237. AR-mediated androgen actions are essential for normal mouse uterine growth and development but not implantation and embryo development

Abstract

Recently the androgen receptor (AR) has been shown definitively to play a role in female reproduction. We generated a homozygous AR^−/− female mouse using Cre/LoxP recombination for an in-frame excision of exon 3, encoding the second zinc finger essential for DNA-binding, while allowing production of an exon 3 deleted mutant AR protein which is nonfunctional as a nuclear transcription factor. AR^−/− females were sub-fertile due primarily to ovulatory dysfunction (1). However, the mechanism(s) of the observed sub-fertility remains to be fully defined. To evaluate the role of AR in uterine function we carried out a morphological and function analysis of the AR^−/− uterus. Uterine weights did not differ, however, AR^−/− females exhibited a significant increase in uterine horn length (P < 0.01), and a significant reduction in uterine diameter (P < 0.01), total uterine area (P < 0.01), endometrial area (P < 0.05) and myometrial area (P < 0.01), indicating a role for genomic AR-mediated actions in physiological uterine growth and development. Furthermore, during late pregnancy AR^−/− females had significantly fewer implantation sites (P < 0.01), fetuses present in utero (P < 0.05) and a lower serum progesterone concentration (P < 0.01). In spite of these findings, AR^−/− females had normal gestational length, parturition and pup weights, as well as similar pre- and post implantation losses compared with AR^+/+ females. Therefore, although AR is not essential for normal uterine reproductive function, disrupting genomic AR signalling in the uterus leads to dysfunctional uterine development which may have important long-term functional consequences for hormone dependent uterine disorders such as endometrial hyperplasia and cancer.

(1) K. A. Walters et al. Endocrinology 148, 3674 (2007).