What are the causes of azoospermia in males of reproductive age?

Causes of Azoospermia

Azoospermia results from either blockage in the reproductive tract (obstructive azoospermia) or failure of sperm production within the testes (non-obstructive azoospermia), with the distinction made through physical examination, FSH levels, and testicular volume assessment. 1

Two Main Categories

Obstructive Azoospermia

Obstructive azoospermia occurs when normal sperm production is blocked from reaching the ejaculate. 1

Congenital causes:

• Congenital bilateral absence of the vas deferens (CBAVD) – presents with low ejaculate volume (<1.4 mL) and acidic pH (<7.0), strongly associated with cystic fibrosis gene mutations 1, 2
• Idiopathic epididymal obstruction – bilateral dilated/indurated epididymides on examination 1, 2
• Ejaculatory duct obstruction (EDO) – low volume, acidic ejaculate similar to CBAVD 1

Acquired causes:

• Vasectomy – most common iatrogenic cause 2
• Infections – sexually transmitted diseases causing inflammatory scarring of the epididymis or vas deferens 3, 2
• Iatrogenic injury – surgical damage to reproductive tract structures 2

Clinical presentation: Normal testicular size and consistency, fully descended testes, FSH typically <7.6 IU/L, normal semen volume and pH (unless distal obstruction present) 1

Non-Obstructive Azoospermia

Non-obstructive azoospermia results from impaired spermatogenesis within the testes, representing the most severe form of male factor infertility. 3, 4, 5

Genetic causes:

• Klinefelter syndrome (47,XXY) and other karyotype abnormalities – established chromosomal causes requiring karyotype testing 3, 4
• Y-chromosome microdeletions – AZFa, AZFb, and AZFc region deletions, with complete AZFa and AZFb deletions predicting near-zero sperm retrieval success 3, 6, 2, 7
• Single gene defects – increasingly recognized as sequencing technologies advance 7

Hormonal causes:

• Primary hypogonadism – testicular failure with elevated FSH (>7.6 IU/L) and low testosterone 3, 4
• Secondary hypogonadism (hypogonadotropic hypogonadism) – hypothalamic or pituitary dysfunction with low FSH, LH, and testosterone; potentially reversible with gonadotropin therapy 3, 4, 5
• Defects in androgen synthesis or response – impaired testosterone production or action 4

Medication and toxin-induced causes:

• Exogenous testosterone use – suppresses FSH and LH through negative feedback, causing complete spermatogenic shutdown 3, 5
• Anabolic steroids – same mechanism as exogenous testosterone 3
• Chemotherapy and radiation – gonadotoxic effects on spermatogenesis 3
• Environmental toxins – lead, cadmium exposure 3
• Occupational exposures – oil and natural gas extraction 3

Anatomical causes:

• Varicocele – may contribute to progressive testicular damage and spermatogenic failure 3, 5
• Cryptorchidism – undescended testes with impaired spermatogenesis 4

Other causes:

• Defective spermatogenesis and sperm maturation – idiopathic in many cases 4, 5
• Maturation arrest – spermatogenesis halts at specific developmental stage 3
• Sertoli cell-only syndrome – complete absence of germ cells 4

Clinical presentation: Testicular atrophy (small, soft testes), FSH >7.6 IU/L, normal ejaculate volume and pH 1, 3

Diagnostic Algorithm

Initial evaluation:

• Confirm azoospermia with at least two semen analyses after centrifugation, examining the pellet under wet mount microscopy for rare sperm 1
• Physical examination assessing testicular size, consistency, presence of vas deferens, epididymal abnormalities, and varicocele 1
• Measure FSH and testosterone levels 1, 2

Distinguishing obstructive from non-obstructive:

• FSH <7.6 IU/L + normal testicular size + palpable vas deferens → likely obstructive 1
• FSH >7.6 IU/L + testicular atrophy → likely non-obstructive 1, 3
• Low volume (<1.4 mL) + acidic pH (<7.0) → distal obstruction (CBAVD or EDO) 1

Genetic testing for non-obstructive azoospermia:

• Karyotype analysis to exclude Klinefelter syndrome and chromosomal abnormalities 1, 3, 2
• Y-chromosome microdeletion testing (AZFa, AZFb, AZFc regions) 1, 3, 2, 7

Critical Pitfalls

Common mistakes to avoid:

• Never prescribe exogenous testosterone to men desiring fertility – it causes azoospermia through suppression of FSH and LH that can take months to years to recover 3, 5
• Do not rely on single semen analysis – parameters are highly variable and at least two analyses one month apart are essential 1
• FSH levels alone cannot definitively predict sperm retrieval success – up to 50% of non-obstructive azoospermia patients have retrievable sperm despite elevated FSH 3, 6
• For CBAVD, always recommend cystic fibrosis gene mutation analysis for the female partner due to high carrier risk 2
• Point-of-care and mail-in semen tests cannot substitute for specialized andrology laboratory analysis 1

Treatment Implications

Obstructive azoospermia:

• Microsurgical reconstruction or transurethral resection of ejaculatory ducts depending on obstruction level 2
• Sperm retrieval (PESA/TESA) with assisted reproduction achieving 25-65% success rates 2, 8

Non-obstructive azoospermia:

• Treat reversible causes (gonadotropin deficiency, varicocele in selected cases) 5
• Microdissection testicular sperm extraction (micro-TESE) offers 30-70% sperm retrieval rates, 1.5 times more successful than conventional TESE 3, 6, 2, 5
• Complete AZFa and AZFb deletions contraindicate sperm retrieval attempts 3, 6