Unveiling the Genetic Complexity of Teratozoospermia: Integrated Genomic Analysis Reveals Novel Insights into lncRNAs' Role in Male Infertility.

Male infertility is a global health issue, affecting over 20 million men worldwide. Genetic factors are crucial in various male infertility forms, including teratozoospermia. Nonetheless, the genetic causes of male infertility remain largely unexplored. In this study, we employed whole-genome sequencing and RNA expression analysis to detect differentially expressed (DE) long-noncoding RNAs (lncRNAs) in teratozoospermia, along with mutations that are exclusive to teratozoospermic individuals within these DE lncRNAs regions. Bioinformatic tools were used to assess variants' impact on lncRNA structure, function, and lncRNA-miRNA interactions. Our analysis identified 1166 unique mutations in teratozoospermic men within DE lncRNAs, distinguishing them from normozoospermic men. Among these, 64 variants in 23 lncRNAs showed potential regulatory roles, 7 variants affected 4 lncRNA structures, while 37 variants in 17 lncRNAs caused miRNA target loss or gain. Pathway Enrichment and Gene Ontology analyses of the genes targeted by the affected miRNAs revealed dysregulated pathways in teratozoospermia and a link between male infertility and cancer. This study lists novel variants and lncRNAs associated for the first time with teratozoospermia. These findings pave the way for future studies aiming to enhance diagnosis and therapy in the field of male infertility.

Administration of low-molecular-weight heparin in patients with two or more unsuccessful IVF/ICSI cycles: a multicenter cohort study.

To compare the effects of the administration of low-molecular-weight heparin (LMWH) in subfertile patients with two or more unsuccessful IVF/ICSI cycles. In this six-center two-arm retrospective cohort study, the study population (230 women) underwent a GnRH-antagonist protocol and was classified into two groups, according to the couse of LMWH or not. Groups were compared regarding the clinical and IVF/ICSI cycle characteristics and reproductive outcomes, whereas clinical pregnancy and miscarriage constituted the primary endpoints. Logistic regression analysis was performed to determine the potential predictors of clinical pregnancy, miscarriage and live birth rates using the Enter method. Baseline characteristics were comparable in the two groups. There was no statistically significant difference between the two study groups with regard neither to clinical pregnancy and miscarriage rates (33/133 vs. 20/97, p = .456 and 15/133 vs. 9/97, p = .624, respectively), nor to the secondary outcomes preset for this study (all p values >.05). Logistic regression revealed that age of the woman and ICSI and dose of gonadotrophins used were predictors of clinical pregnancy and live birth, respectively. In conclusion, there is no evidence to support the standard addition of LMWH in patients with two or more unsuccessful IVF/ICSI cycles.

Embryos from vitrified vs. fresh oocytes in an oocyte donation program: a comparative morphokinetic analysis.

OBJECTIVE: To compare the morphokinetic patterns of human embryos originating from vitrified oocytes (VITRI group) with those derived from freshly collected oocytes (CONTROL group) in oocyte donation cycles. DESIGN: This is a retrospective observational study. SETTING: Embryolab Fertility Clinic, Embryology Lab, Thessaloniki, Greece. PATIENT(S): The study included embryos from 421 vitrified oocytes from 58 oocyte donation cycles and 196 fresh oocytes from 23 oocyte donation cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Key time parameters, dynamic events, fertilization rates, degeneration rates, cleavage rates, blastocyst rates, pregnancy rates, clinical pregnancy rates, implantation rates, and live birth rates were estimated. RESULTS: The mean survival rate of vitrified oocytes was 92.58% (±7.42%). Fertilization rates were significantly different between the 2 groups (VITRI group: 71.92% ± 20.29% and CONTROL group: 80.65% ± 15.22%) whereas the degeneration, cleavage, blastocyst, pregnancy, clinical pregnancy, ongoing pregnancy, implantation, and live birth rates were not significantly different between embryos derived from fresh or vitrified oocytes. Time-lapse analysis showed no significant difference in any key time parameter. However, when examining dynamic parameters, first cell cycle (CC1) (t2 - tPB2: from the second polar body extrusion (tPB2) up to 2 cells (t2)) showed a significant difference whereas CC1a (t2 - tPNf: from fading of the pronuclei (tPNf) up to 2 cells (t2)) was at the threshold of significance. CONCLUSION(S): CC1 in vitrified oocytes exhibited a comparatively slower progression in contrast to fresh oocytes. Conversely, CC1a in vitrified oocytes demonstrated faster progression compared with fresh oocytes. It is worth noting that these temporary deviations had minimal impact on the subsequent development. Despite the clinical outcomes showing a decrease in the vitrified group, none of them reached statistical significance. This lack of significance could be attributed to the limited sample size of the study.

Gene-by-Sex Interactions: Genome-Wide Association Study Reveals Five SNPs Associated with Obesity and Overweight in a Male Population.

Obesity is a chronic health problem associated with severe complications and with an increasing prevalence in the Western world. Body-fat composition and distribution are closely associated with obesity, but the human body's composition is a sexually dimorphic trait, as differences between the two sexes are evident even from fetal life. The effect of sex hormones contributes to this phenomenon. However, studies investigating gene-by-sex interactions for obesity are limited. Therefore, the aim of the present study was to identify single-nucleotide polymorphisms (SNPs) associated with obesity and overweight in a male population. A genome-wide association study (GWAS) that included 104 control, 125 overweight, and 61 obese subjects revealed four SNPs associated with overweight (rs7818910, rs7863750, rs1554116, and rs7500401) and one SNP (rs114252547) associated with obesity in males. An in silico functional annotation was subsequently used to further investigate their role. Most of the SNPs were found in genes regulating energy metabolism and homeostasis, and some of them were expression quantitative trait loci (eQTL). These findings contribute to the understanding of the molecular mechanisms underlying obesity-related traits, especially in males, and pave the road for future research toward the improvement of the diagnosis and therapy of obese individuals.

Ovarian Stimulation with FSH Alone versus FSH plus a GnRH Antagonist for Elective Freezing in an Oocyte Donor/Recipient Programme: A Protocol for a Pilot Multicenter Observational Study.

Preliminary data have shown that it is possible to attempt in vitro fertilization (IVF) treatment in fresh cycles without the use of a gonadotropin-releasing hormone (GnRH) antagonist or any other medication to prevent the luteinizing hormone (LH) surge during ovarian stimulation. To date, there is no information on this topic in the context of a prospective controlled trial. However, as prevention of the LH surge is an established procedure in fresh cycles, the question is whether such a study can be performed in frozen cycles. We aim to perform a pilot study in order to compare the efficacy of a protocol using FSH alone with that of a protocol using follicle-stimulating hormone (FSH) plus a GnRH antagonist for controlled ovarian hyperstimulation (COH) in cycles of elective freezing in the context of a donor/recipient program. This is a seven-center, two-arm prospective pilot cohort study conducted at the respective Assisted Reproductive Units in Greece. The hypothesis to be tested is that an ovarian stimulation protocol that includes FSH alone without any LH surge prevention regimens is not inferior to a protocol including FSH plus a GnRH antagonist in terms of the clinical outcome in a donor/recipient model. The results of the present study are expected to show whether the addition of the GnRH antagonist is necessary in terms of the frequency of LH secretory peaks and progesterone elevations >1 ng/mL during the administration of the GnRH antagonist according to the adopted frequency of blood sampling in all Units.

Whole-Genome Profile of Greek Patients with Teratozοοspermia: Identification of Candidate Variants and Genes.

Male infertility is a global health problem that affects a large number of couples worldwide. It can be categorized into specific subtypes, including teratozoospermia. The present study aimed to identify new variants associated with teratozoospermia in the Greek population and to explore the role of genes on which these were identified. For this reason, whole-genome sequencing (WGS) was performed on normozoospermic and teratozoospermic individuals, and after selecting only variants found in teratozoospermic men, these were further prioritized using a wide range of tools, functional and predictive algorithms, etc. An average of 600,000 variants were identified, and of them, 61 were characterized as high impact and 153 as moderate impact. Many of these are mapped in genes previously associated with male infertility, yet others are related for the first time to teratozoospermia. Furthermore, pathway enrichment analysis and Gene ontology (GO) analyses revealed the important role of the extracellular matrix in teratozoospermia. Therefore, the present study confirms the contribution of genes studied in the past to male infertility and sheds light on new molecular mechanisms by providing a list of variants and candidate genes associated with teratozoospermia in the Greek population.

Poor ovarian response and the possible role of natural and modified natural cycles.

About 20% of women undergoing in vitro fertilization struggle with poor ovarian response, indicating a poor prognosis related to low response following ovarian stimulation. Indeed, poor ovarian response, that is associated with both high cancelation rates and low live birth rates, still represents one of the most important therapeutic challenges in in vitro fertilization. In this context, natural cycle/modified natural cycle-in vitro fertilization, as a 'milder' approach, could be a reasonable alternative to high-dose/conventional ovarian stimulation in poor ovarian responders, with the aim to retrieve a single oocyte with better characteristics that may result in a single top-quality embryo, transferred to a more receptive endometrium. Moreover, modified natural cycle-in vitro fertilization may be cost-effective because of the reduced gonadotropin consumption. Several studies have been published during the last 20 years reporting conflicting results regarding the use of natural cycle/modified natural cycle-in vitro fertilization in women with poor ovarian response; however, while most of the studies concluded that mild stimulation regimens, including natural cycle/modified natural cycle-in vitro fertilization, have low, but acceptable success rates in this difficult group of patients, others did not replicate these findings. The aim of this narrative review is to appraise the current evidence regarding the use of natural cycle/modified natural cycle-in vitro fertilization in poor ovarian responders.

Follitropin Alpha for assisted reproduction: an analysis based on a non-interventional study in Greece.

OBJECTIVE: To conduct an economic evaluation estimating the cost per live birth after controlled ovarian stimulation (COS) using Follitropin Alpha (Gonal-F), in the Greek National Health System setting. A secondary objective was to predict the live birth rateof the In Vitro Fertilization (IVF) procedure. METHODS: A single arm, multi-center, prospective, non-interventional study was conducted on which economic, efficacy and safety data were collected by six of the largest IVF centers. The participants were 350 female patients. Three statistical methods were employed for the analysis of the study outcomes, namely (a) Generalized Linear Modeling for the estimation of the costs of IVF treatment, (b) multivariable logistic regression and (c) an Artificial Neural Network (ANN) model for live birth prediction. RESULTS: The mean total cost of IVF therapy per patient was estimated at €3728 (95% CI: €3679-€3780), while the total cost per live birth was €14,872 (95% CI: €12,441-€17,951). The live birth rate after 3 complete IVF cycles was estimated at 22.9%, while the percentage of those suffering from OHSS was limited at 0.57%. In logistic regression, the Ovarian Sensitivity Index (OSI) was a factor found to be positively associated with live birth (OR 7.39, 95% CI: 1.84-29.71). For the ANN, important predictors included number of gestational sacs and the duration of infertility. CONCLUSION: The present study constitutes the largest single-arm study based on real data in Greece to date. The cost of IVF treatment and the cost per live birth are not insignificant in this NHS setting. The live birth rate, cost per oocyte, and the cost per live birth are in line with literature. OSI was a main contributing factor to the accurate prediction of the live birth rate, while age and BMI were found to be negatively correlated.

Investigating the impact of different strategies for endometrial preparation in frozen cycles considering normal responders undergoing IVF/ICSI cycles: a multicenter retrospective cohort study.

Uncertainty exists concerning the type, adjunct, or dose of regimen to offer in frozen cycles in infertile women undergoing IVF/ICSI. Current systematic reviews have failed to identify one method of endometrial preparation as being more effective than another, whereas many IVF Units use variable and mixed protocols mainly based on their experience and convenience of use. Thus, we performed a four-center two-arm retrospective cohort study, encompassing 439 cycles in 311 women. The modalities analyzed were: Modified natural cycle without and with luteal support (Groups 1,2) and Hormone Replacement cycle (HRC) with and without GnRHa suppression (Groups 3,4). Various schemes of progesterone and estradiol were used and compared. χ2 tests for categorical data and t-tests for continuous data were employed, stratifying by exposure, along with univariate and multivariable Logistic Regression models and subgroup analyses, according to the number of embryos transferred (1 vs. ≥2) and day of transfer (d2 vs. d5). Group 3 presented with statistically significant higher live birth and miscarriage rates in comparison to Group 4 (RR = 5.87, 95%CI: 2.44-14.14 and RR = 0.19, 95%CI: 0.06-0.60, respectively), findings that persisted in subgroup analyses according to the day of transfer and the number of embryos transferred. Progesterone administration through the combination of vaginal tabs and gel was associated with lower clinical pregnancy rates when compared to tabs (RR = 0.19, 95%CI: 0.05-0.71). The stable estrogen protocol compared to increasing estrogen at day 5 was associated with a higher positive hCG test and clinical pregnancy rate, while the progesterone through vaginal tabs was linked with lower miscarriages compared either with gel or combinations. In conclusion, HRC with GnRHa appears to be superior to HRC without GnRHa, concerning live birth and miscarriage, especially when the number of embryos transferred are ≥2 and irrespective of day of transfer. The use of progesterone vaginal tabs compared to gel or combinations is associated with better outcomes. Age is a significant predictor of a negative hCG test and clinical pregnancy rates. A properly conducted RCT is needed to evaluate the optimal frozen embryo transfer preparation strategy.Abbreviations: SD: standard deviation; BMI: body mass index; PCOS: polycystic ovarian syndrome; IQR: interquartile range; FSH: follicle-stimulating hormone; LH: luteinizing hormone; TSH: thyroid-stimulating hormone.

Endometrial injury for patients with endometriosis and polycystic ovary syndrome undergoing medically assisted reproduction: current data and a protocol.

We propose a study protocol capable of improving clinical outcomes following medically assisted reproduction (MAR) in infertile women with endometriosis and polycystic ovary syndrome (PCOS). The proposed research derives from the published evidence on the positive impact from endometrial injury (EI) and the beneficial nature of the intervention towards improved implantation rates. We primarily refer to the cluster of events and hypotheses, such as the mechanical cascade, the inflammatory response per se, the events accompanying wound healing, the immune cell recruitment and protein involvement, alterations in gene expression and the neo-angiogenesis theories, which have been previously investigated for this purpose. We are also exploring the possible problems in MAR cycles with negative outcomes in PCOS and endometriosis patients and we are proposing potential mechanisms on how this intervention might work. Our hypothesis states that the EI before the initiation of the MAR cycle can affect clinical pregnancy rates in patients with the aforementioned pathologies.