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Idoxifene: A Novel Selective Estrogen Receptor Modulator Prevents Bone Loss and Lowers Cholesterol Levels in Ovariectomized Rats and Decreases Uterine Weight in Intact Rats
- Source :
- Endocrinology. 139:5224-5234
- Publication Year :
- 1998
- Publisher :
- The Endocrine Society, 1998.
-
Abstract
- Idoxifene, a novel selective estrogen receptor modulator, was tested for its effects on bone loss, serum cholesterol, and uterine wet weight and histology in the ovariectomized (Ovx) rat. Idoxifene (0.5 mg/kg x day) completely prevented loss of both lumbar and proximal tibial bone mineral density (BMD). In an intervention study, idoxifene (0.5 and 2.5 mg/kg x day) completely prevented further loss of both lumbar and proximal tibial BMD during a 2-month treatment period commencing 1 month after surgery, when significant loss of BMD had occurred in the Ovx control group. Idoxifene reduced total serum cholesterol, which was maximal at 0.5 mg/kg x day. Idoxifene alone displayed minimal uterotrophic activity in Ovx rats and inhibited the agonist activity of estrogen in intact rats. Histologically, myometrial and endometrial atrophy were observed in both idoxifene and vehicle-treated Ovx rats. In this report, we also provide molecular-based evidence to support the observations in vivo of a novel selective estrogen receptor modulator (SERM) mechanism of action in bone and endometrial cells. Idoxifene is an agonist through the estrogen response element (ERE) and exhibits similar postreceptor effects to estrogen in bone-forming osteoblasts. Idoxifene also stimulates osteoclast apoptosis, and these pleiotropic effects ultimately could contribute to the maintenance of bone homeostasis. However, idoxifene differs from estrogen in a tissue-specific manner. In human endometrial cells, where estrogen is a potent agonist through the ERE, idoxifene has negligible agonist activity. Moreover, idoxifene was able to block estrogen induced gene expression in endometrial cells, which is in agreement with the observation in the intact rat study. In the uterus, idoxifene has a pharmacologically favorable profile, lacking agonist and therefore growth-promoting activity. Together with its cholesterol lowering effect and lack of uterotrophic activity, these data suggest that idoxifene may be effective in the prevention of osteoporosis and other postmenopausal diseases without producing unwanted estrogenic effects on the endometrium.
- Subjects :
- Agonist
Idoxifene
medicine.medical_specialty
Time Factors
medicine.drug_class
Ovariectomy
Osteoporosis
Endometrium
Bone and Bones
Rats, Sprague-Dawley
Endocrinology
Bone Density
Osteoclast
Internal medicine
medicine
Animals
Cells, Cultured
Chemistry
Anticholesteremic Agents
Uterus
Estrogen Antagonists
Organ Size
medicine.disease
Rats
Tamoxifen
Cholesterol
medicine.anatomical_structure
Receptors, Estrogen
Selective estrogen receptor modulator
Estrogen
Ovariectomized rat
Female
Biomarkers
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- ISSN :
- 19457170 and 00137227
- Volume :
- 139
- Database :
- OpenAIRE
- Journal :
- Endocrinology
- Accession number :
- edsair.doi.dedup.....f784e999374dcaa73c1dd736960cd9a6