Nongenomic Actions of Estradiol Compared with Estrone and Estriol in Pituitary Tumor Cell Signaling and Proliferation

Physiological estrogens, including estrone (E(1)), estradiol (E(2)), and estriol (E(3)), fluctuate with life stage, suggesting specific roles for them in biological and disease processes. We compared their nongenomic signaling and functional actions in GH3/B6/F10 rat pituitary tumor cells. All hormones caused prolactin release at 1 min; the lowest effective concentrations were 10(-11) M E(2), 10(-10) M E(1), and 10(-7) M E(3). All estrogens increased the oscillation frequency of calcium (Ca) spikes, with the same time delay (approximately 200 s) at all levels (10(-15) to 10(-9) M). At some concentrations, E(1) and E(3) provoked more Ca-responding cells than E(2). The amplitude and volume of Ca peaks were elevated by all hormones at > or = 10(-15) M. All hormones caused cell proliferation, with the lowest effective concentrations of E(2) (10(-15) M) > E(1) (10(-12) M) > E(3) (10(-10) M); E(2) caused higher maximal cell numbers at most concentrations. All estrogens caused oscillating extracellular-regulated kinase (ERK) activations, with relative potencies of E(1) and E(2) > E(3). All estrogens were ineffective in activation of ERKs or causing proliferation in a subline expressing low levels of membrane estrogen receptor-alpha. Dose-response patterns were frequently nonmonotonic. Therefore, the hormones E(1) and E(3), which have been designated "weak" estrogens in genomic actions, are strong estrogens in the nongenomic signaling pathways and functional responses in the pituitary.