In infertile couples whose male partner has alterations in semen parameters frequently, a comprehensive andrological approach is lacking and approximately 30-50% are classified as idiopathic infertility. These couples are often directly addressed to assisted reproduction techniques (ARTs). However, several clinical conditions may benefit from medical treatment. By acting on etiology and/or risk factors, this aims at improving seminal parameters and restoring natural fertility (Grande et al., 2025).

Male fertility results from a complex interplay of physiological, environmental, and genetic factors. It is conditioned by the properly developed anatomy of the reproductive system, hormonal regulation balance, and the interplay between different cell populations that sustain an appropriate and functional environment in the testes. Unfortunately, the mechanisms sustaining male fertility are not flawless, and their perturbation can lead to infertility. Inflammation is one of the factors that contribute to male infertility. In the testes, it can be brought on by varicocele, obesity, gonadal infections, leukocytospermia, physical obstructions or traumas, and consumption of toxic substances. As a result of prolonged or untreated inflammation, the testicular resident cells that sustain spermatogenesis can suffer DNA damage, lipid and protein oxidation, and mitochondrial dysfunction consequently leading to loss of function in affected Sertoli cells (SCs) and Leydig cells (LCs), and the formation of morphologically abnormal dysfunctional sperm cells that lay in the basis of male infertility and subfertility. This is due mainly to the production and secretion of pro-inflammatory mediators, including cytokines, chemokines, and reactive oxygen species (ROS) by local immune cells (macrophages, lymphocytes T, mast cells) and tissue-specific cells [SCs, LCs, peritubular myoid cells (PMCs) and germ cells (GCs)]. Depending on the location, duration, and intensity of inflammation, these mediators can exert their toxic effect on different elements of the testes (Fomichova et al., 2025).

5-lipoxygenase (5-LOX) contributes to male infertility by initiating the breakdown of arachidonic acid (AA), leading to the production of lipid hydroperoxides and highly reactive metabolites like 4-HNE that cause oxidative stress, lipid peroxidation, and protein damage in sperm.

Fomichova, O., Oliveira, P. F., & Bernardino, R. L. (2025). Exploring the interplay between inflammation and male fertility. Febs j, 292(13), 3321-3349. https://doi.org/10.1111/febs.17366

Grande, G., Garolla, A., Graziani, A., Astorri, A. L., Cammarota, M. V., Merola, A., Polidori, M. P., Lulli, E., Busato, E., Pesce, F., Pompa, G., Pontecorvi, A., Milardi, D., & Ferlin, A. (2025). Comprehensive diagnostic and therapeutic approach to male factor infertility aimed at natural fertility: A multicentric retrospective cohort study. Andrology. https://doi.org/10.1111/andr.70006