How to evaluate a patient with azoospermia (absence of sperms in semen analysis)?

Evaluation of Azoospermia

The evaluation of a patient with azoospermia should begin with confirmation through two properly performed semen analyses at least one month apart, followed by a systematic workup to distinguish between obstructive and non-obstructive causes, including hormonal evaluation, physical examination, and appropriate genetic testing. 1

Initial Confirmation and Assessment

• Confirm azoospermia with at least two semen analyses performed at least one month apart, with proper collection technique (2-3 days of abstinence) and examination within one hour of collection 1
• When a semen analysis shows azoospermia, the laboratory should centrifuge the ejaculate and examine the pellet under microscopy for rare sperm 2
• Sperm pellet analysis can identify motile or non-motile sperm in approximately 18-23% of men initially diagnosed with azoospermia by routine semen analysis 3

Physical Examination

• Assess testicular size and consistency: normal-sized testes suggest obstructive azoospermia while atrophic testes indicate non-obstructive azoospermia 2, 1
• Evaluate for presence of vas deferens bilaterally, as congenital bilateral absence of vas deferens is a specific cause of obstructive azoospermia 1
• Check for varicocele, hydrocele, or other scrotal abnormalities that may contribute to impaired spermatogenesis 1
• Examine secondary sex characteristics and perform digital rectal examination to assess prostate as part of a comprehensive evaluation 1

Hormonal Evaluation

• Measure serum testosterone and follicle-stimulating hormone (FSH) levels as the primary hormonal assessment 2, 1
• FSH levels >7.6 IU/L typically suggest non-obstructive azoospermia (spermatogenic failure), while normal FSH levels suggest obstructive azoospermia 2
• Consider measuring luteinizing hormone (LH) as part of the basic hormonal workup 1
• Anti-Müllerian hormone (AMH) testing may be valuable as lower levels may predict better sperm retrieval outcomes in non-obstructive azoospermia 1, 4

Distinguishing Obstructive vs. Non-obstructive Azoospermia

• Obstructive azoospermia is characterized by:

  • Normal-sized testes
  • Normal FSH levels (<7.6 IU/L)
  • Dilated and/or indurated epididymides
  • Possible absence of vas deferens 2

• Non-obstructive azoospermia is characterized by:

  • Atrophic testes
  • Elevated FSH (>7.6 IU/L)
  • Normal epididymides and vas deferens 2, 5

• Low ejaculate volume (<1.5 mL) with acidic pH suggests distal genital tract obstruction 2, 1

Additional Testing

• Post-ejaculatory urinalysis is indicated when ejaculate volume is <1 mL to diagnose retrograde ejaculation 1
• Transrectal ultrasonography (TRUS) is indicated in azoospermic patients with palpable vasa and low ejaculate volumes to evaluate for ejaculatory duct obstruction 1
• Scrotal ultrasonography is indicated when physical examination is difficult or when a testicular mass is suspected 1

Genetic Testing

• Karyotype testing is recommended for all patients with azoospermia or severe oligospermia (<5 million/mL) 2, 1
• Y-chromosome microdeletion analysis is mandatory for those with azoospermia or sperm concentration <1 million/mL 1
• CFTR gene testing should be offered to female partners of men with congenital bilateral absence of vas deferens 1, 5

Management Considerations

• Treatment options depend on the type of azoospermia:

  • Obstructive azoospermia: microsurgical reconstruction, transurethral resection of ejaculatory ducts, or sperm retrieval with assisted reproduction 5
  • Non-obstructive azoospermia: treatment of underlying causes (if identified) or testicular sperm extraction (TESE) with intracytoplasmic sperm injection (ICSI) 5, 6

• Sperm retrieval success rates vary:

  • Obstructive azoospermia: 25-65% pregnancy rates with assisted reproduction 5
  • Non-obstructive azoospermia: sperm retrieval effective in 30-70% of cases, with subsequent pregnancy rates of 20-50% using ICSI 5, 6

• Avoid testosterone replacement therapy in men desiring fertility as it can suppress spermatogenesis 1

Important Considerations and Pitfalls

• FSH levels alone cannot definitively predict sperm retrieval success in all cases, as men with maturation arrest can have normal FSH despite severe spermatogenic dysfunction 1
• Genetic abnormalities are more common in men with severe spermatogenic dysfunction, with potential implications for offspring 1, 6
• Before proceeding with ICSI, patients should be informed about potential genetic abnormalities associated with azoospermia 1
• Emerging biomarkers including specific microRNAs, long non-coding RNAs, and germ-cell-specific proteins show promise for predicting successful sperm retrieval but require further validation 4