Publications by authors named "Gian Mario Tiboni"

58 Publications

Novel Insights on the Role of Nitric Oxide in the Ovary: A Review of the Literature.

Int J Environ Res Public Health 2021 Jan 22;18(3). Epub 2021 Jan 22.

Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio" Chieti-Pescara, Via Dei Vestini 31, 66100 Chieti, Italy.

Nitric oxide (NO) is formed during the oxidation of L-arginine to L-citrulline by the action of multiple isoenzymes of NO synthase (NOS): neuronal NOS (nNOS), endotelial NOS (eNOS), and inducible NOS (iNOS). NO plays a relevant role in the vascular endothelium, in central and peripheral neurons, and in immunity and inflammatory systems. In addition, several authors showed a consistent contribution of NO to different aspects of the reproductive physiology. The aim of the present review is to analyse the published data on the role of NO within the ovary. It has been demonstrated that the multiple isoenzymes of NOS are expressed and localized in the ovary of different species. More to the point, a consistent role was ascribed to NO in the processes of steroidogenesis, folliculogenesis, and oocyte meiotic maturation in in vitro and in vivo studies using animal models. Unfortunately, there are few nitric oxide data for humans; there are preliminary data on the implication of nitric oxide for oocyte/embryo quality and in-vitro fertilization/embryo transfer (IVF/ET) parameters. NO plays a remarkable role in the ovary, but more investigation is needed, in particular in the context of human ovarian physiology.
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http://dx.doi.org/10.3390/ijerph18030980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908174PMC
January 2021

Effects of Obesity and Thrombophilia on the Risk of Abortion in Women Undergoing Fertilization.

Front Endocrinol (Lausanne) 2020 23;11:594867. Epub 2020 Dec 23.

Department of Medical, Oral and Biotechnological Sciences, University G. D'Annunzio, Chieti-Pescara, Italy.

Introduction: Obesity is associated with a higher risk of abortion in women undergoing fertilization (IVF). Whether thrombophilia amplifies this risk is currently unclear. The aim of this study was to evaluate the effects of thrombophilia on the risk of abortion in obese women treated with IVF.

Methods: Patient characteristics, presence of inherited or acquired thrombophilia, and comorbidities were prospectively collected before the procedure in consecutive women undergoing IVF. The primary outcome was the incidence of abortion among women who achieved a clinical pregnancy.

Results: A total of 633 non-obese and 49 obese Caucasian women undergoing IVF were included. 204 (32%) women achieved clinical pregnancy, of whom six had an ectopic pregnancy and 63 experienced an abortion. The incidence of abortion was higher in obese women compared to non-obese women after adjusting for age (64.3% vs. 29.3%, odds ratio [OR] 4.41; 95% CI 1.41 to 13.81). Women with one or more thrombophilia were at increased risk of abortion relative to those without thrombophilia (OR 2.70; 95% CI 1.34 to 5.45), and the risk seemed to be higher with hereditary (OR 5.12; 95% CI 1.77 to 14.8) than acquired thrombophilia (OR 1.92; 95% CI 0.52 to 5.12; p for interaction 0.194). Among obese women, the presence of one or more thrombophilia seemed associated with a substantially increased risk of abortion (unadjusted OR 14.00; 95% CI 0.94 to 207.6).

Conclusions: Obese women undergoing IVF have a high risk of abortion which seems further amplified by the concomitant presence of thrombophilia.
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http://dx.doi.org/10.3389/fendo.2020.594867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786836PMC
December 2020

Maternal use of fluconazole and congenital malformations in the progeny: A meta-analysis of the literature.

Reprod Toxicol 2021 Mar 28;100:42-51. Epub 2020 Dec 28.

Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio" Chieti-Pescara, Via Dei Vestini 31, 66100, Chieti, Italy. Electronic address:

Fluconazole is a bis-triazole agent used in the treatment of superficial and systemic fungal infections, with vaginal candidiasis being one of the commonest indications to fluconazole treatment. There is increasing concern regarding the teratogenic potential of fluconazole. The aim of this meta-analysis is to pool the literature data in order to evaluate the possible association between fluconazole exposure during pregnancy and birth defects. A total of nine studies were included in the meta-analysis. Results were expressed as odds ratios (OR) with 95 % confidence intervals (CI) and statistical heterogeneity between the studies was evaluated with Higgins index (I) and Q-test (Q). A p-value < 0.05 referred to the effect was considered statistically significant. The maternal exposure to fluconazole during the first trimester of pregnancy is correlated with increased prevalence of heart defects in the offspring for both low dose (OR 1.95, 95 % CI 1.18-3.21; P = 0.01) and any dose (OR 1.79, 95 % CI 1.18-2.71; P = 0.01). No association was found between gestational exposure to fluconazole and increased risk of spontaneous abortion or stillbirth. Fluconazole should be regarded as a human teratogen and should be cautiously prescribed to pregnant women and to women of childbearing potential.
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http://dx.doi.org/10.1016/j.reprotox.2020.12.018DOI Listing
March 2021

Valproic acid alters nitric oxide status in neurulating mouse embryos.

Reprod Toxicol 2021 Jan 4;99:152-159. Epub 2020 Nov 4.

Department of Medicine and Science of Aging, University "G. D'Annunzio", Chieti Pescara, Italy. Electronic address:

The molecular bases of the teratogenic effects elicited by valproic acid (VPA) are not fully defined. It was previously shown that inhibition of nitric oxide (NO) synthesis is associated with an enhancement of the teratogenic effects of VPA, while amplification of NO signal by sildenafil prompted a dose-dependent reduction of VPA-induced neural tube defects. In this study, for the first time, the effect of VPA on the NO synthesis was evaluated in mouse embryos during early organogenesis. On gestation day 8, ICR-CD1 mice received 600 mg/kg of VPA. Eight and 24 h later embryos were collected and analyzed for NO synthase (NOS) isoform expression, and for molecular mechanisms involved in their modulation. As main finding, in utero embryonic exposure to VPA determined a time-dependent shift of NOS isoforms expression, with a down regulated expression and activity of constitutive NOS (cNOS) and an increased expression and activity of inducible NOS (iNOS). The teratological relevance of this information remains to be established.
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http://dx.doi.org/10.1016/j.reprotox.2020.08.012DOI Listing
January 2021

Successful pregnancy following the transfer of re-vitrified twice-warmed embryos due to the forced cancellation of the primary FET: A case report.

Cryobiology 2020 Dec 26;97:242-244. Epub 2020 Aug 26.

Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio", Chieti, Pescara, Italy. Electronic address:

Purpose: Embryo cryopreservation represents a central procedure in in-vitro fertilization (IVF) programs. This report documents a Case of a successful pregnancy following the replacement of embryos that had to be re-vitrified due to the forced cancellation of the frozen embryo-transfer (FET).

Principle Results: The 37- year-old patient was referred to our Assisted Reproductive Technology (ART) unit for idiopathic infertility and recurrent implantation failures. The collection cycle resulted in 8 grade-A cleavage embryos (8-10 blastomeres), that were all vitrified to prevent ovarian hyperstimulation syndrome (OHSS). The first frozen embryo transfer (FET) ended in a biochemical pregnancy and the second in an ectopic pregnancy. In the third attempt, three embryos were warmed but the provider could not complete the transfer due to cervical stenosis. The two surviving embryos were therefore re-vitrified. The final FET attempt, 4 months later, was successful and ended with the live birth of a healthy female baby.

Conclusions: The transfer of re-vitrified twice-warmed embryos may represent a possible option when embryo transfer cannot be performed.
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http://dx.doi.org/10.1016/j.cryobiol.2020.08.009DOI Listing
December 2020

Effects of Supplementation with Natural Antioxidants on Oocytes and Preimplantation Embryos.

Antioxidants (Basel) 2020 Jul 12;9(7). Epub 2020 Jul 12.

Dipartimento di Scienze Mediche, Orali e Biotecnologiche, Università "G. d'Annunzio" Chieti-Pescara, Via Dei Vestini 31, 66100 Chieti, Italy.

For most infertile couples, in vitro fertilization (IVF) represents the only chance to conceive. Given the limited success of IVF procedures, novel approaches are continuously tested with the aim of improving IVF outcomes. Growing attention is devoted today to the potential benefit of natural antioxidants in the optimization of infertility treatments. This review summarizes current data in this context, focusing on both experimental studies on oocytes/embryos and clinical trials on antioxidants supplementation. Based on information gained from experimental studies, antioxidant supplementation may have beneficial effects on IVF outcomes in terms of quality and cryotolerance of in vitro produced embryos, together with positive effects on in vitro maturation oocytes and on early embryonic development. Unfortunately, from the clinical side, there is a paucity of evidence favoring the protective qualities of antioxidants. Among the antioxidants considered, coenzyme Q10 may be regarded as one of the most promising for its positive role in rescuing the oxidative stress-induced damages, but further data are needed. It is concluded that further trials are necessary to characterize the potential clinical value of antioxidants in IVF treatments.
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http://dx.doi.org/10.3390/antiox9070612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402117PMC
July 2020

Efficacy and safety of follitropin alpha biosimilars compared to their reference product: a Meta-analysis.

Gynecol Endocrinol 2020 Jul 11:1-9. Epub 2020 Jul 11.

Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy.

Aim: Recently published multicentre, randomized phase III studies suggested the therapeutic equivalence of biosimilar follitropin alpha medicaments compared to the reference product. The aim of this meta-analysis is to pool the results of the three phase III trials in order to provide an overall analysis about the clinical bioequivalence between biosimilars and the originator.

Methods: The studies included in the analysis were pooled together in order to estimate the log odds ratio (OR) for binary outcomes and the weighted mean difference (WMD) for continuous outcomes along with the corresponding 95% confidence intervals (CI) by using a random effects model. The heterogeneity between the studies was evaluated with the Higgins and Chi-square tests.

Results: No differences were found in term of number of oocytes retrieved at ovum pick-up, the primary endpoint recommended by the European Medicines Agency. No statistical differences were also found for biochemical pregnancy rate, take home baby rate, total follitropin alpha dose, duration of stimulation, and OHSS risk. A significantly higher clinical pregnancy rate ( = .03) was observed in the originator group in comparison to the biosimilar follitropin alpha.

Conclusion: Biosimilar follitropin alpha medicaments resulted comparable in comparison to the reference product with respect to the number of oocytes retrieved, that is the primary endpoint recommended by the European Medicines Agency .Further study is needed to evaluate the therapeutic bioequivalence between follitropin alpha biosimilar and the reference medication with respect to secondary endpoints.
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http://dx.doi.org/10.1080/09513590.2020.1792437DOI Listing
July 2020

Whole-body exposure to cigarette smoke alters oocyte miRNAs expression in C57BL/6 mice.

Mol Reprod Dev 2019 11 11;86(11):1741-1757. Epub 2019 Sep 11.

Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy.

Cigarette smoke is toxic for the female reproductive system with particular reference to the ovary. The purpose of the study was to investigate if the microRNAs (miRNAs) pattern could be altered by cigarette smoke exposure in mouse oocytes. For this purpose, C57BL/6 mice were whole-body exposed to three cigarettes daily, 7 days/week, for 2 or 4 months by a specific rodent ventilator. Mice were then superovulated and oocytes collected. MII oocytes pools obtained by single animals were deprived of cumulus cells and used to extract total RNA including miRNAs. TaqMan™ Rodent MicroRNA A Array v2.0 was used to analyze the miRNAs expression profile. The biological functions and the functional networks of the identified up- and downregulated miRNAs were analyzed by ingenuity pathway analysis software. The gene expression of deregulated-miRNAs targets was evaluated. For the first time, the global miRNAs changes in mouse oocyte in response to cigarette smoke exposure were disclosed. Our results revealed significant modulation of miRNAs mainly involved in inflammatory processes, cellular proliferation, and apoptosis. miRNAs expression was altered in a time-dependent manner. Smoke exposure induced an early downregulation of Dicer1. Transcriptional alterations of the modulated miRNAs major targets, estrogen receptor 1, peroxisome proliferator-activated receptor-alpha, and tumor protein 53, as well as that of other key regulatory genes, were evidenced. Cigarette smoke represents a stimulus able to alter miRNAs pattern in mouse oocyte. This study increases our understanding of the ovarian toxicity profile of cigarette smoke, and open new roads toward the identification of biomarkers of oocyte toxicity and dysregulation.
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http://dx.doi.org/10.1002/mrd.23267DOI Listing
November 2019

Dynactin pathway-related gene expression is altered by aging, but not by vitrification.

Reprod Toxicol 2019 09 28;88:48-55. Epub 2019 Jun 28.

Laboratory of Molecular Genetics, Department of Psychological, Health and Territorial Sciences (DISPUTer), School of Medicine and Health Sciences "G. d'Annunzio" University Chieti-Pescara Italy, Via Dei Vestini 31, 66100, Chieti, Italy; CESI-Met Research Center "G. d'Annunzio" University Chieti-Pescara, Via Luigi Polacchi 1, 66100, Chieti, Italy. Electronic address:

The storage of surplus oocytes by cryopreservation (OC) is a widely used tool in assisted reproductive technology, but there is a great debate about the effects of cryopreservation on oocyte competence. It is known that OC may affect meiotic spindles but remains unclear if OC may increase the risk of aneuploidy. The aim of this study was to test the effects of OC and women aging on the expression of cytokinesis-related genes playing an important role in the segregation of chromosomes (DCTN1, DCTN2, DCTN3, DCTN6 and PLK1). Results highlighted that OC do not modify the expression of the selected genes, whereas women aging modulate the expression of all transcripts, confirming that aging is the crucial factor affecting meiosis and aneuploidy risk. A new role for Dynactin and PLK1 was shed in light, providing information on the ageing process in the oocyte which may be associated to reduced fertility.
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http://dx.doi.org/10.1016/j.reprotox.2019.06.011DOI Listing
September 2019

MRAP2 regulates endometrial receptivity and function.

Gene 2019 Jun 3;703:7-12. Epub 2019 Apr 3.

Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, "G. d'Annunzio" University Chieti-Pescara, Via Dei Vestini 31, 66100 Chieti, Italy; Functional Genetics Unit, Center of Excellence on Aging (Ce.S.I.-MeT), Via Luigi Polacchi 11, 66100 Chieti, Italy. Electronic address:

A successful embryo implantation depends on the synchronization between a competent blastocyst and a receptive endometrium. Recently, potential modulators of endometrial receptivity (OVGP1, MRAP2, ZCCHC12, and HAP1) have been reported likely with a functional role during embryo implantation. The aim of this study was to evaluate the gene expression of these genes in the endometrium of infertile women. Eighteen endometrial biopsies, during secretory lutheal phase, were recruited from women with unexplained infertility and women who cannot conceive due to their partners' fertility problems. qRT-PCR was carried out to evaluate MRAP2, OVGP1, ZCCHC12 and HAP1 gene expression. MRAP2 expression was also detected by western blot and it was localized by immunohistochemistry. Morphological analysis was performed by light microscopy. MRAP2 was significantly up-regulated in study vs. control group. Western blot analysis confirmed the observed MRAP2 up-expression. MRAP2 resulted mainly localized in the epithelial cells of uterine glands. Morphological analysis displayed that the epithelium of the uterine glands undergo hypertrophy in women with unexplained infertility in respect to women with male infertility factor. MRAP2 could be considered a mediator of endometrial receptivity likely acting on endometrial stability by binding to MCRs and PKR1.
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http://dx.doi.org/10.1016/j.gene.2019.04.001DOI Listing
June 2019

VEGFR2 Expression Is Differently Modulated by Parity and Nulliparity in Mouse Ovary.

Biomed Res Int 2018 16;2018:6319414. Epub 2018 Sep 16.

Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.

Parity and nulliparity exert opposite effects on women's health, as parity is considered a protective factor for several reproductive diseases. This study is aimed at determining if ovarian VEGF and VEGFR2 expression are differently modulated in the ovaries of parous and nulliparous mice. To this end primiparous and nulliparous fertile mice were sacrificed at postovulatory stage. Whole ovaries, corpus luteum, and residual stromal tissues were analyzed to assess VEGF/VEGFR2 expression levels. Ovarian mRNA amounts of ( and ) and were comparable between primiparous and nulliparous mice; both isoforms and receptor were accumulated mainly in corpus luteum tissues. VEGF 120 and 164 protein accumulation and distribution mirrored that of mRNA. Conversely, VEGFR2 protein content was significantly higher in ovaries of nulliparous mice and was more efficiently phosphorylated in ovaries of primiparous mice. In both groups, VEGFR2 was preferentially expressed in corpus luteum, while its phosphorylated form was equally distributed in two somatic compartments. We suggest that parity influences VEGFR2/phospho-VEGFR2 expression and tissue distribution. This difference could be part of a more complex mechanism that at least in mice is activated after the first pregnancy and likely aims to preserve female health.
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http://dx.doi.org/10.1155/2018/6319414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166384PMC
January 2019

Cigarette smoking impairs clinical outcomes of assisted reproductive technologies: A meta-analysis of the literature.

Reprod Toxicol 2018 09 12;80:49-59. Epub 2018 Jun 12.

Dipartimento di Medicina e Scienze dell'Invecchiamento, University "G. d'Annunzio" Chieti-Pescara, Italy. Electronic address:

There is convincing evidence that cigarette smoking can impair female reproductive potential. This meta-analysis updates the knowledge regarding the effects of cigarette smoking on clinical outcomes of assisted reproductive technologies (ART). Twenty-six studies were included in this meta-analysis. Results were expressed as odds ratios (OR) with 95% confidence intervals (CI) and statistical heterogeneity between the studies was evaluated with Higgins (I), Breslow (τ), Birge's ratio (H) indices and Chi-square test (χ). A P-value < 0.05 was considered statistically significant. The analysis showed a significant decrease in live birth rate per cycle for smoking patients (OR 0.59, 95% CI 0.44-0.79; P = 0.0005), a significant lower clinical pregnancy rate per cycle for smoking women (OR 0.53, 95% CI 0.41-0.68; P < 0.0001), and a significant increase in terms of spontaneous miscarriage rate (OR 2.22, 95% CI 1.10-4.48; P = 0.025) for smokers. These findings demonstrate clear negative effects of cigarette smoking on the outcome of ART programs.
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http://dx.doi.org/10.1016/j.reprotox.2018.06.001DOI Listing
September 2018

Effects of multiple inherited and acquired thrombophilia on outcomes of in-vitro fertilization.

Thromb Res 2018 07 9;167:26-31. Epub 2018 May 9.

Department of Medical, Oral and Biotechnological Sciences, Gabriele D'Annunzio University, Chieti, Italy. Electronic address:

Introduction: The effects of multiple inherited and acquired thrombophilic defects on the outcome of in-vitro fertilization (IVF) remain unexplored. The aim of this study was to evaluate the association between multiple thrombophilia and clinical outcomes in a large prospective cohort of women undergoing IVF.

Materials And Methods: Consecutive women scheduled for IVF were eligible. The primary study outcome was live birth. Secondary outcomes included spontaneous abortion, clinical pregnancy, and symptomatic venous thromboembolism.

Results: 687 women with a mean age of 34.6 (±3.2) years were included. Overall, 22 women (3.2%) had two or more thrombophilic defects. The probability of live birth was not statistically significantly different between women with ≥2 thrombophilia (odds ratio [OR] 0.62; 95% confidence interval [CI], 0.18 to 2.11) or ≥1 thrombophilia (OR 0.67;95% CI, 0.41 to 1.09) and women without any thrombophilia. None of the individual inherited thrombophilia nor positivity to antiphospholipid antibodies or lupus anticoagulant were associated with live birth. Single positivity for lupus anticoagulant carried a more than threefold higher risk of abortion (OR 3.74; 95% CI, 1.30 to 10.75). There were no statistically significant associations between individual or multiple thrombophilic defects and clinical pregnancy or pregnancy test results. No woman had a history of venous thromboembolism and none developed a thrombotic event during the study.

Conclusions: In women undergoing IVF, the presence of two or more thrombophilic defects was rare and showed no statistically significant associations with IVF outcomes.
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http://dx.doi.org/10.1016/j.thromres.2018.05.006DOI Listing
July 2018

Increased rounds of gonadotropin stimulation have side effects on mouse fallopian tubes and oocytes.

Reproduction 2018 03 4;155(3):245-250. Epub 2018 Jan 4.

Department of LifeHealth and Environmental Sciences, University of L'Aquila, L'Aquila, Italy

In this study, it was evaluated if increased rounds of gonadotropin stimulation could affect in mice: (i) expression levels of proteins regulating cell cycle and DNA repair in fallopian tubes and (ii) meiotic spindle morphology of ovulated oocytes. To this end, adult female mice were subjected or not (Control) to 6 or 8 rounds of gonadotropin stimulation. Ovulated oocytes were incubated with anti A/B tubulin to evaluate spindle morphology. Fallopian tubes were analyzed to detect Cyclin D1, phospho-p53/p53, phospho-AKT/AKT, phospho-GSK3B/GSK3B, SOX2, OCT3/4, phospho-B-catenin/B-catenin, phospho-CHK1 and phospho-H2A.X protein levels. After 6 rounds, Cyclin D1, p53 and phospho-p53 contents were higher than Control. After 8 rounds, the contents of phosphorylated AKT, GSK3B and p53 as well as of total p53, Cyclin D1 and OCT3/4 significantly increased in comparison with Control. Conversely, SOX2 and B-catenin were similarly expressed among all experimental groups. The finding that phospho-CHK1 and phospho-H2A.X protein levels were undetectable supported the absence of extensive DNA damage. Oocytes number and percentage of normal meiotic spindles drastically decreased from 6 rounds onward. Altogether, our results demonstrated that 6 and 8 cycles of gonadotropin stimulation reduce mouse reproductive performances by inducing over-expression and over-activation of proteins controlling cell cycle progression in fallopian tubes and by impairing oocyte spindle.
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http://dx.doi.org/10.1530/REP-17-0687DOI Listing
March 2018

Editorial: New Horizons in Controlled Ovarian Stimulation.

Curr Pharm Biotechnol 2017 11;18(8):608

Department of Medicine and Aging Sciences University "G.d'Annunzio" Chieti Pescara, Italy.

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http://dx.doi.org/10.2174/138920101808171110141105DOI Listing
November 2017

Editorial: Teratology and Reproductive Toxicology of Anticancer Agents.

Anticancer Agents Med Chem 2017 ;17(9):1170

Department of Medicine and Aging Sciences University of Chieti Pescara 66100 Chieti CH. Italy.

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http://dx.doi.org/10.2174/187152061709170912113703DOI Listing
April 2019

Folate serum levels in Italian women entering an in vitro fertilization program.

Gynecol Endocrinol 2017 Nov 19;33(11):861-863. Epub 2017 Jul 19.

a Department of Medicine and Aging Sciences , University "G. d'Annunzio" of Chieti-Pescara , Chieti , Italy.

Italian public health authorities recommend women of childbearing age to assume a daily dose of 0.4 mg of folic acid (FA) from at least one month before conception in order to reduce the risk of having children affected by neural tube defects (NTDs). In this study, folate, homocysteine and vitamin B12 serum levels were determined in 77 women entering an in vitro fertilization program. About 75% of patients had serum folate values compatible with the intake of the recommended dose of FA for at least three months, whereas only the 61% of them reached or exceeded the serum folate concentration regarded as the optimal concentration during the periconceptional period. Mean vitamin B12 serum levels and mean homocysteine plasma levels resulted in normal range in all the women with mean values of 381.2 ± 2.2 pg/ml and 8.48 ± 2.2 μmol/l, respectively. In conclusion, only a portion of women entering an IVF program presents proper folate levels.
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http://dx.doi.org/10.1080/09513590.2017.1334197DOI Listing
November 2017

Ovotoxicity of cigarette smoke: A systematic review of the literature.

Reprod Toxicol 2017 09 3;72:164-181. Epub 2017 Jul 3.

Department of Medicine and Aging Sciences, University "G. d'Annunzio" of Chieti-Pescara, Italy. Electronic address:

This study reviews the scientific literature on the noxious effects of cigarette smoke on the ovarian follicle, and the cumulative data on the impact of smoking on in vitro fertilization (IVF) cycle outcome. There is a close association between tobacco smoke and accelerated follicle loss, abnormal follicle growth and impairment of oocyte morphology and maturation. There is an increasing amount of evidence indicating that smoke can directly derange folliculogenesis. Increased cellular apoptosis or autophagy, DNA damage and abnormal crosstalk between oocyte and granulosa cells have been implicated in the demise of ovarian follicles. It becomes increasingly clear that maternal smoking can exert multigenerational effects on the ovarian function of the progeny. Growing evidence suggests that cigarette smoke is associated with decreased results after IVF. Further research is needed to better define the molecular mechanisms behind smoking-induced ovarian disruption.
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http://dx.doi.org/10.1016/j.reprotox.2017.06.184DOI Listing
September 2017

Cigarette smoke is associated with altered expression of antioxidant enzymes in granulosa cells from women undergoing in vitro fertilization.

Zygote 2017 Jun 21;25(3):296-303. Epub 2017 Jun 21.

Department of Medicine and Aging Sciences,University 'G. d'Annunzio' Chieti-Pescara,Via dei Vestini 66013 Chieti,Italy.

This study was undertaken to evaluate whether cigarette smoke is associated with changes in the expression of antioxidant enzymes in granulosa cells of women undergoing IVF treatments. For this aim, the expression of three antioxidant enzymes (SOD1, SOD2 and catalase) in non-smokers (n = 20) and smokers (n = 20) was analyzed. There was a statistically significant overexpression of SOD2 and catalase mRNA levels in smokers in comparison with non-smokers. Cigarette smoking was associated with a lower fertilization rate, implantation rate and pregnancy rate in comparison with non-smokers. There was no effect on retrieved oocytes number, metaphase II oocytes number, quality of embryos transferred and live birth rate. These findings suggest that cigarette smoke initiates oxidative stress in granulosa cells.
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http://dx.doi.org/10.1017/S0967199417000132DOI Listing
June 2017

Clinical experience with an ovarian stimulation protocol for intrauterine insemination adopting a gonadotropin releasing hormone antagonist at low dose.

Gynecol Endocrinol 2017 Mar 6;33(3):208-211. Epub 2016 Dec 6.

a Department of Medicine and Aging Sciences , University "G. d'Annunzio" of Chieti-Pescara , Chieti , Italy.

Studies testing the effectiveness of GnRH antagonists in controlled ovarian stimulation (COS) for intrauterine insemination (IUI) have provided controversial results. The present study was undertaken to evaluate, whether the use of a half of the conventional dose of the GnRH antagonist cetrorelix can be effective in increasing the successful rate of IUI cycles. Patients started COS with human menopausal gonadotropin (hMG) on day three of the menstrual cycle. Cetrorelix was started when at least one follicle of ≥14 mm, was detected at the ultrasound scan, according to the flexible multiple daily dose protocol, and continued until the trigger day with recombinant hCG. Patients adopting GnRH antagonist at low dose had a pregnancy rate (21.7%) that was significantly higher (p < 0.05) in comparison to women receiving hMG only (8.7%). These results suggest that adding a reduced dose of GnRH antagonist to the COS for IUI cycles significantly improves the outcome of the procedure.
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http://dx.doi.org/10.1080/09513590.2016.1252327DOI Listing
March 2017

Fetal safety profile of aromatase inhibitors: Animal data.

Reprod Toxicol 2016 12 30;66:84-92. Epub 2016 Sep 30.

Department of Medicine and Aging Sciences, University "G. d'Annunzio" of Chieti-Pescara, Italy. Electronic address:

Aromatase inhibitors (AIs) are a class of drugs that act by blocking the production of estrogens from androgens. The current review concentrates on the prenatal developmental toxicity of AIs in experimental models. Available data indicate that AIs may affect pregnancy at human therapeutic or lower doses. The window of vulnerability to AIs is not limited to organogenesis, but also includes the preimplantation stage and fetal periods. Decreased embryo/fetal survival was the prominent treatment-related effect. Morphological anomalies noted in fetuses exposed to AIs included skeletal anomalies, abnormal head morphology, increased ano-genital distance in female fetuses, and minor urinary tract system anomalies. Placental enlargement was consistently reported in rats and non-human primates after maternal treatment with several AIs. In conclusion, data from basic scientific research suggest that low intensity exposure to AIs applied during a wide gestational window can profoundly affect prenatal development.
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http://dx.doi.org/10.1016/j.reprotox.2016.09.016DOI Listing
December 2016

Reducing the trigger dose of recombinant hCG in high-responder patients attending an assisted reproductive technology program: an observational study.

Drug Des Devel Ther 2016 18;10:1691-4. Epub 2016 May 18.

Department of Medicine and Aging Sciences, University "G d'Annunzio" of Chieti-Pescara, Chieti, Italy.

Decreasing the dose of human chorionic gonadotropin (hCG) used to trigger final oocyte maturation in assisted reproductive technology programs is regarded as a useful intervention in the prevention of ovarian hyperstimulation syndrome, but the minimal effective dose has not been yet identified. In this study, the capacity of a reduced dose of recombinant hCG (r-hCG) to provide adequate oocyte maturation was tested for the first time. Thirty-five high-responder patients received a dose of 125 µg (half of the standard dose) of r-hCG for triggering final oocyte maturation. The number of oocytes retrieved per patient and the proportion of mature oocytes were evaluated. As a result, a mean number of 14 oocytes were retrieved, of which 85% were found to be mature (MII). There was only one patient developing a moderate form of ovarian hyperstimulation syndrome and not requiring hospitalization. It is suggested that r-hCG at 125 µg can be effective in triggering final oocyte maturation in high-responder patients. Additional properly powered and controlled studies are needed to support this contention.
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http://dx.doi.org/10.2147/DDDT.S105607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876795PMC
March 2017

Corifollitropin alfa compared to daily FSH in controlled ovarian stimulation for in vitro fertilization: a meta-analysis.

J Ovarian Res 2015 Jun 3;8:33. Epub 2015 Jun 3.

Dipartimento di Medicina e Scienze dell'Invecchiamento, University "G. d'Annunzio" of Chieti-Pescara, Chieti, Italy.

The present study offers a meta-analysis of published randomized controlled trials (RCTs) evaluating the outcomes of in vitro fertilization (IVF) cycles using corifollitropin alfa for controlled ovarian stimulation (COS) in comparison with daily recombinant FSH (rFSH). The study examined seven RCTs including 2138 patients receiving corifollitropin alfa and 1788 women receiving daily rFSH for COS. As a novel aspect, this meta-analysis included two specific subpopulations of IVF patients, i.e. egg donors and poor responders. There were no significant differences between corifollitropin alfa and rFSH with respect to the majority of the clinical parameters considered, and comparable were the outcomes in terms of live birth rate, ongoing pregnancy rate, and clinical pregnancy rate. Women receiving corifollitropin alfa had a significantly higher number of metaphase II oocytes at ovum pick-up, and number of formed embryos, in comparison to rFSH. The risk of cycle cancellation due to overstimulation was significantly higher in the corifollitropin alfa group. Ovarian hyperstimulation syndrome (OHSS) incidence was statistically comparable between patients receiving long lasting or daily rFSH. Nevertheless, in view of the fact that corifollitropin alfa resulted in a higher number of metaphase II oocytes collected and a higher number of cycles cancelled due to overstimulation, corifollitropin alfa should be cautiously considered in women with the potential of being hyper responders.
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http://dx.doi.org/10.1186/s13048-015-0160-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465305PMC
June 2015

Prevention of valproic acid-induced neural tube defects by sildenafil citrate.

Reprod Toxicol 2015 Aug 20;56:175-9. Epub 2015 Mar 20.

Dipartimento di Medicina e Scienze dell'Invecchiamento, Università "G. d'Annunzio" Chieti-Pescara, Italy.

This study was undertaken to test the effects of sildenafil citrate (SC), a type 5 phosphodiesterase inhibitor, on valproic acid (VPA)-induced teratogenesis. On gestation day (GD) 8, ICR (CD-1) mice were treated by gastric intubation with SC at 0 (vehicle), 1.0, 2.5, 5.0 or 10mg/kg. One hour later, animals received a teratogenic dose of VPA (600mg/kg) or vehicle. Developmental endpoints were evaluated near the end of gestation. Twenty-eighth percent of fetuses exposed to VPA had neural tube defects (exencephaly). Pretreatment with SC at 2.5, 5.0 or 10mg/kg significantly reduced the rate of VPA-induced exencephaly to 15.9%, 13.7%, and 10.0%, respectively. Axial skeletal defects were observed in 75.8% of VPA-exposed fetuses. Pre-treatment with SC at 10mg/kg, but not at lower doses, significantly decreased the rate of skeletally affected fetuses to 61.6%. These results show that SC, which prolongs nitric oxide (NO) signaling action protects from VPA-induced teratogenesis.
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http://dx.doi.org/10.1016/j.reprotox.2015.03.004DOI Listing
August 2015

Plasma concentrations of D-dimer and outcome of in vitro fertilization.

J Ovarian Res 2014 22;7:58. Epub 2014 May 22.

Department of Medicine and Aging, University "G. D'Annunzio" of Chieti-Pescara, Chieti, Italy.

Background: The activation of blood coagulation could contribute to the failure of in-vitro fertilization (IVF) techniques. The aim of this study was to assess the predictive value of D-dimer levels for pregnancy outcome in women undergoing IVF.

Findings: A prospective study was performed in 105 women undergoing IVF. D-dimer was measured before and one week after the administration of recombinant human chorionic gonadotropin (r-hCG). The primary outcome of the study was clinical pregnancy. The mean age was 36 years (range 26 to 43 years). The main indications for IVF were infertility due to a tubaric (n = 21, 20%) or male factor (n = 37, 35%) and idiopathic infertility (n = 30, 29%) which altogether accounted for 84% of the total. Clinical pregnancy was achieved by 40/105 (38%) women of whom 32 (80%) delivered a live child. On the day of r-hCG administration, D-dimer concentrations were significantly higher in patients not achieving a clinical pregnancy (141 ng/dL vs. 115 ng/dL, p = 0.035) which remained statistically significant after correction for age and indications for IVF in multivariable analysis (p = 0.032). One week after r-hCG, the levels of D-dimer were significantly increased both in women with and without a clinical pregnancy with no differences between the groups (748 ng/dL vs. 767 ng/dL, p = 0.88).

Conclusions: D-dimer concentrations seem to predict a higher risk of pregnancy failure in women undergoing IVF. If confirmed in future prospective studies, D-dimer could help identifying a group of patients who could benefit from prophylaxis to increase the pregnancy success rate.
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http://dx.doi.org/10.1186/1757-2215-7-58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049404PMC
October 2015

Nitric oxide and teratogenesis: an update.

Curr Pharm Des 2014 ;20(34):5443-7

Department of Medicine and Aging Sciences, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini Chiet, Italy.

Nitric oxide (NO), generated by NO synthase (NOS) enzymes, is an important bioactive molecule involved in the regulation of several biological phenomena that are crucial for organogenesis, including gene expression, cell growth, matrix remolding, proliferation, differentiation and apoptosis. The expression of NOS isoforms in embryonic tissues is temporally and spatially regulated, and disruption of endogenous NO can lead to developmental defects. Maternal treatment with pan NOS inhibitors during early organogenesis caused severe malformations of the axial skeleton. In utero exposure during the fetal period induced limb reduction defects of vascular origin. Knock-out mice have been used to define the role of the various NOS isoforms on the origin of the abnormal development. Cardiovascular malformations, limb reduction defects, reduced growth and reduced survival have been observed in knock-out mice with targeted disruption of endothelial NOS (eNOS). Limited morphological changes were observed in mice lacking inducible NOS (iNOS) or neuronal NOS n(NOS). Results obtained with in vitro studies suggest that optimal levels of NO are required for neural tube closure. Disregulation of NO production was also recently proposed as a contributing mechanism in the origin of malformations associated with exposure to known environmental teratogens, such as valproic acid, thalidomide, copper deficiency, and diabetes.
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http://dx.doi.org/10.2174/1381612820666140205150437DOI Listing
June 2015

Editorial: Advances in developmental and reproductive toxicology.

Curr Pharm Des 2014 ;20(34):5363

Department of Medicine and Aging Sciences University "G. d'Annunzio" of Chieti-Pescara Via dei Vestini, Chieti, Italy.

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http://dx.doi.org/10.2174/1381612820666140205151500DOI Listing
June 2015

Inhibition of nitric oxide synthesis enhances teratogenic effects induced by valproic Acid.

In Vivo 2013 Jul-Aug;27(4):513-8

Department of Medicine and Aging Sciences, Faculty of Medicine, University G. d'Annunzio of Chieti-Pescara, Ortona, Italy.

Background/aim: The mechanism of valproic acid (VPA)-induced teratogenicity is poorly known. This study was carried out to probe into the potential consequences of nitric oxide (NO) deprivation on VPA teratogenicity.

Materials And Methods: On gestation day 8, mice were injected with a non-teratogenic dose (20 mg/kg) of the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl esther (L-NAME). Thirty minutes later, animals received a teratogenic dose of VPA (400 or 500 mg/kg). Developmental end-points were evaluated near the end of gestation.

Results: After treatment with VPA at 400 mg/kg, 35.2% of fetuses exhibited skeletal teratogenesis. The rate of skeletally affected fetuses significantly increased to 53.7% after L-NAME co-administration. In the group treated with VPA at 500 mg/kg group, L-NAME pre-treatment increased the incidence of exencephaly from 5.4% to 22.2%.

Conclusion: Inhibition of NO synthesis can result in an enhancement of VPA-induced teratogenesis.
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January 2014

mTrop1/Epcam knockout mice develop congenital tufting enteropathy through dysregulation of intestinal E-cadherin/β-catenin.

PLoS One 2012 28;7(11):e49302. Epub 2012 Nov 28.

Unit of Cancer Pathology, CeSI, University G. d'Annunzio Foundation, Chieti, Italy.

Congenital tufting enteropathy (CTE) is a life-threatening hereditary disease that is characterized by enteric mucosa tufting degeneration and early onset, severe diarrhea. Loss-of-function mutations of the human EPCAM gene (TROP1, TACSTD1) have been indicated as the cause of CTE. However, loss of mTrop1/Epcam in mice appeared to lead to death in utero, due to placental malformation. This and indications of residual Trop-1/EpCAM expression in cases of CTE cast doubt on the role of mTrop1/Epcam in this disease. The aim of this study was to determine the role of TROP1/EPCAM in CTE and to generate an animal model of this disease for molecular investigation and therapy development. Using a rigorous gene-trapping approach, we obtained mTrop1/Epcam -null (knockout) mice. These were born alive, but failed to thrive, and died soon after birth because of hemorrhagic diarrhea. The intestine from the mTrop1/Epcam knockout mice showed intestinal tufts, villous atrophy and colon crypt hyperplasia, as in human CTE. No structural defects were detected in other organs. These results are consistent with TROP1/EPCAM loss being the cause of CTE, thus providing a viable animal model for this disease, and a benchmark for its pathogenetic course. In the affected enteric mucosa, E-cadherin and β-catenin were shown to be dysregulated, leading to disorganized transition from crypts to villi, with progressive loss of membrane localization and increasing intracellular accumulation, thus unraveling an essential role for Trop-1/EpCAM in the maintenance of intestinal architecture and functionality.Supporting information is available for this article.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049302PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509129PMC
June 2013