The regulation of FSH transcription by gonadal steroids: testosterone and estradiol modulation of the activin intracellular signaling pathway

Burger LL, Haisenleder DJ, Wotton GM, Aylor KW, Dalkin AC, Marshall JC. The regulation of FSH transcription by gonadal steroids: testosterone and estradiol modulation of the activin intracellular signaling pathway. Am J Physiol Endocrinol Metab 293: E277–E285, 2007. First published April 3, 2007; doi:10.1152/ajpendo.00447.2006.—Recent reports suggest that androgens increase FSH transcription directly via the androgen receptor and by modulating activin signaling. Estrogens may also regulate FSH transcription in part through the activin system. Activin signaling can be regulated extracellularly via activin, inhibin, or follistatin (FS) or intracellularly via the Smad proteins. We determined the effects of androgen and estrogen on FSH primary transcript (PT) concentrations in male and female rats, and we correlated those changes with pituitary: activin B mRNA, FS mRNA, the mRNAs for Smads2, -3, -4, and -7, and the phosphorylation (p) status of Smad2 and -3 proteins. In males, testosterone (T) increased FSH PT twoto threefold between 3 and 24 h and was correlated with reduced FS mRNA, transient increases in Smad2, -4, and -7 mRNAs, and a sixto 10-fold increase in pSmad2, and activin B mRNA was unchanged. In females, T also increased FSH PT twofold and pSmad2 threefold but had no effect on activin B, FS, or the Smad mRNAs. Androgen also increased Smad2 phosphorylation in gonadotrope-derived T3 cells. In contrast, estradiol had no effect on FSH PT but transiently increased activin B mRNA and suppressed FS mRNA before increasing FS mRNA at 24 h and increased Smads2, -3, and -7 mRNAs and pSmad2 threefold. In conclusion, T acts on the pituitary to increase FSH PT in both sexes and modulates FS mRNA, Smad mRNAs, and/or Smad2 phosphorylation. These findings suggest that T regulates FSH transcription, in part, through modulation of various components of the activin-signaling system.