What is the diagnosis and treatment approach for a male patient with two years of infertility?

Diagnostic Evaluation for Male Infertility After Two Years of Trying to Conceive

All men with two years of infertility require a comprehensive reproductive history, physical examination by a trained examiner, semen analysis (at least two samples), and hormonal evaluation including FSH and testosterone. 1

Initial Diagnostic Workup

Reproductive History

The evaluation must document the following specific elements 1:

• Coital frequency and timing – assess whether intercourse is occurring during the fertile window 1
• Duration of infertility and any previous pregnancies with current or prior partners 1
• Childhood illnesses including cryptorchidism, mumps orchitis, or delayed puberty 1
• Systemic medical conditions such as diabetes mellitus, upper respiratory diseases, or chronic illnesses 1
• Previous surgeries particularly inguinal, scrotal, or retroperitoneal procedures 1
• Medications and allergies including current and past medication use 1
• Sexual history including sexually transmitted infections, erectile function, and libido 1
• Gonadotoxin exposures including environmental toxins, heat exposure, smoking, alcohol, anabolic steroids, and occupational hazards 1

Physical Examination

A physical examination should be performed as part of the initial evaluation, not deferred until after abnormal semen results. 1 This approach identifies significant medical conditions that would be missed by limiting assessment to history and semen analysis alone—studies show 0.16% of men have significant medical conditions despite normal semen parameters. 1

The examination must assess 1, 2:

• Testicular size and consistency using Prader orchidometer (normal volume ≥15 mL) 1, 3
• Presence and consistency of vas deferens bilaterally 2
• Varicocele detection on standing examination 2
• Epididymal abnormalities 2
• Secondary sexual characteristics 2

Semen Analysis

At minimum two semen analyses are required, separated by 2-3 months, with each sample collected after 2-3 days of abstinence. 1, 3 The analysis should include 1:

• Sperm concentration (normal ≥16 million/mL per WHO criteria) 3
• Total sperm count (normal ≥39 million per ejaculate) 3
• Motility assessment 1
• Morphology evaluation 1
• Semen volume and pH 3
• Post-centrifugation examination to confirm true azoospermia if no sperm initially seen 3

Hormonal Evaluation

Hormonal testing should include FSH and testosterone for all men with oligozoospermia (sperm concentration <15 million/mL), impaired sexual function, or clinical findings suggesting endocrinopathy. 1 Some experts recommend hormonal evaluation for all infertile men. 1

The hormonal pattern helps distinguish diagnostic categories 1, 3:

• FSH >7.6 IU/L with testicular atrophy suggests non-obstructive azoospermia or severe oligospermia 3
• Elevated FSH with normal testicular volume may indicate maturation arrest 3
• Low FSH and low testosterone indicates hypogonadotropic hypogonadism 1
• Normal FSH with azoospermia and normal testicular volume suggests obstructive azoospermia 3

Additional hormonal tests to consider 1, 3:

• LH measurement to distinguish primary testicular failure from secondary hypogonadism 3
• Prolactin if clinical suspicion of hyperprolactinemia 3
• Thyroid function tests as thyroid disorders commonly affect reproductive hormones 3

Genetic Testing Indications

Genetic testing is mandatory in specific circumstances 1, 2:

• Karyotype analysis for men with:

  • Severe oligozoospermia (sperm concentration <5 million/mL) 3, 2
  • Non-obstructive azoospermia 3, 2
  • To exclude Klinefelter syndrome (47,XXY) and other chromosomal abnormalities 3

• Y-chromosome microdeletion testing (AZFa, AZFb, AZFc regions) for men with:

  • Azoospermia 1, 2
  • Severe oligozoospermia (sperm concentration <1 million/mL) 3, 2
  • Complete AZFa and AZFb deletions predict near-zero sperm retrieval success 3

• CFTR mutation analysis if congenital bilateral absence of vas deferens (CBAVD) detected on physical examination 2

Common Diagnostic Pitfalls to Avoid

Do not delay specialist referral waiting for a third semen analysis—two abnormal analyses are sufficient to warrant full evaluation. 2 In low- to middle-income settings where clinic visits are restricted by geography and cost, performing the physical examination at the initial visit is particularly important as men are less likely to return even with abnormal results. 1

Do not assume "idiopathic infertility" without complete workup, as over 50% of cases have identifiable causes. 2 The evaluation must systematically exclude all major categories: male factor, ovulatory dysfunction, tubal disease, uterine abnormalities, and peritoneal factors. 4

Do not overlook the female partner—concurrent evaluation of both partners is essential. 2 Male factors are solely responsible for 20-30% of infertility cases but contribute to 50% of cases overall. 5

Never prescribe testosterone replacement therapy if the patient desires fertility, as it suppresses spermatogenesis through negative feedback and can cause azoospermia requiring months to years for recovery. 1, 2

Health Implications Beyond Fertility

Clinicians must counsel infertile men that abnormal semen parameters are associated with increased health risks. 1 Men with abnormal semen analyses have higher rates of testicular cancer and increased overall mortality compared to fertile men. 1, 2 Infertile men have more comorbidities than fertile controls, making this evaluation important for overall health screening. 1, 2

Men with specific identifiable causes of infertility should be informed of relevant associated health conditions. 1 For example, men with non-obstructive azoospermia may have underlying genetic conditions, and those with severe oligospermia warrant evaluation for systemic diseases affecting reproductive function. 1