What are the diagnosis and treatment options for a male patient of reproductive age with azoospermia (absence of sperm in the ejaculate)?

Azoospermia: Diagnosis and Treatment

Initial Diagnostic Approach

Azoospermia is confirmed by the complete absence of sperm in the ejaculate after centrifugation and microscopic examination of at least two semen analyses obtained one month apart. 1

Distinguishing Obstructive from Non-Obstructive Azoospermia

The physical examination and hormonal profile provide >90% accuracy in differentiating these two categories 2:

Obstructive Azoospermia:

• Normal-sized testes (typically >12 mL), fully descended 1
• Bilaterally dilated and/or indurated epididymides with or without absent vas deferens 1
• FSH levels typically <7.6 IU/L 1
• Low ejaculate volume (<1.4 mL) with acidic pH (<7.0) suggests distal obstruction (CBAVD or ejaculatory duct obstruction) 1

Non-Obstructive Azoospermia:

• Testicular atrophy (volume <12 mL) 1, 3
• FSH levels >7.6 IU/L 1, 3
• Normal semen volume and pH 3
• Indicates primary testicular failure with spermatogenic dysfunction 3, 4

Mandatory Genetic Testing

All men with severe oligozoospermia (<5 million/mL) or azoospermia must undergo karyotype analysis and Y-chromosome microdeletion testing before any therapeutic procedure. 1

Karyotype Analysis

• Identifies Klinefelter syndrome (47,XXY) and chromosomal translocations 1
• Incidence of chromosomal abnormalities is significantly elevated in azoospermic men 1
• Results guide ICSI planning and allow preimplantation genetic screening for balanced embryos 1

Y-Chromosome Microdeletion Testing

• Complete AZFa or AZFb deletions predict near-zero sperm retrieval success—TESE is contraindicated 1, 3
• AZFc deletions allow sperm retrieval in 53-75% of cases via TESE 3
• All male offspring will inherit the microdeletion 1

Cystic Fibrosis Mutation Analysis

• Mandatory for men with CBAVD and their female partners 1
• The vast majority of CBAVD patients carry mutations in both CF alleles 1
• Female partner testing is essential due to high carrier risk 2

Additional Diagnostic Studies

For suspected obstructive azoospermia with palpable vas deferens and low ejaculate volume, transrectal ultrasound (TRUS) evaluates ejaculatory duct obstruction. 5

Hormonal evaluation should include FSH, LH, and testosterone to characterize the hypothalamic-pituitary-testicular axis. 3

Treatment of Obstructive Azoospermia

Microsurgical reconstruction of the reproductive tract is preferred over sperm retrieval when the female partner has normal fertility, as it can restore natural fertility. 5

Surgical Options by Obstruction Level:

• Vasovasostomy or vasoepididymostomy: For post-vasectomy or epididymal obstruction 2
• Transurethral resection of ejaculatory ducts (TURED): When obstruction is confirmed by imaging or seminal vesicle aspiration shows sperm 5

Sperm Retrieval Alternatives:

• Microsurgical epididymal sperm aspiration (MESA): Gold standard for epididymal retrieval 6
• Testicular sperm extraction (TESE): When epididymal sperm unavailable 6
• Success rates with ICSI: 25-65% pregnancy rates reported 2

Treatment of Non-Obstructive Azoospermia

Medical Management (Limited Evidence)

The 2024 AUA/ASRM guidelines recognize that selective estrogen receptor modulators (SERMs), aromatase inhibitors, and gonadotropins may be attempted before surgery, though supporting data are limited. 5

Critical pitfall: Never prescribe exogenous testosterone to men desiring fertility—it completely suppresses spermatogenesis through negative feedback, causing azoospermia that can take months to years to recover. 3

Surgical Sperm Retrieval

Microdissection testicular sperm extraction (micro-TESE) is the gold standard for non-obstructive azoospermia, retrieving sperm in 30-70% of cases even with elevated FSH. 5, 2, 7

• Micro-TESE is 1.5 times more successful than conventional TESE 3
• Up to 50% of NOA patients with elevated FSH have retrievable sperm 3
• Complete AZFa/AZFb deletions contraindicate TESE due to near-zero retrieval rates 1, 3

Assisted Reproductive Technology Outcomes

IVF with ICSI using retrieved sperm achieves pregnancy rates of 20-50% per cycle, with live birth rates of approximately 37% per initiated cycle. 5, 2

Outcomes are closely tied to female partner age, with progressively lower success beyond age 35. 5

Special Consideration for DNA Fragmentation:

• For non-azoospermic men with elevated sperm DNA fragmentation index (DFI), testicular sperm may offer improved clinical outcomes 5
• Testicular sperm in high-DFI cases show similar fertilization rates but improved clinical pregnancy rates, live birth rates, and reduced pregnancy loss 5

Prognostic Factors

FSH levels >7.6 IU/L strongly suggest non-obstructive azoospermia when accompanied by testicular atrophy, but cannot definitively predict sperm retrieval success. 1, 3

Hormonal levels have variable correlation with sperm retrieval outcomes—even men with significantly elevated FSH may have focal areas of sperm production. 3

Men with maturation arrest can have normal FSH and testicular volume despite severe spermatogenic dysfunction, highlighting the limitations of hormonal prediction. 3

Critical Management Pitfalls to Avoid

• Never operate on men with complete AZFa or AZFb deletions—sperm retrieval is futile 1, 3
• Always obtain at least two semen analyses before confirming azoospermia 1
• Avoid exogenous testosterone in any man with current or future fertility desires 3, 5
• Consider sperm cryopreservation (2-3 ejaculates) before any gonadotoxic therapy or in men with declining testicular reserve 3
• Perform genetic counseling before ICSI to discuss inheritance risks of chromosomal abnormalities and Y-microdeletions 1