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Background and aims Sphingosine-1 phosphate (S1P) is a lysosphingolipid present in the ovarian follicular fluid. The role of the lysosphingolipid in gonads of the female is widely unclear. At nanomolar concentrations, S1P binds and activates five specific G protein-coupled receptors (GPCRs), known as S1P1-5, modulating different signaling pathways. S1P1 and S1P3 are highly expressed in human primary granulosa lutein cells (hGLC), as well as in the immortalized human primary granulosa cell line hGL5. In this study, we evaluated the signaling cascade activated by S1P and its synthetic analogues in hGLC and hGL5 cells, exploring the biological relevance of S1PR-stimulation in this context. METHODS AND RESULTS. hGLC and hGL5 cells were treated with a fixed dose (0.1 μM) of S1P, or by S1P1- and S1P3-specific agonists SEW2871 and CYM5541. In granulosa cells, S1P and, at a lesser extent, SEW2871 and CYM5541, potently induced CREB phosphorylation. No cAMP production was detected and pCREB activation occurred even in the presence of the PKA inhibitor H-89. Moreover, S1P-dependent CREB phosphorylation was dampened by the mitogen-activate protein kinase (MEK) inhibitor U0126 and by the L-type Ca2+ channel blocker verapamil. The complete inhibition of CREB phosphorylation occurred by blocking either S1P2 or S1P3 with the specific receptor antagonists JTE-013 and TY52156, or under PLC/PI3K depletion. S1P-dependent CREB phosphorylation induced FOXO1 and the EGF-like epiregulin-encoding gene (EREG), confirming the exclusive role of gonadotropins and interleukins in this process, but did not affect steroidogenesis. However, S1P or agonists did not modulate granulosa cell viability and proliferation in our conditions. Conclusions This study demonstrates for the first time that S1P may induce a cAMP-independent activation of pCREB in granulosa cells, although this is not sufficient to induce intracellular steroidogenic signals and progesterone synthesis. S1P-induced FOXO1 and EREG gene expression suggests that the activation of S1P–S1PR axis may cooperate with gonadotropins in modulating follicle development.

This study assessed the relationship between regular physical activity and reproductive performance in obese infertile patients who receive assisted reproduction cycles with stable bodyweight. A total of 216 obese infertile women at their first fresh assisted reproduction attempt with stable body mass index (BMI) and available data on their physical activity carried out up to the beginning of the treatment cycle were enrolled in this observational cohort study. Clinical and biological data were recorded and analysed. There were 41 obese patients who did regular physical activity and 175 obese controls who did not. Total pregnancies (16/41, 39.0% versus 28/175, 16.0%, respectively; P = 0.002) and live births (10/41, 24.4% versus 13/175, 7.4%, respectively; P = 0.004) were significantly higher in patients who did physical activity regularly compared with those who did not. After adjusting for confounders, in obese infertile patients who did physical activity regularly, the relative risks for a clinical pregnancy and live birth were 3.22 (95% CI 1.53-6.78; P = 0.002) and 3.71 (95% CI 1.51-9.11; P = 0.004), respectively. In conclusion, regular physical activity carried out before a assisted reproduction cycle is significantly related with improved reproductive performance in obese infertile patients, irrespective of bodyweight loss. Body weight loss improves not only spontaneous pregnancy rates but also those of assisted reproductive techniques (ARTs). Moreover, almost all studies refer to body weight loss due to lifestyle intervention programs consisting in hypocaloric diet and increased physical activity. Instead, very little is known about the specific effects of physical activity alone on human reproduction. Based on these considerations, we designed the present study to assess the relationship between regular physical activity and reproductive outcome in infertile obese patients who receive ARTs. Two-hundred-sixteen obese infertile women with stable body mass index (BMI) and at their first fresh ART attempt were enrolled, and clinical and biological data were recorded and analyzed. Our results demonstrate that the chances to obtain a pregnancy and a baby are 3-fold higher in obese infertile patients who does physical activity regularly in comparison with those who does not, suggesting that regular physical activity before ART cycles improves the reproductive performance in obese women irrespective to body weight loss.

Objective To evaluate the effect of the 2004 Italian regulations (insemination of ≤3 oocytes/cycle, transfer of all embryos, prohibition of embryo cryopreservation) on outcomes of assisted reproduction treatment (ART). Design Case-control study. Setting The Center of Reproductive Medicine, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy. Patient(s) Women undergoing ART for the first time. Intervention(s) Comparing outcomes of ART between 2 years before (n = 900) and after (n = 936) the law's implementation (March 10, 2004). Main Outcome Measure(s) Rates of fertilization, pregnancy, "take-home baby," and multiple pregnancies. Result(s) During the pre-law period, statistically significantly more patients reached embryo transfer (odds ratio 1.9; 95% CI, 1.5, 2.5), and embryo transfer rate per cycle was statistically significantly higher (3.1 ± 1.7 vs. 2.2 ± 0.7), but the overall transfer of good embryos was lower (OR 0.6; 95% CI, 0.5, 0.8). The pregnancy rates per aspiration cycle were similar between the periods, but the pregnancy rate per embryo transfer and birth rate with at least one liveborn baby per embryo transfer were statistically significantly lower in the pre-law period (OR 0.7; 95% CI, 0.5, 0.9). The multiple births rate was not different between the two periods. Conclusion(s) In contrast to prior pessimistic expectations, the obligation to transfer all available embryos produced from ≤3 inseminated oocytes neither reduced success rates of ART nor increased the multiple births rate.

To determine whether pregnancies after IVF, with and without intracytoplasmic sperm injection (ICSI), have different early spontaneous loss rates.Retrospective analysis of IVF/ICSI dataset.The Center of Reproductive Medicine, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.Women undergoing IVF with or without ICSI.First-trimester sonography at 6-7 weeks to count the number of embryos with positive heartbeat. The number of embryos lost was calculated from a second-trimester sonogram.Embryonic loss rates related to the initial number of embryos, maternal age35 oror =35 years, and IVF procedure.In vitro fertilization and ICSI had similar embryonic loss rates (odds ratio [OR] 1.2, 95% confidence interval [CI] 0.9-1.7, and OR 1.3, 95% CI 0.9-1.8 for women aged35 years andor =35 years, respectively). Younger women had fewer losses after IVF (OR 0.7, 95% CI 0.5-0.9). Multiples had lower loss rates compared with singleton pregnancies.In vitro fertilization and ICSI have similar spontaneous embryonic loss rates. Factors other than the initial number of embryos, maternal age, and IVF technique, such as embryo quality or uterine environment, might be involved in the outcome of multiple pregnancies in assisted reproductive technology procedures.

Survivors of the "vanishing" twin syndrome, which occurred in dichorionic twins only, and singletons that began as singletons, had similar mean gestational duration and birth weights, as well as similar frequencies of maternal and neonatal complications. This similarity persisted when conventional IVF and IVF plus ICSI cases were separately evaluated.