Comparative uterotrophic effects of endoxifen and tamoxifen in ovariectomized sprague-dawley rats

Karen M. Schweikart, Sandy R. Eldridge, Stephanie L. Safgren, Toufan Parman, Joel M Reid, Matthew M. Ames, Matthew Philip Goetz, Myrtle A. Davis

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Endoxifen (4-hydroxy-N-desmethyl-tamoxifen), one of the major active metabolites of tamoxifen, has substantially greater estrogen antagonist properties and antiproliferative effects in breast tumor cells than tamoxifen, a mixed estrogen agonist/antagonist. An associated risk of endometrial cancer and hyperplasia has been linked to the estrogen agonist properties of tamoxifen. We evaluated endoxifen using a classic uterotrophic effects method. Rats were given endoxifen or tamoxifen orally for 3 days. Estradiol was the positive control. Endoxifen and tamoxifen plasma levels exceeded those previously observed clinically. Uterine weight was 3-fold higher in the estradiol group than in the tamoxifen or endoxifen groups, which did not differ from vehicle controls. Tamoxifen and endoxifen caused a greater increase in luminal epithelial cell height than estradiol. Both tamoxifen and endoxifen produced an increase in the stromal BrdU labeling index (LI) that was ≤ estradiol and inversely related to dose, but did not affect luminal epithelial cell BrdU LI. As expected, estradiol increased luminal epithelial cell proliferation. These results indicate that endoxifen induces uterotrophic effects, but is less potent than estradiol in eliciting these effects. Given prior preclinical observations that endoxifen has superior antitumor activity than tamoxifen, the observations of similar uterine effects suggest that the endoxifen risk/benefit ratio may be superior to tamoxifen.

Original languageEnglish (US)
Pages (from-to)1188-1196
Number of pages9
JournalToxicologic Pathology
Volume42
Issue number8
DOIs
StatePublished - Dec 29 2014

Fingerprint

Tamoxifen
Sprague Dawley Rats
Rats
Estradiol
Estrogen Antagonists
Epithelial Cells
Bromodeoxyuridine
Labeling
Estrogens
4-hydroxy-N-desmethyltamoxifen
Endometrial Hyperplasia
Cell proliferation
Endometrial Neoplasms
Metabolites
Tumors
Odds Ratio
Cells
Cell Proliferation
Breast Neoplasms
Plasmas

Keywords

  • endometrial cell proliferation.
  • endoxifen
  • tamoxifen

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Toxicology
  • Cell Biology
  • Molecular Biology

Cite this

Schweikart, K. M., Eldridge, S. R., Safgren, S. L., Parman, T., Reid, J. M., Ames, M. M., ... Davis, M. A. (2014). Comparative uterotrophic effects of endoxifen and tamoxifen in ovariectomized sprague-dawley rats. Toxicologic Pathology, 42(8), 1188-1196. https://doi.org/10.1177/0192623314525688

Comparative uterotrophic effects of endoxifen and tamoxifen in ovariectomized sprague-dawley rats. / Schweikart, Karen M.; Eldridge, Sandy R.; Safgren, Stephanie L.; Parman, Toufan; Reid, Joel M; Ames, Matthew M.; Goetz, Matthew Philip; Davis, Myrtle A.

In: Toxicologic Pathology, Vol. 42, No. 8, 29.12.2014, p. 1188-1196.

Research output: Contribution to journalArticle

Schweikart, Karen M. ; Eldridge, Sandy R. ; Safgren, Stephanie L. ; Parman, Toufan ; Reid, Joel M ; Ames, Matthew M. ; Goetz, Matthew Philip ; Davis, Myrtle A. / Comparative uterotrophic effects of endoxifen and tamoxifen in ovariectomized sprague-dawley rats. In: Toxicologic Pathology. 2014 ; Vol. 42, No. 8. pp. 1188-1196.
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