How can male fertility issues go undetected even when standard semen analysis results appear normal?
“Unexplained infertility” is a term used when no identifiable cause of infertility is found, despite a couple being unable to achieve pregnancy. In many cases, however, infertility may remain labelled as “unexplained” because a full and comprehensive male fertility evaluation has not been carried out. This can mean that certain underlying male fertility factors are missed during routine investigations.
While a standard semen analysis is often the first step in assessing male fertility, normal results do not always reflect the true fertility potential of the patient. Traditional semen analysis primarily evaluates sperm count, motility, and morphology, but it may not detect more complex issues such as sperm DNA fragmentation, oxidative stress, or functional abnormalities that can impact fertilisation, embryo development, and pregnancy outcomes.
For this reason, couples who are experiencing recurrent miscarriage, repeated failed fertility treatments, or difficulty conceiving should be referred for advanced diagnostic testing. A more detailed male fertility workup can help identify hidden factors that may otherwise go undetected, allowing for a more accurate diagnosis and a more targeted treatment approach.
What advanced sperm function tests may help identify hidden causes of unexplained infertility?
These advanced sperm function tests are supported by established guidance and peer-reviewed evidence in reproductive medicine, including standards set out by the World Health Organization in the WHO Laboratory Manual for the Examination and Processing of Human Semen (6th edition, 2021). While routine semen analysis provides important information on sperm count, motility, and morphology, it does not assess several functional, immunological, genetic, or biochemical factors that may also impact fertility.
The MAR (Mixed Antiglobulin Reaction) test is used to detect antisperm antibodies in semen. These antibodies can bind to sperm and impair their ability to move effectively or fertilise an egg. Both the European Association of Urology and the American Society for Reproductive Medicine recognise that immunological factors may contribute to infertility even when standard semen parameters appear normal.
Sperm DNA fragmentation testing assesses the integrity of genetic material within sperm. Unlike routine semen analysis, this test can identify DNA damage that may affect fertilisation, embryo development, implantation, and miscarriage risk. Current guidance from reproductive medicine societies such as the EAU and ASRM highlights the clinical relevance of sperm DNA quality in cases of unexplained infertility.
Reactive Oxygen Species (ROS) testing evaluates oxidative stress within semen. Excess ROS can damage sperm membranes, reduce motility, and lead to DNA fragmentation. This imbalance between oxidative stress and antioxidant defences is widely recognised in andrology literature as a contributing factor to reduced male fertility potential.
Emerging research into the male reproductive microbiome has also shown that bacterial imbalance, or dysbiosis, may negatively affect sperm quality. Changes in the microbiome can contribute to inflammation and oxidative stress, which in turn may impair sperm function. Although this is still an evolving area of study, evidence published in journals such as Human Reproduction Update supports its relevance in male infertility assessment.
Finally, microfluidic sperm selection technologies such as ZyMot are used in assisted reproductive treatments to isolate sperm with improved motility and lower levels of DNA damage. Clinical studies in reproductive medicine journals suggest that these techniques may enhance sperm selection quality compared with conventional laboratory preparation methods.
How do lifestyle factors contribute to unexplained male infertility despite normal reproductive health evaluations?
Lifestyle and environmental factors can have a significant impact on male fertility, even when standard reproductive health assessments and semen analysis results appear normal. Many cases of unexplained male infertility may be linked to underlying sperm dysfunction that is not detected through routine testing, particularly damage to sperm DNA integrity, commonly referred to as sperm DNA fragmentation (SDF).
A wide range of physiological, environmental, and behavioural factors have been associated with increased oxidative stress and reactive oxygen species (ROS), which are major contributors to sperm DNA damage. Obesity, for example, is strongly linked to elevated oxidative stress, chronic systemic inflammation, and hormonal imbalances that can negatively affect sperm quality and DNA integrity. However, studies suggest that improvements in sperm health may be achievable through weight reduction and lifestyle modification (Barbagallo et al., 2021; Mir et al., 2018).
Metabolic and environmental conditions also play an important role. Diabetes has been associated with increased oxidative stress and impaired sperm function, while exposure to air pollution and toxic heavy metals such as lead and cadmium has been shown to contribute to elevated levels of sperm DNA fragmentation (Agbaje et al., 2007; Omolaoye et al., 2024). These environmental toxins can disrupt normal sperm development and impair fertilisation potential, even in men with otherwise normal semen parameters.
In addition, exposure to harmful substances such as cigarette smoke, alcohol, and endocrine-disrupting chemicals including bisphenol A (BPA) can directly damage sperm DNA through oxidative mechanisms. These compounds are known to increase ROS production, leading to cellular stress and reduced sperm function (Mubarak et al., 2022; Aboulmaouahib et al., 2018). Poor diet, lack of physical activity, chronic stress, inadequate sleep, and excessive heat exposure may further exacerbate oxidative damage and negatively influence overall reproductive health.
Even reproductive habits may contribute to sperm DNA damage. Prolonged ejaculatory abstinence has been associated with increased sperm DNA fragmentation, potentially due to extended sperm storage within the epididymis and prolonged exposure to oxidative stress (Borges Jr. et al., 2019).
Collectively, these findings demonstrate that male fertility is influenced by far more than basic semen parameters alone. Lifestyle and environmental factors can significantly impair sperm function and DNA integrity without obvious abnormalities appearing on routine fertility assessments. This highlights the importance of advanced diagnostic testing and lifestyle intervention strategies in couples experiencing unexplained infertility, recurrent miscarriage, or failed fertility treatment outcomes.
Barbagallo, F., Condorelli, R. A., Mongioì, L. M., Cannarella, R., Cimino, L., Magagnini, M. C., Crafa, A., La Vignera, S., & Calogero, A. E. (2021). Molecular Mechanisms Underlying the31 Relationship between Obesity and Male Infertility. Metabolites, 11(12), 840. https://doi.org/10.3390/metabo11120840
Mir, J., Franken, D., Andrabi, S. W., Ashraf, M., & Rao, K. (2018). Impact of weight loss on sperm DNA integrity in obese men. Andrologia, 50(4), e12957. https://doi.org/10.1111/and.12957
Omolaoye, T. S., Skosana, B. T., Ferguson, L. M., Ramsunder, Y., Ayad, B. M., & Du Plessis, S. S. (2024). Implications of Exposure to Air Pollution on Male Reproduction: The Role of Oxidative Stress. Antioxidants, 13(1), 64. https://doi.org/10.3390/antiox13010064
Agbaje, I. M., Rogers, D. A., McVicar, C. M., McClure, N., Atkinson, A. B., Mallidis, C., & Lewis, S. E. M. (2007). Insulin dependant diabetes mellitus: Implications for male reproductive function. Human Reproduction, 22(7), 1871–1877. https://doi.org/10.1093/humrep/dem077
Mubarak, M., Omolaoye, T. S., Al Smady, M. N., Zaki, M. N., & du Plessis, S. S. (2022). Bisphenol A and Male Infertility: Role of Oxidative Stress. In S. Roychoudhury & K. K. Kesari (Eds.), Oxidative Stress and Toxicity in Reproductive Biology and Medicine: A Comprehensive Update on Male Infertility Volume II (pp. 119–135). Springer International Publishing. https://doi.org/10.1007/978-3-031-12966-7_8
Aboulmaouahib, S., Madkour, A., Kaarouch, I., Sefrioui, O., Saadani, B., Copin, H., Benkhalifa, M., Louanjli, N., & Cadi, R. (2018). Impact of alcohol and cigarette smoking consumption in male fertility potential: Looks at lipid peroxidation, enzymatic antioxidant activities and sperm DNA damage. Andrologia, 50(3), e12926. https://doi.org/10.1111/and.12926
Borges Jr., E., Braga, D. P. a. F., Zanetti, B. F., Iaconelli Jr., A., & Setti, A. S. (2019). Revisiting the impact of ejaculatory abstinence on semen quality and intracytoplasmic sperm injection outcomes. Andrology, 7(2), 213–219. https://doi.org/10.1111/andr.12572
How can clinicians better assess the male partner when no obvious cause of infertility is identified?
Clinicians can improve the assessment of the male partner in cases of unexplained infertility by ensuring that both partners undergo a comprehensive and evidence-based evaluation. This includes confirming that all routine investigations have been appropriately completed and interpreted for each individual, rather than focusing primarily on the female partner. A detailed medical, reproductive, and lifestyle history should be obtained, alongside a thorough physical examination and standard fertility investigations.
Where no clear cause is identified through initial testing, clinicians should consider whether advanced diagnostic investigations may be beneficial for both partners. These may include hormonal profiling, genetic testing, sperm DNA fragmentation analysis, imaging studies, or other specialised assessments depending on the clinical presentation and history.
In couples who have experienced recurrent miscarriage, further targeted investigations should also be undertaken to identify any underlying male or female factors that may contribute to pregnancy loss. Adopting a more holistic and collaborative approach to fertility assessment can help ensure that potentially overlooked male-factor contributors are identified and managed appropriately.
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