, 1608 items were identified and screened. We included all prospective or retrospective clinical studies and randomized-controlled-trials (RCTs) that assessed any feature associated with live-birth rates (LBR) and/or miscarriage rates (MR) among non-mosaic euploid blastocyst transfer after TE biopsy and PGT-A. In total, 41 reviews and 372 papers were selected, clustered according to a common focus, and thoroughly reviewed. The PRISMA guideline was followed, the PICO model was adopted, and ROBINS-I and ROB 2.0 scoring were used to assess putative bias. Bias across studies regarding the LBR was also assessed using visual inspection of funnel plots and the trim and fill method. Categorical data were combined with a pooled-OR. The random-effect model was used to conduct the meta-analysis. Between-study heterogeneity was addressed using I2. Whenever not suitable for the meta-analysis, the included studies were simply described for their results. The study protocol was registered at http://www.crd.york.ac.uk/PROSPERO/ (registration number CRD42021275329). OUTCOMES: We included 372 original papers (335 retrospective studies, 30 prospective studies and 7 RCTs) and 41 reviews. However, most of the studies were retrospective, or characterized by small sample sizes, thus prone to bias, which reduces the quality of the evidence to low or very low. Reduced inner cell mass (7 studies, OR: 0.37, 95% CI: 0.27-0.52, I2 = 53%), or TE quality (9 studies, OR: 0.53, 95% CI: 0.43-0.67, I2 = 70%), overall blastocyst quality worse than Gardner's BB-grade (8 studies, OR: 0.40, 95% CI: 0.24-0.67, I2 = 83%), developmental delay (18 studies, OR: 0.56, 95% CI: 0.49-0.63, I2 = 47%), and (by qualitative analysis) some morphodynamic abnormalities pinpointed through time-lapse microscopy (abnormal cleavage patterns, spontaneous blastocyst collapse, longer time of morula formation I, time of blastulation (tB), and duration of blastulation) were all associated with poorer reproductive outcomes. Slightly lower LBR, even in the context of PGT-A, was reported among women ≥38 years (7 studies, OR: 0.87, 95% CI: 0.75-1.00, I2 = 31%), while obesity was associated with both lower LBR (2 studies, OR: 0.66, 95% CI: 0.55-0.79, I2 = 0%) and higher MR (2 studies, OR: 1.8, 95% CI: 1.08-2.99, I2 = 52%). The experience of previous repeated implantation failures (RIF) was also associated with lower LBR (3 studies, OR: 0.72, 95% CI: 0.55-0.93, I2 = 0%). By qualitative analysis, among hormonal assessments, only abnormal progesterone levels prior to transfer were associated with LBR and MR after PGT-A. Among the clinical protocols used, vitrified-warmed embryo transfer was more effective than fresh transfer (2 studies, OR: 1.56, 95% CI: 1.05-2.33, I2 = 23%) after PGT-A. Lastly, multiple vitrification-warming cycles (2 studies, OR: 0.41, 95% CI: 0.22-0.77, I2 = 50%) or (by qualitative analysis) a high number of cells biopsied may slightly reduce the LBR, while simultaneous zona-pellucida opening and TE biopsy allowed better results than the Day 3 hatching-based protocol (3 studies, OR: 1.41, 95% CI: 1.18-1.69, I2 = 0%). WIDER IMPLICATIONS: Embryo selection aims at shortening the time-to-pregnancy, while minimizing the reproductive risks. Knowing which features are associated with the reproductive competence of euploid blastocysts is therefore critical to define, implement, and validate safer and more efficient clinical workflows. Future research should be directed towards: (i) systematic investigations of the mechanisms involved in reproductive aging beyond de novo chromosomal abnormalities, and how lifestyle and nutrition may accelerate or exacerbate their consequences; (ii) improved evaluation of the uterine and blastocyst-endometrial dialogue, both of which represent black boxes themselves; (iii) standardization/automation of embryo assessment and IVF protocols; (iv) additional invasive or preferably non-invasive tools for embryo selection. Only by filling these gaps we may finally crack the riddle behind 'the black box of implantation'.

Ovarian reserve in patients with multiple sclerosis: A systematic review and meta-analysis.

OBJECTIVE: To summarize recent evidence about ovarian reserve markers in women affected by multiple sclerosis (MS) compared with healthy controls, as women with MS seem to be characterized by lower anti-Müllerian hormone (AMH) levels. METHODS: The research was conducted using PubMed (MEDLINE), Scopus, ClinicalTrial.gov, OVID and Cochrane Library from inception of each database to June 30, 2022. Studies comparing ovarian reserve markers between women with MS and healthy controls were considered eligible for inclusion. The primary outcome was serum AMH (ng/mL) levels. Results were reported as pooled odds ratio (OR) for categorical outcomes and as mean difference (MD) for continuous variables, with their 95% confidence intervals (CIs). The random effect model of DerSimonian and Laird was adopted for all analyses. A P-value less than 0.05 was considered significant. RESULTS: Serum AMH circulating levels were not significantly different (MD -0.25, 95% CI -0.83 to 0.32; P = 0.390), as well as blood levels of follicle-stimulating hormone or ovarian volume. However, antral follicle count (AFC) and estradiol blood levels were significantly lower, and luteinizing hormone (LH) levels were significantly higher in women with MS than in controls. CONCLUSION: A significant difference in AFC, estradiol and LH levels was observed, but not for AMH levels.

Fertility in Acromegaly: A Single-Center Experience of Female Patients During Active Disease and After Disease Remission.

CONTEXT: Fertility represents a major concern in patients with acromegaly. OBJECTIVE: The current retrospective study aimed to investigate gonadal function and fertility rates in acromegalic women. METHODS: In this referral-center study, 50 acromegalic women with disease onset within reproductive age were evaluated for prevalence of gonadal dysfunction and infertility. Anthropometric, metabolic, hormonal parameters, and gynecological ultrasound were evaluated at diagnosis and after disease control. Data about menstrual disturbances, pregnancy, and polycystic ovarian morphology (PCOM) were investigated at disease onset, at diagnosis, and after disease control. RESULTS: At presumed disease onset, menstrual disturbances were reported in 32% of patients. Uterine leiomyoma, ovarian cysts, and PCOM were diagnosed in 18%, 12%, and 8%, respectively; 36.8% of patients were infertile. At diagnosis, menstrual disturbances were found in 58.1% (P = .02), being significantly more prevalent in patients with higher insulin-like growth factor-I quartiles (Q) (P = .03, Q1 vs Q4). Gynecological ultrasound revealed uterine leiomyoma, ovarian cysts, and PCOM in 39.1% (P = .04), 28.2% (P = .09), and 13% (P = .55), respectively. The infertility rate was 100% (P = .02). At disease control, menstrual disturbances were slightly decreased as compared to diagnosis (P = .09). Noteworthy, menstrual disturbances (P = .05) and particularly amenorrhea (P = .03) were significantly more frequent in patients with active disease duration greater than 5 years (median) as compared to those achieving disease control in less than 5 years. Among patients with pregnancy desire, 73.3% conceived at least once, with resulting infertility significantly decreased compared to diagnosis (26.7%; P = .01). At-term deliveries, preterm deliveries, and spontaneous abortions were recorded in 86.7%, 6.6%, and 6.6%, respectively, of the 15 pregnancies reported by the patients. No neonatal malformations and/or abnormalities were recorded. CONCLUSION: Gonadal dysfunction and infertility are common in acromegalic women within reproductive age, being directly influenced by disease status and/or duration.

Cryopreservation of ovarian tissue: the biggest challenge of oncofertility.

Survival rates after cancer diagnosis and treatment have been raising through the last decades. Nowadays, oncofertility represents a useful strategy for young women affected by cancer to preserve their ovarian function and their family planning opportunity. Apart from more diffused techniques as cryopreservation of mature oocytes after controlled ovarian stimulation and gonadal downregulation with gonadotropin-releasing hormone agonist depots, the cryopreservation of the cortical region of the ovarian tissue, which contains 90% of the follicular reserve, and later autologous transplant represent a possible and intriguing strategy. Nonetheless, the safety of the procedure is still a matter of debate and is a topic of great interest in both oncologic and reproductive fields. Especially, in order to improve the efficacy of the strategy the open questions are: 1) how to search for malignant cells; 2) slow freezing vs. vitrification; 3) state of the art on the "artificial ovary." The aim of this review was to summarize the recent advances in ovarian tissue cryopreservation and present future perspectives.

Management and treatment of brain tumors during pregnancy: an Italian survey.

PURPOSE: The management of brain tumors during pregnancy is challenging. The clinical rarity and prognostic heterogeneity of such condition makes it difficult to develop standardized guidelines of treatment. The aim of this study was to assess the treatment options used in pregnant women with brain tumors that are currently used in Italy, considering the management of these patients reported in current literature in this field. METHODS: A survey addressing the treatments options and management of brain tumors during pregnancy was designed on behalf of an ad-hoc task-force Neuro-Oncology committee of the Società Italiana di Neurochirurgia (SINch) to analyze the management of pregnant patients with brain tumors. We conducted a search of the literature published between January 2011 and September 2021, using MEDLINE (PubMed) in accordance to PRISMA guidelines. Data were discussed to obtain recommendations after evaluation of the selected articles and discussion among the experts. RESULTS: A total of 18 Neurosurgical centers participated in the survey. A total of 31 pregnant women were included in this retrospective study. Meningiomas and gliomas were the two most common types of brain tumors diagnosed during pregnancy. An emergency surgical procedure was required in 12.9% of cases. CONCLUSION: A multidisciplinary and tailored approach is fundamental. In women showing clinical stability, neurosurgical options should preferably be delayed if possible, and considered during the second trimester or after delivery. In patients with acute neurological symptoms or tumor progression, medical abortion in the first trimester or a C-section in the second and third trimester need to be considered.

Ovarian Hyperstimulation Syndrome after GnRH Agonist Triggering and Freeze-All Protocol? Never Not, Hardly Ever: A Systematic Review of Case Reports.

INTRODUCTION: Ovarian hyperstimulation syndrome (OHSS) is a severe complication associated with controlled ovarian stimulation (COS). GnRH agonist (GnRH-a) triggering is considered an efficient strategy to prevent OHSS in the high-risk patient. METHODS: We performed a review of 11 cases of early and severe OHSS following GnRH-a triggering and freeze-all protocol. Electronic databases were searched from inception of each database until October 2021, to identify case reports and case series that reported OHSS after GnRH-a triggering and freeze-all approach describing patient demographics, COS protocol, and patient outcomes. RESULTS: From the literature review, it is possible to suggest that (1) following GnRH-a triggering, the risk of early and severe OHSS is not totally cancelled; (2) despite it is not possible to predict the event, polycystic ovary syndrome is the most common risk factor; (3) the use of GnRH antagonist starting from the day of PU may represent a valid strategy for preventing OHSS in women with high-risk profile; (4) following the unexpected onset of OHSS, measuring serum levels of human chorionic gonadotropin (hCG) is helpful to exclude an inadvertent exogenous administration or a pregnancy. CONCLUSION: The statement that OHSS risk is eliminated when GnRH-a triggering, a freeze-all strategy, and no hCG in the luteal phase may generate the idea that this event cannot occur. Although rare, these cases have been observed in a relatively short period of time.

Effectiveness of progesterone supplementation in women presenting low progesterone levels on the day of frozen embryo transfer: a randomised controlled trial.

INTRODUCTION: Progesterone is an essential hormone involved in the process of implantation and pregnancy maintenance. Evidence from recent studies has supported the importance of serum progesterone level around the time of embryo transfer in hormonal replacement therapy frozen embryo transfer cycles and recommended the need for individualised luteal support. Low progesterone around the time of embryo transfer is found to be associated with decreased rate of pregnancy after frozen embryo transfer. This single-centre, longitudinal, randomised, interventional controlled study aims to compare the rate of ongoing pregnancy between two groups of women with progesterone level below 10 ng/mL on the day of frozen embryo transfer: the study group using 800 mg vaginal micronised progesterone supplemented with 50 mg intramuscular progesterone per day and the control group using only 800 mg vaginal micronised progesterone. METHODS AND ANALYSIS: We enrol patients who are undergoing frozen embryo transfers with blastocyst-stage or cleavage-stage embryos and who satisfy the inclusion and exclusion criteria. After signing the informed consent, participants are randomised into two groups: the study group using vaginal micronised progesterone supplemented with progesterone intramuscular 50 mg per day and the control group using only vaginal micronised progesterone. Randomisation will be performed using R software at a 1:1 allocation ratio. Sequentially numbered, opaque sealed envelopes are used for allocation. The primary outcome is the rate of ongoing pregnancy. To demonstrate a difference of 10% with regard to rate of ongoing pregnancy, at least 370 participants per arm are required (type I error α=0.05, power=0.8). Assuming a dropout rate of 10%, a total of 824 patients (412 per group) will be invited. ETHICS AND DISSEMINATION: This study was approved by the Ethics Committee of Tu Du Hospital on 17 May 2021 (reference number: 1251/QD-BVTD). All participants provide informed consent before being enrolled in the study. The results of our study will be submitted to reproductive medicine conferences and journals. TRIAL REGISTRATION NUMBER: NCT04897269.

The negative impact of most relevant infections on fertility and assisted reproduction technology.

Infections may act with variable impact on the physiopathology of the reproductive organs, determining infertility or reducing the outcomes of assisted reproduction technology. The aim of this narrative review is to describe the existing evidence regarding the pathogens with a supposed or recognized role in reproductive medicine. Viral hepatitis, as well as HIV, can reduce sperm quality. Syphilis carries a risk of erectile dysfunction and increased endometrial thickness. Chlamydia is the main cause of pelvic inflammatory disease. In relation to Mycoplasma and Ureaplasma spp., only few species seem to show a correlation with infertility and poor in-vitro fertilization outcomes. There is evidence of a role for bacterial vaginosis in early pregnancy loss. HPV infection in males seems to determine infertility. Herpesviruses are more a risk for fetuses than for fertility itself. Zika virus is responsible for altered early embryo development and waiting to conceive is recommended in suspected or confirmed cases. The impact of SARS-CoV-2 is yet to be elucidated. Rubella and toxoplasmosis can provoke important congenital defects and therefore screening is mandatory before conception; a vaccine for Rubella is recommended. Further and well-designed studies are still needed to better elucidate the role of some infectious agents, to improve fertility and its treatments.

Meningioma during pregnancy: what can influence the management? A case series and review of the literature.

Purpose: Meningioma is a benign tumor, more frequent in female population. During pregnancy, distinguishing a meningioma from other common conditions presenting with similar symptoms (headache, vomiting, visual impairment) is challenging. Moreover, the management must consider not only maternal but also fetal health. The rarity of the condition does not allow to define the features to which look in order to stratify the risk for the need of surgery during pregnancy. We reported three cases of meningioma in pregnant women treated at our department and reviewed those previously reported in the literature. The aim of this review is to evaluate which factors are more determinant in such management.Methods: Electronic databases were searched from year 2000 until June 2020, to identify clinical studies on management of meningioma diagnosed during pregnancy. The primary outcome was surgical timing. Secondary outcomes were delivery methods, maternal and neonatal outcomes.Results: Surgery after pregnancy is more frequently performed in PR + tumor (p-value 0.038) and with HA (p-value 0.0445), as well as in meningioma diagnosed during the third trimester, compared to those diagnosed before (p-value 0.0012). Surgery during pregnancy was more frequent in patients with visual loss (p-value 0.006). No significant differences were found in surgical management, according to age, WHO grade, tumor location, lesion diameter and ER positivity. Delivery method is independent from both hormonal receptor status and main symptoms, but women who had neurosurgery during pregnancy delivered more frequently with spontaneous vaginal delivery (p-value <0.01).Conclusion: The decision regarding surgical timing of meningioma diagnosed during pregnancy depends on PR + and impending symptoms as visual loss or headache. It seems that timing of neurosurgery does not affect the delivery method. A multidisciplinary approach is always useful to perform a rapid and appropriate diagnosis and to better evaluate pros and cons of surgery during pregnancy and following management both for maternal and fetal wellness.

Optimising Follicular Development, Pituitary Suppression, Triggering and Luteal Phase Support During Assisted Reproductive Technology: A Delphi Consensus.

Background: A Delphi consensus was conducted to evaluate global expert opinions on key aspects of assisted reproductive technology (ART) treatment. Methods: Ten experts plus the Scientific Coordinator discussed and amended statements plus supporting references proposed by the Scientific Coordinator. The statements were distributed via an online survey to 35 experts, who voted on their level of agreement or disagreement with each statement. Consensus was reached if the proportion of participants agreeing or disagreeing with a statement was >66%. Results: Eighteen statements were developed. All statements reached consensus and the most relevant are summarised here. (1) Follicular development and stimulation with gonadotropins (n = 9 statements): Recombinant human follicle stimulating hormone (r-hFSH) alone is sufficient for follicular development in normogonadotropic patients aged <35 years. Oocyte number and live birth rate are strongly correlated; there is a positive linear correlation with cumulative live birth rate. Different r-hFSH preparations have identical polypeptide chains but different glycosylation patterns, affecting the biospecific activity of r-hFSH. r-hFSH plus recombinant human LH (r-hFSH:r-hLH) demonstrates improved pregnancy rates and cost efficacy versus human menopausal gonadotropin (hMG) in patients with severe FSH and LH deficiency. (2) Pituitary suppression (n = 2 statements): Gonadotropin releasing hormone (GnRH) antagonists are associated with lower rates of any grade ovarian hyperstimulation syndrome (OHSS) and cycle cancellation versus GnRH agonists. (3) Final oocyte maturation triggering (n=4 statements): Human chorionic gonadotropin (hCG) represents the gold standard in fresh cycles. The efficacy of hCG triggering for frozen transfers in modified natural cycles is controversial compared with LH peak monitoring. Current evidence supports significantly higher pregnancy rates with hCG + GnRH agonist versus hCG alone, but further evidence is needed. GnRH agonist trigger, in GnRH antagonist protocol, is recommended for final oocyte maturation in women at risk of OHSS. (4) Luteal-phase support (n = 3 statements): Vaginal progesterone therapy represents the gold standard for luteal-phase support. Conclusions: This Delphi consensus provides a real-world clinical perspective on the specific approaches during the key steps of ART treatment from a diverse group of international experts. Additional guidance from clinicians on ART strategies could complement guidelines and policies, and may help to further improve treatment outcomes.

The pleiotropic roles of leptin in metabolism, immunity, and cancer.

The discovery of the archetypal adipocytokine leptin and how it regulates energy homeostasis have represented breakthroughs in our understanding of the endocrine function of the adipose tissue and the biological determinants of human obesity. Investigations on leptin have also been instrumental in identifying physio-pathological connections between metabolic regulation and multiple immunological functions. For example, the description of the promoting activities of leptin on inflammation and cell proliferation have recognized the detrimental effects of leptin in connecting dysmetabolic conditions with cancer and with onset and/or progression of autoimmune disease. Here we review the multiple biological functions and complex framework of operations of leptin, discussing why and how the pleiotropic activities of this adipocytokine still pose major hurdles in the development of effective leptin-based therapeutic opportunities for different clinical conditions.

Effect of Dexamethasone Co-Treatment During Ovarian Stimulation in Women of Different Reproductive Age With Elevated Early Follicular Phase Progesterone Level: a Prospective Longitudinal Study.

The aim of this paper was to estimate the effect of dexamethasone during ovarian stimulation in women of different reproductive age with elevated early follicular phase progesterone level undergoing fresh IVF cycle. This study is a prospective longitudinal analysis of consecutive women who underwent fresh IVF cycles at a single center, between January 2012 to December 2013. Women with early follicular phase progesterone above 0.50 ng/ml, assessed in day 0 or day 5 of stimulation, were included. Study group (n = 113) included women who underwent dexamethasone supplementation until the day of triggering. Women who did not undergo dexamethasone treatment formed the control group (n = 109). We further stratified our study population according to age ranges: (1) ≤ 34 years, (2) between 35 and 39 years, and (3) ≥ 40 years. Significantly lower progesterone levels were observed in study than in control group (0.59 ± 0.21 vs 0.94 ± 0.42, p < 0.001). Such difference is not observed in women above 39 years old. Higher, albeit not significant, live birth rate was detected in the study versus control group, considering the overall population. In women ≤ 34 years old, a significantly higher live birth rate was observed in women who underwent dexametasone treatment than in the control group (67.5% vs 47.2%, p = 0.04). Conversely, live birth rates were similar between groups in women above 34 years old. Our data suggest that dexamethasone helps to modulate progesterone levels during the follicular phase and might improve live birth rate of women below 34 years old.

Caloric Restriction Promotes Immunometabolic Reprogramming Leading to Protection from Tuberculosis.

There is a strong relationship between metabolic state and susceptibility to Mycobacterium tuberculosis (MTB) infection, with energy metabolism setting the basis for an exaggerated immuno-inflammatory response, which concurs with MTB pathogenesis. Herein, we show that controlled caloric restriction (CR), not leading to malnutrition, protects susceptible DBA/2 mice against pulmonary MTB infection by reducing bacterial load, lung immunopathology, and generation of foam cells, an MTB reservoir in lung granulomas. Mechanistically, CR induced a metabolic shift toward glycolysis, and decreased both fatty acid oxidation and mTOR activity associated with induction of autophagy in immune cells. An integrated multi-omics approach revealed a specific CR-induced metabolomic, transcriptomic, and proteomic signature leading to reduced lung damage and protective remodeling of lung interstitial tightness able to limit MTB spreading. Our data propose CR as a feasible immunometabolic manipulation to control MTB infection, and this approach offers an unexpected strategy to boost immunity against MTB.

SARS-CoV-2 pandemic and repercussions for male infertility patients: A proposal for the individualized provision of andrological services.

The prolonged lockdown of health facilities providing non-urgent gamete cryopreservation-as currently recommended by many reproductive medicine entities and regulatory authorities due to the SARS-CoV-2 pandemic will be detrimental for subgroups of male infertility patients. We believe the existing recommendations should be promptly modified and propose that the same permissive approach for sperm banking granted for men with cancer is expanded to other groups of vulnerable patients. These groups include infertility patients (eg, azoospermic and cryptozoospermic) undergoing medical or surgical treatment to improve sperm quantity and quality, as well as males of reproductive age affected by inflammatory and systemic auto-immune diseases who are about to start treatment with gonadotoxic drugs or who are under remission. In both scenarios, the "fertility window" may be transitory; postponing diagnostic semen analysis and sperm banking in these men could compromise the prospects of biological parenthood. Moreover, we provide recommendations on how to continue the provision of andrological services in a considered manner and a safe environment. Our opinion is timely and relevant given the fact that fertility services are currently rated as of low priority in most countries.