Male Fertility

Introduction

Male fertility refers to a male’s capacity to initiate a pregnancy.  Male infertility is defined clinically as the failure to achieve a pregnancy after at least 12 months of regular unprotected intercourse.  It is a common public‑health issue that affects couples worldwide.  Studies estimate that infertility affects ~17.5 % of adults globally—about one in six people—and approximately 15 % of couples struggle to conceive .  Male factors contribute to ~50 % of these cases and are the sole cause in around 20 % of infertile couples.  In the United States, male infertility affects roughly 10–15 % of men attempting to conceive .  Global burden studies report that, in 2019, ~56.5 million men were living with infertility, an increase of 76.9 % since 1990 .  This burden peaks in men aged 30–34 years and is higher in middle‑income regions .

Physiology of male fertility

Normal male reproductive function depends on coordinated interactions between the hypothalamus–pituitary–gonadal (HPG) axis and the testes.  Gonadotropin‑releasing hormone (GnRH) from the hypothalamus stimulates the anterior pituitary to release luteinizing hormone (LH) and follicle‑stimulating hormone (FSH).  LH stimulates Leydig cells to produce testosterone, while FSH acts on Sertoli cells to support spermatogenesis.  The testes produce spermatozoa via a cycle lasting ~74 days; the epididymis provides further maturation over ~12 days.  Adequate spermatogenesis requires a temperature a few degrees below core body temperature, intact blood‑testis barrier, functional androgen receptors, and sufficient nutrients (e.g., zinc, selenium, folate).

Epidemiology and impact

• Prevalence and burden:  Male infertility affects an estimated 7 % of men worldwide .  Population‑based surveys suggest that ~186 million individuals globally suffer from infertility, and male factors account for about half of cases .  Age‑standardised prevalence was ~1,403 per 100,000 in 2019 .
• Outcome in couples:  Approximately 1 in 3 infertile couples have male factor infertility alone, another third have combined male and female factors, and a third have female factors alone .
• Health implications:  Infertility is linked with psychological distress and may be a biomarker for future health; men with poor semen quality have higher risks of testicular cancer, metabolic disorders and early mortality.

Causes and risk factors

Male infertility results from pre‑testicular, testicular or post‑testicular factors.  Often multiple factors interact.  Idiopathic infertility is common (~25–30 %).

Pre‑testicular (endocrine/hormonal) causes

• Hypogonadotropic hypogonadism – reduced GnRH, LH or FSH secretion leading to low testosterone and spermatogenic failure (e.g., Kallmann syndrome).
• Hyperprolactinaemia – elevated prolactin suppresses GnRH and reduces FSH/LH.
• Thyroid dysfunction – both hypo‑ and hyperthyroidism may impair sperm production.
• Systemic illness – severe chronic diseases (renal failure, liver disease), anorexia and malnutrition impair hormone production and libido.

Testicular causes

The testes may be damaged by congenital or acquired factors.  The European Association of Urology (EAU) guidelines list congenital causes such as chromosomal and genetic abnormalities, cryptorchidism, congenital absence of the vas deferens, and testicular trauma, and acquired causes like mumps orchitis, varicocele, radiation, chemotherapy, systemic diseases, obesity, various toxins, and idiopathic causes .  Major testicular causes include:

1. Genetic abnormalities
   
   • Karyotype abnormalities:  Klinefelter syndrome (47,XXY) is the most common chromosomal anomaly causing azoospermia.  Other structural abnormalities or translocations can impair spermatogenesis.  The EAU guidelines note a higher prevalence of chromosomal abnormalities in men with severe spermatogenic damage, particularly non‑obstructive azoospermia .
   • Y‑chromosome microdeletions (YCMD):  Deletions of azoospermia factor (AZF) regions on the Y chromosome are a major genetic cause of severe male infertility.  A scoping review found that azoospermia affects ~1 % of men and 10–15 % of infertile men, and YCMDs occur more frequently in infertile men than in the general population .  Routine screening of men with non‑obstructive azoospermia using polymerase‑chain‑reaction (PCR) markers (sY84/sY86 for AZFa, sY127/sY134 for AZFb, and sY254/sY255 for AZFc) is recommended .  Deletions of AZFa and AZFb regions generally have a poor prognosis because they result in Sertoli‑cell‑only syndrome or arrest of spermatogenesis, whereas AZFc deletions may still allow sperm retrieval for assisted reproduction.
   • CFTR mutations:  Congenital bilateral absence of the vas deferens (CBAVD) is often caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.  The EAU guidelines recommend testing men with CBAVD and screening their female partners; if both carry pathogenic CFTR mutations, there is a high risk (25–50 %) that offspring will develop cystic fibrosis .
3. Varicocele
   A varicocele is an abnormal dilation of the pampiniform plexus.  It is present in ~15 % of the general male population, in 25 % of men with abnormal semen analyses, and in 35–40 % of infertile men【769793007907605†L1362-L1401】.  The incidence is higher in secondary infertility.  Varicoceles raise scrotal temperature, cause hypoxia and reflux of adrenal or renal metabolites, and increase oxidative stress, leading to impaired spermatogenesis and increased sperm DNA damage【769793007907605†L1362-L1401】.
4. Testicular injury and infection
   
   • Mumps orchitis, sexually transmitted infections, epididymo‑orchitis and severe systemic infections can damage the seminiferous epithelium.  Testicular trauma or torsion may also cause permanent damage.
6. Radiation and chemotherapy
   Cancer treatments can cause temporary or permanent azoospermia.  Cryopreservation before therapy is recommended.
7. Endocrine disruptors and toxins
   Exposure to endocrine‑disrupting chemicals (EDCs)—such as polychlorinated biphenyls (PCBs), bisphenol A (BPA), phthalates, alkyl phenols, DDT and methoxychlor—can mimic or block natural hormones.  These chemicals interfere with androgen biosynthesis in Leydig cells, alter steroid hormone receptor binding, and disrupt the hypothalamic–pituitary–gonadal axis.  Animal studies show that pesticides like chlorpyrifos and BPA reduce sperm counts and motility, decrease testosterone, and increase oxidative stress and DNA damage.  Heavy metals such as cadmium and lead inhibit androgen production and microtubule movement in sperm; exposure increases cytokine production, induces DNA breaks and hypermethylation, disrupts the blood–testis barrier, and causes teratozoospermia and asthenozoospermia .
8. Environmental pollution and microplastics
   
   • Air pollution:  Rising levels of air pollutants are linked to decreased semen volume, sperm concentration, motility and normal morphology.  A meta‑analysis found that pollutants such as sulfur dioxide (SO₂) and nitrogen oxides (NO₂) negatively correlate with semen parameters; exposure to car exhaust, heavy metals and polycyclic aromatic hydrocarbons causes high sperm DNA fragmentation through oxidative stress .
   • Microplastics:  Micro‑ and nanoplastics accumulate in the environment and adsorb persistent organic pollutants and metals.  They have been detected in human faeces, urine, semen and even testes.  Studies in rodents show that polystyrene microplastics accumulate in the testis, disrupt the blood‑testis barrier, decrease FSH, LH and testosterone, cause oxidative stress and apoptosis, and reduce sperm count and motility .  A multi‑site Chinese human study found microplastics in all semen and urine samples; exposure to polytetrafluoroethylene was significantly associated with decreased semen quality .
   • PFAS (per‑ and polyfluoroalkyl substances):  Exposure to PFAS such as PFOA and PFOS is linked to decreased progressive sperm motility and total sperm counts.  Maternal PFOA exposure during pregnancy is associated with higher FSH/LH and lower sperm counts in adult sons.  Men with higher PFAS levels have smaller sperm heads, increased DNA fragmentation and lower testicular steroid bioavailability .
10. Lifestyle factors
    
    • Age:  Male fertility declines gradually with age, particularly after 40 years, due to decreased testosterone and increased sperm DNA fragmentation.
    • Obesity:  High body mass index (BMI > 25 kg/m²) is associated with decreased sperm count and testosterone .  Obesity promotes inflammation and oxidative stress.
    • Diet and nutrition:  Western diets high in saturated fats and processed sugars impair fertility.  Diets rich in fruits, vegetables, antioxidants (vitamins C, E, zinc, selenium), omega‑3 fatty acids and folate support sperm health.  Deficiency of micronutrients like vitamin D, folate, and carnitine impairs spermatogenesis.
    • Smoking:  Tobacco smoke contains nicotine, cadmium and polycyclic aromatic hydrocarbons.  A meta‑analysis of 5,865 men showed that cigarette smoking reduces sperm count and motility and increases sperm DNA fragmentation; moderate to heavy smokers show pronounced effects.  E‑cigarette vapours also have adverse effects on male fertility.
    • Alcohol:  Chronic heavy drinking lowers testosterone, reduces semen volume and sperm morphology, and increases oxidative stress and DNA damage.  Moderate intake may have less clear effects.
    • Recreational drugs:  Marijuana, opioids and anabolic steroids impair spermatogenesis and endocrine function.
    • Psychological stress:  Prolonged stress elevates cortisol, suppresses GnRH, LH and FSH, reduces testosterone and sperm production, and increases susceptibility to oxidative DNA damage.  Stress also promotes unhealthy behaviours (smoking, poor diet) and sexual dysfunction.
    • Physical activity and temperature:  Moderate physical activity improves endocrine profile and reduces inflammation.  However, excessive endurance training or anabolic steroid use lowers testosterone and sperm quality.  Prolonged exposure to high temperatures (hot baths, saunas, tight clothing) raises scrotal temperature and impairs spermatogenesis.
    • Electronic devices and RF‑EMF:  Prolonged exposure to radio‑frequency electromagnetic fields from mobile phones and laptops may decrease sperm motility and viability and increase DNA fragmentation.

Post‑testicular causes

• Obstructive disorders (e.g., congenital absence of vas deferens, infections leading to epididymal blockage, previous vasectomy).  Seminal tract obstruction results in normal spermatogenesis but no sperm in the ejaculate.
• Ejaculatory dysfunction – retrograde ejaculation, erectile dysfunction, or failure of emission due to neurological or pharmacological causes.

Evaluation of the infertile man

Comprehensive evaluation is essential to identify treatable causes and guide appropriate therapy.  Key steps include:

1. History and physical examination – record duration of infertility, sexual history, frequency of intercourse, previous pregnancies, systemic illnesses, surgeries, medications, exposures to heat, toxins or radiation, lifestyle factors, and family history.  Physical examination assesses secondary sexual characteristics, testicular size and consistency, varicocele, epididymal induration and presence of vas deferens.
2. Semen analysis – at least two semen samples collected after 2–7 days abstinence.  WHO reference values for lower 5th percentile include semen volume ≥1.4 mL, sperm concentration ≥16 million/mL, total sperm count ≥39 million, progressive motility ≥30 %, total motility ≥42 %, normal morphology ≥4 % and vitality ≥54 %.  These values guide diagnosis but do not define fertility.
3. Hormonal evaluation – measurement of FSH, LH, total testosterone, prolactin and thyroid hormones.  Elevated FSH suggests primary testicular failure, while low FSH/LH indicates hypothalamic or pituitary dysfunction.
4. Genetic testing – karyotyping for men with sperm counts <10 million/mL or with azoospermia, PCR assays for Y‑chromosome AZF microdeletions, and CFTR mutation analysis in men with azoospermia and congenital absence of vas deferens .  Genetic counselling is essential because of the risk of transmitting mutations to offspring .
5. Scrotal ultrasound – to evaluate testicular size, varicocele, hydrocele, epididymal cysts and vasal obstruction.
6. Transrectal ultrasound – to assess prostatic and seminal vesicle abnormalities and ejaculatory duct obstruction.
7. Other tests – sperm DNA fragmentation assays, antisperm antibody testing, and assessment of oxidative stress may assist in select cases.  Hormone stimulation tests (e.g., hCG) can differentiate between spermatogenic failure and obstruction.

Management and treatment

Lifestyle modification and counselling

First‑line management involves optimizing modifiable factors.  Clinicians should advise weight loss, regular moderate exercise, a diet rich in antioxidants and omega‑3 fatty acids, smoking cessation, limiting alcohol and avoiding recreational drugs, and reducing heat and RF‑EMF exposure.  Stress management and adequate sleep are important.  The Cleveland Clinic emphasises that lifestyle changes can improve sperm health and success rates .

Medical treatments

• Hormonal therapy – men with hypogonadotropic hypogonadism benefit from pulsatile GnRH or gonadotropin injections (hCG plus FSH) to stimulate spermatogenesis.  Aromatase inhibitors (e.g., anastrozole), selective estrogen receptor modulators (e.g., clomiphene citrate) and antiestrogens may increase endogenous testosterone in select men with low testosterone/estradiol ratios.
• Antioxidants and nutraceuticals – supplements containing coenzyme Q10, carnitine, vitamins C and E, selenium, zinc and folate may improve sperm motility and DNA integrity by reducing oxidative stress.  Evidence from small studies suggests benefit, but high‑quality trials are limited.
• Treatment of infections – antibiotics for sexually transmitted infections or prostatitis.
• Anti‑inflammatory agents – some studies propose that elevated neutrophil–lymphocyte ratio predicts poor outcome after varicocelectomy; management of systemic inflammation may benefit fertility.
• Emerging therapies: probiotics – A 2024 systematic review included four randomized trials using Lactobacillus and Bifidobacterium strains.  These probiotics improved sperm motility, concentration, morphology, semen volume and total sperm counts.  For example, Lactobacillus rhamnosus CECT8361 combined with Bifidobacterium longum CECT7347 increased sperm motility and reduced DNA fragmentation .  Lactobacillus paracasei with prebiotics improved ejaculate volume, sperm concentration, motility and morphology and raised FSH, LH and testosterone levels .  Multi‑strain probiotics also increased total motility and reduced inflammatory markers .  The review concluded that probiotics are safe, affordable and may enhance sperm parameters; however, more large‑scale trials are needed .

Surgical options

• Varicocelectomy – Surgical or microsurgical repair of a varicocele is indicated for symptomatic or palpable varicoceles with abnormal semen parameters.  Meta‑analysis shows that varicocelectomy significantly improves sperm concentration and total sperm count in men with abnormal semen analyses (including non‑obstructive azoospermia) and reduces sperm DNA damage【769793007907605†L1362-L1401】.  Open microscopic subinguinal approaches offer high success rates with low complications.
• Surgical correction of obstructive azoospermia – Vasovasostomy or vasoepididymostomy can restore patency after vasectomy or congenital obstruction.
• Sperm retrieval techniques – Testicular sperm extraction (TESE) or micro‑TESE for men with non‑obstructive azoospermia, or percutaneous epididymal sperm aspiration for obstructive azoospermia, combined with intracytoplasmic sperm injection (ICSI).

Assisted reproductive technologies (ART)

When natural conception is unlikely, ART offers options:

• Intrauterine insemination (IUI) – suitable for mild male factor infertility; processed semen is placed directly into the uterus around ovulation.
• In vitro fertilization (IVF) – eggs and sperm are combined in a laboratory.  A sperm count above 1 million/mL is generally required.
• Intracytoplasmic sperm injection (ICSI) – a single sperm is injected directly into the oocyte; used for severe male factor infertility or following surgical sperm retrieval.  Use of sperm from men with genetic defects (e.g., AZFc deletions) requires counselling because the defect may be passed to male offspring.

Preventive measures and public health implications

• Reduce environmental exposures:  Regulatory actions to limit EDCs, heavy metals, microplastics and PFAS in consumer products and food.  Policies to reduce air pollution and occupational exposures can protect reproductive health.  Farmers and industrial workers should use protective equipment when handling pesticides and solvents.
• Education and early intervention:  Adolescents and young adults should be educated about the impact of smoking, alcohol, drugs, obesity and heat on fertility.  Men planning families should seek preconception counselling and consider semen analysis if risk factors are present.
• Sperm banking:  Men undergoing chemotherapy or radiotherapy, or those considering gender‑affirming hormonal treatment, should bank sperm prior to therapy.
• Research priorities:  Further studies are needed on the effects of microplastics, PFAS and emerging pollutants on sperm quality; mechanisms of gene–environment interactions; long‑term health of offspring conceived via ART; and development of novel therapeutics such as targeted antioxidants, stem‑cell therapy and gene editing.

Conclusion

Male fertility depends on the complex interplay between hormonal regulation, genetic integrity, and environmental and lifestyle factors.  Approximately half of infertility cases involve male factors, with varicocele, genetic abnormalities, endocrine disorders, lifestyle and environmental exposures being major contributors.  Comprehensive evaluation—including history, semen analysis, hormonal profile and genetic testing—allows clinicians to identify treatable causes.  Lifestyle modifications, judicious use of medical therapy, varicocelectomy and ART can improve fertility outcomes.  Emerging evidence suggests that probiotics and mitigation of environmental toxins may play supportive roles.  Given the rising prevalence of male infertility and the potential for intergenerational effects, public‑health measures to reduce exposure to endocrine disruptors and pollutants, and to promote healthy lifestyles, are essential.  Early counselling and interventions can improve not only reproductive outcomes but also overall health and quality of life for men.