Exploring Human Sperm Metabolism and Male Infertility: A Systematic Review of Genomics, Proteomics, Metabolomics, and Imaging Techniques
Abstract
1. Introduction
2. Methods
2.1. Search Strategy
2.2. Inclusion and Exclusion Criteria
2.3. Data Extraction and Synthesis
3. Results
4. Energy Metabolism Pathways in Spermatozoa
5. Metabolic Substrates and Adaptations
5.1. Metabolic Substrates and Transport
5.2. Metabolic Adaptations During Maturation and Transit
6. Molecular Biomarkers and Oxidative Stress
7. Influence of the Seminal Microbiome
8. Advanced Techniques and Tools for Evaluating Sperm Metabolism
9. Clinical Implications: Metabolic Dysfunction in Male Infertility
9.1. Diagnostic Implications
9.2. Prognostic Potential
9.3. Therapeutic Strategies
9.4. Integration with Clinical Workflows
9.5. Disadvantages of Current Methods and Tools to Evaluate Sperm Metabolism
9.6. Complementary Strengths of Metabolic Assessment Techniques
10. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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(A) Genomics Studies Based on Techniques Used in Sperm Metabolism and Male Infertility | |||||
Methods/Tools | Study Aim | Results | Sample Size | Study Type | References |
| Evaluate seminal plasma exosomal MiRNAs as markers for Azoospermia origin and sperm presence | Mir-31-5p as biomarker for azoospermia origin combined with FSH improves prediction | 39 | Case-control prospective study | Barceló et al., 2018 [14] |
| Identify lncRNA mutations and expression in teratozoospermia | 1166 unique mutations in Differentially Expressed lncRNAs Variants affect structure/function and MiRNA interactions | N/A * | Observational study | Kyrgiafini et al., 2023 [15] |
| Small RNA profiling in seminal extracellular vesicles for azoospermia classification | Canonical and isomiR microRNAs discriminate azoospermia origin tRNA and piRNAs less discriminatory | 17 | Observational case-control study | Larriba et al., 2024 [16] |
| Investigate DNA methylation patterns in asthenozoospermia | 238 differentially methylated regions annotated to 114 genes related to spermatogenesis and motility | 12 | Comparative observational study | Li et al., 2022 [17] |
| Study microRNA profiles in semen and testicular tissue of azoospermic men | Mir-202-3p reduced in azoospermic semen mir-370-3p elevated in azoospermia without sperm in testis | 54 | Observational comparative study | Wainstein et al., 2023 [18] |
| Seminal plasma miRNAs in infertile men and diagnostic value | Seven miRNAs altered miRNAs better diagnostic markers than routine parameters | 457 | Observational case-control study | Wang et al., 2011 [19] |
(B) Proteomics studies based on techniques used in sperm metabolism and male infertility | |||||
Methods/Tools | Study Aim | Results | Sample size | Study Type | References |
| Identify seminal plasma proteins involved in ROS-mediated male infertility | Membrane Metallo-Endopeptidase (MME) overexpressed; Proteins modulated in infertile groups 35-protein pathway linked to sperm dysfunction | 59 | Comparative observational study | Agarwal et al., 2015 [20] |
| Characterize human sperm tail proteome, focusing on metabolism-related proteins | 1049 proteins identified; lipid metabolism enzymes prominent Mitochondrial and peroxisomal pathways active | N/A * | Experimental proteomic study | Amaral et al., 2013 [8] |
| Identify and localize AMP- activated protein kinase (AMPK) in human sperm and evaluate its role in sperm motility | AMPK localized in acrosome, midpiece, tail Active AMPK higher in high motility sperm; inhibition reduces motility | N/A * | Experimental study | Calle-Guisado et al., 2017 [21] |
| Profile seminal plasma lipid composition in necrozoospermia and evaluate lipid biomarkers | Identified 1267 lipids; 20 lipids predictive for necrozoospermia Lipidomics improves diagnosis | 56 | Comparative observational study | Deng et al., 2024 [22] |
| Discover seminal plasma biomarkers for non-invasive differential diagnosis of Obstructive Azoospermia (OA) vs. Non-Obstructive Azoospermia (NOA) | 42 proteins downregulated in NOA SCO patients Testis-specific proteins as biomarkers | 30 | Prospective observational proteomic study | Fietz et al., 2024 [23] |
| Identify novel biomarkers for asthenozoospermia via sperm tail proteomic analysis | 14 proteins altered in asthenozoospermia including tubulin beta 2B, glutathione S-transferase Mu 3, clusterin | N/A * | Experimental proteomic study | Hashemitabar et al., 2015 [24] |
| Proteomic profiling of sperm in severe oligoasthenoteratozoospermia | 938 proteins differentially expressed Metabolic pathways enriched YBX1 upregulated AK1 and ACO2 downregulated | N/A * | Experimental proteomic study | Liang et al., 2021 [25] |
| Proteomic profile changes in spermatozoa with elevated ROS | 15 proteins differentially expressed Energy metabolism and oxidative stress pathways affected | 52 | Prospective observational proteomic study | Sharma et al., 2013 [12] |
| Proteomic analysis of sperm in fertilization failure after ICSI | Altered mitochondrial and proteasomal proteins in fertilization failure | 17 | Observational proteomic study | Massana et al., 2021 [26] |
| Identify seminal biomarkers for secondary male hypogonadism (HH) | 33 proteins absent in hypogonadic patients 14 recovered after testosterone therapy | 30 | Observational proteomic study | Milardi et al., 2014 [10] |
| Identify seminal plasma proteins as biomarkers of sperm quality | 20 proteins differentially expressed Biological regulation affected | N/A * | Observational proteomic study | Sharma et al., 2013 [11] |
| Characterize seminal plasma proteome in primary and secondary infertility | Dysregulated proteins linked to secretion and immune response | 59 | Pilot observational proteomic study | Martins et al., 2020 [27] |
| Fertility-predictive model profiles of spermatozoa | High diagnostic accuracy Proteins involved in energy metabolism and sperm structure | N/A * | Experimental study | Soler et al., 2016 [28] |
| Phospholipid expression in Sertoli cell-only syndrome (SCOS) testis | Phospholipid levels correlated with spermatogenesis Potential microTESE diagnostic tool | N/A * | Experimental study | Sulc et al., 2024 [29] |
| Ribonuclease (RNASET2) levels in sperm and relation to motility | RNASET2 elevated in asthenozoospermia Inversely correlated with motility Interacts with AKAP4 | 205 | Experimental observational study | Xu et al., 2018 [30] |
(C) Metabolomics studies based on techniques used in sperm metabolism and male infertility | |||||
Methods/Tools | Study Aim | Results | Sample size | Study Type | References |
| Assess metabolomic signatures of seminal plasma in severe Oligoasthenospermia | Decreased metabolites linked to sperm membrane deterioration and energy defects | 40 | Comparative observational study | Boguenet et al., 2020 [31] |
| Investigate sperm metabolism | Sperm metabolize glucose, fructose, pyruvate to lactate Motile sperm show higher glycolytic activity | 97 | Experimental observational study | Calvert et al., 2019 [32] |
| Investigate seminal microbiome and metabolome role in high sperm DNA fragmentation index (HDFI) | Lactobacillus iners enriched in HDFI Microbial profiles linked to sperm DNA fragmentation Butanoate fermentation implicated | 102 | Observational case-control study | He et al., 2024 [9] |
| Analyze seminal plasma metabolic profiles in idiopathic/male factor infertility | Distinct metabolic profiles in idiopathic infertility: Altered lysine, arginine, tyrosine, citrate, fructose | 103 | Observational comparative study | Jayaraman et al., 2014 [33] |
| Correlate metabolomic profiles with semen quality in young men | Metabolites including acyl-carnitines and steroids distinguish low vs. high sperm count | 2700 | Observational cohort study | Olesti et al., 2023 [34] |
| Develop steroidomics strategy for human seminal fluid | Detected 41 steroids including androgens; steroid profile stable | 7 | Method development and validation study | Olesti et al., 2020 [35] |
| Comprehensive metabolomic characterization of human sperm cell | Identified 69 metabolites Pathways linked to sperm physiology and dysfunction | N/A * | Methodological study | Paiva et al., 2015 [36] |
| Metabolic profiling of unexplained male infertility (UMI) | Identified 44 differential metabolites Metabolic pathways altered | N/A * | Two-stage population observational study | Qiao et al., 2017 [37] |
| Examine sperm molecules | Density gradient concentration (DGC) with two washes minimized contamination Metabolite peaks differed between sperm populations | 20 | Experimental observational study | Reynolds et al., 2017 [38] |
| Metabolic profiling of idiopathic asthenozoospermia sperm cells | 33 metabolites identified Disturbed energy and amino acid metabolism | 213 | Experimental observational study | Zhao et al., 2018 [39] |
| Semen metabolic profiling in oligospermia patients | 72–89 metabolites as potential markers Altered amino acid and ketone body metabolism | 40 | Comparative observational study | Zhao et al., 2024 [40] |
(D) Imaging, functional assays, and other techniques used in sperm metabolism and male infertility | |||||
Methods/Tools | Study Aim | Results | Sample size | Study Type | References |
| Quantify testicular sperm apoptosis via active caspase-3 in normal and impaired spermatogenesis | Higher active caspase-3 rates in obstructive azoospermia (OA) and hypospermatogenesis Distinct localization patterns | 24 | Observational comparative study | Almeida et al., 2011 [41] |
| Analyze mitochondrial function and oxidative stress in human sperm affecting fertility | Mitochondrial dysfunction correlated with reduced motility with nitro-oxidative modifications in midpiece and head | N/A * | Experimental observational study | Cassina et al., 2015 [42] |
| Assess sperm mitochondrial metabolism and ROS production as tools to complement semen analysis | Mitochondrial respiratory control ratio correlates with motility; H2O2 inversely correlated | N/A * | Experimental observational study | Irigoyen et al., 2022 [43] |
| Assess impact of seminal clusterin level on spermatogenesis and sperm retrieval in infertile men | Seminal clusterin lower in NOA and oligozoospermia Correlation with testicular expression FSH and clusterin predict retrieval | 89 | Observational clinical study | Fukuda et al., 2016 [44] |
| Correlate sperm mitochondrial integrity with motility | Positive correlation between mitochondrial membrane potential and sperm motility | 213 | Experimental study | Paoli et al., 2011 [45] |
| Assessement of sperm DNA damage and biochemical features | DNA damage detected only in dry conditions Technique applicable to live sperm analysis | N/A * | Experimental methodological study | Costa et al., 2018 [46] |
| Identify spermatogenesis in testicular tissue | Raman spectra distinguished NOA from OA with ~90% sensitivity and 86% specificity | 52 | Observational diagnostic study | Liu et al., 2014 [47] |
| Determine cell type contributions to intracellular H2O2 and peroxynitrite production in sperm | Cell-type specific ROS production H2O2 and peroxynitrite correlated | 197 | Prospective observational study | Aziz et al., 2010 [48] |
| Progesterone-induced Ca2+ oscillations in human sperm | Ca2+ oscillations generated by CatSper channels Membrane potential modulates oscillations | 20 | Laboratory experimental study | Nitao et al., 2021 [49] |
| Evaluate seminal plasma biochemical and immunological markers in male infertility | 15 markers significantly altered Monocytes/lymphocytes in NOA Platelets in asthenozoospermia | 100 | Observational case-control study | Vashisht et al., 2021 [50] |
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Zakaria, A.; Diawara, I.; Bouziyane, A.; Louanjli, N. Exploring Human Sperm Metabolism and Male Infertility: A Systematic Review of Genomics, Proteomics, Metabolomics, and Imaging Techniques. Int. J. Mol. Sci. 2025, 26, 7544. https://doi.org/10.3390/ijms26157544
Zakaria A, Diawara I, Bouziyane A, Louanjli N. Exploring Human Sperm Metabolism and Male Infertility: A Systematic Review of Genomics, Proteomics, Metabolomics, and Imaging Techniques. International Journal of Molecular Sciences. 2025; 26(15):7544. https://doi.org/10.3390/ijms26157544
Chicago/Turabian StyleZakaria, Achraf, Idrissa Diawara, Amal Bouziyane, and Noureddine Louanjli. 2025. "Exploring Human Sperm Metabolism and Male Infertility: A Systematic Review of Genomics, Proteomics, Metabolomics, and Imaging Techniques" International Journal of Molecular Sciences 26, no. 15: 7544. https://doi.org/10.3390/ijms26157544
APA StyleZakaria, A., Diawara, I., Bouziyane, A., & Louanjli, N. (2025). Exploring Human Sperm Metabolism and Male Infertility: A Systematic Review of Genomics, Proteomics, Metabolomics, and Imaging Techniques. International Journal of Molecular Sciences, 26(15), 7544. https://doi.org/10.3390/ijms26157544