Estradiol is known to increase lactotropic cell proliferation, but estradiol susceptibility varies among human populations and among various strains of rats. We had reported that folicullostellate (FS) cells regulate estradiol's mitogenic action on lactotropes, therefore, we studied their role in determining the susceptibility to estradiol in a high estradiol-responsive rat strain, Fischer 344 (F344), and in a low-responsive strain, Sprague Dawley (SD). Determination of total S-100 positive FS cells in the pituitary revealed that F344 rats have significantly more FS cells than do SD rats. Estradiol treatment did not change the number of FS cells in both F344 and SD rats. When co-transplanted with F344 pituitaries under the kidney capsule or co-cultured with F344-derived lactotropes in vitro, FS cells derived from F344 rats increased estradiol's mitogenic action. They also increased estradiol mitogenic action on SD-derived lactotropes in primary cultures. However, SD-derived FS cells failed to increase estrogen's action on F344- or SD-derived lactotropes. The levels of bFGF production and secretion by TGF-3 and estradiol were much higher in F344-derived FS cells than in SD-derived FS cells. However, lactotropes' growth response to bFGF was similar in both strains. These data suggest that cell-cell interaction between FS cells and lactotropes regulates estradiol's mitogenic action on lactotropes and also determines lactotrpes susceptibility to the steroid.