Molecular and Genetic Mechanisms of Male Infertility

Male infertility arises from complex interactions between genetic anomalies and molecular pathways that govern spermatogenesis and testicular function. Central to these mechanisms are defects in germ cell development, hormonal regulation, DNA repair and chromosomal integrity. Monogenic and polygenic mutations affecting key regulators—such as transcription factors, structural proteins of the sperm flagellum and proteins involved in meiotic recombination—have been increasingly implicated in conditions ranging from oligozoospermia to non-obstructive azoospermia. Advances in high-throughput sequencing, single-cell transcriptomics and genome editing have revealed novel candidate genes and pathways, including those modulating cell cycle progression, energy metabolism and cell–cell communication between Sertoli cells and germ cells. Moreover, disruptions in androgen signalling and innate immune responses have emerged as contributors to genomic instability in the testis. A growing body of evidence emphasises the importance of integrating genetic screening into clinical practice, not only to improve diagnostic yield but also to guide personalised therapeutic strategies and reproductive counselling. This overview summarises the current state of knowledge, highlights technological breakthroughs and underscores the translational potential of genetic and molecular research in addressing male infertility.

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Molecular and Genetic Mechanisms of Male Infertility publication trend

The graph below shows the total number of articles in molecular and genetic mechanisms of male infertility across all publications each year (not limited to Nature Index journals).

Technical terms

Non-obstructive azoospermia: absence of sperm in the ejaculate due to defective spermatogenesis rather than physical blockage.

Spermatogenesis: the multi-stage process by which spermatogonial stem cells develop into mature spermatozoa.

Single-cell transcriptomics: a method to profile gene expression in individual cells, revealing cellular heterogeneity and lineage-specific regulation.

Germ cells: reproductive cells that give rise to spermatozoa following a programme of mitotic and meiotic divisions.

CRISPR/Cas9 genome editing: a technology that enables precise alteration of specific DNA sequences to investigate gene function and disease mechanisms.

Haploinsufficiency: a condition in which a single functional copy of a gene is insufficient to maintain normal function, leading to disease.

References

1. Deciphering the Molecular Characteristics of Human Idiopathic Nonobstructive Azoospermia from the Perspective of Germ Cells. Advanced Science (2023).
2. X-linked RBBP7 mutation causes maturation arrest and testicular tumors. Journal of Clinical Investigation (2023).
3. Effects of Tcte1 knockout on energy chain transportation and spermatogenesis: implications for male infertility. Human Reproduction Open (2024).