Mutational Screening of Androgen Receptor Gene in 8224 Men of Infertile Couples

雄激素受体 男性不育 错义突变 内分泌学 内科学 背景(考古学) 不育 睾酮(贴片) 促黄体激素 医学 队列 生物 男科 妇科 基因 遗传学 激素 突变 怀孕 古生物学 癌症 前列腺癌
作者
Maria Santa Rocca,Giovanni Minervini,Cinzia Vinanzi,Alberto Bottacin,Federica Lia,Carlo Foresta,Maria Pennuto,Alberto Ferlin
出处
期刊:The Journal of Clinical Endocrinology and Metabolism [Oxford University Press]
卷期号:108 (5): 1181-1191 被引量:3
标识
DOI:10.1210/clinem/dgac671
摘要

Abstract Context Mutations in the androgen receptor (AR) gene might be associated with infertility mainly because they cause various degrees 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. Methods A total of 8224 males of Italian idiopathic infertile couples were referred to the University Hospital of Padova. The main outcome measures were 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 = .048), higher testosterone (T) concentration (P < .0001), and higher androgen sensitivity index (ASI) (luteinizing hormone × T, P < .001) than patients without variants. Statistical analyses found T ≥ 15.38 nmol/L and ASI ≥ 180 IU × nmol/L2 as the threshold values to discriminate with good accuracy patients with AR variants. Patients with oligozoospermia and T ≥ 15.38 nmol/L had a 9-fold increased risk of harboring mutations compared with patients with normal sperm count and T < 15.38 nmol/L (odds ratio 9.29, 95% CI 5.07-17.02). Using computational and functional approaches, we identified 2 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.
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