Activation of a uterine insulin-like growth factor I signaling pathway by clinical and environmental estrogens: requirement of estrogen receptor-alpha

Endocrinology. 2000 Sep;141(9):3430-9. doi: 10.1210/endo.141.9.7649.


Recent data indicate that insulin-like growth factor I (IGF-I) may have a function in mediating the mitogenic effects of 17beta-estradiol (E2) in the uterus and in regulating the growth of uterine neoplasms. This study was designed to determine whether synthetic and plant-derived chemicals that interact with estrogen receptor-alpha (ERalpha) and elicit estrogenic responses also mimic E2 by activating the uterine IGF-I signaling pathway. Ovariectomized adult female mice were treated with both environmental and clinically relevant chemicals previously reported to display estrogenic and/or antiestrogenic properties, and their uteri were evaluated for an activated IGF-I signaling pathway. Diethylstilbestrol, 4-hydroxytamoxifen, the raloxifene analog LY353381, 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), bisphenol A, and genistein were shown to mimic E2 in the uterus by increasing the level of IGF-I messenger RNA, inducing IGF-I receptor (IGF-IR) tyrosine phosphorylation, stimulating the formation of IGF-IR signaling complexes, and increasing both proliferating cell nuclear antigen expression and the number of mitotic cells in the epithelium. The dose of chemical necessary to activate IGF-I signaling varied, with the order of potency: E2 = diethylstilbestrol > LY353381 > 4-hydroxytamoxifen > genistein > HPTE > bisphenol A. Administration of the chemicals to ERalpha knockout mice did not activate IGF-IR, indicating that ERalpha is required for activation of uterine IGF-IR by these diverse chemicals. This study demonstrates that several chemicals shown previously to display estrogenic activities also mimic E2 by activating uterine IGF-I signaling.

MeSH terms

  • Animals
  • Benzhydryl Compounds
  • Blotting, Northern
  • Estradiol Congeners / pharmacology*
  • Estrogen Antagonists / pharmacology
  • Estrogen Receptor alpha
  • Estrogens / pharmacology*
  • Estrogens, Non-Steroidal / pharmacology
  • Female
  • Insulin-Like Growth Factor I / metabolism
  • Insulin-Like Growth Factor I / physiology*
  • Mice
  • Mice, Knockout
  • Mitosis / drug effects
  • Ovariectomy
  • Phenols / pharmacology
  • Piperidines / pharmacology
  • Precipitin Tests
  • Proliferating Cell Nuclear Antigen / metabolism
  • RNA, Messenger / biosynthesis
  • Receptors, Estrogen / agonists
  • Receptors, Estrogen / drug effects
  • Receptors, Estrogen / metabolism*
  • Ribonucleases / metabolism
  • Signal Transduction / physiology*
  • Tamoxifen / analogs & derivatives
  • Tamoxifen / pharmacology
  • Thiophenes / pharmacology
  • Uterus / metabolism*


  • Benzhydryl Compounds
  • Estradiol Congeners
  • Estrogen Antagonists
  • Estrogen Receptor alpha
  • Estrogens
  • Estrogens, Non-Steroidal
  • Phenols
  • Piperidines
  • Proliferating Cell Nuclear Antigen
  • RNA, Messenger
  • Receptors, Estrogen
  • Thiophenes
  • Tamoxifen
  • afimoxifene
  • Insulin-Like Growth Factor I
  • LY 353381
  • Ribonucleases
  • 2,2-bis(4-hydroxyphenyl)-1,1,1-trichloroethane
  • bisphenol A