Paternal Effects on Embryonic, Fetal and Offspring Health: The Role of Epigenetics in the ICSI and ROSI Era

Paternal effects on the developmental potential of human embryos have been studied since the early 1990s, particularly with respect to newly emerging assisted reproduction technologies. Both genetic and epigenetic paternal effects can influence postfertilization development and cause implantation failure or miscarriage. However, it is only over the last few years that issues related to paternal effects associated with different assisted reproduction techniques on the health status of newborn and adult progeny have been focused. At the same time, new findings point out different, yet unexplored, areas of research into the potentially responsible factors, including the activity of the sperm-derived oocyte-activating factor and the oocyte signaling pathways mediating its action, the methylation status of both imprinted and non-imprinted genes, correct replacement of sperm nuclear protamines with oocyte-derived histones, the histone acetylation status, and the function of sperm-borne small RNAs. It is increasingly important to know how these developmentally important epigenetic regulators can be altered in the context of the current micromanipulation-assisted fertilization techniques, intracytoplasmic sperm injection (ICSI) and round spermatid injection (ROSI). Last but not least, transgenerational transmission of acquired, environmentally conditioned disorders from fathers to offspring is a newly emerging issue which warrants further research

Patient-tailored reproductive health care

Patient-tailored reproductive health care represents an important challenge for the current practice of infertility prevention, diagnosis and treatment. This approach is based on the concept of precision medicine, taking into account genetic, epigenetic, metabolic and lifestyle characteristics of each individual patient. Even though this goal is still far from being wholly achieved, some aspects can already be put into practice nowadays. Personalization can be based on a comprehensive analysis and synthesis of the patients' personal and familial history, taking into account outcomes of previous assisted reproduction technique (ART) attempts, if available, and confronting these data with the past and the latest clinical and laboratory examination outcomes. As to the male fertility status, there is an urgent need for the inclusion of an accurate diagnostic workup of infertile men leading to the choice of the most adequate follow-up for each particular pathological condition. The follow-up of women who have become pregnant as a result of the ART attempt has also to be personalized. This should be done taking into account both the basic data extracted from the patient's file and those derived from the experience gathered during the latest attempt. Last but not least, the individual condition of each couple has to be taken into account when counseling the patients as to the urgency of the actions to be taken to resolve their fertility problem

Application of a new ultrasound criterion for the diagnosis of polycystic ovary syndrome

Objective: To define which ultrasound criteria could replace the classic Rotterdam criteria as the best indicator of the risk of developing endocrine– metabolic changes in women with polycystic ovary syndrome (PCOS). Materials and methods: This multicenter cross-sectional study included 200 women with PCOS and one control group of 111 women without PCOS. The primary outcomes to be considered were follicular count, hirsutism, total testosterone levels, free androgen index (FAI), and insulin sensitivity (HOMAIR), and the secondary outcome was the anti-Müllerian hormone (AMH) level. Results: The main finding in this study points toward a different ultrasound criterion—23 or more follicles of any size in at least one ovary, which is postulated as an alternative to the classic criterion described in the Rotterdam consensus. This criterion correlates better with the other two PCOS criteria and also identifies women at increased risk of hirsutism (Ferriman–Gallwey score: 6.08 ± 3.54 vs. 4.44 ± 3.75, p < 0.0001), total testosterone levels (2.24 ± 0.298 vs. 1.42 ± 1.530, p = 0.0001), FAI (4.85 ± 0.83 vs. 2.12 ± 1.93, p < 0.001), and insulin resistance (HOMA-IR: 1.74 ± 0.182 vs. 1.504 ± 0.230, p = 0.001) more accurately. Regarding AMH, large differences in their mean values were observed between the groups (7.07 vs. 4.846 ng/ml, p = 0.000). However, these differences depended on age. Conclusion: The ovarian ultrasound examination with 23 or more follicles of any size in any of the ovaries constitutes a powerful tool to accurately diagnose PCOS and to associate it with metabolic–endocrine processes such as hyperandrogenism and insulin resistance

Assessing the testicular sperm microbiome: a low-biomass site with abundant contamination

We thank all men who generously donated testicular material for the purpose of this study. We also acknowledge the research support by Copan Italia S.p.A Inc., and Clearblue, SPD Swiss Precision Diagnostics GmbH. This study is part of a PhD Thesis conducted at the Official Doctoral Program in Biomedicine of the University of Granada, Spain. This work was supported by the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and European Regional Development Fund (FEDER): grant numbers RYC-2016-21199 and ENDORE (SAF2017-87526-R); by FEDER/Junta de Andalucia-Consejeria de Economia y Conocimiento: MENDO (B-CTS-500-UGR18); by Junta de Andalucia: (PAIDI P20_00158) by the University of Granada, Plan Propio de Investigacion 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES), and the Junta de Andalucia, Consejeria de Conocimiento, Investigacion y Universidades and European Regional Development Fund: (SOMM17/6107/UGR); by Spanish Ministry of Science, Innovation, and Universities: (PRE2018085440 and FPU19/01638); and by Spanish Ministry of Education, Culture, and Sport: (FPU15/01193). Funding for open access charge: Universidad de Granada/CBUA Sequence data of all testicular spermatozoa and negative control samples have been deposited in the National Centre for Biotechnology Information (NCBI) Sequence Read Archive (SRA) database (http://www.ncbi.nlm.nih.gov/sra) under the BioProject ID PRJNA643898. The preliminary results of this study were presented as a poster communication at the 35th Annual ESHRE Meeting (Vienna, 2019).Research question: The semen harbours a diverse range of microorganisms. The origin of the seminal microbes, however, has not yet been established. Do testicular spermatozoa harbour microbes and could they potentially contribute to the seminal microbiome composition? Design: The study included 24 samples, comprising a total of 307 testicular maturing spermatozoa. A high-throughput sequencing method targeting V3 and V4 regions of 16S rRNA gene was applied. A series of negative controls together with stringent in-silico decontamination methods were analysed. Results: Between 50 and 70% of all the detected bacterial reads accounted for contamination in the testicular sperm samples. After stringent decontamination, Blautia (P = 0.04), Cellulosibacter (P = 0.02), Clostridium XIVa (P = 0.01), Clostridium XIVb (P = 0.04), Clostridium XVIII (P = 0.02), Collinsella (P = 0.005), Prevotella (P = 0.04), Prolixibacter (P = 0.02), Robinsoniella (P = 0.04), and Wandonia (P = 0.04) genera demonstrated statistically significant abundance among immature spermatozoa. Conclusions: Our results indicate that the human testicle harbours potential bacterial signature, though in a low-biomass, and could contribute to the seminal microbiome composition. Further, applying stringent decontamination methods is crucial for analysing microbiome in low-biomass site.Copan Italia S.p.A Inc.ClearblueSPD Swiss Precision Diagnostics GmbHSpanish GovernmentEuropean Commission RYC-2016-21199 SAF2017-87526-RFEDER/Junta de Andalucia-Consejeria de Economia y Conocimiento: MENDO B-CTS-500-UGR18 Junta de Andalucia PAIDI P20_00158University of Granada, Plan Propio de Investigacion 2016, Excellence actions: Units of ExcellenceUnit of Excellence on Exercise and Health (UCEES)Junta de Andalucia Consejeria de Conocimiento, Investigacion y UniversidadesEuropean Commission SOMM17/6107/UGRSpanish Government PRE2018085440 FPU19/01638 FPU15/01193Universidad de Granada/CBUA Sequence BioProject PRJNA64389

Tubal factor infertility: which is the possible role of tubal microbiota? A fresh look to a busy corner focusing on the potential role of hysteroscopy.

There is a growing body of evidence regarding the importance of the urogenital microbiota associated to reproductive outcomes, both for achieving pregnancy naturally or with the use of assisted reproductive technology (ART). The role of the vaginal and endometrial microbiota in potential infertility can be applied to the tubal milieu, which is currently a hot topic in clinical research. Given that the incidence of tubal infertility factor is constantly increasing, and the incidence of previously known infectious causes is declining, it is extremely important to encourage research to identify the real composition of the tubal microbiota. On the other hand, the potential importance of the role of hysteroscopy in elucidating tubal infertility factor is currently underestimated and not completely clarified. This short review article presents the most recent evidence on the possible role of tubal microbiota on female infertility, focusing on the role of its potential diagnostic effectiveness and, in particular, on the role of hysteroscopy

CD3- Leukocytes Present in the Human Uterus During Early Placentation: Phenotypic and Morphologic Characterization of the CD56++ Population

In this study, the CD3- LGL/NK cells present in the pregnant human uterus have been characterized. Phenotypic and morphologic analyses of decidual LGL revealed many similarities to the minor CD56bright+, CD16- subset in peripheral blood, but there were some important differences. The relative surface density of CD56+ is greatly increased on decidual LGL to 22 x that found on the majority of CD56 peripheral blood NK cells. The CD56bright cells in decidua show LGL morphology, whereas in peripheral blood, they are .mainly agranular. Proliferation of CD56+ cells occurs predominantly during the nonpregnant secretory (luteal) phase, indicating these CD56+ uterine LGL do not migrate as terminally differentiated cells. The appearance of CD56 cells was examined at the ultrastructural level using immunoelectron microscopy. Cells with phenotypic characteristics of decidual LGL occur in a higher percentage (1.11%) in the peripheral blood of women of reproductive age than in men (0.66%). On the basis of these results, it is proposed that the CD56bright+ uterine leukocytes represent a distinctive, hormonally regulated subset possibly adapted to control human placentation.Peer Reviewe

Vitamin D and Gestational Diabetes Mellitus: is there a link?

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Molecular Clues to Understanding Causes of Human-Assisted Reproduction Treatment Failures and Possible Treatment Options

More than forty years after the first birth following in vitro fertilization (IVF), the success rates of IVF and of IVF-derived assisted reproduction techniques (ART) still remain relatively low. Interindividual differences between infertile couples and the nature of the problems underlying their infertility appear to be underestimated nowadays. Consequently, the molecular basis of each couple’s reproductive function and of its disturbances is needed to offer an individualized diagnostic and therapeutic approaches to each couple, instead of applying a standard or minimally adapted protocols to everybody. Interindividual differences include sperm and oocyte function and health status, early (preimplantation) embryonic development, the optimal window of uterine receptivity for the implanting embryo, the function of the corpus luteum as the main source of progesterone production during the first days of pregnancy, the timing of the subsequent luteoplacental shift in progesterone production, and aberrant reactions of the uterine immune cells to the implanting and recently implanted embryos. In this article, the molecular basis that underlies each of these abnormalities is reviewed and discussed, with the aim to design specific treatment options to be used for each of them