Length of the human androgen receptor glutamine tract determines androgen sensitivity in vivo

A well established functional polymorphism of the human androgen receptor (hAR) is the length of AR’s N-terminal glutamine tract (Q-tract). This tract is encoded by a CAG trinucleotide repeat and varies from 8 to 33 codons in the healthy population. Q-tract length is inversely correlated with AR transcriptional activity in vitro, but whether endogenous androgen action is affected is not consistently supported by results of clinical and epidemiological studies. To test whether Q-tract length influences androgen sensitivity in vivo, we examined effects of controlled androgen exposure in “humanized” mice with hAR knock-in alleles bearing 12, 21 or 48 CAGs. Mature male mice were analyzed before or 2 weeks after orchidectomy, with or without a subdermal dihydrotestosterone (DHT) implant to attain stable levels of this non-aromatizable androgen. The validity of this DHT clamp was demonstrated by similar serum levels of DHT and its two primary 3αDiol and 3βDiol metabolites, regardless of AR Q-tract length. Q-tract length was inversely related to DHT-induced suppression of castrate serum LH (p = 0.005), as well as seminal vesicle (SV) weight (p = 0.005) and prostate lobe weights (p < 0.006). This confirms that the hAR Q-tract polymorphism mediates in vivo tissue androgen sensitivity by impacting negative hypothalamic feedback and trophic androgen effects on target organs. In this manner, AR Q-tract length variation may influence numerous aspects of male health, from virilization to fertility, as well as androgen-dependent diseases, such as prostate cancer.

► We determine the in vivo influence of AR Q-tract length on androgen sensitivity.
► We utilize DHT clamp and “humanized” AR mouse model with 12, 21 or 48 CAG repeats.
► In vivo AR activity correlates inversely with Q-tract length.
► Q-tract length influences negative hypothalamic feedback.
► Q-tract length modifies trophic androgen effects on target organs.