Multiple Factors Behind Male Infertility

It's reported that one in seven couples experience infertility, with half of these cases attributed to male factors. Various factors contribute to the increasing prevalence of male infertility. Below are the primary reasons responsible for male infertility.

Genetics[1]

Although recognized genetic factors contribute to 10% of the cases, there is a widespread belief that a significant portion of unexplained spermatogenic failure may stem from genetic abnormalities that have not been thoroughly investigated in current clinical assessments.

A research team led by Professors Maris Laan from the Institute of Biomedicine and Translational Medicine at the University of Tartu, and Margus Punab from the Andrology Clinic at Tartu University Hospital, conducted investigations to determine the extent to which male infertility can be attributed to a single faulty gene. Their study revealed that about 12% of the individuals analyzed had heterogeneous genetic causes. They identified disease-causing variations in 39 genes responsible for regulating spermatogenesis, genital development during fetal stages, and reproductive endocrinology. Some of these variants were found to be recurrent, observed in multiple patients within the ESTAND cohort or reported in other populations. Additionally, some patients were found to carry multiple genetic defects contributing to their spermatogenic failure.

Diet[2]

Consuming a high-calorie diet leads to obesity, which is associated with insulin resistance, notably hyperinsulinemia and hyperglycemia. Obesity prompts alterations in sperm glucose metabolism, resulting in impaired glycolysis. This impairment exacerbates oxidative stress, impacting sperm quality and male reproductive function.

A study performed included 300 males who were not classified as obese, with an average age of 34.6 years. Among them, approximately 32%, 36.7%, and 31% demonstrated low, medium, and high adherence to the Mediterranean diet (MD), respectively. Interestingly, smokers and non-smokers exhibited varying degrees of adherence to the MD.

The level of adherence to the MD was significantly associated with sperm parameters. Obesity or being overweight had a negative impact on the hypothalamic-pituitary-gonadal axis, influencing spermatogenesis and energy metabolism. Adhering to the MD helped prevent unfavorable metabolic characteristics in men.

Obesity[3]

In a study conducted, semen samples were obtained from 32 individuals classified as obese and 32 individuals with a normal body mass index (BMI), all under the age of 45. These participants were chosen from those seeking routine fertility assessment at a fertility clinic before attempting to conceive.

Those selected for the study did not exhibit signs of Klinefelter's syndrome, varicocele, anatomical abnormalities, genital infections, azoospermia, or hypogonadism. Furthermore, none of the participants had diabetes, were smokers, consumed alcohol, were taking cholesterol-lowering medications, or had a history of weight loss.

The study revealed a negative correlation between obesity and sperm volume, progressive motility, and total sperm count. Furthermore, it suggested that obesity is associated with increased sperm DNA fragmentation, elevated intracellular reactive oxygen species (ROS) levels, and a higher proportion of sperm with immature chromatin, which aligns with previous findings.

Insulin resistance among men is often connected with the metabolic syndrome and obesity, recognized as risk factors of decreased sperm quality. Both these diseases are connected with impaired lipoprotein concentration. As far as lipoprotein metabolism is concerned, there are studies showing correlations between insulin resistance and elevated triglyceride levels and reduced HDL. Due to the fact that insulin resistance is increasingly often being diagnosed in the population, it demands a closer scrutiny in the context of semen quality.

Previous research has underscored the impact of altered DNA integrity on male fertility and embryonic development. As mentioned earlier, ROS plays a crucial role in oxidative stress (OS) generation, detrimentally affecting sperm by causing damage to both single- and double-stranded DNA.

In line with earlier investigations, this study observed that obesity diminishes sperm viability by hastening apoptosis. Notably, the percentages of spermatozoa undergoing early apoptosis and necrosis were comparable between obese individuals and those with normal BMI. Hence, the authors assert that this is the first study to document reduced sperm viability in obese individuals due to a higher prevalence of late apoptosis.

Physical activity[4],[5],[6]

The impact of physical activity on semen quality appears to be a topic of conflicting findings, with some studies suggesting no effect while others demonstrate a beneficial influence, especially among both healthy and infertile men. For instance, Danielewicz et al. found a positive correlation between physical activity level and sperm count, progressive motile sperm count, and morphologically normal sperm count. Moreover, when coupled with the DASH diet, physical activity showed positive correlations with various sperm parameters.

Researchers have also examined specific sports disciplines or types of physical activity. Maleki and Tartibian revealed that resistance exercises can reduce inflammation and oxidative stress levels, leading to improved semen quality and reduced DNA damage. Gaskins et al. reported that weight training and outdoor exercises were beneficial for sperm concentration, possibly due to the influence of strength training on testosterone levels and insulin resistance reduction.

However, certain types of physical activity, such as cycling, have been associated with a negative impact on semen quality, likely due to excessive physical effort diminishing antioxidative capacities in the body. It's noted that intense training, regardless of the discipline, might have adverse effects on semen quality compared to recreational training.

Physical activity is recognized as a factor that reduces insulin resistance, which can have implications for semen quality. Studies in overweight or obese individuals, including children and adults, have shown that aerobic exercise can reduce insulin resistance markers. Therefore, early introduction of regular physical activity could potentially improve semen quality and prevent metabolic disorders, thus contributing to overall reproductive health.

Cigarette smoking[7]

Around 37% of men in their reproductive years are cigarette smokers, and Europe exhibits the highest tobacco usage among all World Health Organization (WHO) regions. The toxins from cigarette smoking have the potential to impact sperm development and function, leading to adverse effects on semen parameters.

The meta-analysis comprised twenty studies involving 5865 participants. Exposure to cigarette smoking was linked to decreased sperm count (mean difference [MD]: -9.72×106/ml; 95% confidence interval [CI], -13.32 to -6.12), motility (MD: -3.48%; 95% CI, -5.53 to -1.44), and morphology (MD: -1.37%; 95% CI, -2.63 to -0.11). Subgroup analyses revealed that the effect size was more pronounced in infertile men compared to the general population and in moderate/heavy smokers compared to mild smokers. While the overall effect size on semen volume, sperm count, and motility remained consistent when using the 2010 and earlier WHO manuals for semen analysis, it was lower concerning sperm morphology.

Alcohol consumption[8]

Alcohol consumption has been associated with reduced morphologically normal sperm count and sperm DNA damage. Additionally, some studies indicate its negative impact on fertility. Furthermore, excessive tobacco smoking and alcohol consumption can lead to increased secretion of Reactive Oxygen Species (ROS), triggering inflammation in the body and disrupting the balance between ROS and antioxidants. This imbalance can further compromise semen quality and reproductive health.

Stress[9],[10],[11]

Stress can trigger numerous adverse processes in the body, yet its connection to our health is significant. Mental stress disrupts the secretion of hormones crucial for male fertility, consequently diminishing semen quality. This impact on semen quality is mediated through neuroendocrine pathways; for instance, elevated glucocorticoid levels can reduce testosterone secretion from Leydig cells, thereby impairing spermatogenesis. Additionally, stress induces oxidative stress, exacerbates insulin resistance, and initiates a cascade of proinflammatory cytokines, all of which contribute to a decline in semen quality.

A study conducted by Zou et al. demonstrated that high levels of work-related stress adversely affect semen parameters, such as sperm concentration and total sperm count.

Conclusions

In summary, lifestyle choices and insulin resistance are intricately linked to semen quality. It's imperative to educate men of reproductive age about how lifestyle and environmental factors, as well as associated diseases, can impact semen quality and overall reproductive health. Notably, lifestyle components influencing semen quality often coincide with insulin resistance. Therefore, further research is warranted to explore the relationship between insulin resistance and semen quality comprehensively.

Moreover, while these factors frequently co-occur in studies, some research fails to establish clear correlations or causal relationships among them, highlighting a significant knowledge gap in understanding their interdependencies. Addressing this gap could pave the way for novel insights into male fertility diagnostics and treatment. Conducting studies comparing semen quality between insulin-resistant and non-insulin-resistant men could offer valuable insights and potentially lead to new approaches to addressing male infertility.

References

• Lillepea, K., et al. (2024). Toward clinical exomes in diagnostics and management of male infertility. American Journal of Human Genetics. doi.org/10.1016/j.ajhg.2024.03.013.
• Petre, G. C., Di Nisio, A., De Toni, L., et al. (2023). Observational Cross-Sectional Study on Mediterranean Diet and Sperm Parameters. Nutrients 15(23); 4989. doi:10.3390/nu15234989
• Raee, P. et al. (2023) Male obesity is associated with sperm telomere shortening and aberrant mRNA expression of autophagy-related genes. Basic and Clinical Andrology. 33, 13. https://doi.org/10.1186/s12610-023-00188-w https://bacandrology.biomedcentral.com/articles/10.1186/s12610-023-00188-w
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