Maturation Arrest of Spermatogenesis

Maturation arrest of spermatogenesis is a histological pattern in which germ cell development stops at a defined stage, so mature sperm are not formed. Arrest may occur at the spermatogonial, primary spermatocyte or spermatid stage.

The spermatocyte stage is the most common. It may be complete (all tubules) or incomplete (some tubules with later stages).

It is found in about 5 to 25% of nonobstructive azoospermia biopsies. It causes azoospermia or severe oligospermia with normal sized testes and usually normal or mildly raised FSH.

Pathophysiology. Arrest has genetic and acquired causes.

Genetic: AZFb and AZFc Y chromosome deletions, translocations and other chromosomal abnormalities, and gene mutations affecting meiosis (for example TEX11, SYCP3, MEIOB).

Acquired: cryptorchidism, chemotherapy, radiotherapy, febrile illness, hormone suppression and toxins. Many cases are idiopathic.

Testosterone production is normal, because Leydig cells are intact.

Primary infertility with azoospermia or severe oligospermia. Testicular volume is normal or mildly reduced. Virilisation is normal. History of cryptorchidism, torsion, mumps, chemotherapy or a family history of infertility.

• Semen analysis on at least two samples with centrifugation.
• FSH (normal in a substantial minority, or mildly raised), LH, total testosterone and inhibin B. These do not reliably separate arrest from other forms.
• Karyotype and Y chromosome microdeletion testing.
• Scrotal ultrasound for testicular size, microlithiasis and masses.
• Testicular biopsy or micro-dissection testicular sperm extraction with histology: spermatogonia and spermatocytes but no spermatids (spermatocyte arrest), or round spermatids without elongated forms (spermatid arrest). Incomplete arrest has some tubules with later stages.
• Exome or targeted gene panels in research or specialist settings, for familial disease.

Differential diagnosis.

• Sertoli cell only syndrome
• Hypospermatogenesis
• Obstructive azoospermia (normal FSH and sperm in biopsy)
• Klinefelter syndrome
• Hypogonadotropic hypogonadism
• Delayed processing artefact of the biopsy

• No medical treatment reliably restores sperm production.
• Micro-dissection testicular sperm extraction with intracytoplasmic sperm injection. Sperm are retrieved in about 25 to 50% of men. Rates are higher in incomplete arrest and spermatid stage arrest, and lower in complete spermatocyte arrest. Complete AZFb deletion rarely allows retrieval, and AZFc deletion allows retrieval in about 50 to 70%.
• Hormone optimisation before extraction in 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 1500 to 3000 IU two to three times weekly, for about 3 months. Evidence is limited and use is off label.
• Round spermatid injection is experimental and not offered routinely.
• 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 about donor sperm, adoption and childfree living when no sperm is found, and genetic counselling for transmission of mutations to children.
• Testosterone replacement is withheld while fertility is sought, and given after sperm retrieval if androgen deficiency exists.

Monitoring. Testosterone and FSH 3 to 6 months after sperm extraction, since testosterone falls in some men and usually recovers over 12 months. Yearly testicular ultrasound for cancer surveillance.

Referral and escalation. Refer to urology or andrology, a fertility unit and genetics. Urgent referral for a testicular mass.