In the early 1950s, Austin and Chang independently described the changes that are required for the sperm to fertilize oocytes in vivo. These changes were originally grouped under name of "capacitation" and were the first step in the development of in vitro fertilization (IVF) in humans. Following these initial and fundamental findings, a remarkable number of observations led to characterization of the molecular steps behind this process. The discovery of certain sperm-specific molecules and the possibility to record ion currents through patch-clamp approaches helped to integrate the initial biochemical observation with the activity of ion channels. This is of particular importance in the male gamete due to the fact that sperm are transcriptionally inactive. Therefore, sperm must control all these changes that occur during their transit through the male and female reproductive tracts by complex signaling cascades that include post-translational modifications. This review is focused on the principal molecular mechanisms that govern human sperm capacitation with particular emphasis on comparing all the reported pieces of evidence with the mouse model.

/pdf/molecular-basis-of-human-sperm-capacitation-21lz0t04hp.pdf

Molecular Basis of Human Sperm Capacitation.

Background The presence of miRNAs in human reproductive tissue is intriguing and suggests the possibility that these important regulatory molecules play a role in reproductive function. However, the regulatory role of miRNAs in reproductive tissue remains poorly understood with a significant amount of controversial and contradicting data. Objectives To systematically review the high-quality studies published to date investigating miRNAs associated with male human reproduction in order to describe their roles and relations with infertility and update the knowledge in the field. Materials and methods A comprehensive systematic review of the published literature in MEDLINE-PubMed and EMBASE databases from the earliest available online indexing year until June 2018 (complimentary search until July 2019) was performed, in accordance with the PRISMA guidelines. We have included descriptive, case-control, cross-sectional, and observational prospective and retrospective studies in which fertile/infertile men were well-defined. The primary outcome was the miRNA expression in testis, epididymis, sperm cells, seminal plasma, and extracellular vesicles (i.e., exosomes and microvesicles). Results We identified 25,204 articles, of which 42 were selected for qualitative analysis. Of the 42 articles included, 15 evaluated the miRNAs in testis, five in epididymis, 13 in spermatozoa, and 11 in seminal plasma and/or extracellular vesicles. Two studies tackled more than one sub-group. As far as miRNA presence and content, the results of this systematic review indicated that every tissue/cell contains a well-defined and stable population of miRNAs that could be potentially related to spermatogenesis and embryogenesis. Discussion and conclusion Our systematic review of descriptive and observational studies shows a consistent relationship between aberrant miRNA expression and infertility. Therefore, it seems reasonable that measuring the expression of particular miRNAs might be useful not only as infertility biomarkers, but also for developing therapeutic strategies.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/andr.12714

The role of miRNAs in male human reproduction: a systematic review.

BACKGROUND: Development of new methods of male contraception would address an unmet need for men to control their fertility and could increase contraceptive options for women. Pharmaceutical research and development for male contraception was active in the 1990s but has been virtually abandoned. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) has supported a contraceptive development program since 1969 and supports the majority of hormonal male contraceptive development. Nonhormonal methods are also in development but are at earlier stages. CONTENT: Several hormonal male contraceptive agents have entered clinical trials. Single-agent products being evaluated include dimethandrolone undecanoate, 11β-methyl-nortestosterone dodecyl carbonate, and 7α-methyl-19-nortestosterone. A contraceptive efficacy trial of Nestorone® gel and testosterone gel in a single application will begin in 2018. Potential nonhormonal methods are at preclinical stages of development. Many nonhormonal male contraceptive targets that affect either sperm production or sperm function have been identified. Targeted pathways include the retinoic acid pathway, bromodomain and extraterminal proteins, and pathways for Sertoli cell–germ cell adhesion or sperm motility. Druggable targets include CatSper, the sperm Na+/K+-exchanger, TSSK, HIPK4, EPPIN, and ADAMs family proteins. Development of a procedure to reversibly block the vas deferens (initially developed in India in the 1980s) is undergoing early stage research in the US under the trade name Vasalgel™. SUMMARY: NICHD has supported the development of reversible male contraceptive agents. Other organizations such as the World Health Organization and the Population Council are pursuing male contraceptive development, but industry involvement remains dormant.

/pdf/male-contraceptive-development-update-on-novel-hormonal-and-44egofse8z.pdf

Male Contraceptive Development: Update on Novel Hormonal and Nonhormonal Methods

Imidacloprid disrupts the endocrine system by interacting with androgen receptor in male mice.

Background The advent of new methods of male contraception would increase contraceptive options for men and women and advance male contraceptive agency. Pharmaceutical R&D for male contraception has been dormant since the 1990s. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) has supported a contraceptive development program since 1969 and supports most ongoing hormonal male contraceptive development. Nonhormonal methods are in earlier stages of development. Content Several hormonal male contraceptive agents have entered clinical trials. Novel single agent products being evaluated include dimethandrolone undecanoate, 11β-methyl-nortestosterone dodecylcarbonate, and 7α-methyl-19-nortestosterone. A contraceptive efficacy trial of Nestorone®/testosterone gel is underway. Potential nonhormonal methods are at preclinical stages of development. Many nonhormonal male contraceptive targets that affect sperm production, sperm function, or sperm transport have been identified. Summary NICHD supports development of reversible male contraceptive agents. Other organizations such as the World Health Organization, the Population Council, and the Male Contraception Initiative are pursuing male contraceptive development, but industry involvement remains limited.

Update on Novel Hormonal and Nonhormonal Male Contraceptive Development.

Many studies have shown that microRNAs (miRNAs) play vital roles during the spermatogenesis. However, little is known about the altered miRNA profiles of testicular tissues in nonobstructive azoospermia (NOA). Using microarray technology, the miRNA expression profiles of testicular biopsies from patients with NOA and of normal testicular tissues were determined. Bioinformatics analyses were conducted to predict the enriched biological processes and functions of identified miRNAs. The microarray data were validated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), the results of which were then validated with a larger sample size. Correlations between the miRNA expression levels and clinical characteristics were analyzed. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic ability of miRNAs for azoospermia. Hierarchical clustering showed that 129 miRNAs were significantly differentially expressed between the NOA and control groups. Bioinformatics analysis indicated that the differentially expressed miRNAs were involved in spermatogenesis, cell cycle, and mitotic prometaphase. In the subsequent qRT-PCR assays, the selected miRNA expression levels were consistent with the microarray results, and similar validated results were obtained with a larger sample size. Some clinical characteristics were significantly associated with the expression of certain miRNAs. In particular, we identified a combination of two miRNAs (miR-10b-3p and miR-34b-5p) that could serve as a predictive biomarker of azoospermia. This study provides altered miRNA profiles of testicular biopsies from NOA patients and examines the roles of miRNAs in spermatogenesis. These profiles may be useful for predicting and diagnosing the presence of testicular sperm in individuals with azoospermia.

Altered microRNA profiles of testicular biopsies from patients with nonobstructive azoospermia.

Stem cell therapy is a potentially promising option for erectile dysfunction; however, its risk of tumorigenicity is a clinical hurdle and the risk is positively related to the number of injected cells. Our previous study showed that nanotechnology improved adipose-derived stem cell (ADSC) therapy for erectile dysfunction of cavernous nerve injury (CNI) by attracting cells in the corpus cavernosum. These results indicated the possibility of using a reduced dosage of ADSCs for intracavernous injection. In this exploratory study, we used lower dosage (2 × 105 cells) of ADSCs for intracavernous injection (ICI) and the nanotechnology approach. Intracavernous pressure and mean arterial pressure were measured at day 28 to assess erectile function. The low-dose ADSC therapy group showed favorable treatment effects, and nanotechnology further improved these effects. In vivo imaging of ICI cells revealed that the fluorescein signals of NanoShuttle-bound ADSCs (NanoADSCs) were much stronger than those of ADSCs at days 0, 1, and 3. Both immunofluorescence and Western blot analysis showed a significant increase in smooth muscle, endothelium, and nerve tissue in the ADSC group compared to that in the CNI group; further improvement was achieved with assisted nanotechnology. These findings demonstrate that nanotechnology can be used to further improve the effect of small dosage of ADSCs to improve erectile function. Abundant NanoADSCs remain in the corpus cavernosum in vivo for at least 3 days. The mechanism of erectile function improvement may be related to the regeneration of the smooth muscle, endothelium, and nerve tissues.

Nanotechnology-assisted adipose-derived stem cell (ADSC) therapy for erectile dysfunction of cavernous nerve injury: In vivo cell tracking, optimized injection dosage, and functional evaluation

Sperm-specific sodium-hydrogen exchanger (sNHE) is essential to maintain sperm normal function in mice; however, its role in human sperm has not been clarified to date. The aim of this study is to investigate the expression pattern of sNHE in human spermatozoa and its relationship with sperm functional parameters. Semen samples from 68 asthenozoospermic and 61 normozoospermic men were analyzed for sperm concentration, motility, and acrosome reaction, and high motile spermatozoa were collected by swim-up method. The expression of sNHE in spermatozoa was detected by Western blot and immunofluorescence staining. The relationship between sNHE expression and sperm parameters was assessed. We identified sNHE is mainly localized to the principal piece of the human sperm tail. The expression of sNHE was positively correlated with sperm concentration, total number, and progressive motility. Moreover, sNHE expression was upregulated in swim-up sperm and associated with most of sperm motility parameters including straight line velocity and curvilinear velocity. Our results also showed that sNHE expression is decreased in sperm from patients with asthenozoospermia compared with that from normal controls. However, no correlation was found between sNHE expression and acrosome reaction in spermatozoa. The expression pattern of sNHE suggested that this protein may be involved in the regulation of sperm motility, and aberration of its expression in sperm may contribute to the pathogenesis of asthenozoospermia.

/pdf/sodium-hydrogen-exchanger-expression-in-human-sperm-and-its-21bt0d1yw9.pdf

Sodium-Hydrogen-Exchanger expression in human sperm and its relationship with semen parameters

Male infertility is considered a common health problem, and non-obstructive azoospermia with unclear pathogenesis is one of the most challenging tasks for clinicians. The objective of this study was to investigate the differential serum metabolic pattern in non-obstructive azoospermic men and to determine potential biomarkers related to spermatogenic dysfunction. Serum samples from patients with non-obstructive azoospermia (n = 22) and healthy controls (n = 31) were examined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Serum metabolomic profiling could differentiate non-obstructive azoospermic patients from healthy control subjects. A total of 24 metabolites were screened and identified as potential markers, many of which are involved in energy production, oxidative stress and cell apoptosis in spermatogenesis. Moreover, the results showed that various metabolic pathways, including d-glutamine and d-glutamate metabolism, taurine and hypotaurine metabolism, pyruvate metabolism, the citrate cycle and alanine, aspartate and glutamate metabolism, were disrupted in patients with non-obstructive azoospermia. Our results indicated that the serum metabolic disorders may contribute to the etiology of non-obstructive azoospermia. This study suggested that serum metabolomics could identify unique metabolic patterns of non-obstructive azoospermia and provide novel insights into the pathogenesis underlying male infertility.

Serum Metabolomic Profiling Identifies Characterization of Non-Obstructive Azoospermic Men.

Hepatitis E virus (HEV) RNA has been recently discovered in semen samples of Chinese infertile man with a remarkably high rate of 28.1% (52/185, table 1).1 All HEV isolates belong to HEV genotype 4 (HEV4), which is the dominant strain prevalent in China. This intriguing discovery has aroused our attention. In a recent response to the work done by Huang et al , researchers in Germany tested 87 semen samples collected from infertile men, but the HEV RNA positive rate is 0% (table 1).2 Germany is prevalent with HEV3, so the authors suggested that HEV genotype-specific or variant-specific pathophysiology may explain the contrary results. However, the two studies both have limitations to reach a more accurate conclusion. The size of patients included in both studies is relatively small, and …

https://gut.bmj.com/content/gutjnl/69/7/1363.full.pdf

Yuzhuo Yang

Papers

Altered microRNA profiles of testicular biopsies from patients with nonobstructive azoospermia.

Nanotechnology-assisted adipose-derived stem cell (ADSC) therapy for erectile dysfunction of cavernous nerve injury: In vivo cell tracking, optimized injection dosage, and functional evaluation

Sodium-Hydrogen-Exchanger expression in human sperm and its relationship with semen parameters

Serum Metabolomic Profiling Identifies Characterization of Non-Obstructive Azoospermic Men.

Absence of hepatitis E virus RNA in semen samples of infertile male in China