scholarly journals Idoxifene: A Novel Selective Estrogen Receptor Modulator Prevents Bone Loss and Lowers Cholesterol Levels in Ovariectomized Rats and Decreases Uterine Weight in Intact Rats

Endocrinology ◽  
1998 ◽  
Vol 139 (12) ◽  
pp. 5224-5234 ◽  
Author(s):  
Mark E. Nuttall ◽  
Jeremy N. Bradbeer ◽  
George B. Stroup ◽  
Daniel P. Nadeau ◽  
Sandra J. Hoffman ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Bone Loss ◽  
Selective Estrogen Receptor Modulator ◽  
Ovariectomized Rats ◽  
Uterine Weight ◽  
Receptor Modulator ◽  
Cholesterol Levels ◽  
Intact Rats

scholarly journals A New Selective Estrogen Receptor Modulator with Potent Uterine Antagonist Activity, Agonist Activity in Bone, and Minimal Ovarian Stimulation

Endocrinology ◽  
2005 ◽  
Vol 146 (10) ◽  
pp. 4524-4535 ◽  
Author(s):  
Andrew G. Geiser ◽  
Conrad W. Hummel ◽  
Michael W. Draper ◽  
Judith W. Henck ◽  
Ilene R. Cohen ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Bone Loss ◽  
Ovarian Stimulation ◽  
Selective Estrogen Receptor Modulator ◽  
Agonist Activity ◽  
Uterine Weight ◽  
Antagonist Activity ◽  
Cell Hyperplasia ◽  
Receptor Modulator ◽  
Estrogen Antagonist

The use of selective estrogen receptor modulators for the treatment of estrogen-dependent diseases in premenopausal women has been hindered by undesirable ovarian stimulation and associated risks of ovarian cysts. We have identified a selective estrogen receptor modulator compound (LY2066948) that is a strong estrogen antagonist in the uterus yet has minimal effects on the ovaries of rats. LY2066948 binds with high affinity to both estrogen receptors and has potent estrogen antagonist activity in human uterine and breast cancer cells. Oral administration of LY2066948 to immature rats blocked uterine weight gain induced by ethynyl estradiol with an ED50 of 0.07 mg/kg. Studies in mature rats demonstrated that LY2066948 decreases uterine weight by 51% after 35 d treatment, confirming potent uterine antagonist activity over several estrous cycles. This strong uterine response contrasted with the minimal effects on the ovaries: serum estradiol levels remained within the normal range, whereas histologic evaluation showed granulosa cell hyperplasia in few of the rats. Bone studies demonstrated that LY2066948 prevented ovariectomy-induced bone loss and treatment of ovary-intact rats caused no bone loss, confirming estrogen receptor agonist skeletal effects. Collectively, these data show that LY2066948 exhibits a tissue-specific profile consistent with strong antagonist activity in the uterus, agonist activity in bone, and minimal effects in the ovaries.

scholarly journals Raloxifene, a Selective Estrogen Receptor Modulator, Reduces Carrageenan-Induced Acute Inflammation in Normal and Ovariectomized Rats

Endocrinology ◽  
2005 ◽  
Vol 146 (8) ◽  
pp. 3301-3308 ◽  
Author(s):  
Emanuela Esposito ◽  
Anna Iacono ◽  
Giuseppina Mattace Raso ◽  
Maria Pacilio ◽  
Anna Coppola ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Acute Inflammation ◽  
Selective Estrogen Receptor Modulator ◽  
Ovariectomized Rats ◽  
Receptor Modulator

scholarly journals Evidence for selective estrogen receptor modulator activity in a black cohosh (Cimicifuga racemosa) extract: comparison with estradiol-17beta

2003 ◽  
pp. 351-362 ◽  
Author(s):  
D Seidlova-Wuttke ◽  
O Hesse ◽  
H Jarry ◽  
V Christoffel ◽  
B Spengler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Estrogen Receptor ◽  
Selective Estrogen Receptor Modulator ◽  
Ovariectomized Rats ◽  
Tartrate Resistant Acid Phosphatase ◽  
Complement Protein ◽  
Cimicifuga Racemosa ◽  
Mineral Density ◽  
Receptor Modulator ◽  
Igf I

OBJECTIVE: Some phytoestrogens are believed to have selective estrogen receptor modulator (SERM) activity with no action in the uterus but beneficial effects in the hypothalamo/pituitary unit and in the bone and are presently the focus of clinical interest. In the present experiments, the effects of the clinically used Cimicifuga racemosa (CR) extract BNO 1055 in the uterus, in the bone and on serum luteinizing hormone (LH) were compared with the effects of estradiol-17beta (E(2)) under acute and chronic conditions in ovariectomized rats. METHODS: Ovariectomized rats were treated either acutely (6 h) or chronically (3 Months) with E(2) or the CR extract. Gene expression of some estrogen-regulated genes in the metaphysis of the tibia and the uterus was determined. Furthermore, bone mineral density was measured by quantitative computer tomography. RESULTS: When given acutely, both E(2) and the CR extract inhibited LH secretion and slightly stimulated gene expression of IGF-I, collagen-1alpha1, osteoprotegerin and osteocalcin (all osteoblast products), and of tartrate-resistant acid phosphatase (TRAP, an osteoclast product) in the metaphysis of the femur. While E(2) stimulated uterine weight and expression of progesterone receptor (PR), the complement protein (C3) and IGF-I genes, and inhibited gene expression of the estrogen receptor beta (ERbeta) in the uterus, no such effect was observed under acute CR treatment. After chronic application with pelleted food over 3 Months E(2) had profound effects in the uterus on weight and gene expression (ERbeta, PR, C3 and IGF-I) which were not seen in the CR-treated animals. Within 3 Months after ovariectomy, control rats had lost more than 50% of the metaphyseal bone mass of the tibia, an effect prevented by E(2) and partially by CR supplementation. CONCLUSIONS: These data confirm the concept that the CR extract BNO 1055 contains as yet unidentified substances with SERM properties which act in the hypothalamo/pituitary unit and in the bone but not in the uterus.

scholarly journals Selective Estrogen Receptor Modulator LY353381.HCl-Mediated Neuroprotection and BCL-2 Expression After Experimental Stroke

Stroke ◽  
2001 ◽  
Vol 32 (suppl_1) ◽  
pp. 327-327
Author(s):  
Mark Rossberg ◽  
Nabil J Alkayed ◽  
Hung D Joh ◽  
Stephanie J Murphy ◽  
Richard J Trastman ◽  
...  
Keyword(s):  
Blood Flow ◽  
Estrogen Receptor ◽  
Selective Estrogen Receptor Modulator ◽  
Ovariectomized Rats ◽  
Experimental Stroke ◽  
Ribonuclease Protection Assay ◽  
Cerebral Tissue ◽  
Doppler Flowmetry ◽  
Receptor Modulator ◽  
Ovx Rats

62 Estrogen replacement in ovariectomized rats reduces cerebral tissue infarction sustained after experimental stroke. We hypothesized that LY353381.HCl, a selective estrogen receptor modulator (SERM), reduces cerebral tissue infarction after middle cerebral artery occlusion (MCAO), and that the mechanism of protection is not related to preservation of blood flow. After 5–9 days of treatment with LY353381.HCl (LY) or vehicle (VEH), ovariectomized rats were subjected to 2 hours of MCAO under halothane anesthesia, followed by 22 hours of recovery. Ischemia was confirmed by laser-Doppler flowmetry. MAP, blood gases, and rectal and temporalis muscle temperature were controlled. Infarct volumes were measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining and digital image analysis. Ovariectomized (OVX) rats treated with LY (n=16) had smaller infarct volumes in the caudoputamen (CP) than VEH (n=14) treated rats, 49%±6% vs. 64%±4% of ipsilateral CP, respectively, P <0.05. Cerebral cortical (CTX) infarct size was not statistically different between treatment groups (7%±3% vs. 13%±4% for LY vs. VEH, respectively). In a second cohort of OVX rats, end ischemic regional cerebral blood flow (CBF) was measured by 14 C-iodoantipyrine autoradiography in LY (n=4) and VEH (n=3) treated rats. Absolute ischemic CBF and tissue volume distribution to low flow zones were similar in both groups. In a final cohort, 22 hours post MCAO, tissue was sampled from representative regions of CTX and CP in OVX (n=5) and LY (n=4) treated groups and analyzed for BCL-2 mRNA expression using ribonuclease protection assay. LY increased BCL-2 mRNA in both ipsilateral CTX and CP. We conclude that LY353381.HCl confers protection from focal cerebral ischemia by mechanisms that are not related to CBF but may involve increased BCL-2 expression.

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