1. Male immune infertility : a million dollar question in medically assisted reproductionSanja Ozimič, Aleksander Andjelić, Helena Ban Frangež, Martin Štimpfel, 2026, pregledni znanstveni članek Povzetek: Male factor infertility accounts for approximately 30–50% of all infertility cases. The primary causes include genetic abnormalities, sexually transmitted infections, physical or anatomical issues, hormonal imbalances, lifestyle factors, and environmental influences. Despite significant advances in diagnostic techniques, an identifiable cause remains elusive in nearly 40% of cases. One less commonly recognized factor is male immune infertility, which results from the presence of antisperm antibodies (ASA) in semen. These antibodies are typically identified through an extended semen analysis. Under normal physiological conditions, spermatogenesis and sperm transport occur within an immune-privileged environment. However, when the blood-testis barrier is compromised due to trauma, infection, or surgery, ASA may form. The effects of ASA on fertility can vary, but evidence indicates that ASA presence may impair sperm motility and capacitation, promote sperm agglutination, and be associated with DNA fragmentation. To address these challenges, assisted reproductive technologies (ART), including intrauterine insemination (IUI), in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI), are commonly used. These methods have proven to be effective in overcoming ASA-related infertility and improving reproductive outcomes. Given the ongoing debate and uncertainty surrounding the clinical relevance of ASA, this paper aims to review existing literature, explore the concept of male immune infertility, identify its risk factors, outline current methods for ASA detection, evaluate the role of ASA in ART, highlight both the strengths and limitations of current research, and contribute to a clearer understanding of this complex condition. After our literature review, we could confirm that multicentric studies with large groups of patients related to this topic are rarely found, and that there are many uncertainties regarding the clinical significance of ASA. The complete system of diagnosing male immune infertility lacks precise guidelines that infertility clinics could use in their routine male infertility check-ups.
Ključne besede: male infertility, male immune infertility, antisperm antibodies, mixed antiglobulin reaction test, MAR test, assisted reproductive technology
Objavljeno v DiRROS: 13.03.2026; Ogledov: 6; Prenosov: 4
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2. The role of DNA mismatch repair mutS/mutL homolog genes in spermatogenesis and male infertility : a systematic review and cohort studyRebeka Podgrajšek, Alenka Hodžić, Aleš Maver, Martin Štimpfel, Aleksander Andjelić, Olivera Miljanović, Momčilo Ristanović, Borut Peterlin, 2025, izvirni znanstveni članek Povzetek: Background: Recent research in male infertility genetics has identified numerous candidate genes, some of which were also involved in DNA repair. Mismatch repair (MMR) genes, such as MSH4 and MSH5, have been linked to male infertility due to their role in meiosis, suggesting that other MMR genes may also contribute to impaired spermatogenesis. To investigate the role of MMR genes in male infertility, we first conducted a systematic review focusing on their involvement in impaired spermatogenesis, which was followed by a multicenter cohort study assessing the occurrence of rare deleterious variants in MMR genes among men with severely impaired fertility. The present study aimed to assess the contribution of MMR genes to male infertility and to evaluate their potential clinical utility in the diagnostic workup of men with severely impaired fertility. Methods: A systematic review was conducted through a PubMed database search with a focus on the role of MMR genes in spermatogenesis. We additionally prepared a cohort study, including whole-exome sequencing data from 244 infertile men presenting azoospermia or severe oligozoospermia (< 5 million spermatozoa/ml). Rare, deleterious variants in MMR genes were classified using the ACGS Guidelines for Variant Classification 2020. Results: Following a systematic review of the literature, we gathered robust evidence supporting the strong involvement of MSH4 and MSH5 variants in male infertility, moderate evidence for MLH3, and limited evidence for other MMR genes. From our cohort, we identified likely pathogenic or pathogenic variants in two individuals: one with two MSH4 variants and another with a PMS2 variant. Conclusions: The present study identifies MSH4 and MSH5 as strong candidate genes for male infertility, supporting the integration of their testing into the clinical diagnosis of infertile men, particularly those exhibiting non-obstructive azoospermia. Although current evidence suggests that genetic variants in most MMR genes do not cause infertility, genetic defects in MMR genes can still impair spermatogenesis due to their critical role in sperm DNA repair and maintenance of genome integrity.
Ključne besede: male infertility, spermatogenesis, mismatch repair, gens, MSH, MLH
Objavljeno v DiRROS: 22.12.2025; Ogledov: 227; Prenosov: 105
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3. ACE gene and male infertility : a South Slavic case-control study and multi-omics data integrationTanja Kunej, Rebeka Podgrajšek, Helena Jaklič, Alenka Hodžić, Martin Štimpfel, Olivera Miljanović, Momčilo Ristanović, Ivana Novaković, Dijana Plašeska Karanfilska, Predrag Noveski, Saša Ostojić, Alena Buretić-Tomljanović, Antun Gršković, Borut Peterlin, 2025, izvirni znanstveni članek Povzetek: Components of the renin-angiotensin system (RAS) are expressed in both female and male reproductive tracts, with angiotensin I converting enzyme (ACE) being an important component for male reproductive function, as shown in animal models. The most studied ACE polymorphism is the Alu insertion-deletion (I/D), which has been proposed to have a negative effect on male fertility. Given the conflicting evidence in the literature, we conducted a multicentric case-control study to investigate the association between the ACE Alu I/D polymorphism and impaired spermatogenesis. Using PCR amplification and agarose electrophoresis, we genotyped the ACE gene Alu I/D polymorphism in 745 South Slavic men. The study group consisted of 457 patients with impaired spermatogenesis, 239 with non-obstructive azoospermia (NOA) and 218 with oligoasthenoteratozoospermia (OAT) and a control group of 288 fertile men. No association was found between the Alu I/D polymorphism and these semen phenotypes, suggesting that it is not associated with NOA or severe OAT in this cohort. To provide a broader regulatory context, we also developed an integrative atlas of ACE regulatory elements by in silico multi-omics analysis using genomics databases and bioinformatics tools. Data integration revealed various regulatory mechanisms at multiple omics levels, including genomics, epigenomics, miRNAomics, transcriptomics, proteomics and epiproteomics. These include genomic variants with predicted deleterious effects, a CpG island, microRNAs (miRNAs) and post-translational modifications (PTMs). In addition, protein interaction analysis revealed that ACE is indirectly linked to several proteins previously associated with male infertility and is also targeted by miRNA previously associated with oligozoospermia. This comprehensive, multi-faceted approach, combining genetic association analysis with bioinformatics, provides insights into ACE regulation in its broader molecular context. These results emphasize the importance of further integrative multi-omics and systems biology research to better understand the role of ACE in male reproductive function.
Ključne besede: angiotensin I converting enzyme (ACE), male infertility, azoospermia, oligozoospermia, multi-omics
Objavljeno v DiRROS: 09.12.2025; Ogledov: 263; Prenosov: 117
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4. The role of preconception parental health on embryo quality - preliminary results of a prospective study using non-invasive preimplantation genetic testing for aneuploidyMaja Tomic, Eda Vrtačnik-Bokal, Martin Štimpfel, 2025, izvirni znanstveni članek Povzetek: In this study, we aimed to correlate embryonic ploidy status studied with non-invasive preimplantation genetic testing for aneuploidy with the basic patient characteristics of the infertile couple to gain insight into the effects of parental physical health on embryo ploidy. We recruited 131 couples, who were stratified into 4 groups based on female age. We gathered general patient characteristics of the couple and determined the female’s hormonal status. We included 316 embryos in our study. Embryos were either transferred in the uterus in a fresh cycle or vitrified for later use. We collected spent embryo culture medium on either day 5 or 6 and performed whole genome amplification before using Next Generation Sequencing. Pregnancy outcomes were noted and cross-referenced with patient characteristics and the embryo’s ploidy status in a retrospective manner. While we have indirectly observed a level of maternal contamination, we nevertheless found a significant correlation between embryo ploidy status and cell free deoxyribonucleic acid concentration in spent embryo culture, as well a correlation between female age and embryo ploidy status. We observed a significant correlation between male body mass index and cell free deoxyribonucleic acid concentration in spent embryo culture medium and between male body mass index and pregnancy outcome. We illustrated a connection between male body mass index and cell free deoxyribonucleic acid, independent of female markers. This is the first study to observe not only female but male parameters in correlation to cell free deoxyribonucleic acid.
Ključne besede: non-invasive preimplantation genetic testing, aneuploidy, next-generation sequencing, embryo ploidy, male weight, female age, body mass index
Objavljeno v DiRROS: 26.11.2025; Ogledov: 310; Prenosov: 148
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5. The outcome of IVF/ICSI cycles in male cancer patients : retrospective analysis of procedures from 2004 to 2018Tanja Burnik Papler, Eda Vrtačnik-Bokal, Sašo Drobnič, Martin Štimpfel, 2021, izvirni znanstveni članek Ključne besede: assisted reproduction techniques, fertility preservation, infertility, pregnancy, sperm cryopreservation
Objavljeno v DiRROS: 22.07.2024; Ogledov: 974; Prenosov: 291
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