Azoospermia factor (AZF) region of the Y chromosome

Y chromosome infertility usually presents in adult men evaluated for reproductive failure. Affected individuals have azoospermia or oligozoospermia. The testicular histology spans Sertoli cell-only syndrome, maturation arrest and hypospermatogenesis, and the testes may be small. The prognosis for sperm retrieval by testicular sperm extraction (TESE) depends on the deleted region. It is generally poor for complete AZFa or AZFb deletions but more favourable for AZFc deletions, in which sperm sufficient for intracytoplasmic sperm injection (ICSI) may be recovered.

defines the prevalence of Y-chromosome microdeletions in the general male population to be around 1 in 4,000. However, Y-chromosome microdeletions are present in approximately 5% of men with severe oligozoospermia and approximately 10% of men with azoospermia.

Y chromosome infertility is caused by recurrent germline microdeletions of the AZF regions on Yq11, arising through non-allelic homologous recombination between repeated sequence blocks (HERV15 repeats for AZFa; most commonly palindromes P5/proximal or distal P1, P4/distal P1, b2/b4 and gr/gr for AZFb and AZFc). These deletions remove multiple testis-expressed genes, including the single-copy AZFa genes USP9Y and DDX3Y and the multi-copy AZFb/c families (24 genes including e.g. the DAZ genes). Loss of function arises through hemizygosity and reduced gene dosage in spermatogonia and spermatocytes

AZF microdeletions show Y-linked transmission, so an affected father transmits the deletion to all of his sons but to none of his daughters. Because the deletion impairs spermatogenesis, natural conception is uncommon; transmission to sons, therefore occurs predominantly through assisted reproduction, most commonly ICSI. Sons who inherit the deletion are expected to manifest a similar spermatogenic defect and infertility phenotype.

The diagnosis is established by molecular detection of AZF-region microdeletions on Yq11. Semen analysis per Laboratory Manual reference values is the clinical entry point. Azoospermia or severe oligozoospermia (<5 million sperm/mL, yet deletions are mainly found in patients with <2 million sperm/mL) is the indication for Y-chromosome microdeletion testing per the EAA/EMQN best practice guidelines, in which multiplex PCR followed by deletion-extension analysis remains the reference methodology. Complete AZFa or AZFb deletions are typically associated with azoospermia, whereas AZFc deletions produce a more variable phenotype ranging from azoospermia to oligozoospermia.

Main differential diagnoses include:

• Klinefelter syndrome (47,XXY): azoospermia with small firm testes, distinguished by karyotype showing a supernumerary X chromosome
• CFTR-related : obstructive azoospermia with bilateral absent vas deferens
• and isolated GnRH deficiency: hypogonadotrophic hypogonadism with anosmia and prepubertal testicular volume; associated genes ANOS1, FGFR1 and others

• Genetic testing supports establishing the diagnosis by identifying the underlying AZF microdeletion, clarifying the genetic aetiology and providing a basis for genetic counselling.
• A confirmed result supports condition-specific management options, including decisions on assisted reproduction, which the treating physicians decide together with the affected individual.
• A known familial variant supports predictive testing of at-risk male relatives, so they can clarify their personal reproductive risk and access counselling where indicated.

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