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

Recent reports suggest that androgens increase FSH beta transcription directly via the androgen receptor and by modulating activin signaling. Estrogens may also regulate FSH beta 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 beta primary transcript (PT) concentrations in male and female rats, and we correlated those changes with pituitary: activin beta 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 beta PT two- to threefold between 3 and 24 It and was correlated with reduced FS mRNA, transient increases in Smad2, -4, and -7 mRNAs, and a six- to 10-fold increase in pSmad2, and activin beta B mRNA was unchanged. In females, T also increased FSH beta PT twofold and pSmad2 threefold but had no effect on activin beta B, FS, or the Smad mRNAs. Androgen also increased Smad2 phosphorylation in gonadotrope-derived alpha T3 cells. In contrast, estradiol had no effect on FSH beta PT but transiently increased activin beta B mRNA and suppressed FS mRNA before increasing FS mRNA at 24 It and increased Smads2, -3, and -7 mRNAs and pSmad2 threefold. In conclusion, T acts on the pituitary to increase FSH beta PT in both sexes and modulates FS mRNA, Smad mRNAs, and/or Smad2 phosphorylation. These findings suggest that T regulates FSH beta transcription, in part, through modulation of various components of the activin-signaling system.