Background: Mutations in the androgen receptor (AR) gene may be associated with male infertility, primarily because they cause varying degrees of androgen insensitivity.
Objective: The aim of this study was to assess the frequency and type of AR gene variants in a large cohort of infertile men.
Methods: A total of 8,224 males from Italian couples with idiopathic infertility were referred to the University Hospital of Padua. The main outcome measures included AR gene mutational screening, as well as computational and functional analyses.
Results: We identified 131 patients (1.6%) carrying 45 AR gene variants, 18 of which were novel missense variants. Patients with AR variants had lower sperm counts (P = 0.048), higher testosterone (T) concentrations (P 0.0001), and higher androgen sensitivity index (ASI; luteinizing hormone × T, P 0.001) compared with patients without variants. Statistical analyses identified T ≥ 15.38 nmol/L and ASI ≥ 180 IU × nmol/L² as threshold values that discriminated AR-variant carriers with good accuracy.
Patients with oligozoospermia and T 15.38 nmol/L had a ninefold increased risk of harboring AR mutations compared with men with normal sperm counts and T < 15.38 nmol/L (odds ratio 9.29, 95% CI 5.07–17.02). Using computational and functional approaches, we identified two novel variants, L595P and L791I, as potentially pathogenic.
Conclusion: This is the largest AR gene variant screening study conducted in men from idiopathic infertile couples. We found that the prevalence of AR variants increased to 3.4% in subjects with oligozoospermia and T ≥ 15.38 nmol/L. Conversely, over 80% of men carrying AR variants exhibited low sperm counts and elevated T levels. Based on our findings, we propose AR gene sequencing as a routine genetic test in cases of idiopathic oligozoospermia with T ≥ 15.38 nmol/L.
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