Linkage between male infertility and trinucleotide repeat expansion in theandrogen-receptor gene

Background Androgens acting via the androgen receptor bring about stimulati on and maintenance of spermatogenesis. If mutations in the androgen-recepto r gene interfere with the receptor's function, this effect may partly accou nt for impaired spermatogenesis. We aimed to find out whether expansion of a trinucleotide repeat in the androgen-receptor gene is associated with mal e infertility. Methods We analysed 67 coded semen and blood samples from a predominantly w hite group of male infertility patients and controls. Clinical analyses inc luded cause of infertility, sperm count, and reproductive hormone concentra tions. Analysis of trinucleotide (CAG) repeal length and point mutations in the androgen-receptor gene was done by PCR, single-stranded conformational polymorphism, and DNA sequencing. Findings Screening and characterisation of the androgen-receptor gene in 35 patients and 32 controls showed no point mutations in the gene. 30 of the infertile patients had idiopathic azoospermia or oligozoospermia, and these men had significantly longer CAG repeat tracts than controls (mean 23.2 [S E 0.7] vs 20.5 [0.3], p=0.0001). The odds of having CAG repeat lengths of 2 0 were six-fold higher for fertile men than for men with a spermatogenic di sorder. Interpretation Our results indicate a relation between CAG repeat length in the androgen-receptor gene and the risk of defective spermatogenesis. With the use of intracytoplasmic sperm injection, this mutation could be inheri ted. possibly leading to an increase in male infertility in future generati ons. Should further elongation of the CAG repeat occur in these future gene rations, there is an added risk of increased severity of male infertility, and potentially an increased incidence of neurodegenerative disease.