title: Androgen/androgen receptor pathway regulates expression of the genes for cyclooxygenase-2 and amphiregulin in periovulatory granulosa cells.
abstract: It is well known that the androgen/androgen receptor (AR) pathway is involved in both male and female fertility in mammals. AR knockout female mice are reported to exhibit various abnormalities in follicle development, and a subfertile phenotype. In exogenous gonadotropin-induced superovulation, serum androgen levels were robustly elevated in female mice at the periovulatory stage after human chorionic gonadotropin (hCG) treatment. At this stage, ovarian AR proteins were strongly expressed in cumulus cells. Because these results suggested that the androgen/AR pathway is involved in ovulation, we investigated the expression of ovulation-related genes in the mouse ovary treated with the nonaromatizable androgen, 5α-dihydrotestosterone (DHT). DHT treatment induced the expression of the genes for cyclooxyganase-2 (Cox-2 or prostaglandin endoperoxidase synthase 2) and the epidermal growth factor-like factor, amphiregulin (Areg), in the ovary, whereas their hCG-induced expression was suppressed by the AR antagonist flutamide. These genes were also induced by DHT in AR-expressing primary granulosa and granulosa tumor-derived cells. Reporter assays, electrophoretic shift mobility assays and chromatin immunoprecipitation assays demonstrated that androgen response sequence(s) existing upstream of each gene were responsible for androgen responsiveness and were occupied by the AR in periovulatory granulosa cells. Our results suggest that the androgen/AR pathway is involved in the ovulatory process via expression of the Cox-2 and Areg genes in periovulatory granulosa cells.
authors: Department of Biochemistry, Faculty of Medical Sciences, University of Fukui, Matsuoka, Fukui, Japan. yazawa@u-fukui.ac.jp
authors: Takashi
authors: T
authors: Yazawa
authors: Shinya
authors: S
authors: Kawabe
authors: Masafumi
authors: M
authors: Kanno
authors: Tetsuya
authors: T
authors: Mizutani
authors: Yoshitaka
authors: Y
authors: Imamichi
authors: Yunfeng
authors: Y
authors: Ju
authors: Takehiro
authors: T
authors: Matsumura
authors: Yukiko
authors: Y
authors: Yamazaki
authors: Yoko
authors: Y
authors: Usami
authors: Mayu
authors: M
authors: Kuribayashi
authors: Masayuki
authors: M
authors: Shimada
authors: Takeshi
authors: T
authors: Kitano
authors: Akihiro
authors: A
authors: Umezawa
authors: Kaoru
authors: K
authors: Miyamoto
mesh_terms: D066258:Amphiregulin; D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000494:pharmacology*; D066255:EGF Family of Proteins; D005260:Female; D005485:Flutamide / Q000494:pharmacology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D059002:Androgen Receptor Antagonists; D000728:Androgens; C587849:Areg protein, mouse; D006063:Chorionic Gonadotropin; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D013196:Dihydrotestosterone; D005485:Flutamide; D051546:Cyclooxygenase 2