Skeletal and uterotrophic effects of endoxifen in female rats

Anne Gingery, Urszula T. Iwaniec, Malayannan Subramaniam, Russell T. Turner, Kevin S. Pitel, Renee M. McGovern, Joel M Reid, Ronald J Marler, James N. Ingle, Matthew Philip Goetz, John R Hawse

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Endoxifen, the primary active metabolite of tamoxifen, is currently being investigated as a novel endocrine therapy for the treatment of breast cancer. Tamoxifen is a selective estrogen receptor modulator that elicits potent anti-breast cancer effects. However, long-Term use of tamoxifen also induces bone loss in premenopausal women and is associated with an increased risk of endometrial cancer in postmenopausal women. For these reasons, we have used a rat model system to comprehensively characterize the impact of endoxifen on the skeleton and uterus. Our results demonstrate that endoxifen elicits beneficial effects on bone in ovary-intact rats and protects against bone loss following ovariectomy. Endoxifen is also shown to reduce bone turnover in both ovaryintact and ovariectomized rats at the cellular and biochemical levels. With regard to the uterus, endoxifen decreased uterine weight but maintained luminal epithelial cell height in ovariectomized animals. Within luminal epithelial cells, endoxifen resulted in differential effects on the expression levels of estrogen receptors a and b as well as multiple other genes previously implicated in regulating epithelial cell proliferation and hypertrophy. These studies analyze the impact of extended endoxifen exposure on both bone and uterus using a Food and Drug Administration- recommended animal model. Although endoxifen is a more potent breast cancer agent than tamoxifen, the results of the present study demonstrate that endoxifen does not induce bone loss in ovary-intact rats and that it elicits partial agonistic effects on the uterus and skeleton in ovariectomized animals.

Original languageEnglish (US)
Pages (from-to)3354-3368
Number of pages15
JournalEndocrinology
Volume158
Issue number10
DOIs
StatePublished - Oct 1 2017

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Tamoxifen
Uterus
Bone and Bones
Epithelial Cells
Breast Neoplasms
Skeleton
Ovary
Selective Estrogen Receptor Modulators
4-hydroxy-N-desmethyltamoxifen
Bone Remodeling
Ovariectomy
United States Food and Drug Administration
Endometrial Neoplasms
Estrogen Receptors
Hypertrophy
Animal Models
Cell Proliferation
Weights and Measures
Therapeutics
Genes

ASJC Scopus subject areas

  • Endocrinology

Cite this

Gingery, A., Iwaniec, U. T., Subramaniam, M., Turner, R. T., Pitel, K. S., McGovern, R. M., ... Hawse, J. R. (2017). Skeletal and uterotrophic effects of endoxifen in female rats. Endocrinology, 158(10), 3354-3368. https://doi.org/10.1210/en.2016-1871

Skeletal and uterotrophic effects of endoxifen in female rats. / Gingery, Anne; Iwaniec, Urszula T.; Subramaniam, Malayannan; Turner, Russell T.; Pitel, Kevin S.; McGovern, Renee M.; Reid, Joel M; Marler, Ronald J; Ingle, James N.; Goetz, Matthew Philip; Hawse, John R.

In: Endocrinology, Vol. 158, No. 10, 01.10.2017, p. 3354-3368.

Research output: Contribution to journalArticle

Gingery, A, Iwaniec, UT, Subramaniam, M, Turner, RT, Pitel, KS, McGovern, RM, Reid, JM, Marler, RJ, Ingle, JN, Goetz, MP & Hawse, JR 2017, 'Skeletal and uterotrophic effects of endoxifen in female rats', Endocrinology, vol. 158, no. 10, pp. 3354-3368. https://doi.org/10.1210/en.2016-1871
Gingery A, Iwaniec UT, Subramaniam M, Turner RT, Pitel KS, McGovern RM et al. Skeletal and uterotrophic effects of endoxifen in female rats. Endocrinology. 2017 Oct 1;158(10):3354-3368. https://doi.org/10.1210/en.2016-1871
Gingery, Anne ; Iwaniec, Urszula T. ; Subramaniam, Malayannan ; Turner, Russell T. ; Pitel, Kevin S. ; McGovern, Renee M. ; Reid, Joel M ; Marler, Ronald J ; Ingle, James N. ; Goetz, Matthew Philip ; Hawse, John R. / Skeletal and uterotrophic effects of endoxifen in female rats. In: Endocrinology. 2017 ; Vol. 158, No. 10. pp. 3354-3368.
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