Infertility affects 190 million people worldwide. Out of which, male-related infertility problems make up half of these cases and affect 7% of men. Between 1990 and 2019, male infertility increased by 76.9% globally, particularly in countries with middle and higher incomes, and was caused by environmental pollution and lifestyle changes. 

Genital tract infections affect 10–20% of infertility cases and are among the treatable medical explanations for male infertility.¹

Pyospermia, also known as leukocytospermia, is a disorder in which leukocytes or white blood cells (WBCs) are found in the sperm with a concentration exceeding 1 million per milliliter, as defined by the World Health Organization. 

Pyospermia is associated with male infertility, affecting up to 30% of infertile men. It is often linked to genitourinary infections, although non-infectious factors like varicocele and smoking contribute to pyospermia. Notably, in approximately 80% of leukocytospermia infertile males, no microbial infection can be detected in their semen, highlighting the complexity of its aetiology.² 

What is pyospermia?

Pyospermia is a condition in which blood cells are present in semen. WBC in sperm is a negative prognostic factor for fertility due to its multiple impacts on sperm health. WBC can cause impaired spermatogenesis and sperm maturation, therefore,interfering with the development of sperm cells and the maturation process. The infection and inflammation of the genital tract leads to the following:

• Cytokine levels are disrupted thus affecting Sertoli cell performance, which facilitate spermatogenesis
• White blood cells in semen generate reactive oxygen species (ROS) and interferon-γ, which impair sperm function and increase oxidative stress, particularly affecting sperm membranes rich in polyunsaturated fatty acids (PUFAs)
• Sperm in people with pyospermia have defects in sperm tail function, which leads to increased percentages of teratozoospermia and necrozoospermia
• WBCs further reduces sperm fertilization potential by disrupting the acrosome reaction and sperm-egg fusion, making it a significant prognostic factor for invitro-fertilization (IVF) failure² 

Despite the harmful effects of leukocyte-produced cytokines and ROS, sperm separation techniques effectively remove dysfunctional sperm, enriching the proportion of functional sperm. As a result, pyospermia is less concerning for embryologists during oocyte insemination.¹

What happens to human sperm in pyospermia?

The plasma membrane of the human sperm contains a high concentration of PUFAs. These fatty acids are highly susceptible to oxidative stress, also known as lipid peroxidation. The sperm undergoes lipid peroxidation in three steps:

• Initiation
• Propagation
• Termination

Lipid peroxidation is driven by ROS through the Fenton and Haber–Weiss reactions. Excessive ROS production can damage the sperm nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Additionally, modifications made to sperm by silent genital tract infections cause changes in gene expression and additional reproductive and sperm function impairments. Studies must undertake further research to determine this relationship more completely.¹

The oxidative stress leads to:

• DNA fragmentation
• Telomere shortening
• Epigenetic changes
• Mutation due to strand breaks and base oxidation
• Mitochondrial apoptosis by activating p53 and caspase pathway

The process decreases the membrane's fluidity; thus causing impairment to fundamental sperm functions like capacitation, acrosome reaction, and sperm–oocyte fusion. Lipid peroxidation forms various mutagenic substances, which create DNA adducts (DNA segments with substances added to them) that cause indirect damage to sperm DNA.¹

Infectious causes of pyospermia

Establishing a pyospermia threshold is challenging due to uncertainty about whether WBCs in semen indicate infection or inflammation. This ambiguity complicates diagnosis and treatment decisions.³ 

Bacterial infections

Male infertility accounts for about 10-15% of couples globally. Bacterial infections are most common that affect the urogenital tract in males. 

• Common bacterial pathogens that affect the male genital tract are Chlamydia trachomatis (chlamydia), Neisseria gonorrhoeae (gonorrhoeae), Mycoplasma species, Ureaplasma species, Treponema pallidum (syphilis), and Enterococcus faecalis. These infections can trigger inflammatory processes, affect spermatogenesis, and could lead to seminal tract obstructions, adversely affecting male fertility⁴ 
• Escherichia coli is a major cause of epididymo-orchitis and prostatitis, responsible for 65–80% of cases of urogenital infections. These and other pathogens, including Trypanosoma spp., can infect the entire male reproductive system, leading to infertility and long-term sexual health complications¹
• Two bacterial strains, Corynebacterium and E. coli, attack sperm cells through pili attachment, which reduces sperm mobility
• Bacteria such as Escherichia coli and Staphylococcus aureus create sperm immobilization factors that contribute to reproductive toxicity and secret toxins including lipopolysaccharides and hemolysins¹

The bacterial infections affecting infertile patients with asymptomatic genital infections were studied through pyospermia research involving 60 subjects. Analysis of antibiotic therapy established that exposure to these drugs during 30 days resulted in better semen parameter outcomes, including increased volume and pH, enhanced sperm concentration, and progressive motility.⁵

The main infectious agents responsible for male genital tract inflammations originate from sexually transmitted infections (STIs) alongside uropathogens. The key outcome of chronic prostatitis remains insignificant for ejaculate variables, however, acute epididymitis can result in 10% of patients can develop azoospermia and 30% develop oligozoospermia, which causes duct blockage and spermatogenesis dysfunction.¹ 

Viral infections

Viral infections and pyospermia could trigger genital tract inflammation and affect the reproductive health of males. Semen quality and fertility decrease when inflammation develops in the genital tract. Additionally, viruses including herpes simplex virus (HSV), human papillomavirus (HPV), and cytomegalovirus (CMV) affect the male reproductive system.

Sperm concentration, motile sperm concentration, and total sperm count decreased while neutral α-glucosidase levels declined when STI DNA was detected. The existence of subclinical genital tract infections proves to greatly diminish semen quality, exemplifying the importance of enhancing diagnostic methods and therapeutic practices.⁶ 

Fungal and parasitic infections

Trichomoniasis represents a sexually transmitted infection caused by Trichomonas vaginalis protozoan parasites. The parasite T. vaginalis invades the urethra in men and it extends its reach to the prostate gland and epididymis tissues. 

The genital tract of men with T. vaginalis infection develops inflammation because of urethritis and prostatitis. When inflammation occurs, it raises leukocyte numbers in semen and causes pyospermia. The elevated count of leukocytes produces reactive oxygen species (ROS) that cause sperm cell damage through oxidative stress, which affects sperm motility and overall functionality. T. vaginalis infection weakens sperm motility and viability, which adds to the development of male infertility in pyospermia.⁷

Non-infectious causes of pyospermia

Exposure to tobacco, alcohol, marijuana, and environmental pollutants can result in noninfectious causes of pyospermia. Additionally, the causes of pyospermia include varicocele, autoimmune disorders, poor sperm viability, and chronic prostatitis. Posterior urethral valves and congenital genitourinary defects contribute to pyospermia.³ 

Inflammatory conditions

The functions of the immune system, immune cells, and cytokines have prolific effects on male reproductive health; this demonstrates how infections, autoimmune diseases, and environmental elements impact fertility.⁸

The toxins within our environment, including endocrine disruptors, heavy metals, and pesticides, effectively cause infertility through hormonal disruptions and damage to gamete quality. 

Multiple reproductive health problems build up because of environmental toxins, which block specific fertility outcomes through distinct interference mechanisms. Healthcare professionals need to develop protective strategies to decrease exposure risks and enhance reproductive health.⁹ 

Genitourinary trauma or surgery

Vasectomy is a preferred male contraceptive method in developing countries, however, its long-term effects on oxidative stress, inflammation, and semen microbiota remain insufficiently explored. However, further research is necessary to understand how vasectomy could disrupt biological homeostasis and reproductive health.¹⁰ 

Men require suitable spermatogenesis for fertility, however, pro-inflammatory cytokines at elevated levels disturb this process and, subsequently, result in poor sperm production. The damage to sperm DNA and the cellular death process known as apoptosis is caused by oxidative stress, which is strongly tied to inflammation, however, does not produce symptoms.¹¹

Chronic diseases and lifestyle factors

Lifestyle diseases, including diabetes, are prone to elevated risk for infections that target both the respiratory, gastrointestinal, and genitourinary systems. The infections affect patients more frequently and at a faster pace, andthey prove difficult to treat with time. Research shows that insulin combined with metformin administration results in better immune function, along with improved infection outcomes for patients with hyperglycemia.¹²

Genomic stability depends on non-coding nucleotide sequences called telomeres, and their reduction can cause reproductive problems. Oxidative stress is the main factor responsible for telomere length reduction, which causes adverse effects on sperm quality and male fertility. Oxidative stress develops from combinations of age-based elements alongside smoking, dietary choices, and infections. Current scientific reports demonstrate no established linkage between leukocytospermia and telomere shortening, however, infection-induced oxidative stress could play a role in this mechanical process.¹

Clinical implications and treatment

The key requirement for reproductive health improvement consists of altering lifestyle through smoking cessation, decreasing alcohol consumption, and drug avoidance. Surgical repair procedures enhance sperm concentration and motility in patients with varicocele, however, research does not address its effects on seminal leukocyte counts.¹ 

The first step in managing leukocytospermia should focus on addressing its underlying causes, however, physicians usually treat oxidative stress along with systemic inflammation by administering antioxidants.¹ 

• The treatment of bacterial infections that cause pyospermia requires antibiotics to treat infections and reduce semen leukocyte counts
• Doctors provide antiviral and antifungal medication treatments to patients with viral or fungal infections identified as the cause of their pyospermia condition​
• People who change their lifestyle toward healthier activities, such as smoking cessation, alcohol management, and improved nutrition, will experience decreased semen oxidative stress resulting in decreased seminal leukocyte numbers
• Additionally, obtaining an ideal weight, performing regular physical activity, reducing stress, and reducing exposure to environmental toxins enhances sperm health¹³ 

Summary

Early diagnosis and targeted treatment of pyospermia are crucial in reducing its impact on male fertility. While infectious causes can often be effectively managed with antimicrobial therapies, non-infectious aetiologies require a comprehensive approach, including lifestyle modifications and anti-inflammatory treatments. Further research is required to understand the mechanisms underlying non-infectious causes.