How to evaluate and manage azoospermia?

Evaluation and Management of Azoospermia

Initial Diagnostic Workup

Confirm azoospermia with at least two semen analyses performed at least one month apart, with 2-3 days of abstinence before collection, and examine the centrifuged pellet under microscopy for rare sperm, as this identifies motile or non-motile sperm in 18-23% of men initially diagnosed with azoospermia. 1, 2

Essential Physical Examination Findings

• Assess testicular size and consistency: Normal-sized testes (>15 mL) suggest obstructive azoospermia (OA), while small, atrophic testes (<10 mL) indicate non-obstructive azoospermia (NOA). 1, 2
• Palpate for bilateral vas deferens: Absence indicates congenital bilateral absence of vas deferens (CBAVD), which can be diagnosed by physical examination alone. 1, 2
• Examine for varicoceles: Only palpable varicoceles warrant treatment; do not use ultrasound to hunt for subclinical varicoceles. 1, 3
• Assess epididymal consistency: Dilated or indurated epididymides suggest obstruction. 2
• Perform digital rectal examination: Evaluate prostate size and consistency. 1, 2

Mandatory Laboratory Testing

• Measure serum FSH and testosterone: FSH >7.6 IU/L strongly suggests NOA (spermatogenic failure), while normal FSH with normal testicular volume suggests OA. 1, 2
• Check semen volume and pH: Low volume (<1.5 mL) with acidic pH (<7.0) indicates ejaculatory duct obstruction or CBAVD. 1, 2
• Perform post-ejaculatory urinalysis when volume <1 mL (except in bilateral vasal agenesis or hypogonadism) to diagnose retrograde ejaculation. 1, 2
• Consider anti-Müllerian hormone (AMH) testing: Lower preoperative AMH levels are associated with higher sperm retrieval success rates in microdissection TESE (mTESE). 1

Genetic Testing Requirements

All men with azoospermia must undergo karyotype testing and Y-chromosome microdeletion analysis before any therapeutic intervention. 1, 2

• Karyotype abnormalities occur in the highest frequency in NOA men, particularly Klinefelter syndrome (47,XXY), which has variable spermatogenesis but allows sperm retrieval in 20-50% of cases. 1
• Y-chromosome microdeletion testing is mandatory: Complete AZFa or AZFb deletions predict zero sperm retrieval success, so TESE should not be attempted in these patients. 1
• AZFc deletions are associated with variable presentation and allow successful sperm retrieval in 53-75% of men. 1
• CFTR gene testing must be offered to female partners of men with CBAVD before proceeding with assisted reproduction, as most carry CF mutations. 1, 2

Imaging Studies (When Indicated)

• Transrectal ultrasound (TRUS): Indicated for suspected ejaculatory duct obstruction when semen is acidic, volume <1.5 mL, azoospermic, with normal testosterone and palpable vas deferens. 1, 2
• Scrotal ultrasound: Only when physical examination is difficult/inadequate or testicular mass is suspected—not for routine varicocele screening. 1, 2

Management Based on Etiology

Obstructive Azoospermia (OA)

Microsurgical reconstruction (vasovasostomy or vasoepididymostomy) is the preferred first-line treatment when feasible, as it permits natural conception without IVF. 4, 5, 6

• For ejaculatory duct obstruction: Transurethral resection of ejaculatory ducts (TURED) is definitive treatment when TRUS/MRI confirms dilated seminal vesicles and ducts. 3
• For CBAVD: No medical or surgical treatment restores ejaculatory volume; proceed directly to sperm retrieval (TESE/MESA) with ICSI after confirming female partner CFTR status. 3
• When reconstruction is not feasible: Microsurgical epididymal sperm aspiration (MESA) or testicular sperm extraction (TESE) with IVF/ICSI achieves pregnancy rates of 25-65%. 4, 7

Non-Obstructive Azoospermia (NOA)

Microdissection TESE (mTESE) is the gold standard for sperm retrieval in NOA, with retrieval rates of 40-60% in most cases and 20-50% pregnancy rates with ICSI. 1, 4

Pre-Surgical Medical Optimization (Limited Evidence)

• For hypogonadotropic hypogonadism (low testosterone with low/normal FSH): Human chorionic gonadotropin (hCG) 500-2500 IU 2-3 times weekly is first-line treatment to restore testosterone and spermatogenesis, followed by FSH if needed. 1
• For NOA with abnormal hormones: Selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), or gonadotropins may be considered before surgery, though data supporting improved sperm retrieval rates are limited. 1

Critical Contraindications

• Do not attempt TESE in men with complete AZFa or AZFb deletions—sperm retrieval success is zero. 1
• Never prescribe exogenous testosterone to men desiring fertility—it suppresses spermatogenesis and can cause azoospermia, with recovery taking months to years after cessation. 1, 3

Special Considerations for Varicocele

Varicocelectomy may restore sperm to the ejaculate in azoospermic men with palpable varicoceles, particularly those with hypospermatogenesis on histology. 3

• Treatment is only indicated for palpable varicoceles with abnormal semen parameters. 3
• Subclinical (non-palpable) varicoceles detected only by ultrasound should not be treated—this does not improve outcomes. 1, 3

Post-Gonadotoxic Therapy

For men persistently azoospermic after chemotherapy or radiation, mTESE is a viable treatment option, though sperm retrieval rates are lower than in non-cancer populations. 1

Critical Pitfalls to Avoid

• FSH levels alone cannot predict sperm retrieval success: Men with maturation arrest can have normal FSH and testicular volume despite severe spermatogenic dysfunction. 1, 2
• Do not delay genetic testing: Results directly impact counseling, treatment decisions, and whether to proceed with TESE versus donor sperm. 1, 2
• Avoid routine abdominal imaging for isolated right varicoceles: No difference in cancer diagnoses exists based on varicocele laterality. 1
• Do not perform TRUS as part of initial evaluation: Reserve for cases with clear clinical suspicion of ejaculatory duct obstruction (low volume, acidic, azoospermic semen with normal testosterone and palpable vas). 3
• Genetic counseling is mandatory before ICSI: Chromosomal abnormalities and Y-chromosome microdeletions will be transmitted to male offspring. 1, 2