Larger trinucleotide repeat size in the androgen receptor gene of infertile men with extremely severe oligozoospermia

Androgens are significant regulators of human spermatogenesis. Their action is mediated through the androgen receptor (AR), which binds to the androge n responsive element on DNA and regulates gene transcription. Men become in fertile with spinobulbar muscular atrophy (Kennedy disease) caused by a tri nucleotide repeat expansion, greater than or equal to 40 CAG repeats, in th e AR gene located on the X chromosome. In this prospective study, we invest igated whether the variable size, larger repeats, of this trinucleotide cou ld alter AR function and result in impaired spermatogenesis. A total of 69 infertile men were studied. Clinical and laboratory analysis showed idiopat hic, nonobstructive azoospermia in 16 men, extremely severe oligozoospermia in 27 men (<1 million sperm/mL), and severe oligozoospermia in 26 men (1 t o 5 million sperm/mL). Fertile control men (n = 45) were selected by docume nted paternity proven by linkage analysis; Leukocyte DNA was analyzed by po lymerase chain reaction (PCR) amplification across the AR repeat region. Ac curate size determination of the PCR product using an ABI 373 DNA sequencer allowed precise calculation of CAG repeat sizes. The AR gene was not analy zed for other types of mutations. The difference in CAG repeat size between infertile men and proven fertile controls was statistically significant, P = .03. Patients with extremely severe oligozoospermia had significantly lo nger CAG repeat tracts (mean, 25.4 +/- 4.0; P = .0005; range 20-39) than co ntrols (mean, 22 +/- 2.8; range 12-30) or patients with severe oligozoosper mia (mean, 22.2 +/- 2.3; range 18-26). None of the 26 infertile men with sp erm counts <1 million/mL had less than or equal to 19 CAG, repeats compared with 6 out of 45 controls (13%; P = .06). This study suggests that some me n with severe impairment of spermatogenesis have longer trinucleotide repea ts in the AR gene. Although direct evidence is missing, lower affinity betw een androgen and the AR protein or decreased AR protein availability with l onger repeats could be responsible for a diminished androgen effect on sper matogenesis. Two of the patients in the extremely severe oligozoospermia gr oup had 35 and 39 CAG repeats, respectively (normal range is 11 to 33). Alt hough not yet considered a mutation, longer trinucleotide repeats are unsta ble and might either expand or contract between generations. If they expand , conception through the use of intracytoplasmic sperm injection (ICSI), co uld result in the son of an ICSI daughter being affected not only by infert ility hut also by Kennedy disease.