Androgen receptor repression of GnRH gene transcription

Mol Endocrinol. 2012 Jan;26(1):2-13. doi: 10.1210/me.2011-1015. Epub 2011 Nov 10.


Alterations in androgen levels lead to reproductive defects in both males and females, including hypogonadotropic hypogonadism, anovulation, and infertility. Androgens have been shown to down-regulate GnRH mRNA levels through an androgen receptor (AR)-dependent mechanism. Here, we investigate how androgen regulates expression from the GnRH regulatory region in the GT1-7 cell line, a model of GnRH neurons. A synthetic androgen, R1881, repressed transcription from the GnRH promoter (GnRH-P) in an AR-dependent manner, and liganded AR associated with the chromatin at the GnRH-P in live GT1-7 cells. The three known octamer-binding transcription factor-1 (Oct-1) binding sites in GnRH-P were required for AR-mediated repression, although other sequences were also involved. Although a multimer of the consensus Oct-1 binding site was not repressed, a multimer of the cluster of Oct-1, Pre-B cell leukemia transcription factor (Pbx)/Prep, and NK2 homeobox 1 (Nkx2.1) binding sites, found at -106/-91 in GnRH-P, was sufficient for repression. In fact, overexpression of any of these factors disrupted the androgen response, indicating that a balance of factors in this tripartite complex is required for AR repression. AR bound to this region in EMSA, indicating a direct interaction of AR with DNA or with other transcription factors bound to GnRH-P at this sequence. Collectively, our data demonstrate that GnRH transcription is repressed by AR via multiple sequences in GnRH-P, including three Oct-1 binding sites, and that this repression requires the complex interaction of several transcription factors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / metabolism
  • Binding Sites
  • Cell Line
  • Chromatin
  • Female
  • Gonadotropin-Releasing Hormone / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Male
  • Metribolone / pharmacology
  • Neurons / metabolism
  • Nuclear Proteins / metabolism
  • Octamer Transcription Factor-1 / metabolism
  • Promoter Regions, Genetic
  • RNA, Messenger / biosynthesis
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Thyroid Nuclear Factor 1
  • Transcription Factors / metabolism
  • Transcription, Genetic* / drug effects


  • Androgens
  • Chromatin
  • Homeodomain Proteins
  • Nuclear Proteins
  • Octamer Transcription Factor-1
  • PKNOX1 protein, human
  • RNA, Messenger
  • Receptors, Androgen
  • Thyroid Nuclear Factor 1
  • Transcription Factors
  • Metribolone
  • Gonadotropin-Releasing Hormone