Evista
Evidence for an estrogen-like action of raloxifene upon the hypothalamic-pituitary unit: raloxifene inhibits luteinizing hormone secretion and stimulates prolactin secretion in ovariectomized female rats.

Pinilla L, Gonzalez LC, Tena-Sempere M, Aguilar E.

Department of Cell Biology, Physiology and Immunology, University of Cordoba School of Medicine, Cordoba, Spain.

Selective estrogen receptor modulators (SERMs) constitute a new family of drugs with growing interest in the management of estrogen-associated pathology. Raloxifene is a SERM that is used to treat and prevent osteoporosis in postmenopausal women. The actions of raloxifene on bone, breast, uterus and serum cholesterol have been widely analyzed, but very few studies have been carried out to evaluate whether raloxifene has an estrogenic activity upon the hypothalamic-pituitary axis in the rat. For this purpose, adult female rats were ovariectomized or sham ovariectomized. One week later, the rats were implanted with intracardiac canullae and 24 h after injected daily with raloxifene (500 microg/rat/day) or vehicle for 5 days. One hour after the last injection, blood samples were obtained at 5 min intervals for a 3 h. period (10:00-13:00 h). Our results indicate that raloxifene inhibits the pulsatile nature of the post-ovariectomy hypersecretion of luteinizing hormone (LH) and increases prolactin (PRL) secretion in ovariectomized animals. These effects are suggestive of an estrogenic activity of raloxifene on LH and PRL secretion in ovariectomized females.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11578816&dopt=Abstract raloxifene Evista



Evista
Selective estrogen-receptor modulators in 2001.

O'Regan RM, Gradishar WJ.

Division of Hematology and Medical Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA.

Tamoxifen (Nolvadex), a selective estrogen-receptor modulator, or SERM, is currently the endocrine therapy of choice for all stages of hormone-responsive breast cancer. Only tamoxifen has been approved by the US Food and Drug Administration to reduce the incidence of breast cancer in high-risk women. Despite tamoxifen's antiestrogenic effects in breast tissue, it exhibits paradoxical estrogenic effects in other tissues in the body. These effects result in the maintenance of bone mineral density, but a three- to fourfold increase in endometrial cancer in postmenopausal women. Additionally, tamoxifen can result in troublesome hot flashes and serious thromboembolic events. For this reason, current research is focusing on new agents that may maintain the beneficial effects of tamoxifen while reducing its adverse effects. Raloxifene (Evista) is another SERM, approved for the prevention of osteoporosis in postmenopausal women and now being compared with tamoxifen in an ongoing breast cancer prevention trial. Like tamoxifen, raloxifene is associated with hot flashes and thromboembolic events, but its association with the risk of endometrial cancer is unknown. A number of new SERMs are in preclinical or clinical development in an attempt to improve upon the safety profile of tamoxifen. Additionally, selective aromatase inhibitors are being examined in the early breast cancer setting.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11589065&dopt=Abstract raloxifene Evista



Evista
Induction of endothelial nitric-oxide synthase phosphorylation by the raloxifene analog LY117018 is differentially mediated by Akt and extracellular signal-regulated protein kinase in vascular endothelial cells.

Hisamoto K, Ohmichi M, Kanda Y, Adachi K, Nishio Y, Hayakawa J, Mabuchi S, Takahashi K, Tasaka K, Miyamoto Y, Taniguchi N, Murata Y.

Department of Obstetrics and Gynecology, Osaka University Medical School, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.

Raloxifene is a tissue-selective estrogen receptor modulator. The effect of estrogen on cardiovascular disease is mainly dependent on direct actions on the vascular wall involving activation of endothelial nitric oxide synthase (eNOS) via Akt and extracellular signal-regulated protein kinase (ERK) cascades. Although raloxifene is also known to activate eNOS in the vascular endothelium, the molecular mechanism responsible for this effect remains to be elucidated. In studies of both human umbilical vein endothelial cells and simian virus 40-transformed rat lung vascular endothelial cells (TRLECs), the raloxifene analog LY117018 caused acute phosphorylation of eNOS that was unaffected by actinomycin D and was blocked by the pure estrogen receptor antagonist ICI182,780. Activation of Akt by raloxifene reached a plateau at 15-30 min and declined thereafter, a similar time frame to that of Akt activation by 17beta-estradiol. On the other hand, both activation and phosphorylation of ERK by raloxifene showed a biphasic pattern (peaks at 5 min and 1 h), whereas ERK activation and phosphorylation by 17beta-estradiol reached a plateau at 5 min and declined thereafter. A MEK inhibitor, PD98059, had no effect on the raloxifene-induced Akt activity, suggesting an absence of cross-talk between the ERK and Akt cascades. Either exogenous expression of a dominant-negative Akt or pretreatment of TRLECs with PD98059 decreased the raloxifene-induced eNOS phosphorylation. Moreover, raloxifene stimulated the activation of Akt, ERK, and eNOS in Chinese hamster ovary cells expressing estrogen receptor alpha but not Chinese hamster ovary cells expressing estrogen receptor beta. Our findings suggest that raloxifene-induced eNOS phosphorylation is mediated by estrogen receptor alpha via a nongenomic mechanism and is differentially mediated by Akt- and ERK-dependent cascades.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11595733&dopt=Abstract raloxifene Evista



Evista
Activity of a tamoxifen-raloxifene hybrid ligand for estrogen receptors at an AP-1 site.

Weatherman RV, Carroll DC, Scanlan TS.

Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California--San Francisco, CA 94143-0446, USA.

To test the effect of ligand flexibility on the selective transcriptional activities of ERalpha and ERbeta from an AP-1 site, an analogue of raloxifene was made that removed the ketone functionality and made the ligand more planar and conformationally more similar to 4-hydroxytamoxifen. Desketoraloxifene was found to be a much stronger activator at an AP-1 site with ERalpha than with ERbeta, mimicking 4-hydroxytamoxifen more than raloxifene.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11720858&dopt=Abstract raloxifene Evista



Evista
Neuroendocrine effects of raloxifene hydrochloride in postmenopausal women.

Florio P, Quirici B, Casarosa E, Lombardi I, Luisi M, Genazzani AD, Petraglia F, Genazzani AR.

Department of Obstetrics and Gynecology, University of Siena, Italy.

Raloxifene is a selective estrogen modulator able to exert an estrogen-like action on some target tissues and a specific antiestrogenic action on the uterus and breast. In ovariectomized rats, it has been shown to stimulate the beta-endorphin and allopregnanolone concentrations of the anterior and neurointermediate pituitary lobes, the hypothalamus and the hippocampus. The present study aimed to evaluate, in 12 healthy postmenopausal women, the effect of 60 mg/day raloxifene hydrochloride administration for 6 months on plasma beta-endorphin and allopregnanolone levels, and on the dynamic changes of both beta-endorphin and allopregnanolone secretion after the administration of: (1) clonidine, an alpha 2-presynaptic adrenergic agonist; (2) naloxone, an opioid receptor antagonist; and (3) fluoxetine, a serotonin selective reuptake inhibitor. The administration of raloxifene significantly increased both circulating beta-endorphin and allopregnanolone concentrations, at both the third and sixth months of treatment (p < 0.01). Clonidine, fluoxetine and naloxone administration before therapy was not able to stimulate the release of beta-endorphin, but the response was completely restored after raloxifene administration. Before therapy, clonidine and naloxone tests were accompanied by a significant rise in allopregnanolone secretion; the same changes were observed after raloxifene administration, but with significantly higher allopregnanolone concentrations at each time considered. While the fluoxetine test before therapy failed to increase the release of allopregnanolone, the same test after 6 months of raloxifene administration was characterized by a significant release of allopregnanolone at 60 and 90 minutes. The present data indicate that raloxifene has an estrogen-like effect on neuroendocrine pathways in postmenopausal women.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11727358&dopt=Abstract raloxifene Evista



Evista
The role of serial bone mineral density testing for osteoporosis.

Crandall C.

Department of Medicine, UCLA School of Medicine, Iris Cantor-UCLA Women's Health Center, 100 UCLA Medical Plaza, Suite 250, Los Angeles, CA 90095-7023, USA.

As a whole, groups of women who gain more bone mineral density (BMD) on antiresorptive medications experience greater fracture protection, although the relationship is not clear on the individual level. A literature search (Medline 1966 to present) for randomized, controlled trials was performed with keywords serial bone density, osteoporosis, dual-energy x-ray absorptiometry, fracture, alendronate, risedronate, calcitonin, estrogen replacement therapy, and raloxifene. Also, reference lists and tables of contents from journals were searched manually for additional relevant randomized controlled trials. Trials were 2-3 years in duration, and the number of subjects ranged from 670 to 3954. Medications analyzed include alendronate, either 5 mg/day or 5 mg/day, followed by 10 mg/day; raloxifene, 60 or 120 mg/day; and combination hormone replacement therapy (HRT) of four different regimen types. There have been no controlled studies showing that change in treatment based on serial bone density measurement results in improved patient outcomes. Whereas studies have shown changes in BMD during antiresorptive therapy to be predictive of fracture reduction in groups of patients, their utility in individual patients remains inconclusive. Osteoporotic women who lose BMD in the first year of alendronate or raloxifene use will likely gain BMD in the second year of treatment, illustrating regression to the mean. Effective medication for osteoporosis should not be changed solely because of BMD loss occurring after the first year of treatment. Young, healthy, postmenopausal women taking commonly prescribed doses of estrogen or estrogen/progestin (HRT) rarely lose BMD. Bone loss over the first 12 months of HRT is independent of bone loss in the next 24 months. If bone is not lost in the first 12 months of HRT, there is a significant chance that bone density will be lost later in treatment. Half of placebo-treated women do not lose BMD over 3 years. Treatment should be continued in patients who initially lose bone density on therapy because most will gain density with continued treatment and end in gaining bone overall. Also, patients who gain large amounts of bone in the first year and lose in the second year are not necessarily failing therapy but rather may be showing that a random error in the earlier bone density change corrects itself later. Loss of BMD with alendronate, raloxifene, or combination conjugated equine estrogen/ medroxyprogesterone acetate is likely to convert to gain in BMD. More research is needed to confirm that this regression to the mean may apply to all densitometry techniques, antiresorptives, age groups, and genders.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11747684&dopt=Abstract raloxifene Evista