Male Infertility: Evidence-Based Evaluation for FRCS Urology Preparation

Male infertility contributes to approximately 50% of all infertility cases worldwide, and its evaluation is a critical component of urological practice. For FRCS Urology trainees, a structured understanding of diagnostic approaches, guided by WHO criteria and international guidelines, is essential. This article outlines the standard WHO parameters for semen analysis, key aspects of hormonal evaluation, and current evidence-based treatment strategies recommended by the European Association of Urology (EAU) Guidelines on Sexual and Reproductive Health (2025) and NICE guidance.

Understanding Male Infertility: Key WHO Diagnostic Criteria

Male infertility is typically defined as the inability to achieve conception after 12 months of regular, unprotected intercourse in a couple not using contraception. The cornerstone of investigation remains semen analysis, which should be performed according to the World Health Organization (WHO) Laboratory Manual for the Examination and Processing of Human Semen, 6th Edition (2021).

WHO 2021 Reference Values (5th Percentile)

The WHO 6th edition provides lower reference limits (5th percentile) based on fertile men whose partners conceived within 12 months:

Semen volume: ≥1.4 mL (previously ≥1.5 mL)
Sperm concentration: ≥16 million/mL
Total sperm number: ≥39 million per ejaculate
Progressive motility: ≥30% (now subdivided into fast progressive [grade a] and slow progressive [grade b])
Total motility: ≥42%
Morphology: ≥4% normal forms by strict Kruger criteria
Vitality: ≥54% live spermatozoa

Key Change in 6th Edition: The WHO 2021 manual reintroduced the four-category classification of sperm motility (grade a: fast progressive; grade b: slow progressive; grade c: non-progressive; grade d: immotile), requiring pre-warmed slides at 37°C. Importantly, the manual emphasizes that these reference values represent “decision limits” rather than absolute thresholds for normal versus abnormal, and abnormal values are suggestive of possible male factor infertility rather than diagnostic.

Results deviating from these reference limits warrant repeat analysis after 2–12 weeks (ideally after at least one spermatogenic cycle of approximately 3 months) to confirm abnormality and account for intra-individual variability.

Comprehensive Semen Analysis

Beyond basic parameters, microscopic examination can reveal specific patterns indicative of underlying pathologies:

Elevated leukocytes (>1×10⁶/mL): Suggests infection or inflammation (leukocytospermia)
Agglutination: May indicate antisperm antibodies
Abnormal viscosity: Can suggest accessory gland dysfunction
Low pH (<7.2): May indicate ejaculatory duct obstruction or absence of seminal vesicle contribution
Azoospermia: Complete absence of spermatozoa (requires centrifugation to confirm)

The EAU Guidelines 2025 recommend comprehensive history and physical examination alongside semen testing, focusing on:

Previous genitourinary infections (especially epididymo-orchitis, STIs)
Testicular trauma or torsion
Varicocele examination
Cryptorchidism history
Exposure to gonadotoxins (chemotherapy, radiation, environmental toxins, anabolic steroids)
Sexual dysfunction
Family history of infertility or genetic disorders
Testicular volume assessment (Prader orchidometer or ultrasound)

Clinical Interpretation

Interpretation of semen results should always consider intra-individual variability. A single abnormal result does not confirm infertility, nor does a normal result exclude it. NICE CG156 (Fertility problems: assessment and treatment, 2013) emphasizes that clinicians should integrate semen findings with clinical context and other investigations, including hormonal assays or genetic testing when indicated.

Early referral to a fertility specialist is advised if:

Azoospermia is confirmed
Severe oligozoospermia (<5 million/mL)
Female partner aged ≥36 years
Known causes or predisposing factors for infertility

The WHO 6th edition has removed terminology such as “normozoospermia,” “oligozoospermia,” “asthenozoospermia,” and “teratozoospermia,” emphasizing that semen analysis should be interpreted in the full clinical context rather than relying on categorical labels.

Hormonal Assessment and Evidence-Based Treatment Options

Hormonal Evaluation

Hormonal evaluation is fundamental when semen analysis reveals oligozoospermia or azoospermia. The EAU 2025 Guidelines recommend baseline testing including:

Initial Hormonal Panel:

Serum follicle-stimulating hormone (FSH)
Luteinizing hormone (LH)
Total testosterone (ideally measured in morning sample between 0700-1100h)
Prolactin

Additional Testing When Indicated:

Estradiol (if gynecomastia, obesity, or suspected aromatase excess)
Thyroid function tests (TSH, free T4)
Sex hormone-binding globulin (SHBG) to calculate free/bioavailable testosterone

Interpretation of Hormonal Patterns

Elevated FSH + low/normal testosterone: Primary testicular failure (hypergonadotropic hypogonadism)
Low FSH + low LH + low testosterone: Secondary (hypogonadotropic) hypogonadism
Elevated prolactin: Consider pituitary adenoma, medications, hypothyroidism
Normal hormones with oligozoospermia: Consider obstructive causes, varicocele, idiopathic infertility

The EAU 2025 Guidelines advise repeating any abnormal hormone result to confirm, particularly if the patient has acute illness, confounding medication use, or results obtained at suboptimal timing.

Evidence-Based Treatment Strategies

Hypogonadotropic Hypogonadism: Pulsatile GnRH therapy (in specialized centers) or gonadotropin therapy (hCG with or without FSH) can restore spermatogenesis. The EAU 2025 Guidelines strongly recommend effective drug therapy for inducing spermatogenesis in men with congenital or acquired hypogonadotropic hypogonadism who wish to conceive:

Human chorionic gonadotropin (hCG)
Human menopausal gonadotropins (hMG)
Recombinant FSH or highly purified FSH

Idiopathic Infertility: For idiopathic infertility with normal hormones, empirical medical therapy remains controversial. The EAU 2025 Guidelines provide weak recommendations:

Do NOT routinely treat idiopathic infertility with:
- Antioxidants
- Prebiotics/probiotics
- Selective estrogen receptor modulators (SERMs) such as clomiphene citrate
- Aromatase inhibitors (AIs)
Do NOT use high-dose FSH for idiopathic infertility
Do NOT start hormonal stimulation prior to TESE in non-obstructive azoospermia (outside clinical trials)

NICE CG156 similarly emphasizes limited high-quality evidence for routine use of these therapies.

Hyperprolactinemia: Offer dopamine agonist therapy (e.g., cabergoline or bromocriptine) in men with proven hyperprolactinemia to improve sperm quality and restore gonadal function.

Anabolic Steroid Abuse: Withdraw anabolic steroids in infertile men for 6-12 months before considering treatment with SERMs or gonadotropin therapy to induce spermatogenesis.

Surgical Management

Obstructive Azoospermia: The EAU 2025 Guidelines recommend:

Microsurgical vasovasostomy or epididymovasostomy for azoospermia caused by vasal or epididymal obstruction in men with female partners with good ovarian reserve
Surgical sperm retrieval (percutaneous epididymal sperm aspiration [PESA], testicular sperm aspiration [TESA], or testicular sperm extraction [TESE]) combined with ICSI when reconstruction is not feasible or has failed

Varicocele Management: Varicocele management remains subject to ongoing debate. The EAU 2025 Guidelines recommend varicocelectomy (microsurgical or laparoscopic) in men with:

A palpable (clinical) varicocele
Abnormal semen parameters
Otherwise unexplained infertility
Female partner with good ovarian reserve

However, the evidence remains limited, and the guidelines note that varicocelectomy does not necessarily improve the probability of conception in all cases.

Non-Obstructive Azoospermia (NOA):

Conventional TESE or microdissection TESE (micro-TESE) remains the surgical modality of choice
Micro-TESE may offer higher sperm retrieval rates with less testicular tissue removal
Do NOT perform routine testicular fine-needle aspiration mapping as insufficient evidence supports its use as a predictive tool

Assisted Reproductive Technologies (ART)

For men with severe oligozoospermia, poor sperm quality, or testicular failure, intracytoplasmic sperm injection (ICSI) combined with IVF provides the best chance of conception. The EAU 2025 Guidelines emphasize:

Parallel assessment of female partner’s fertility status (including ovarian reserve) during diagnosis and management of male infertility, as this determines timing and therapeutic strategies
Genetic counseling and testing when indicated:
- Karyotyping for severe oligozoospermia (<5 million/mL) or azoospermia
- Y chromosome microdeletion testing for severe oligozoospermia or azoospermia
- Cystic fibrosis transmembrane conductance regulator (CFTR) mutation screening for obstructive azoospermia

Additional Considerations

Sperm DNA Fragmentation: While the WHO 6th edition discusses sperm DNA fragmentation (SDF) testing, it does not provide specific decision limits. The EAU 2025 Guidelines note that SDF has emerged as a novel biomarker that can identify infertile men and provide information on outcomes from ART, though standardization remains an issue.

Lifestyle Modifications: The EAU 2025 Guidelines strongly recommend informing infertile men about detrimental effects of:

Obesity (BMI >30)
Low physical activity
Smoking
High alcohol intake

These factors adversely affect sperm quality and testosterone levels. Advise infertile men to improve lifestyle factors to improve chances of conception.

Male Accessory Gland Infections: Treat male accessory gland infections as it may improve sperm quality, although it does not necessarily improve the probability of conception. Refer sexual partners of patients with infections caused by sexually transmitted diseases for evaluation and treatment.

Testosterone Therapy: Do NOT use testosterone therapy for the treatment of male infertility (strong recommendation). However, provide testosterone therapy for symptomatic patients with primary and secondary hypogonadism who are not considering parenthood.

Psychological and Holistic Care

Where fertility is irreversibly impaired, early counseling regarding:

Sperm cryopreservation (prior to gonadotoxic therapy)
Donor sperm use
Adoption

Psychological support should form part of holistic care, aligning with NICE recommendations emphasizing patient-centered management. Consider referral for counseling at all stages of investigation and/or treatment because of the impact of infertility and infertility treatment on mental health and relationships.

Conclusion

Male infertility management requires an evidence-driven, structured approach rooted in WHO 2021 semen criteria, detailed hormonal evaluation, and individualized therapy. For FRCS Urology trainees, understanding includes:

Proper application of WHO 6th edition reference values and their limitations
Comprehensive clinical and hormonal assessment
Recognition that empirical medical therapy has limited evidence
Appropriate patient selection for surgical interventions (varicocelectomy, reconstruction, sperm retrieval)
Integration of ART with urological management
Parallel assessment of female partner fertility
Holistic approach including lifestyle modification and psychological support

The urologist’s role in accurate diagnosis, appropriate investigation, and timely specialist referral remains central to achieving optimal reproductive outcomes. As assisted reproductive technologies advance, evidence-based practice aligned with EAU 2025 and NICE guidance ensures the highest standard of patient care.

References:

World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen, 6th Edition. Geneva: WHO; 2021.
Minhas S, Boeri L, Capogrosso P, et al.; EAU Working Group on Sexual and Reproductive Health. European Association of Urology Guidelines on Male Sexual and Reproductive Health: 2025 Update on Male Infertility. Eur Urol. 2025;87(5):601-616.
National Institute for Health and Care Excellence. Fertility problems: assessment and treatment. Clinical guideline [CG156]. London: NICE; 2013 (updated 2017).