Conversion from stimulation to inhibition of the action of estrogen on cell proliferation

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Studies using rat lactotrophs in primary culture in 20011 Estradiol (E2) stimulated basal proliferation of lactotrophs in primary culture with a long latency, 96 h, while it inhibited insulin-induced proliferation within 12 h. The ED50 were 8 and 85 pM for the E2 mitogenic and antimitogenic actions, respectively.2 This antimitogenic action was dependent upon the estrogen activity and not observed for androgens and progestins.3 In addition to the mitogenic action, the E2 antimitogenic action was antagonized by antiestrogens, indicating an estrogen receptor-mediated action.4 E2 inhibited not only insulin-induced lactotroph proliferation but also insulin-like growth factor-1 (IGF-1)-induced proliferation while it enhanced proliferation induced by serum or increased levels of intracellular cyclic AMP, suggesting that the E2 antimitogenic action is not dependent upon proliferative levels but mitogen-specific.Studies using prolactin-producing cell lines in 20021 In GH_3 cells, E2 inhibited IGF-1-induced proliferation and stimulated serum-induced proliferation as in lactotrophs in primary culture. However, E2 failed to stimulate basal proliferation of GH_3 cells.2 In another prolactin-producing cell line, GH_4C_1 cells, E2 inhibited IGF-1-induced proliferation and, unlike to GH_3 cells, stimulated basal proliferation.3 Double immunostaining for prolactin and the cell cycle-regulating protein cyclin D1 revealed that stimulation and inhibition of lactotroph proliferation induced by the mitogenic and antimitogenic actions of E2, respectively, were associated with parallel changes in the number of cyclin D1-immunoreactive lactotrophs.