Premature Ovarian Failure in Androgen Receptor-Deficient Mice

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-01, Vol.103 (1), p.224-229
• Main Authors: Shiina, Hiroko, Matsumoto, Takahiro, Sato, Takashi, Igarashi, Katsuhide, Miyamoto, Junko, Takemasa, Sayuri, Sakari, Matomo, Takada, Ichiro, Nakamura, Takashi, Metzger, Daniel, Chambon, Pierre, Kanno, Jun, Yoshikawa, Hiroyuki, Kato, Shigeaki
• Format: Article
• Language: English
• Subjects: Androgens; Animals; Biochemistry, Molecular Biology; Biological Sciences; Blotting, Western; Chromosomes; Female; Female animals; Follicles; Follicular development; Genotypes; Granulosa cells; Immunohistochemistry; Life Sciences; Luciferases; Mice; Mice, Knockout; Molecular biology; Nucleotides; Oligonucleotide Array Sequence Analysis; Ovarian Failure, Premature; Ovarian Follicle; Ovarian Follicle - anatomy & histology; Ovarian Follicle - growth & development; Ovaries; Primary Ovarian Insufficiency - genetics; Receptors, Androgen; Receptors, Androgen - deficiency; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Reproductive system; Reverse Transcriptase Polymerase Chain Reaction; RNA; Rodents; Sex chromosomes; Women; X Chromosome; X Chromosome - genetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0506736102

Premature ovarian failure (POF) syndrome, an early decline of ovarian function in women, is frequently associated with X chromosome abnormalities ranging from various Xq deletions to complete loss of one of the X chromosomes. However, the genetic locus responsible for the POF remains unknown, and no candidate gene has been identified. Using the Cre/LoxP system, we have disrupted the mouse X chromosome androgen receptor (Ar) gene. Female$AR^{-/-}$mice appeared normal but developed the POF phenotype with aberrant ovarian gene expression. Eight-week-old female$AR^{-/-}$mice are fertile, but they have lower follicle numbers and impaired mammary development, and they produce only half of the normal number of pups per litter. Forty-week-old$AR^{-/-}$mice are infertile because of complete loss of follicles. Genome-wide microarray analysis of mRNA from$AR^{-/-}$ovaries revealed that a number of major regulators of folliculogenesis were under transcriptional control by AR. Our findings suggest that AR function is required for normal female reproduction, particularly folliculogenesis, and that AR is a potential therapeutic target in POF syndrome.