What are the evaluation and management options for a patient with azoospermia?

Evaluation and Management of Azoospermia

Initial Diagnostic Approach

The first critical step is differentiating obstructive from non-obstructive azoospermia through clinical examination, FSH levels, and testicular volume, as this distinction fundamentally determines treatment strategy and prognosis. 1

Confirm True Azoospermia

• Perform at least two semen analyses with centrifugation separated by 2-3 months to confirm complete absence of sperm, as single analyses can be misleading due to natural variability 1
• Each specimen should be examined after centrifugation to detect even rare sperm 2, 3

Clinical Differentiation

Obstructive Azoospermia (OA) presents with:

• Normal testicular size and consistency (typically >15 mL per testis) 1, 4
• Normal or low-normal FSH (<7.6 IU/L) 1, 5
• Palpable vas deferens bilaterally 1, 6
• Low ejaculate volume (<1.5 mL) with acidic pH (<7.0) suggests distal obstruction 1, 7
• Dilated or indurated epididymis on examination 7, 6

Non-Obstructive Azoospermia (NOA) presents with:

• Testicular atrophy (volume <12 mL) and soft consistency 1, 5
• Elevated FSH (typically >7.6 IU/L) 1, 5
• Normal semen volume and pH 5, 2
• Small, soft testes bilaterally 4, 3

Mandatory Laboratory Evaluation

Hormonal Assessment

• FSH, LH, and total testosterone measured in morning fasting sample 1
• FSH >7.6 IU/L strongly suggests NOA with >90% predictive accuracy when combined with testicular atrophy 1, 5
• Testosterone and LH help distinguish primary testicular failure from secondary hypogonadism 4, 8

Genetic Testing (Mandatory Before Any Sperm Retrieval)

For all azoospermic men planning assisted reproduction:

• Karyotype analysis to detect Klinefelter syndrome (47,XXY) and other chromosomal abnormalities 1, 7
• Y-chromosome microdeletion testing (AZFa, AZFb, AZFc regions) 1, 7
• Complete AZFa or AZFb deletions predict near-zero sperm retrieval success and contraindicate testicular sperm extraction 1, 5
• AZFc deletions allow sperm retrieval in 53-75% of cases 5

For obstructive azoospermia with congenital bilateral absence of vas deferens (CBAVD):

• CFTR mutation analysis for both partners, as the male has high probability of being a cystic fibrosis carrier 1, 2, 6

Imaging Studies

Transrectal Ultrasound (TRUS)

• Indicated when ejaculate volume <1.5 mL, acidic pH, palpable vas deferens, and normal testosterone suggest ejaculatory duct obstruction 1, 7
• Do not perform TRUS in men with CBAVD, as it does not contribute to diagnosis or treatment 1

Scrotal Ultrasound

• Reserved for obese patients or when physical examination is difficult 1
• Not routinely recommended for varicocele detection, as treatment of subclinical varicoceles is not beneficial 1

Renal Ultrasound

• Mandatory for all men with vasal agenesis to evaluate for renal abnormalities 1

Management of Obstructive Azoospermia

Microsurgical reconstruction is preferred over sperm retrieval when the female partner has normal fertility, as it can restore natural conception ability. 7, 6

Surgical Reconstruction Options

• Microsurgical vasovasostomy for post-vasectomy obstruction or mid-ductal obstruction 4, 6
• Microsurgical vasoepididymostomy for epididymal obstruction 4, 6
• Transurethral resection of ejaculatory ducts (TURED) when imaging confirms ejaculatory duct obstruction or seminal vesicle aspiration reveals sperm 1, 7

Sperm Retrieval for Assisted Reproduction

• Testicular or epididymal sperm extraction can be performed from either site with equivalent ICSI success rates 1
• Sperm can be cryopreserved prior to ART cycles, as fresh versus frozen sperm show no outcome differences in obstructive azoospermia 1
• Success rates of 25-65% per cycle reported across centers 2

Management of Non-Obstructive Azoospermia

Medical Management (Limited Role)

For hypogonadotropic hypogonadism specifically:

• Treatment with hCG followed by FSH analogues successfully initiates spermatogenesis in 75% of men 5
• Response correlates with baseline testicular size 5

For idiopathic NOA with preserved testicular volume:

• Selective estrogen receptor modulators (SERMs), aromatase inhibitors, or gonadotropins may be tried before surgery, though evidence is limited and benefits modest 1, 7
• These therapies are not FDA-approved for male infertility and offer inferior results compared to ART 5

Surgical Sperm Retrieval

Microdissection testicular sperm extraction (micro-TESE) is the gold standard for NOA, retrieving sperm in 30-70% of cases despite elevated FSH. 1, 7

• Micro-TESE is 1.5 times more successful than conventional TESE and 2 times more successful than testicular aspiration 1
• Causes less testosterone suppression than conventional TESE, though testosterone deficiency requiring replacement remains a risk 1
• Some centers perform simultaneous sperm retrieval with ART for NOA because sperm numbers may be limited and may not survive cryopreservation 1

Assisted Reproductive Technology Outcomes

• IVF/ICSI with retrieved sperm achieves 37% live birth rate per cycle initiated 7
• Outcomes are closely tied to female partner age, with progressively lower success beyond age 35 7
• For men with high sperm DNA fragmentation, testicular sperm use improves clinical pregnancy rates and reduces miscarriage rates compared to ejaculated sperm 7

Special Considerations for Ejaculatory Dysfunction

Retrograde Ejaculation

• Treat with sympathomimetics and urine alkalinization with or without urethral catheterization 1
• Alternatives include induced ejaculation or surgical sperm retrieval 1

Aspermia (Complete Absence of Ejaculation)

• Options include surgical sperm extraction, penile vibratory stimulation, electroejaculation, or sympathomimetic agents depending on etiology and clinician experience 1

Critical Pitfalls to Avoid

Never Prescribe Exogenous Testosterone

• Exogenous testosterone completely suppresses spermatogenesis through negative feedback on FSH and LH, causing azoospermia that takes months to years to recover 5, 7
• This applies to all testosterone formulations and anabolic steroids 5

Diagnostic Biopsy Rarely Needed

• Clinical and laboratory findings provide >90% accuracy in differentiating OA from NOA 1, 2
• Diagnostic testis biopsy is reserved for rare cases with normal semen volume, normal testicular volume, FSH <7.6 IU/L, and no epididymal engorgement 1
• Always attempt sperm cryopreservation if diagnostic biopsy is performed and ART is an option 1

Genetic Counseling Mandatory

• Men with NOA using retrieved sperm for ICSI must receive genetic counseling before proceeding, as chromosomal abnormalities and Y-chromosome microdeletions will be transmitted to male offspring 1, 8

Varicocele Considerations

• Treatment of clinical (palpable) varicoceles may be offered when abnormal semen parameters exist and minimal female factors are present 1
• Do not routinely image for isolated small or moderate right varicoceles, as treatment of subclinical varicoceles is not helpful 1
• Consider abdominal imaging only for new-onset, non-reducible, or large varicoceles 1