Nonobstructive Azoospermia

Nonobstructive azoospermia is the absence of sperm in the ejaculate because the testes produce few or no sperm, or because sperm production is not driven by the pituitary. It makes up about 60% of azoospermia and affects about 0.6% of men.

Some men have patches of sperm production that can be retrieved surgically. Hypogonadotropic hypogonadism is the one subgroup in which drug treatment can induce sperm in the ejaculate.

Pathophysiology. Causes:

• Pretesticular: hypogonadotropic hypogonadism (Kallmann syndrome, pituitary tumour, hyperprolactinaemia, exogenous testosterone or anabolic steroids, opioids, haemochromatosis, critical illness).
• Testicular: Klinefelter syndrome (47,XXY, about 10% of azoospermic men), Y chromosome microdeletions (AZFa, AZFb, AZFc, about 8 to 10%), other chromosomal abnormalities, cryptorchidism, torsion, mumps orchitis, chemotherapy (alkylating agents), radiotherapy, severe varicocele, gonadotoxins, and idiopathic disease in about a third.
• Histology ranges from hypospermatogenesis to maturation arrest and Sertoli cell only pattern, often mixed in the same testis.

Testicular cancer is more common in infertile men and may be found at assessment.

Primary infertility. Small, soft testes (volume under 12 mL) with normal epididymis and vasa. Features of androgen deficiency: reduced libido, fatigue, reduced body hair, gynaecomastia and low bone density. Klinefelter syndrome: tall stature, small firm testes and eunuchoid proportions. Hypogonadotropic hypogonadism: delayed puberty, anosmia (Kallmann syndrome), headaches or visual field defects from pituitary lesions.

History of cryptorchidism, torsion, mumps, chemotherapy, radiotherapy, testosterone or anabolic steroid use, and opioids.

• Two semen analyses with centrifugation. Semen volume and pH are normal.
• FSH, LH, total testosterone (morning), oestradiol, prolactin and sex hormone binding globulin. Raised FSH (usually over 7.6 IU/L) with small testes indicates primary testicular failure. Low FSH and LH with low testosterone indicates hypogonadotropic hypogonadism. Raised FSH does not predict sperm retrieval.
• Karyotype and Y chromosome microdeletion testing in all men with azoospermia and sperm concentration under 5 million/mL.
• Pituitary MRI for hypogonadotropic hypogonadism with raised prolactin, or other pituitary hormone deficiency. Iron studies and other pituitary hormones when indicated.
• Scrotal ultrasound for testicular volume, microlithiasis, varicocele and tumour.
• Bone density scan for long standing hypogonadism. Diagnostic biopsy or micro-dissection testicular sperm extraction when retrieval is planned.

Differential diagnosis.

• Obstructive azoospermia
• Hypogonadotropic hypogonadism
• Retrograde ejaculation
• Cryptozoospermia
• Sertoli cell only syndrome and maturation arrest (histological subtypes)
• Drug induced suppression of spermatogenesis

• Stop gonadotoxins and suppressive drugs (testosterone, anabolic steroids, opioids), then recheck semen after 3 to 6 months. Testosterone replacement is not given to men who want fertility.
• Hypogonadotropic hypogonadism: gonadotrophin therapy induces sperm in most men.
  • Human chorionic gonadotrophin 1500 IU subcutaneously or intramuscularly twice weekly, increased to a range of 1500 to 5000 IU two to three times weekly, titrated to a mid-normal serum testosterone.
  • Add recombinant FSH 75 to 150 IU subcutaneously three times weekly if no sperm appear after 3 to 6 months. Continue for up to 12 to 24 months before judging failure.
  • Treat the pituitary cause (cabergoline for prolactinoma, dopamine agonists, surgery).
• Primary testicular failure:
  • Micro-dissection testicular sperm extraction with intracytoplasmic sperm injection. Sperm are retrieved in about 40 to 60% overall, with about 50% in Klinefelter syndrome and about 50 to 70% in AZFc deletion. Retrieval does not occur in complete AZFa or AZFb deletions, and surgery is not offered to these men.
  • Hormone optimisation before surgery in selected men with low testosterone (under about 10 nmol/L): clomifene citrate 25 mg orally daily, or anastrozole 1 mg orally daily, or human chorionic gonadotrophin, for about 3 months. Evidence is limited and the use is off label.
  • Varicocelectomy in men with a large clinical varicocele may allow sperm to appear in some, though evidence is weak.
• Post-extraction: testicular haematoma and infection are possible. Perioperative cefazolin 2 g intravenously (3 g if over 120 kg) as a single dose, with paracetamol 1 g every 6 hours (maximum 4 g daily) and ibuprofen 400 mg every 8 hours for 3 to 5 days.
• Counselling on donor sperm, adoption and living without children when no sperm is found. Genetic counselling for transmission of Y microdeletions to sons and chromosomal risk.
• Fertility preservation: adolescents with Klinefelter syndrome and boys before gonadotoxic cancer treatment should be referred early.

Special groups. Men with Klinefelter syndrome need lifelong testosterone replacement after sperm retrieval, and monitoring of bone density, metabolic risk and breast cancer risk.

Monitoring. Testosterone and FSH 3 to 6 months after sperm extraction, since a fall in testosterone occurs in roughly a third and usually recovers over 12 months. Serum testosterone and semen every 3 months during gonadotrophin therapy. Yearly testicular ultrasound for cancer surveillance when the testes are abnormal.

Referral and escalation. Refer to urology or andrology and a fertility unit. Urgent referral for a testicular mass, visual field loss or suspected pituitary tumour.