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Research ArticleEndocrine and Diabetes

Tamoxifen Regulation of Bone Growth and Endocrine Function in the Ovariectomized Rat: Discrimination of Responses Involving Estrogen Receptor α/Estrogen Receptor β, G Protein-Coupled Estrogen Receptor, or Estrogen-Related Receptor γ Using Fulvestrant (ICI 182780)

James M. Fitts, Robert M. Klein and C. Andrew Powers
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 246-254; DOI: https://doi.org/10.1124/jpet.110.173955
James M. Fitts
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Robert M. Klein
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C. Andrew Powers
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Abstract

Tamoxifen is a selective estrogen receptor (ER) modulator, but it is also a deactivating ligand for estrogen-related receptor-γ (ERRγ) and a full agonist for the G protein-coupled estrogen receptor (GPER). Fulvestrant is a selective ER down-regulator that lacks agonist effects on ERα/ERβ, is inactive on ERRγ, but acts as a full agonist on GPER. Fulvestrant effects on tamoxifen actions on uterine and somatic growth, bone, the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis, and pituitary prolactin were analyzed to pharmacologically discriminate tamoxifen effects that may be mediated by ERα/ERβ versus ERRγ versus GPER. Ovariectomized rats received tamoxifen (0.6 mg/kg/daily) plus fulvestrant at 0, 3, 6, or 12 mg/kg/daily for 5 weeks; controls received vehicle or 6 mg/kg fulvestrant daily. Tamoxifen effects to increase uterine weight, decrease serum IGF-I, increase pituitary prolactin, and increase bone mineral density could be fully blocked by fulvestrant, indicating mediation by ERα/ERβ. Tamoxifen effects to decrease pituitary GH, tibia length, and body weight were only partially blocked by fulvestrant, indicating involvement of mechanisms unrelated to ERα/ERβ. Fulvestrant did not inhibit tamoxifen actions to reduce total pituitary protein, again indicating effects not mediated by ERα/ERβ. Tamoxifen actions to reduce serum GH were mimicked rather than inhibited by fulvestrant, pharmacological features consistent with GPER involvement. However, fulvestrant alone increased IGF-I and also blocked tamoxifen-evoked IGF-I decreases; thus fulvestrant effects on serum GH might reflect increased IGF-I feedback inhibition. Fulvestrant alone had no effect on the other parameters. The findings indicate that mechanisms unrelated to ERα/ERβ contribute to tamoxifen effects on body weight, bone growth, and pituitary function.

Footnotes

  • This work was supported in part by an award from the Dr. I. Fund Foundation.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.110.173955.

  • ABBREVIATIONS:

    ER
    estrogen receptor
    ERR
    estrogen-related receptor
    GH
    growth hormone
    GPER
    G protein-coupled estrogen receptor
    IGF-I
    insulin-like growth factor I
    SERM
    selective estrogen receptor modulator
    PRL
    prolactin
    TM
    tamoxifen
    ICI
    fulvestrant
    ICI 182780
    7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10)-triene-3,17-diol
    CNS
    central nervous system
    V
    vehicle
    LBD
    ligand-binding domain
    BMD
    bone mineral density
    RIA
    radioimmunoassay
    BBB
    blood-brain barrier.

  • Received August 10, 2010.
  • Accepted March 21, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Tamoxifen Regulation of Bone Growth and Endocrine Function in the Ovariectomized Rat: Discrimination of Responses Involving Estrogen Receptor α/Estrogen Receptor β, G Protein-Coupled Estrogen Receptor, or Estrogen-Related Receptor γ Using Fulvestrant (IC…
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Research ArticleEndocrine and Diabetes

Tamoxifen Regulation of Bone Growth and Endocrine Function in the Ovariectomized Rat: Discrimination of Responses Involving Estrogen Receptor α/Estrogen Receptor β, G Protein-Coupled Estrogen Receptor, or Estrogen-Related Receptor γ Using Fulvestrant (ICI 182780)

James M. Fitts, Robert M. Klein and C. Andrew Powers
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 246-254; DOI: https://doi.org/10.1124/jpet.110.173955

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Research ArticleEndocrine and Diabetes

Tamoxifen Regulation of Bone Growth and Endocrine Function in the Ovariectomized Rat: Discrimination of Responses Involving Estrogen Receptor α/Estrogen Receptor β, G Protein-Coupled Estrogen Receptor, or Estrogen-Related Receptor γ Using Fulvestrant (ICI 182780)

James M. Fitts, Robert M. Klein and C. Andrew Powers
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 246-254; DOI: https://doi.org/10.1124/jpet.110.173955
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