The role of androgens in female reproduction is not well defined despite the androgen receptor (AR) being expressed throughout various female organs. Female mice homozygous for AR knockout (ARKO) were developed using the Cre/LoxP system and exhibit significant changes in ovarian function, uterine development and fertility¹ . As the AR is expressed in the uterus, we hypothesized, that through the AR, androgens play a role in uterine development and physiology.

Probasin Cre (PbCre) mice were used to inactivate AR specifically in the uterine glands (utARKO). Specificity of Cre activity was confirmed using ROSA reporter mice and detection of mutated functionally inactive Ar mRNA only in the uterus. The functional effects of Cre activity in the uterus were confirmed by development of endometrial cancer following PbCre mediated PTEN tumor suppressor inactivation. Uterus weights in sexually mature females at estrus were increased in utARKO (112±10 vs 145±14mg [mean±SE]) and in ARKO females (99±9 vs 125±16), compared with respective WTs. While uterine morphology was not affected in utARKOs, the global ARKO’s had significantly reduced areas of myometrium and endometrium compared to the WT and the utARKO’s. In addition, while the fertility is significantly reduced in ARKO females¹ , the pups per litter (WT 11.1±0.83, utARKO 10.5±1.03, p>0.05) and the cumulative pups over a 150 day trial period (WT 50.8±1.96, utARKO 47.0±1.04, p>0.05) demonstrated no significant difference between the WT and utARKO’s. Thus uterine morphology and physiology is significantly affected by global AR loss but not by selective AR inactivation in uterine glands alone. This suggests the uterine effects in ARKO females could be due to 1) systemic effects caused from global loss of the AR, 2) a significant role of stromal AR in the uterus or 3) AR effects during the early pre-pubertal period prior to PbCre activation at 4 weeks of age.