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Nongenomic actions of estradiol compared with estrone and estriol in pituitary tumor cell signaling and proliferation

Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas, USA

¹ Correspondence: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-0645, USA

Physiological estrogens, including estrone (E₁), estradiol (E₂), and estriol (E₃), 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 E₂, 10^–10 M E₁, and 10^–7 M E₃. All estrogens increased the oscillation frequency of calcium (Ca) spikes, with the same time delay (200 s) at all levels (10^–15 to 10^–9 M). At some concentrations, E₁ and E₃ provoked more Ca-responding cells than E₂. The amplitude and volume of Ca peaks were elevated by all hormones at 10^–15 M. All hormones caused cell proliferation, with the lowest effective concentrations of E₂ (10^–15 M) > E₁ (10^–12 M) > E₃ (10^–10 M); E₂ caused higher maximal cell numbers at most concentrations. All estrogens caused oscillating extracellular-regulated kinase (ERK) activations, with relative potencies of E₁ and E₂ > E₃. All estrogens were ineffective in activation of ERKs or causing proliferation in a subline expressing low levels of membrane estrogen receptor-. Dose-response patterns were frequently nonmonotonic. Therefore, the hormones E₁ and E₃, which have been designated "weak" estrogens in genomic actions, are strong estrogens in the nongenomic signaling pathways and functional responses in the pituitary.—Watson, C. S., Jeng, Y.-J., Kochukov, M. Y. Nongenomic actions of estradiol compared with estrone and estriol in pituitary tumor cell signaling and proliferation.

Key Words: calcium • ERK activation • prolactin release • nonmonotonic dose responses • membrane estrogen receptors