Pharmacogenetics of FSH Action in the Male

Male infertility is a major contributor to couple infertility, however in most cases it remains “idiopathic” and putative treatment regimens are lacking. This leads to a scenario in which intra-cytoplasmic spermatozoa injection (ICSI) is widely used in idiopathic male infertility, though the treatment burden is high for the couple and it entails considerable costs and risks. Given the crucial role of the Follicle-stimulating hormone (FSH) for spermatogenesis, FSH has been used empirically to improve semen parameters, but the response to FSH varied strongly among treated infertile men. Single nucleotide polymorphisms (SNPs) within FSH ligand/receptor genes (FSHB/FSHR), significantly influencing reproductive parameters in men, represent promising candidates to serve as pharmacogenetic markers to improve prediction of response to FSH. Consequently, several FSH-based pharmacogenetic studies have been conducted within the last years with unfortunately wide divergence concerning selection criteria, treatment and primary endpoints. In this review we therefore outline the current knowledge on single nucleotide polymorphisms (SNPs) in the FSH and FSH receptor genes and their putative functional effects. We compile and critically assess the previously performed pharmacogenetic studies in the male and propose a putative strategy that might allow identifying patients who could benefit from FSH treatment

Mutations in a Novel, Cryptic Exon of the Luteinizing Hormone/Chorionic Gonadotropin Receptor Gene Cause Male Pseudohermaphroditism

Joerg Gromoll and colleagues describe the identification and characterization of a novel exon that appears to be a new regulatory element within the luteinizing hormone/chorionic gonadotropin receptor gene of three individuals with Leydig cell hypoplasia

Machine learning based prediction models in male reproductive health: Development of a proof-of-concept model for Klinefelter Syndrome in azoospermic patients

Background Due to the highly variable clinical phenotype, Klinefelter Syndrome is underdiagnosed. Objective Assessment of supervised machine learning based prediction models for identification of Klinefelter Syndrome among azoospermic patients, and comparison to expert clinical evaluation. Materials and methods Retrospective patient data (karyotype, age, height, weight, testis volume, follicle-stimulating hormone, luteinizing hormone, testosterone, estradiol, prolactin, semen pH and semen volume) collected between January 2005 and June 2019 were retrieved from a patient data bank of a University Centre. Models were trained, validated and benchmarked based on different supervised machine learning algorithms. Models were then tested on an independent, prospectively acquired set of patient data (between July 2019 and July 2020). Benchmarking against physicians was performed in addition. Results Based on average performance, support vector machines and CatBoost were particularly well-suited models, with 100% sensitivity and >93% specificity on the test dataset. Compared to a group of 18 expert clinicians, the machine learning models had significantly better median sensitivity (100% vs. 87.5%, p = 0.0455) and fared comparably with regards to specificity (90% vs. 89.9%, p = 0.4795), thereby possibly improving diagnosis rate. A Klinefelter Syndrome Score Calculator based on the prediction models is available on . Discussion Differentiating Klinefelter Syndrome patients from azoospermic patients with normal karyotype (46,XY) is a problem that can be solved with supervised machine learning techniques, improving patient care. Conclusions Machine learning could improve the diagnostic rate of Klinefelter Syndrome among azoospermic patients, even more for less-experienced physicians

A microRNA cluster in the Fragile-X region expressed during spermatogenesis targets FMR1.

Testis-expressed X-linked genes typically evolve rapidly. Here, we report on a testis-expressed X-linked microRNA (miRNA) cluster that despite rapid alterations in sequence has retained its position in the Fragile-X region of the X chromosome in placental mammals. Surprisingly, the miRNAs encoded by this cluster (Fx-mir) have a predilection for targeting the immediately adjacent gene, Fmr1, an unexpected finding given that miRNAs usually act in trans, not in cis Robust repression of Fmr1 is conferred by combinations of Fx-mir miRNAs induced in Sertoli cells (SCs) during postnatal development when they terminate proliferation. Physiological significance is suggested by the finding that FMRP, the protein product of Fmr1, is downregulated when Fx-mir miRNAs are induced, and that FMRP loss causes SC hyperproliferation and spermatogenic defects. Fx-mir miRNAs not only regulate the expression of FMRP, but also regulate the expression of eIF4E and CYFIP1, which together with FMRP form a translational regulatory complex. Our results support a model in which Fx-mir family members act cooperatively to regulate the translation of batteries of mRNAs in a developmentally regulated manner in SCs

Применение микробиологических методов для повышения нефтеотдачи на примере нефтяного месторождения Мухто (Сахалинская область)

Подбор и применение микробиологического метода увеличения нефтеотдачи на месторождении РН-Сахалинморнефтегаз.Актуальность этого метода заключается в том, что этот метод позволяет извлекать трудноизвлекаемые запасы нефти, которые увеличиваются с каждым годом. В этой работе выбирается наиболее эффективный микробный агент, и рассчитывается рентабельность этого нововведения для компании.Selection and application of the microbiological method of increasing oil recovery at the RN-Sakhalinmorneftegaz.The relevance of this method lies in the fact that this method allows you to extract hard-to-recover oil reserves, which increase every year. In this paper, the most effective microbial agent is selected, and the profitability of this innovation for the company is calculated

Interindividual variation in DNA methylation at a putative POMC metastable epiallele Is associated with obesity

The estimated heritability of human BMI is close to 75%, but identified genetic variants explain only a small fraction of interindividual body-weight variation. Inherited epigenetic variants identified in mouse models named “metastable epialleles” could in principle explain this “missing heritability.” We provide evidence that methylation in a variably methylated region (VMR) in the pro-opiomelanocortin gene (POMC), particularly in postmortem human laser-microdissected melanocyte-stimulating hormone (MSH)-positive neurons, is strongly associated with individual BMI. Using cohorts from different ethnic backgrounds, including a Gambian cohort, we found evidence suggesting that methylation of the POMC VMR is established in the early embryo and that offspring methylation correlates with the paternal somatic methylation pattern. Furthermore, it is associated with levels of maternal one-carbon metabolites at conception and stable during postnatal life. Together, these data suggest that the POMC VMR may be a human metastable epiallele that influences body-weight regulation

Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility

We conducted a genome-wide association study in a large population of infertile men due to unexplained spermatogenic failure (SPGF). More than seven million genetic variants were analysed in 1,274 SPGF cases and 1,951 unaffected controls from two independent European cohorts. Two genomic regions were associated with the most severe histological pattern of SPGF, defined by Sertoli cell-only (SCO) phenotype, namely the MHC class II gene HLA-DRB1 (rs1136759, P = 1.32E-08, OR = 1.80) and an upstream locus of VRK1 (rs115054029, P = 4.24E-08, OR = 3.14), which encodes a protein kinase involved in the regulation of spermatogenesis. The SCO-associated rs1136759 allele (G) determines a serine in the position 13 of the HLA-DR beta 1 molecule located in the antigen-binding pocket. Overall, our data support the notion of unexplained SPGF as a complex trait influenced by common variation in the genome, with the SCO phenotype likely representing an immune-mediated condition. A GWAS in a large case-control cohort of European ancestry identifies two genomic regions, the MHC class II gene HLA-DRB1 and an upstream locus of VRK1, that are associated with the most severe phenotype of spermatogenic failure

A One-Step Real-Time Multiplex PCR for Screening Y-Chromosomal Microdeletions without Downstream Amplicon Size Analysis

BACKGROUND: Y-chromosomal microdeletions (YCMD) are one of the major genetic causes for non-obstructive azoospermia. Genetic testing for YCMD by multiplex polymerase chain reaction (PCR) is an established method for quick and robust screening of deletions in the AZF regions of the Y-chromosome. Multiplex PCRs have the advantage of including a control gene in every reaction and significantly reducing the number of reactions needed to screen the relevant genomic markers. PRINCIPAL FINDINGS: The widely established "EAA/EMQN best practice guidelines for molecular diagnosis of Y-chromosomal microdeletions (2004)" were used as a basis for designing a real-time multiplex PCR system, in which the YCMD can simply be identified by their melting points. For this reason, some AZF primers were substituted by primers for regions in their genomic proximity, and the ZFX/ZFY control primer was exchanged by the AMELX/AMELY control primer. Furthermore, we substituted the classical SybrGreen I dye by the novel and high-performing DNA-binding dye EvaGreen™ and put substantial effort in titrating the primer combinations in respect to optimal melting peak separation and peak size. SIGNIFICANCE: With these changes, we were able to develop a platform-independent and robust real-time based multiplex PCR, which makes the need for amplicon identification by electrophoretic sizing expendable. By using an open-source system for real-time PCR analysis, we further demonstrate the applicability of automated melting point and YCMD detection

Bringing epigenetics into the diagnostics of the andrology laboratory: challenges and perspectives

Recent studies have shown significant associations of aberrant DNA methylation in spermatozoa with idiopathic male infertility, increased frequency of spontaneous abortions and imprinting disorders. Thus, the analysis of DNA methylation of specific genes in spermatozoa has the potential to become a new valuable diagnostic marker in clinical andrology. This perspective article discusses the current state and value of DNA methylation analysis in the diagnostic setup of infertile men and outlines challenges and perspectives. It highlights the potential of DNA methylation in andrological diagnostics and its putative benefit in the examination of hitherto idiopathic infertile patients is described