Lack of GNAS re-methylation during oogenesis may be a cause of sporadic pseudohypoparathyroidism type Ib (PHP1B)

Context Pseudohypoparathyroidism type Ib (PHP1B) is characterized by hypocalcemia and hyperphosphatemia due to PTH-resistance in the proximal renal tubules. Maternal pathogenic STX16/GNAS variants leading to maternal epigenetic GNAS changes impair expression of the stimulatory G protein alpha-subunit (Gsα) thereby causing autosomal dominant PHP1B (AD-PHP1B). In contrast, genetic defects responsible for sporadic PHP1B (sporPHP1B) remain mostly unknown. Objective Determine whether PHP1B encountered after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) causes GNAS re-methylation defects similar to those in sporPHP1B. Design Retrospective analysis. Results Nine among thirty-six sporPHP1B patients investigated since 2000, all with LOM at the three maternal GNAS DMRs and gain-of-methylation (GOM) at the paternal NESP DMR, had been conceived through IVF or ICSI. Besides abnormal GNAS methylation, IVF/ICSI-PHP1B cases revealed no additional imprinting defects. Three of these PHP1B patients have dizygotic twins and four have IVF/ICSI-conceived siblings, all with normal GNAS methylation; two unaffected younger siblings were conceived naturally. Conclusion Sporadic and IVF/ICSI-conceived PHP1B patients revealed indistinguishable epigenetic changes at all four GNAS DMRs thus suggesting a similar underlying disease mechanism. Given that re-methylation at the three maternal DMRs occurs during oogenesis, male factors are unlikely to cause LOM post-fertilization. Instead, at least some of the sporPHP1B variants could be caused by a defect(s) in an oocyte-expressed gene that is required for fertility and for re-establishing maternal GNAS methylation imprints. It remains uncertain, however, whether lack of GNAS re-methylation alone impairs oocyte maturation because of insufficient Gsα expression, thus necessitating Assisted Reproductive Technology (ART) for conception.

Genetic Regulation of Avian Testis Development

As in other vertebrates, avian testes are the site of spermatogenesis and androgen production. The paired testes of birds differentiate during embryogenesis, first marked by the development of pre-Sertoli cells in the gonadal primordium and their condensation into seminiferous cords. Germ cells become enclosed in these cords and enter mitotic arrest, while steroidogenic Leydig cells subsequently differentiate around the cords. This review describes our current understanding of avian testis development at the cell biology and genetic levels. Most of this knowledge has come from studies on the chicken embryo, though other species are increasingly being examined. In chicken, testis development is governed by the Z-chromosome-linked DMRT1 gene, which directly or indirectly activates the male factors, HEMGN, SOX9 and AMH. Recent single cell RNA-seq has defined cell lineage specification during chicken testis development, while comparative studies point to deep conservation of avian testis formation. Lastly, we identify areas of future research on the genetics of avian testis development.

Changing trends of causative factors in antenatal mothers with bad obstetric history: a retrospective study

Background: The death of an infant, in utero or after birth has been a devastating experience for parents and clinicians alike. Various efforts are being made to make an accurate diagnosis of such pregnancy losses at the earliest to prevent the emotional and physical stress that the woman undergoes. This study aims to assess the changing trends in risk factors and outcome of pregnancies in cases of bad obstetric history (BOH) and to identify the newly emerging maternal and fetal factors contributing to incidence of pregnancy loss.Methods: This study is a retrospective analysis of antenatal women with BOH attending the obstetrics and gynecology OPD at Chettinad hospital. The study was conducted during a time period of 1 year (May 2019 to May 2020).Results: The medical complications and underlying causes for BOH were analysed among the study group. Out of 41 women, 6 were diagnosed to have gestational diabetes mellitus (GDM), 8 were found to be hypertensive and 1 APLA positive. Neonatal mortality was encountered in 2 cases, attributing to Inborn error of metabolism. However, the cause for BOH remained unexplained in 3 individuals.Conclusions: A full work-up can be initiated after two consecutive losses to identify and treat the various causes responsible for BOH. Lot of further studies and research are being conducted to unravel the mystery in these cases. Despite these efforts, the male factors contributing to recurrent pregnancy loss have remained largely unexplored.

Nutraceutical management of male infertility-towards new generation therapeutics

Infertility is one of the most significant public health-related concerns globally. Both male and female factors can cause it. Male factors include poor sperm quality, idiopathic oligospermia, asthenozoospermia, and isolated asthenozoospermia. Many substances, collectively known as nutraceuticals, have been studied for their capacity to enhance hormonal state and sperm parameters through different mechanisms. Nutraceuticals are components in dietary supplements prescribed to prevent or treat a wide range of diseases. This article aims to highlight certain nutrients that can help improve male fertility based on recent advancements in the management of male infertility.

Oxidative Stress and Male Fertility: Role of Antioxidants and Inositols

Infertility is defined as a couple’s inability to conceive after at least one year of regular unprotected intercourse. This condition has become a global health problem affecting approximately 187 million couples worldwide and about half of the cases are attributable to male factors. Oxidative stress is a common reason for several conditions associated with male infertility. High levels of reactive oxygen species (ROS) impair sperm quality by decreasing motility and increasing the oxidation of DNA, of protein and of lipids. Multi-antioxidant supplementation is considered effective for male fertility parameters due to the synergistic effects of antioxidants. Most of them act by decreasing ROS concentration, thus improving sperm quality. In addition, other natural molecules, myo-inositol (MI) and d-chiro–inositol (DCI), ameliorate sperm quality. In sperm cells, MI is involved in many transduction mechanisms that regulate cytoplasmic calcium levels, capacitation and mitochondrial function. On the other hand, DCI is involved in the downregulation of steroidogenic enzyme aromatase, which produces testosterone. In this review, we analyze the processes involving oxidative stress in male fertility and the mechanisms of action of different molecules.

P–568 Homozygous Pathogenic Variants in ACTL9 Cause Fertilization Failure and Male Infertility in Human and Mouse

Study question What are the other male factors that cause total fertilization failure (TFF) excepting for variants in PLCZ1? Summary answer Homozygous variants in ACTL9 (actin like 9) cause abnormal localization of PLCζ in a loosened perinuclear theca (PT) structure and leads to TFF. What is known already In previous studies, investigators have reported that the female factors in TFF after intracytoplasmic sperm injection (ICSI) include pathogenic variants in WEE2, TLE6, and TUBB8, whereas for male factors, pathogenic variants in PLCZ1 were reported to be the primary cause of TFF, which account for approximately 30% of couples with male factors in TFF excluding globozoospermia. Most recently, it was reported that pathogenic variants in ACTL7A led to reduced expression and abnormal localization of PLCζ, thereby identifying this genetic variant as a potential cause of TFF. Study design, size, duration Fifty-four infertile couples with TFF or poor fertilization (fertilization rate of < 20%) at the Reproductive and Genetic Hospital of CITIC-Xiangya during January 2014 to June 2020 were recruited into this study. Participants/materials, setting, methods Male factors were identified in (MOAT). WES analysis was used to analyze the genetic factors of individuals with male factors. Sperm morphological study was conducted by H&E staining and TEM. Immunostaining of PLCζ was used to analyze the status of sperm-borne activation factor. A knock-in mouse model was generated by CRISPER-Cas9 technology. Sperm from homozygous Actl9 variant mice were analyzed by TEM and ICSI. ICSI with AOA was performed in couples with ACTL9 variants. Main results and the role of chance A total of 54 couples with TFF or poor fertilization were screened, with 21 couples determined to have a male infertility factor by MOAT. Whole-exome sequencing of these 21 male individuals identified three homozygous pathogenic variants in ACTL9 in three individuals. ACTL9 variations led to abnormal ultrastructure of the PT, with PLCζ absent in the head and present in the neck of the mutant sperm, which contributed to failed normal calcium oscillations in oocytes and subsequent TFF. The key roles of ACTL9 in the PT structure and TFF after ICSI were further confirmed in Actl9-mutated mouse model. Furthermore, assisted oocyte activation by calcium ionophore exposure successfully overcame TFF and achieved live births in a couple with an ACTL9 variant. Limitations, reasons for caution The mechanism of how ACTL9 regulate PLCζ remains unknown. Wider implications of the findings: It provided a genetic marker and a therapeutic option for individuals who have undergone ICSI without successful fertilization. Trial registration number not applioable

Treatment of Human Infertility

The human infertility is a major problem at this time in entire world. Some important factors that responsible for this cause like as Daily routine, Food contents, less physical activity etc. About 40% infertility cases count due to male factors. The spermatogenetic failure is one of the major causes of male infertility while the in female infertility is due to Pelvic inflammatory disease (PID), uterine problems, previous tubal ligation, Endometriosis etc. A number of medicinal plants used in the treatment of this disorder. So in this review, we have summarized most of the data dealing with the positive effects of plant extracts on spermatogenesis.

Dietary Antioxidants in the Treatment of Male Infertility: Counteracting Oxidative Stress

Infertility affects about 15% of the population and male factors only are responsible for ~25–30% of cases of infertility. Currently, the etiology of suboptimal semen quality is poorly understood, and many environmental and genetic factors, including oxidative stress, have been implicated. Oxidative stress is an imbalance between the production of free radicals, or reactive oxygen species (ROS), and the capacity of the body to counteract their harmful effects through neutralization by antioxidants. The purpose of this review, by employing the joint expertise of international researchers specialized in nutrition and male fertility areas, is to update the knowledge about the reproductive consequences of excessive ROS concentrations and oxidative stress on the semen quality and Assisted Reproduction Techniques (ART) clinical outcomes, to discuss the role of antioxidants in fertility outcomes, and finally to discuss why foods and dietary patterns are more innocuous long term solution for ameliorating oxidative stress and therefore semen quality results and ART fertility outcomes. Since this is a narrative review and not a systematic/meta-analysis, the summarized information in the present study should be considered cautiously.

Maternal and Paternal Representations in Assisted Reproductive Technology and Spontaneous Conceiving Parents: A Longitudinal Study

Aim of this study was to investigate whether parental mental representations during pregnancy and after delivery differed between parents who conceived after Assisted Reproductive Treatments (ART) and spontaneous conceiving (SC) parents. Effects of specific ART variables (previous ART attempts, treatment type and cause of infertility) were also taken into account. Seventeen ART couples and 25 SC couples were recruited at Santa Maria Nuova Hospital (Reggio Emilia, Italy). At both 32 weeks of gestation (T1) and 3 months postpartum (T2) participants completed the Semantic Differential of the IRMAG, a self-report tool which measures specific domains of mental representations pertaining either individual (Child, Self-as-woman/man, and Partner) or parental (Self-as-parent, Own parent) characteristics. Results showed that ART parents had significantly more positive representations of the child compared to SC parents, while the scores at Partner dimension improved from T1 to T2 for SC parents only. With regards to ART history, scores at the Self-as-woman/man dimension were significantly less positive for ICSI than IVF parents and improved substantially from T1 to T2 only in case of mothers with previous ART attempts and of fathers at the first ART cycle. The representation of own parents increased from T1 to T2 in case of infertility diagnosis due to male factors, while a decrease emerged when infertility was due to female factors. Findings suggest the need to investigate parental mental representations after ART, in order to improve the understanding on the transition to parenthood of infertile couples and to target more specific intervention for parenting support.