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In internally fertilizing species, sperm transfer is not always immediately followed by egg fertilization, and female sperm storage (FSS) may occur. FSS is a phenomenon in which females store sperm in a specialized organ for periods lasting from a few hours to several years, depending on the species. Eusocial hymenopterans (ants, social bees, and social wasps) hold the record for FSS duration. In these species, mating takes place during a single nuptial flight that occurs early in adult life for both sexes; they never mate again. Males die quickly after copulation but survive posthumously as sperm stored in their mates' spermathecae. Reproductive females, also known as queens, have a much longer life expectancy, up to 20 years in some species. Here, we review what is currently known about the molecular adaptations underlying the remarkable FSS capacities in eusocial hymenopterans. Because sperm quality is crucial to the reproductive success of both sexes, we also discuss the mechanisms involved in sperm storage and preservation in the male seminal vesicles prior to ejaculation. Finally, we propose future research directions that should broaden our understanding of this unique biological phenomenon., (© 2022 Cambridge Philosophical Society.)

Background: The development of mass spectrometric (MS) techniques now allows the investigation of very complex protein mixtures ranging from subcellular structures to tissues. Body fluids are also popular targets of proteomic analysis because of their potential for biomarker discovery. Seminal plasma has not yet received much attention from the proteomics community but its characterization could provide a future reference for virtually all studies involving human sperm. The fluid is essential for the survival of spermatozoa and their successful journey through the female reproductive tract., Results: Here we report the high-confidence identification of 923 proteins in seminal fluid from a single individual. Fourier transform MS enabled parts per million mass accuracy, and two consecutive stages of MS fragmentation allowed confident identification of proteins even by single peptides. Analysis with GoMiner annotated two-thirds of the seminal fluid proteome and revealed a large number of extracellular proteins including many proteases. Other proteins originated from male accessory glands and have important roles in spermatozoan survival., Conclusion: This high-confidence characterization of seminal plasma content provides an inventory of proteins with potential roles in fertilization. When combined with quantitative proteomics methodologies, it should be useful for studies of fertilization, male infertility, and prostatic and testicular cancers.

Male factor issues are responsible for 50% of couples infertility. Seminal oxidative stress is one of the major factors that affect the normal physiological aspects of sperm function such as motility and progression, hyperactivation, capacitation, acrosome reaction and zona-pellucida penetration prior to fertilization. In recent times, high-throughput proteomic platforms are used to identify the proteins associated with these aspects of sperm function as associated with oxidative stress. In this review, we have provided a workflow that includes an overview of advanced proteomic techniques and bioinformatic tools used to interpret proteomic results. Furthermore, we have highlighted proteins associated with dysregulated molecular pathways in sperm and seminal plasma due to oxidative stress. We have also described the molecular interactions between proteins associated with oxidative stress and their potential role in male infertility., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein with glutamate carboxypeptidase activity. However, its precise function in the prostate, prostasomes and seminal plasma with regard to male fertility remains unknown. This study was conducted to investigate the seminal plasma PSMA levels in fertile men and patients with oligoasthenoteratozoospermia (OAT) and to analyse its association with sperm parameters. Twenty fertile men and twenty patients admitted at the urology clinic of our institution with the diagnosis of OAT were included in the study. Following semen analysis, seminal plasma was isolated from semen ejaculates. PSMA concentrations in the seminal plasma were determined by ELISA. The correlations between seminal PSMA concentrations and semen parameters were statistically analysed. Seminal plasma PSMA concentration was significantly lower in OAT patients compared to fertile controls (p < .01). In fertile men, PSMA concentration was significantly correlated with the sperm concentration (r = -.481, p < .05), whereas in the patient group no statistically significant correlation was found between the sperm parameters and seminal PSMA level. This is the first study in the literature to investigate PSMA levels in the seminal plasma from infertile men. Decreased levels of seminal plasma PSMA might suggest a role for compromised prostasome function in the pathogenesis of OAT syndrome., (© 2020 Wiley-VCH GmbH.)

Background: Seminal plasma is a promising diagnostic fluid for male infertility. In assisted reproduction, the seminal plasma-based characteristics of normozoospermic men achieving successful clinical pregnancy through rescue intracytoplasmic sperm injection after in vitro fertilization failure remain unclear., Objective: To identify potential seminal plasma proteins to contribute to a new understanding of unexplained male factor infertility., Materials and Methods: An approach with isobaric tags for relative and absolute quantification labeling coupled with liquid chromatography matrix-assisted laser desorption ionization mass spectrometry was applied to investigate differentially expressed proteins in the seminal plasma of a rescue intracytoplasmic sperm injection pregnancy group versus an in vitro fertilization pregnancy group of normozoospermic men., Result(s): The present work revealed seventy-three differentially expressed seminal plasma proteins between the in vitro fertilization and rescue intracytoplasmic sperm injection groups. Forty-five proteins were upregulated, and 28 proteins were downregulated in the rescue intracytoplasmic sperm injection group compared with the in vitro fertilization group. Bioinformatics analyses showed that these altered proteins were involved in various functions, including the kallikrein-related proteolytic cascade, immune response, and heparin binding. Furthermore, the validity of the proteomic results was verified by Western blot analysis of the proteins (lactoferrin [LTF], fibronectin [FN1], creatine kinase B type [CKB], kallikrein-2 [KLK2], aminopeptidase N [ANPEP], extracellular matrix protein 1 [ECM1], glycodelin [PAEP], alpha-1-antitrypsin [SERPINA1], and semenogelin-1 [SEMG1]) and immunofluorescence. Moreover, 16% of the seminal plasma proteins identified in the present work have not been reported in previous studies., Discussion: This panel of altered seminal plasma proteins associated with unexplained male factor infertility might have clinical relevance and may be useful in the diagnosis and prognosis of idiopathic infertility in in vitro fertilization., Conclusions: Our work not only provides a new complementary high-confidence dataset of seminal plasma proteins but also shines new light onto the molecular characteristics of seminal plasma from normozoospermic men with different assisted reproductive outcomes., (© 2019 American Society of Andrology and European Academy of Andrology.)

Simple Summary: Proteomics aims to identify proteins present in a sample and to study their expression during various physiological or pathological conditions. The proteome includes all proteins present in a cell or a tissue at any given time; this takes into account all post-translational modifications that occur, and is highly dynamic. The present work used high-throughput technologies to study the proteome of the semen of dogs. In total, 42 proteins were identified in the semen sperm-rich fraction and 43 proteins in the semen prostatic fraction. In general, the proteins identified are involved mostly in supporting spermatozoan maturation, survival and motility, enhancing the reproductive performance of male animals. Future work can focus on the quantification of proteins identified in semen and compare findings with results in samples from animals with suboptimal fertility. The findings can provide a potential for proteomics examination of semen as a tool in se-men evaluation. This can be particularly useful in stud animals, also given its advantage as a non-invasive method. The objectives of the present work were to evaluate the semen of dogs by means of proteomics methods and to compare with proteomics results of the blood of the animals, in order to increase available knowledge on the topic and present relevant reference values for semen samples. Semen samples were collected from five Beagle-breed dogs. Reproductive assessment of the animals by means of clinical, ultrasonographic and seminological examinations confirmed their reproductive health. The sperm-rich fraction and the prostatic fraction of semen were processed for proteomics evaluation. LC-MS/MS analysis was performed by means of a LTQ Orbitrap Elite system. The technology combines high separation capacity and strong qualitative ability of proteins in biological samples that require deep proteome coverage. Protein classification was performed based on their functional annotations using Gene Ontology (GO). In blood plasma, semen sperm-rich fraction, and semen prostatic fraction, 59, 42 and 43 proteins, respectively, were detected. Two proteins were identified simultaneously in plasma and the semen sperm-rich fraction, 11 proteins in plasma and the semen prostatic fraction, and three proteins in the semen sperm-rich and prostatic fractions. In semen samples, most proteins were related to cell organization and biogenesis, metabolic processes or transport of ions and molecules. Most proteins were located in the cell membrane, the cytosol or the nucleus. Finally, most proteins performed functions related to binding or enzyme regulation. There were no differences between the semen sperm-rich fraction and prostatic fractions in terms of the clustering of proteins. In conclusion, a baseline reference for proteins in the semen of Beagle-breed dogs is provided. These proteins are involved mostly in supporting spermatozoan maturation, survival and motility, enhancing the reproductive performance of male animals. There appears potential for the proteomics examination of semen to become a tool in semen evaluation. This analysis may potentially identify biomarkers for reproductive disorders. This can be particularly useful in stud animals, also given its advantage as a non-invasive method. [ABSTRACT FROM AUTHOR]

(E) Two spEV protein biomarker for noninvasive differential diagnosis of azoospermia (NOA vs. However, the choices for high sensitivity and specificity in the noninvasive differential diagnosis of azoospermia are limited.3 Extracellular vesicles (EVs) are increasingly being considered as a promising source of novel diagnostic biomarkers due to their noninvasive nature and high reproducibility.4 In this study, we revealed that two proteins SLC5A12 and HIST1H2BA from human seminal plasma extracellular vesicle (spEV) could differentially diagnose azoospermia with high sensitivity and specificity. Dear Editor, Azoospermia, which accounts for about 10%-15% of infertile men, is generally classified as obstructive azoospermia (OA) due to male reproductive tract obstruction and nonobstructive azoospermia (NOA) due to testicular failure.1 NOA has three major forms: hypospermatogenesis (HS), germ cell arrest (MA), and Sertoli cell-only (SCO) based on the histopathological examination of testicular tissue.2 An accurate diagnosis of the subtype of azoospermia is crucial and mandatory, as the treatment approach differs between NOA and OA. Thus, significant decrease of spEV SLC5A12 is expected in OA patients, but not NOA patients. [Extracted from the article]

Purpose: Based on prior reports demonstrating that neutral endopeptidase (NEP) inhibitors increase sperm motility, the goal of our studies was to identify endogenous seminal peptides that inhibit NEP and investigate their potential effect on sperm motility. Methods: Peptidomic analysis was performed on human seminal fluid, identifying 22 novel peptides. One peptide, named RSIY-11, derived from semenogelin-1, was predicted through sequence analysis to be a substrate and/or potential inhibitor of NEP. Enzymatic analysis was conducted to determine the inhibitory constant (Ki) of RSIY-11 as an inhibitor of NEP. Total and progressive sperm motility was determined at baseline and 30 and 60 min following addition of RSIY-11 to seminal fluid in 59 patients undergoing an infertility workup at an urban medical center. Additionally, the effects of RSIY-11 on sperm motility were evaluated in 15 of the 59 patients that met criteria for asthenospermia. Results: RSIY-11 was shown to act as a competitive inhibitor of NEP with a Ki of 18.4 ± 1.6 μM. Addition of RSIY-11 at concentrations of 0.75 μM, 7.5 μM, and 75 μM significantly increased sperm motility at all time points investigated, with increases of 6.1%, 6.9%, and 9.2% at 60 min, respectively. Additionally, within the subgroup of patients with asthenospermia, RSIY-11 at concentrations of 0.75 μM, 7.5 μM, and 75 μM significantly increased sperm motility at all time points investigated, with increases of 7.6%, 8.8%, and 10.6% at 60 min, respectively. Conclusions: RSIY-11 is a newly identified semenogelin-1-derived peptide present in seminal fluid. RSIY-11 acts as a potent competitive inhibitor of NEP, which when added to seminal fluid significantly increases sperm motility. RSIY-11 could play a potential role in the treatment for male factor infertility related to asthenospermia and improve intrauterine insemination outcomes. [ABSTRACT FROM AUTHOR]

Objective To evaluate the effect of smoking on sperm functional quality and seminal plasma proteomic profile. Patients and Methods Sperm functional tests were performed in 20 non-smoking men with normal semen quality, according to the World Health Organization (2010) and in 20 smoking patients. These included: evaluation of DNA fragmentation by alkaline Comet assay; analysis of mitochondrial activity using DAB staining; and acrosomal integrity evaluation by PNA binding. The remaining semen was centrifuged and seminal plasma was used for proteomic analysis (liquid chromatography-tandem mass spectrometry). The quantified proteins were used for Venn diagram construction in Cytoscape 3.2.1 software, using the PINA4 MS plug-in. Then, differentially expressed proteins were used for functional enrichment analysis of Gene Ontology categories, Kyoto Encyclopedia of Genes and Genomes and Reactome, using Cytoscape software and the Clue GO 2.2.0 plug-in. Results Smokers had a higher percentage of sperm DNA damage (Comet classes III and IV; P < 0.01), partially and fully inactive mitochondria ( DAB classes III and IV; P = 0.001 and P = 0.006, respectively) and non-intact acrosomes ( P < 0.01) when compared with the control group. With respect to proteomic analysis, 422 proteins were identified and quantified, of which one protein was absent, 27 proteins were under-represented and six proteins were over-represented in smokers. Functional enrichment analysis showed the enrichment of antigen processing and presentation, positive regulation of prostaglandin secretion involved in immune response, protein kinase A signalling and arachidonic acid secretion, complement activation, regulation of the cytokine-mediated signalling pathway and regulation of acute inflammatory response in the study group (smokers). Conclusion In conclusion, cigarette smoking was associated with an inflammatory state in the accessory glands and in the testis, as shown by enriched proteomic pathways. This state causes an alteration in sperm functional quality, which is characterized by decreased acrosome integrity and mitochondrial activity, as well as by increased nuclear DNA fragmentation. [ABSTRACT FROM AUTHOR]

For men struggling to conceive with their partners, diagnostic tools are limited and often consist of only a standard semen analysis. This baseline test serves as a crude estimation of male fertility, leaving patients and clinicians in need of additional diagnostic biomarkers. Seminal fluid contains the highest concentration of molecules from the male reproductive glands, therefore, this review focuses on current and novel seminal biomarkers in certain male infertility scenarios, including natural fertility, differentiating azoospermia etiologies, and predicting assisted reproductive technique success. Currently available tests include antisperm antibody assays, DNA fragmentation index, sperm fluorescence in situ hybridization, and other historical sperm functional tests. The poor diagnostic ability of current assays has led to continued efforts to find more predictive biomarkers. Emerging research in the fields of genomics, epigenetics, proteomics, transcriptomics, and metabolomics holds promise for the development of novel male infertility biomarkers. Seminal protein-based assays of TEX101, ECM1, and ACRV1 are already available or under final development for clinical use. Additional panels of DNA, RNA, proteins, or metabolites are being explored as we attempt to understand the pathophysiologic processes of male infertility. Future ventures will need to continue data integration and validation for the development of clinically useful infertility biomarkers to aid in male infertility diagnosis, treatment, and counseling. [ABSTRACT FROM AUTHOR]

Immune infertility, in terms of reproductive failure, has become a serious health issue involving approximately 1 out of 5 couples at reproductive age. Semen that is defined as a complex fluid containing sperm, cellular vesicles and other cells and components, could sensitize the female genital tract. The immune rejection of male semen in the female reproductive tract is explained as the failure of natural tolerance leading to local and/or systemic immune response. Present active immune mechanism may induce high levels of anti-seminal/sperm antibodies. It has already been proven that iso-immunization is associated with infertility. Comprehensive studies with regards to the identification of antibody-targets and the determination of specific antibody class contribute to the development of effective immuno-therapy and, on the other hand, potential immuno-contraception, and then of course to complex patient diagnosis. This review summarizes the aspects of female immune infertility. [ABSTRACT FROM AUTHOR]

The increasing use of '-omics' (genomic, transcriptomic, proteomic, epigenomic, and metabolomic) high-throughput measurement technologies over the past decade is beginning to reveal the complexity of human biology and physiology through the interactions of DNA, RNA, related proteins and small molecules. In reproductive medicine, the majority of this work, has thus far focused on the female factors, e.g., the oocyte, since they provide both the environment and the majority of elements required for embryogenesis. State-of-the-art sequencing and computational analyses have enabled a deeper understanding of the underlying components. Contrary to being simply a silent delivery vehicle to the oocyte of the packaged male DNA, sperm provide both a specific epigenetically marked genome together with a complex population of RNAs and proteins that are crucial for early embryogenesis. In addition to the sperm, seminal fluid appears to serve multiple roles providing a supplementary series of components that allow the sperm to successfully reach and fertilize the oocyte and prepare the female immune system to tolerate the semiallosteric embryo. A global analysis and review of what is presently known regarding the unique role of each component of the male factor and their associated interactions begins to shed light on this emergent field. [ABSTRACT FROM AUTHOR]

Problem Galectin-3 is a β-galactoside binding protein with immunomodulatory properties and exerts its extracellular functions via interactions with glycoconjugate ligands. Therefore, to elucidate the function of galectin-3, binding ligands in human seminal plasma were investigated. Method of study Galectin-3 binding proteins were isolated from seminal plasma by affinity chromatography, and candidate ligands were identified by MS/ MS. Biochemical methods were used to characterize the ability of galectin-3 to bind its ligands. Results Identified galectin-3 ligands included CD13, MUC6, PAP, PSA, and ZAG. 1 D and 2 D electrophoretic analysis of seminal plasma demonstrated that CD13, PAP, PSA, and ZAG immunoreactivity co-migrated with galectin-3-reactive protein bands and spots at expected molecular weights and pIs. Inhibition assays indicated that CD13, PSA, PAP, and ZAG interact with galectin-3 in a protein-carbohydrate manner. Conclusion The galectin-3 binding ligands identified in this study indicate multiple roles for galectin-3 in the reproductive and immunological functions of seminal plasma. [ABSTRACT FROM AUTHOR]

Seminal fluid proteins transferred from males to females during copulation are required for full fertility and can exert dramatic effects on female physiology and behavior. In Drosophila melanogaster, the seminal protein sex peptide (SP) affects mated females by increasing egg production and decreasing receptivity to courtship. These behavioral changes persist for several days because SP binds to sperm that are stored in the female. SP is then gradually released, allowing it to interact with its female-expressed receptor. The binding of SP to sperm requires five additional seminal proteins, which act together in a network. Hundreds of uncharacterized male and female proteins have been identified in this species, but individually screening each protein for network function would present a logistical challenge. To prioritize the screening of these proteins for involvement in the SP network, we used a comparative genomic method to identify candidate proteins whose evolutionary rates across the Drosophila phylogeny co-vary with those of the SP network proteins. Subsequent functional testing of 18 co-varying candidates by RNA interference identified three male seminal proteins and three female reproductive tract proteins that are each required for the long-term persistence of SP responses in females. Molecular genetic analysis showed the three new male proteins are required for the transfer of other network proteins to females and for SP to become bound to sperm that are stored in mated females. The three female proteins, in contrast, act downstream of SP binding and sperm storage. These findings expand the number of seminal proteins required for SP's actions in the female and show that multiple female proteins are necessary for the SP response. Furthermore, our functional analyses demonstrate that evolutionary rate covariation is a valuable predictive tool for identifying candidate members of interacting protein networks. [ABSTRACT FROM AUTHOR]

In species where females mate with multiple males during a single ovulatory cycle, sperm competition is hypothesized to increase the rate of adaptive evolution of proteins expressed in male reproductive tissues through recurrent selective sweeps (positive selection). The hominoids, comprising apes and humans, are a group of closely related primates with extensive variation in mating behaviors and predicted levels of sperm competition. Since previous studies of individual male reproductive genes have shown evidence of positive selection, we estimated rates of evolution of a comprehensive set of proteins expressed in ejaculated semen. Our results show that these proteins in hominoids do not have elevated rates of nonsynonymous substitutions ( Ka) compared with a control dataset of nonreproductive genes. Species with greater sperm competition do not have faster rates of seminal protein evolution. Although at these broad levels our hypotheses were not confirmed, further analyses indicate specific patterns of molecular evolution. Namely, the Ka of seminal genes is more strongly correlated with measures of tissue specificity than nonreproductive genes, suggesting that the former may more readily adapt to tissue-specific functions. Proteins expressed from the seminal vesicles evolve more rapidly than those from other male reproductive tissues. Also, several gene ontology categories show elevated rates of protein evolution, not seen in the control data set. While the generalization that male reproductive genes evolve rapidly in hominoids is an oversimplification, a subset of proteins can be identified that are likely targets for adaptive evolution driven by sexual selection. [ABSTRACT FROM AUTHOR]

Objective To analyse the proteomic profile of seminal plasma with the aim of identifying the proteins and post-genomic pathways associated with sperm DNA fragmentation., Materials and Methods A cross-sectional study including 89 subjects from a human reproduction service was carried out., All semen samples were assessed for sperm DNA fragmentation using a comet assay., Results from 60 sperm were analysed using Komet 6.0.1 software and the ' Olive tail moment' variable was used to stratify these into low and high sperm DNA fragmentation groups., Seminal plasma proteins from the two groups were pooled and used for proteomic analysis., Quantitative data were used for functional enrichment studies., Results Seventy-two proteins were identified or quantified in seminal plasma. Of these, nine were differentially expressed in the low group and 21 in the high group. Forty-two proteins were conserved between these groups., Functional enrichment analysis indicated that sperm DNA fragmentation was related to functions such as lipoprotein particle remodelling and regulation, fatty acid binding and immune response., Proteins found exclusively in the low group may be involved in correcting spermatogenesis and/or improving sperm function. Proteins in the high group were associated with increased innate immune response, sperm motility and/or maturation and inhibition of mitochondrial apoptosis., Conclusion Protein expression and post-genomic pathways of seminal plasma differ according to the rate of sperm DNA integrity. [ABSTRACT FROM AUTHOR]

Background: Alterations at the molecular level in spermatozoa and seminal plasma can affect male fertility. The objective of this study was to determine if analysis of differential expression of proteins in varying semen parameters can serve as potential biomarkers for male infertility. Methods: The differential expression of proteins in the seminal plasma of men based on sperm count and morphology were examined utilizing proteomic tools. Subjects were categorized based on sperm concentration and morphology into 4 groups: 1) normal sperm count and normal morphology (NN); 2) normal sperm count and abnormal morphology (NA); 3) oligozoospermia and normal morphology (ON); and 4) oligozoospermia and abnormal morphology (OA). Proteomic analysis was performed by LC-MS/MS followed by functional bioinformatics analysis. Protein distribution in the NA, ON and OA groups was compared with that of the NN group. Results: Twenty proteins were differentially expressed among the 4 groups. Among the unique proteins identified, 3 were downregulated in the NA group, 1 in the ON group and 1 in the OA group while 2 were upregulated in the ON and OA groups. The functional analysis 1) identified biological regulation as the major processes affected and 2) determined that most of the identified proteins were of extracellular origin. Conclusions: We have identified proteins that are over-or underexpressed in the seminal plasma of men with poor sperm quality. The distinct presence of some of the proteins may serve as potential biomarkers and provide insight into the mechanistic role played by these proteins in male infertility. Further studies using Western Blot analysis are required to validate these findings. [ABSTRACT FROM AUTHOR]

The article discusses potential roles of seminal fluid factors in Caenorhabditis (C.) elegans and possibilities for using TRY-5 sperm-activating protease as a marker for studying seminal fluid secretion and male mating behavior. It states that TRY-5 discovery suggests new directions for understanding how and why seminal fluid factors are transferred by male nematodes with regards to reproduction's mechanisms. It mentions the implications of TRY-5::GFP release from gonad's discrete areas.

The article presents a study on the different functions of seminal plasma proteins. Ejaculated spermatozoa was exposed to most secretions from the accessory sexual glands to analyze the relevance of proteins to sperm function. Based from the result of the study, it is believed that the proteins of the seminal plasma play a role in establishing fertility.

Nonhuman primates are extensively used to assess strategies to prevent infection from sexual exposure to human immunodeficiency virus (HIV) and to study mechanisms of mucosal transmission. However, although semen represents one of the most important vehicles for the virus, the vast majority of preclinical challenge studies have used cell-free simian immunodeficiency virus (SIV) or simian/human immunodeficiency virus (SHIV) viral particles inoculated as diluted culture supernatants. Semen is a complex body fluid containing many factors that may facilitate or decrease HIV infectiousness. The virus in semen is present in different forms: as free virus particles or as cell-associated virus (ie, within infected leukocytes). Although cell-to-cell transmission of HIV is highly efficient, the role of cell-associated virus in semen has been surprisingly poorly investigated in nonhuman primate models. Mucosal exposure of macaques to cell-associated SIV by using infected peripheral blood mononuclear cells or spleen cells has been shown to be an efficient means of infection; however, it has yet to be shown that SIV- or SHIV-infected seminal leukocytes can transmit infection in vivo. Improvement of animal models to better recapitulate the complex microenvironment at portals of HIV entry is needed for testing candidate antiretrovirals, microbicides, and vaccines. [ABSTRACT FROM AUTHOR]

Although sperm dysfunction is the single most common cause of infertility, we have poor methods of diagnosis and surprisingly no effective treatment (excluding assisted reproductive technology). In this review, we challenge the usefulness of a basic semen analysis and argue that a new paradigm is required immediately. We discuss the use of at-home screening to potentially improve the diagnosis of the male and to streamline the management of the sub-fertile couple. Additionally, we outline the recent progress in the field, for example, in proteomics, which will allow the development of new biomarkers of sperm function. This new knowledge will transform our understanding of the spermatozoon as a machine and is likely to lead to non-ART treatments for men with sperm dysfunction. [ABSTRACT FROM AUTHOR]