Molecular Approaches to Male Infertility: From Diagnosis to Decision-Making

Dear Colleagues,

Affecting 2–12% of men globally, male infertility is a common condition that alone or in combination with other aspects is the main contributing factor in approximately 50% of couples seeking fertility treatment. The overall prevalence of male infertility is likely to be underestimated and is set to increase due to the downward trend in sperm concentration and total sperm count over the decades. Therefore, investigating the causes of male infertility and offering therapeutic solutions is essential.

Semen analysis is the first step in the diagnostic evaluation of male infertility. It can show alterations in conventional sperm parameters, with pictures of oligozoospermia, asthenozoospermia, teratozoospermia, and/or azoospermia. Abnormalities of the so-called biofunctional sperm parameters reflect the presence of mitochondrial dysfunction, sperm apoptosis, abnormal chromatin compactness, and/or DNA fragmentation.

Worryingly, despite careful diagnostic work-up, the etiology of male infertility remains unclear in many cases, and, according to some studies, can reach 70%. Advances in molecular biology and “omics” technologies has allowed us a clearer understanding of the fine mechanisms that regulate spermatogenesis, fertilization, and even embryogenesis. Custom-made gene panels using next-generation sequencing (NGS) have allowed the identification of several genes that appear to play a role in the etiology of apparently idiopathic non-obstructive azoospermia (NOA) or even severe oligozoospermia. Recently, research has focused on the possible predictive role of specific gene mutations as they relate to testicular histology, thus granting these panels not only a role in formulating a diagnosis but also in the decision-making process. However, further experimental evidence is needed.

The epigenome is defined as the cellular DNA methylation model. Spermatozoa have a unique pattern of methylation that is completely different from that of somatic cells. Indeed, the DNA of sperm is highly packaged and transcriptional activity is repressed for most of the genes. Furthermore, the sperm methylation pattern of infertile patients differs from that of fertile men, in particular in imprinted genes for which the methylation pattern is inherited by the embryo.

The study of the sperm transcriptome in mice has suggested a role of sperm RNAs in the regulation of spermatogenesis and embryo growth. Furthermore, sperm-carried RNAs can also influence the phenotype of the offspring and their susceptibility to develop several diseases, such as diabetes, depression, etc. Translational research is urgently needed to evaluate whether these mechanisms also occur in humans and the implications of these discoveries in clinical practice.

The evaluation of the proteome in the seminal fluid and spermatozoa has demonstrated a role in fertility. Consequently, sperm-carried specific proteins appear to promote embryo growth and development. Therefore, they represent useful diagnostic targets in patients with idiopathic infertility. Furthermore, proteins in the seminal fluid can accurately predict the chance of sperm recovery after TESE in patients with NOA.

The metabolome is defined as the overall presence of metabolites in a given tissue. Scant data are available on the sperm metabolome, although it appears to differ in infertile patients compared with fertile controls. Finally, in recent years, a great deal of attention has been paid to better understanding the impact of the seminal fluid microbiome on male fertility. In particular, it has been suggested that the microbiome can change under specific diseases (e.g., varicocele, male urogenital tract infections, etc.) with a possible impact on the metabolome and even the sperm epigenome. However, many aspects remain to be clarified.

Despite the growing amount of published research on the molecular biology of male infertility, the male partner is still neglected in the diagnostic work-up of the infertile couple. Consequently, the international guidelines that regulate procedures and best practices in assisted reproductive technique (ART) centers do not account for the presence of an andrologist. Even today, ART centers are led by embryologists and gynecologists who do not have the skills for the comprehensive diagnostic and therapeutic management of infertile male patients, despite evidence to suggest that the treatment of male infertility leads to an improvement in ART outcomes.

This Special Issue aims to collect original and review articles on the use of “omics” technology in the field of male infertility, highlighting its role in diagnosis, prognosis, decision making, and offspring health. Finally, articles on the importance of an adequate diagnostic workup and the treatment of male partners in the ART setting are welcome.

Dr. Rossella Cannarella
Prof. Dr. Aldo E. Calogero
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

• male infertility
• sperm
• omics
• epigenome
• transcriptome
• proteome
• metabolome
• assisted reproductive technique (ART)