Male infertility is responsible for roughly half of all infertility cases worldwide, yet the standard diagnostic tool, conventional semen analysis, leaves a striking proportion of patients without an explanation. When a man’s sperm count, motility, and morphology appear within normal limits, or when the parameters fail to reflect the true underlying problem, clinicians are left with little to offer beyond empirical assisted reproduction. A new systematic review published in the Journal of Molecular Medicine argues that a major part of the missing information may be floating in the fluid surrounding the sperm cells themselves. By systematically cataloguing the small molecules that are deregulated in the seminal plasma of infertile men, a team at the University of Aveiro in Portugal has assembled one of the most comprehensive metabolic maps of male infertility to date.
The research, led by Rafael Santos, Beatriz Marinheiro, and Margarida Ramos under the supervision of Joana Santiago and Margarida Fardilha, took the form of a systematic review conducted according to the PRISMA reporting guidelines. The team searched PubMed, Scopus, and Web of Science for metabolomic studies that directly compared the seminal plasma metabolome of healthy men with that of infertile men, covering the literature published up to December 2025. Twenty studies passed the selection criteria and were included in the final analysis. Rather than treating all infertility as a single entity, the authors stratified the evidence into four clinically meaningful groups: asthenozoospermia, defined by reduced sperm motility; oligozoospermia, defined by low sperm concentration; obesity-associated infertility; and overall male infertility that did not fit a single specific phenotype.
From those twenty studies, the researchers retrieved a total of 284 metabolites whose concentrations had been measured in seminal plasma. The power of the approach lies in the cross-study comparison: metabolites that repeatedly emerge as altered across independent cohorts, analytical platforms, and patient populations are far more likely to represent genuine biological signals than one-off statistical fluctuations. After consolidating the data, the team identified distinct sets of consistently deregulated metabolites for each infertility category. Eleven metabolites were altered in asthenozoospermia, six in obesity-related infertility, and ten in the overall infertility group, while oligozoospermia showed its own characteristic pattern.
The lists themselves are revealing. In asthenozoospermia, the metabolites found at reduced levels included L-tyrosine, D-fructose, L-valine, phenylalanine, proline, D-glucose, L-alanine, leucine, sorbitol, and L-aspartic acid, with only uridine elevated. The obesity group showed decreases in D-fructose, glycine, maleic acid, L-valine, proline, and lysine. In the overall infertility category, L-carnitine, L-tyrosine, L-valine, L-alanine, phenylalanine, proline, D-glucose, leucine, malic acid, and citraconic acid were all reduced. The recurrence of certain molecules across groups is not accidental. Fructose, produced by the seminal vesicles, is the principal energy substrate for sperm motility, so its depletion in men whose sperm move poorly fits a coherent physiological story. D-glucose likewise fuels glycolysis, a pathway that sperm rely on heavily to sustain the relentless ATP demand of flagellar beating.
Equally telling is the repeated appearance of amino acids. L-valine, leucine, phenylalanine, tyrosine, alanine, and proline all surfaced as deregulated in multiple infertility phenotypes. Branched-chain amino acids such as valine and leucine are increasingly recognized as metabolic regulators with links to insulin sensitivity, which may be particularly relevant in obesity-associated infertility, where systemic metabolic derangement is thought to spill over into the reproductive tract. Proline, for its part, has been shown in separate experimental work to act as a protective osmolyte and antioxidant in seminal fluid, and supplementation studies have reported improvements in sperm quality parameters. The consistent depletion of these amino acids in infertile men suggests that the seminal plasma is not merely a passive transport medium but a metabolically active environment whose composition can make or break sperm function.
Perhaps the most clinically intriguing metabolite is L-carnitine, which emerged as reduced in the overall infertility group. Carnitine is essential for the beta-oxidation of long-chain fatty acids, shuttling them into mitochondria where they can be burned for energy. Sperm mitochondria, packed into the midpiece of the cell, drive the vigorous tail movement required to reach and penetrate the egg. A deficit in carnitine therefore points directly at compromised mitochondrial energy production, a mechanism long suspected in asthenozoospermia and supported by proteomic studies showing alterations in mitochondrial and bioenergetic proteins in poorly motile sperm. Sorbitol, also reduced in asthenozoospermia, adds another dimension: experimental work in mice has demonstrated that sorbitol can fuel sperm motility through the enzyme sorbitol dehydrogenase, providing an alternative energy route when glucose metabolism falters.
To move from a list of molecules to an understanding of mechanism, the Aveiro team performed a bioinformatic analysis of the enzymes that act on the deregulated metabolites. Drawing on resources such as the Human Metabolome Database, UniProt, the Human Protein Atlas, and the Gene Ontology knowledgebase, they mapped the altered metabolites onto metabolic pathways and linked the relevant enzymes to sperm biology. The analysis converged on three pathway clusters: phenylalanine and tyrosine metabolism, fructose and mannose degradation, and beta-oxidation of long-chain fatty acids. Crucially, the enzymes involved were associated with key sperm functions, including motility, vitality, and energy metabolism, and with male infertility phenotypes themselves. This enzyme-level view transforms the metabolite lists into testable hypotheses about which biochemical reactions fail first when sperm quality collapses.
The significance of the work becomes clearer when set against the limitations of current diagnostics. Semen analysis, standardized by the World Health Organization, measures physical parameters but says nothing about molecular cause. It fails to explain the underlying problem in an estimated thirty percent of cases, and even when abnormalities are detected, the analysis cannot distinguish between, say, a mitochondrial energy defect and an oxidative stress problem. Metabolomics, the systematic measurement of small molecules in a biological sample, offers a functional readout that sits closer to physiology than genomics or even proteomics, because metabolites are the end products of cellular activity. A metabolic fingerprint in seminal plasma could, in principle, tell a clinician not just that a man’s sperm are slow, but why they are slow, and whether the problem is amenable to nutritional or pharmacological intervention.
The authors are careful to frame their findings as candidate biomarkers rather than ready-made clinical tests. Systematic reviews of metabolomics inherit the heterogeneity of the primary literature: the twenty included studies used different analytical platforms, ranging from nuclear magnetic resonance spectroscopy to liquid and gas chromatography coupled to mass spectrometry, different sample preparation protocols, and different patient selection criteria. Variations in abstinence periods before sample collection, itself known to shift the seminal metabolome, add further noise. The team mitigated these issues through critical appraisal of study quality using established tools and by focusing only on metabolites that showed consistent directionality across studies, but prospective validation in large, well-phenotyped cohorts remains the necessary next step before a metabolite panel could enter the fertility clinic.
Even so, the study delivers something the field has lacked: a curated, cross-validated inventory of the seminal plasma metabolites most reliably associated with male infertility, organized by clinical phenotype and anchored to specific metabolic pathways. The work was funded by the Portuguese Foundation for Science and Technology through the FERTISCAN project, reflecting a broader European push to develop molecular diagnostics for reproductive health. If the candidate biomarkers hold up under validation, the humble semen sample could evolve from a microscope slide into a metabolic report card, one that reveals the biochemical roots of infertility that conventional analysis has overlooked for decades. For the millions of couples navigating unexplained infertility, that would represent not just a scientific advance but a genuinely new starting point for treatment.
Subject of Research: Metabolomic biomarkers of male infertility in seminal plasma
Article Title: Unravelling deregulated metabolites in seminal plasma of infertile men: a systematic review and bioinformatic analysis
Article References: Unravelling deregulated metabolites in seminal plasma of infertile men: a systematic review and bioinformatic analysis. (n.d.). https://doi.org/10.1007/s00109-026-02719-0
Image Credits: AI Generated
DOI: 10.1007/s00109-026-02719-0
Keywords: male infertility, seminal plasma, metabolomics, biomarkers, asthenozoospermia, oligozoospermia, obesity, sperm motility, energy metabolism, L-carnitine, fructose, systematic review
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Tags: asthenozoospermiaBiomarkerscomprehensive metabolite analysis in seminal fluidenergy metabolismfructoseinnovative approaches to male infertility assessmentL-carnitinemale infertilitymale infertility diagnosismetabolic mapping of male infertilitymetabolite fingerprinting in reproductive healthmetabolomic diagnostics in reproductive medicineMetabolomicsobesityoligozoospermiaPRISMA guidelines in fertility researchseminal plasmaseminal plasma metabolomicssmall molecule biomarkers for male infertilitysperm function and metabolic profilesperm motilitysystematic reviewsystematic review of seminal plasma metabolitesunexplained male infertility
