Semaphorin 3A Increases in the Plasma of Women with Diminished Ovarian Reserve Who Respond Better to Controlled Ovarian Stimulation.

Semaphorin 3A (SEMA3A) plays a crucial role in the development, differentiation, and plasticity of specific types of neurons that secrete Gonadotropin-Releasing Hormone (GnRH) and regulates the acquisition and maintenance of reproductive competence in humans and mice. Its insufficient expression has been linked to reproductive disorders in humans, which are characterized by reduced or failed sexual competence. Various mutations, polymorphisms, and alternatively spliced variants of SEMA3A have been associated with infertility. One of the common causes of infertility in women of reproductive age is diminished ovarian reserve (DOR), characterized by a reduced ovarian follicular pool. Despite its clinical significance, there are no universally accepted diagnostic criteria or therapeutic interventions for DOR. In this study, we analyzed the SEMA3A plasma levels in 77 women and investigated their potential role in influencing fertility in patients with DOR. The results revealed that the SEMA3A levels were significantly higher in patients with DOR than in healthy volunteers. Furthermore, the SEMA3A levels were increased in patients who underwent fertility treatment and had positive Beta-Human Chorionic Gonadotropin (ßHCG) values (ß+) after controlled ovarian stimulation (COS) compared to those who had negative ßHCG values (ß-). These findings may serve as the basis for future investigations into the diagnosis of infertility and emphasize new possibilities for the SEMA3A-related treatment of sexual hormonal dysfunction that leads to infertility.

Corrigendum: Endometrial microbiota profile in in-vitro fertilization (IVF) patients by culturomics-based analysis.

[This corrects the article DOI: 10.3389/fendo.2023.1204729.].

Endometrial microbiota profile in in-vitro fertilization (IVF) patients by culturomics-based analysis.

Introduction: It is well recognized that the human uterus and adjoining tissues of the female reproductive tract exist in a non-sterile state where dysbiosis can impact reproductive outcomes. The endometrial microbiota is a part of this greater milieu. To date, it has largely been studied using 16S rRNA or metagenomics-based methodologies. Despite the known advantages of sequencing analysis, several difficulties have been noted including sample contamination and standardization of DNA extraction or sequencing. The aim of this study was to use a culturomics-based method to analyze the endometrial microbiota and correlate the results with ongoing pregnancy rates. Methods: A prospective cohort study was performed at the University of Naples from June 2022 to December 2022. Ninety-three patients undergoing an IVF cycle with single embryo transfer (ET) (fresh or frozen) were enrolled in the study. Following ET, the catheter tip was inserted into brain heart infusion (BHI) medium under sterile conditions for culture. After 24h and 48h of incubation the microorganisms in the colonies were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Results: Overall, 68 (73,92%) patients resulted positive for one or more microbes and 25 patients (26,08%) had no microbial growth. Across all participants, the four most important phyla were Firmicutes (87,76%), Proteobacteria (27,94%), Actinobacteria (10,29%) and Ascomycota (8,82%). Lactobacillus species, in particular, was significantly correlated with ongoing pregnancy rate (p=0,05). On the other hand, Staphylococcus subspecies (spp.) (p<0,05) and Enterobacteriaceae (p<0,001) were found to have a negative impact on the implantation rate. Discussion: Detection of bacteria by culturomics from catheter tips used for embryo transfer has been shown to be a reliable method to detect pathogen growth. Endometrial microbiota testing in clinical practice could certainly offer a means to further improve diagnosis and treatment strategies in IVF patients.

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.

Maternal and perinatal complications according to maternal age: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the risk levels for maternal and perinatal complications at > 40, > 45 and > 50 years old compared with younger controls. METHODS: Electronic databases were searched from their inception until March 2021. We included studies reporting pregnancy outcome in pregnant women aged 40, 45, and 50 years or older compared with controls at the time of delivery. Case reports and case series were excluded. The primary outcome was the incidence of stillbirth. Meta-analysis was performed using the random effects model of DerSimonian and Laird, to produce summary treatment effects in terms of relative risk (RR) with 95% confidence interval (CI). Heterogeneity was measured using I2 (Higgins I2 ). Subgroup analyses in women older than 45 years and in those older than 50 years were performed. RESULTS: Twenty-seven studies, including 31 090 631 women, were included in the meta-analysis. The overall quality of the included studies was moderate to high. Most of the included studies were retrospective cohort studies (21/27), four were population-based studies, and two were cross-sectional studies. Women aged ≥40 years had significantly higher risk of stillbirth (RR 2.16, 95% CI 1.86-2.51), perinatal mortality, intrauterine growth restriction, neonatal death, admission to neonatal intensive care unit, pre-eclampsia, preterm delivery, cesarean delivery, and maternal mortality compared with women younger than 40 years old (RR 3.18, 95% CI 1.68-5.98). The increased risks for maternal mortality were 42.76 and 11.60 for women older than 50 years and for those older than 45 years, respectively, whereas those for stillbirth were 3.72 and 2.32. The risk of stillbirth and cesarean delivery was significantly higher in women >45 years compared with those aged 40-45 years, and in those aged >50 years compared with those aged 45-50 years. The risk of maternal mortality was significantly higher in women aged >50 years compared with those aged 40-45 (RR 60.40, 95% CI 13.28-274.74). CONCLUSION: The risk of stillbirth, cesarean delivery, and maternal mortality increases with advancing maternal age. The risk ratios for maternal mortality were 3.18, 11.60, and 42.76 in women older than 40, older than 45, and older than 50 years, respectively. These data should be used when women with advanced maternal age are counseled regarding their risk in pregnancy. SYSTEMATIC REVIEW REGISTRATION: The review was registered with the PROSPERO International Prospective Register of Systematic Reviews (registration No.: CRD42020208788).

Unravelling the link between phthalate exposure and endometriosis in humans: a systematic review and meta-analysis of the literature.

PURPOSE: Endometriosis is a chronic debilitating inflammatory pathology which interests females in their reproductive age. Its pathogenesis has not yet been clearly defined. Recent evidence linked chemical agents as endocrine-disrupting chemicals to endometriosis. Phthalates are a widely used class of such compounds. This study aimed to summarize the current literature evaluating the link between exposure to phthalates and occurrence of endometriosis. METHODS: A systematic review of literature and meta-analysis has been carried out following PRISMA guidelines to assess such link. Fourteen studies have been included in the review. Risk of bias has been assessed through the Newcastle Ottawa Scale. RESULTS: We observed association between endometriosis and increased urinary levels of MBP/MnBP, MEOHP, and MEHHP, but not for others. Blood-derived analysis showed statistically significant link between endometriosis and BBP, DEHP, DnBP, and MEHP. CONCLUSION: Given the wide heterogeneity of included studies, results should be taken with caution. Further studies with more rigorous methodology are encouraged to unravel the true link between this class of toxic compounds and manifestation of endometriosis.

Luteal Phase Support Using Subcutaneous Progesterone: A Systematic Review.

Luteal phase support (LPS) is crucial in assisted reproductive technology (ART) cycles when the luteal phase has been found to be defective. Such deficiency is most likely related to the supraphysiological steroid levels that usually occurr in stimulated cycles which, in turn, could severely affect luteinizing hormone (LH) secretion and function, thereby negatively influencing the luteal phase. A number of different medications and routes have been successfully used for LPS in ART. Although an optimal protocol has not yet been identified, the existing plethora of medications offer the opportunity to personalize LPS according to individual needs. Subcutaneous administration progesterone has been proposed for LPS and could represent an alternative to a vaginal and intramuscular route. The aim of the present systematic review is to summarize the evidence found in the literature concerning the application of subcutaneous progesterone in ARTs, highlighting the benefits and limits of this novel strategy. With this aim in mind, we carried out systematic research in the Medline, ISI Web of Knowledge, and Embase databases from their inception through to November 2020. Randomized controlled trials (RCTs) were preferred by the authors in the elaboration of this article, although case-control and cohort studies have also been considered. According to our findings, evidence exists which supports that, in women with a good prognosis undergoing a fresh in vitro fertilization (IVF) cycle, subcutaneous Pg is not inferior to vaginal products. In the Frozen-thawed embryo transfer (FET) cycle, data concerning efficacy is mixed with an increased miscarriage rate in women undergoing a subcutaneous route in oocyte donor recipients. Data concerning the acceptance of the subcutaneous route versus the vaginal route are encouraging despite the different scales and questionnaires which were used. In addition, a cost-effective analysis has not yet been conducted.

Defensome against toxic diatom aldehydes in the sea urchin Paracentrotus lividus.

Many diatom species produce polyunsaturated aldehydes, such as decadienal, which compromise embryonic and larval development in benthic organisms. Here newly fertilized Paracentrotus lividus sea urchins were exposed to low concentration of decadienal and the expression levels of sixteen genes, implicated in a broad range of functional responses, were followed by Real Time qPCR in order to identify potential decadienal targets. We show that at low decadienal concentrations the sea urchin Paracentrotus lividus places in motion different classes of genes to defend itself against this toxic aldehyde, activating hsp60 and two proteases, hat and BP10, at the blastula stage and hsp56 and several other genes (14-3-3ε, p38 MAPK, MTase, and GS) at the prism stage. At this latter stage all genes involved in skeletogenesis (Nec, uni, SM50 and SM30) were also down-expressed, following developmental abnormalities that mainly affected skeleton morphogenesis. Moreover, sea urchin embryos treated with increasing concentrations of decadienal revealed a dose-dependent response of activated target genes. Finally, we suggest that this orchestrated defense system against decadienal represents part of the chemical defensome of P. lividus affording protection from environmental toxicants.