Androgen receptor repression of gonadotropin-releasing hormone gene transcription via enhancer 1

Gonadotropin-releasing hormone (GnRH) plays a major role in the hypothalamic-pituitary–gonadal (HPG) axis, and synthesis and secretion of GnRH are regulated by gonadal steroid hormones. Disruptions in androgen levels are involved in a number of reproductive defects, including hypogonadotropic hypogonadism and polycystic ovarian syndrome. Androgens down-regulate GnRH mRNA synthesis in vivo and in vitro via an androgen receptor (AR)-dependent mechanism. Methyltrienolone (R1881), a synthetic AR agonist, represses GnRH expression through multiple sites in the proximal promoter. In this study, we show AR also represses GnRH transcription via the major enhancer (GnRH-E1). A multimer of the −1800/−1766 region was repressed by R1881 treatment. Mutation of two bases, −1792 and −1791, resulted in decreased basal activity and a loss of AR-mediated repression. AR bound to the −1796/−1791 sequence in electrophoretic mobility shift assays, indicating a direct interaction with DNA or other transcription factors in this region. We conclude that AR repression of GnRH-E1 acts via multiple AR-responsive regions, including the site at −1792/−1791.

► AR-mediated repression of GnRH gene expression involves enhancer 1. ► AR represses GnRH enhancer 1 via interaction with the -1796/-1791 region. ► Our study provides a new mechanism involved in the repression of GnRH by androgens.