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Comparative study of the short-term effects of a novel selective estrogen receptor modulator, ospemifene, and raloxifene and tamoxifen on rat uterus.
- Source :
-
The Journal of steroid biochemistry and molecular biology [J Steroid Biochem Mol Biol] 2004 Feb; Vol. 88 (2), pp. 143-56. - Publication Year :
- 2004
-
Abstract
- To investigate the differential short-term effects of selective estrogen receptor (ER) modulators (SERMs) on uterus, we treated adult ovariectomized rats with a novel SERM, ospemifene (Osp), two previously established SERMs (tamoxifen and raloxifene (Ral)) and estradiol. The expression of two estrogen-regulated early response genes c-fos and vascular endothelial growth factor (VEGF), and DNA synthesis were analysed at 1-24 h after treatment of ovariectomized rats. Induction of c-fos mRNA by each of the SERMs showed a biphasic pattern with peaks at 3 and 20 h, respectively. The maximum level of VEGF mRNA was observed at 1 h after raloxifene and 6 h after tamoxifen or ospemifene treatment. Maximum levels of the c-fos and VEGF mRNA after raloxifene treatment were higher than those seen after treatments with E2 or a corresponding dose of tamoxifen or ospemifene. DNA synthesis was significantly increased by ospemifene, tamoxifen and raloxifene both in luminal and glandular epithelium. The stimulation was transient, peaking at 16 h. In comparison, the maximum level observed at 16 h after E2 treatment sustained at least until 24 h. DNA synthesis in stromal cells was increased by the SERMs but not by E2 at 24 h. When treated together with E2, the SERMs were able to antagonise E2-stimulated DNA synthesis at 16 h. Our results demonstrate that the initial response of uterus to ospemifene, raloxifene and tamoxifen includes activation of early response genes and even transient stimulation of DNA synthesis in spite of their different long-term effects. However, the early stimulatory events may be mediated by different mechanisms leading to diverging pathways in various tissue compartments and development of differential SERM-specific long-term responses of uterus.
- Subjects :
- Animals
Base Sequence
DNA Primers
DNA Replication
Female
Gene Expression Regulation drug effects
Genes, fos
Organ Size drug effects
Polymerase Chain Reaction
RNA, Messenger genetics
RNA, Messenger metabolism
Rats
Rats, Sprague-Dawley
Tamoxifen analogs & derivatives
Uterus metabolism
Vascular Endothelial Growth Factor A genetics
Estrogen Receptor Modulators pharmacology
Raloxifene Hydrochloride pharmacology
Tamoxifen pharmacology
Uterus drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0960-0760
- Volume :
- 88
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of steroid biochemistry and molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 15084346
- Full Text :
- https://doi.org/10.1016/j.jsbmb.2003.11.009