Mutational screening of androgen receptor gene in 8224 men of infertile couples.

CONTEXT: Mutations in Androgen receptor (AR) gene might be associated with infertility mainly because they cause various degree of androgen insensitivity.

OBJECTIVE: The aim of the study was to evaluate the frequency and type of AR variants in a large cohort of infertile males.

PATIENTS AND SETTING: 8224 males of Italian idiopathic infertile couples referred University Hospital of Padova.

MAIN OUTCOME MEASURES: Mutational screening of AR, computational and functional analyses.

RESULTS: We found 131 patients (1.6%) harboring 45 variants in AR gene, of which 18 were novel missense AR variants. Patients with AR gene variants had lower sperm count (p = 0.048), higher testosterone concentration (p < 0.0001) and higher androgen sensitivity index (ASI) [LH x testosterone (T), p < 0.001] compared to patients without variants. Statistical analyses found T ≥ 15.38 nmol/l and ASI ≥180 IU × nmol/l2 as threshold values to discriminate with good accuracy patients with AR variants. Patients with oligozoospermia and T ≥ 15.38 nmol/l have a 9-fold increased risk of harboring mutations compared to patients with normal sperm count and T < 15.38 nmol/l (OR 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 study screening AR gene variants in men of idiopathic infertile couples. We found that the prevalence of variants increased to 3.4% in oligozoospermic subjects with T ≥ 15.38 nmol/l. Conversely, more than 80% of men with AR gene variants had low sperm count and high T levels. Based on our findings, we suggest AR sequencing as a routine genetic test in cases of idiopathic oligozoospermia with T ≥ 15.38 nmol/L.