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Results for “Selective Estrogen Receptor Modulators”

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PubMed2001

Arzoxifene, a new selective estrogen receptor modulator for chemoprevention of experimental breast cancer.

Arzoxifene ([6-hydroxy-3-[4-[2-(1-piperidinyl)-ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene) is a selective estrogen receptor modulator (SERM) that is a potent estrogen antagonist in mammary and uterine tissue while acting as an estrogen agonist to maintain bone density and lower serum cholesterol. Arzoxifene is a highly effective agent for prevention of mammary cancer induced in the rat by the carcinogen nitrosomethylurea and is significantly more potent than raloxifene in this regard. Arzoxifene is devoid of the uterotrophic effects of tamoxifen, suggesting that, in contrast to tamoxifen, it is unlikely that the clinical use of arzoxifene will increase the risk of developing endometrial carcinoma.

Animals↗

PubMed2002

Effects of the new generation selective estrogen receptor modulator EM-652 and oral administration of estradiol valerate on circulating, brain, and adrenal beta-endorphin and allopregnanolone levels in intact fertile and ovariectomized rats.

OBJECTIVE: To investigate the effects of oral estradiol valerate (EV); EM-652, a new-generation selective estrogen receptor modulator; and both agents on central and peripheral beta-endorphin (beta-EP) and allopregnanolone levels in fertile and ovariectomized rats. DESIGN: Prospective study. SETTING: Animal laboratory in an academic research environment. ANIMALS: Thirteen groups of eight Wistar female rats received oral EV (0.01 or 0.05 mg/kg of body weight daily), EM-652 (0.1, 1, or 5 mg/kg daily), or EV (0.05 mg/kg daily) and EM-652 (0.1, 1, or 5 mg/kg/daily) for 14 days. INTERVENTION(S): beta-Endorphin levels content in the hypothalamus, hippocampus, anterior and neurointermediate pituitary, and plasma were measured. Allopregnanolone levels in the hypothalamus, hippocampus, anterior pituitary, adrenal glands, and serum were measured. MAIN OUTCOME MEASURE(S): beta-Endorphin and allopregnanolone levels. RESULT(S): In ovariectomized rats, administration of EV or EM-652 reverses changes in beta-EP and allopregnanolone levels induced by ovariectomy. Administration of EM-652 plus EV prevents the increase in beta-EP and allopregnanolone levels induced by EV in the hippocampus, hypothalamus, and pituitary but not in the adrenal glands and serum. CONCLUSIONS: In ovariectomized rats, EM-652 has an estrogen-like action that becomes antiestrogenic in the presence of EV administration. In fertile animals, EM-652 exerts estrogen-like or slight antiestrogenic effects.

Administration, Oral↗

PubMed2004

Impact of the selective estrogen receptor modulator, tamoxifen, on neuronal outgrowth and survival following toxic insults associated with aging and Alzheimer's disease.

We investigated the estrogen agonist/antagonist properties of the selective estrogen receptor modulators (SERMs), tamoxifen (TMX) and 4-hydroxy-tamoxifen (OHT), using an in vitro neuron model system to determine the impact of the neuroprotective and neurotrophic properties of these SERMs. Low concentrations of TMX or OHT were without effect on a marker of neuronal viability, basal release of lactate dehydrogenase (LDH), whereas high concentrations of both SERMs (2500 ng/ml) induced a significant increase in LDH, indicating the potential toxicity of both SERMs at high concentrations. Subsequent experiments revealed that subtoxic concentrations of both TMX and OHT induced significant neuroprotection against beta-amyloid(25-35)-induced toxicity; 15-20% and 10-15% (P < 0.05), respectively and also against glutamate-induced toxicity; 25-30% and 20-40% (P < 0.05 and P < 0.01), respectively. Additional in vitro experiments included analysis of neuron survival to determine whether the SERM, OHT, acted competitively or synergistically with the endogenous estrogen, 17 beta-estradiol (E2). These revealed that neuron survival following exposure to the neurotoxins beta-amyloid and excitotoxic glutamate was significantly increased in cultures treated with OHT (50 ng/ml) (10%, P < 0.01) and that the magnitude of survival was equivalent to E2 (10 ng/ml). The combined presence of OHT and E2 significantly protected against both beta-amyloid(25-35) and excitotoxic glutamate-induced neuron death (10%, P < 0.01) but was not significantly different from either OHT or E2 alone. To assess neurotrophic effects of these same SERMs, cultured neurons from brain regions involved in memory function and Alzheimer's disease were evaluated by morphological analysis of individual neurons. Results of these analyses demonstrated that TMX treatment did not significantly increase the process outgrowth or morphological complexity of cortical, hippocampal, or basal forebrain neurons. Similar analyses showed that OHT also failed to significantly increase the neuronal outgrowth of either cortical or hippocampal neurons. Results of these studies predict that TMX and OHT could exert a neuroprotective function but would not promote estrogen-dependent memory function.

Aging↗

PubMed2002

Amelioration of ischemia- and reperfusion-induced myocardial injury by the selective estrogen receptor modulator, raloxifene, in the canine heart.

OBJECTIVES: We sought to investigate whether raloxifene reduces ischemia-reperfusion injury and what mechanisms are involved in the cardioprotective effects. BACKGROUND: Estradiol-17-beta reduces myocardial infarct size in ischemia-reperfusion injury. Raloxifene, a selective estrogen receptor modulator, demonstrates immediate coronary artery vasorelaxing effects. METHODS: The myocardial ischemia-reperfusion model included anesthetized open-chest dogs after 90-min occlusion of the left anterior descending coronary artery (LAD) and subsequent 6-h reperfusion. Raloxifene and/or other drugs were infused into the LAD from 10 min before coronary occlusion to 1 h after reperfusion without an occlusion period. RESULTS: Infarct size was reduced in the raloxifene (5 microg/kg per min) group compared with the control group (7.2 +/- 2.5% vs. 40.9 +/- 3.9% of the area at risk, p < 0.01). Either N(G)-nitro-L-arginine methyl ester (L-NAME), the inhibitor of nitric oxide (NO) synthase, or charybdotoxin, the blocker of Ca(2+)-activated K+ (K(Ca)) channels, partially attenuated the infarct size-limiting effect, and both of them completely abolished the effect. The incidence of ventricular fibrillation was also less in the raloxifene group than in the control group (11% vs. 44%, p < 0.05). Activity of p38 mitogen-activated protein (MAP) kinase increased with 15-min ischemia, and raloxifene pretreatment inhibited the activity. Myeloperoxidase activity of the 6-h reperfused myocardium was also attenuated by raloxifene. CONCLUSIONS: These data demonstrate that raloxifene reduces myocardial ischemia-reperfusion injury by mechanisms dependent on NO and the opening of K(Ca) channels in canine hearts. Deactivation of p38 MAP kinase and myeloperoxidase by raloxifene may be involved in the cellular mechanisms of cardioprotection.

Animals↗

PubMed2002

Selective estrogen receptor modulators (SERMs) and retinoids in breast cancer chemoprevention.

Tamoxifen has been shown to decrease the risk of invasive breast cancer by 49% and noninvasive breast cancer by 50%. Tamoxifen is also associated with a threefold increased risk of endometrial cancer. Raloxifene, a second-generation selective estrogen receptor modulator (SERM), has not been associated with endometrial cancer risk, and is currently under study in a large, multi-institutional, randomized Study of Tamoxifen and Raloxifene (STAR) for breast cancer prevention in postmenopausal women. A pilot trial of raloxifene in premenopausal women to assess the safety, tolerability, effects on bone mineral density, mammographic density, and other biological endpoints is ongoing. The retinoids have been shown to decrease mammary tumors in rodent carcinogenesis models. The Italian trial of fenretinide (4-HPR) in women with stage I breast cancer randomized women to fenretinide or no intervention. This study did not show an overall effect of decreasing the risk of contralateral breast cancer. However, a protective effect was suggested in premenopausal women. It has been suggested that this effect may be related to insulin-like growth factor 1 (IGF-1), which has been shown to be modulated by fenretinide in premenopausal but not postmenopausal women. Pilot studies of SERMs alone and in combination with retinoids or other agents provide a model for testing the safety and tolerability, pharmacokinetics and pharmacodynamics, and biomarker modulation in high-risk women. These studies can provide information as to both the pathophysiology of carcinogenesis and the mechanism of action of chemopreventive agents, and help select agents and doses for testing in large randomized studies.

Antineoplastic Agents↗

PubMed2001

[An alternative to postmenopausal Hormone Replacement Therapy? Selective Estrogens Receptors Modulators (SERMs)].

Hormone Replacement Therapy (HRT) represents the first and probably sole therapeutically approach for prevention and treatment of medical postmenopausal disease. Nevertheless, the adverse effects and the risks HRT associated, suggested, to clinical and pharmaceutical research new pharmacological treatment options. Actually a group of compounds, SERMs (Selective Estrogen Receptor Modulators), allows a large interest. These pharmacological agents, due to their estrogen agonist/antagonist properties, are able to bind Estrogen Receptors in female target tissues (bone, brain, heart, etc) with different actions; so, by these properties, SERMs represent actually a possible alternative to HRT.

Adult↗

PubMed2001

The human estrogen receptor-alpha is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators.

The human estrogen receptor alpha-isoform (ERalpha) is a nuclear transcription factor that displays a complex pharmacology. In addition to classical agonists and antagonists, the transcriptional activity of ERalpha can be regulated by selective estrogen receptor modulators, a new class of drugs whose relative agonist/antagonist activity is determined by cell context. It has been demonstrated that the binding of different ligands to ERalpha results in the formation of unique ERalpha-ligand conformations. These conformations have been shown to influence ERalpha-cofactor binding and, therefore, have a profound impact on ERalpha pharmacology. In this study, we demonstrate that the nature of the bound ligand also influences the stability of ERalpha, revealing an additional mechanism by which the pharmacological activity of a compound is determined. Of note we found that although all ERalpha-ligand complexes can be ubiquitinated and degraded by the 26 S proteasome in vivo, the mechanisms by which they are targeted for proteolysis appear to be different. Specifically, for agonist-activated ERalpha, an inverse relationship between transcriptional activity and receptor stability was observed. This relationship does not extend to selective estrogen receptor modulators and pure antagonists. Instead, it appears that with these compounds, the determinant of receptor stability is the ligand-induced conformation of ERalpha. We conclude that the different conformational states adopted by ERalpha in the presence of different ligands influence transcriptional activity directly by regulating cofactor binding and indirectly by modulating receptor stability.

Estrogen Antagonists↗

PubMed2005

Gene expression changes induced by estrogen and selective estrogen receptor modulators in primary-cultured human endometrial cells: signals that distinguish the human carcinogen tamoxifen.

Tamoxifen has long been the endocrine treatment of choice for women with breast cancer and is now employed for prophylactic use in women at high risk from breast cancer. Other selective estrogen receptor modulators (SERMs), such as raloxifene, mimic some of tamoxifen's beneficial effects and, like tamoxifen, exhibit a complex mixture of organ-specific estrogen agonist and antagonistic properties. However, accompanying the positive effects of tamoxifen has been the emergence of evidence for an increased risk of endometrial cancer associated with its use. A more complete understanding of the mechanism(s) of SERM carcinogenicity and endometrial effects is therefore required. We have sought to compare and characterise the transcript profile of tamoxifen, raloxifene and the agonist estradiol in human endometrial cells. Using primary cultures of human endometria, to best emulate the in vivo responses in a manageable in vitro system, we have shown 230 significant changes in gene expression for epithelial cultures and 83 in stromal cultures, either specific to 17beta-estradiol, tamoxifen or raloxifene, or changed across more than one of the treatments. Considering the transcriptome as a whole, the endometrial responses to raloxifene or tamoxifen were more similar than either drug was to 17beta-estradiol. Treatment of endometrial cultures with tamoxifen resulted in the largest number of gene changes relative to control cultures and a high proportion of genes associated with regulation of gene transcription, cell-cycle control and signal transduction. Tamoxifen-specific changes that might point towards mechanisms for its proliferative response in the endometrium included changes in retinoblastoma and c-myc binding proteins, the APCL, dihydrofolate reductase (DHFR) and E2F1 genes and other transcription factors. Tamoxifen was also found to give rise to the highest number of gene expression changes common to those that characterise malignant endometria. It is anticipated that this study will provide leads for further and more focused investigation into SERM carcinogenicity.

Cells, Cultured↗

PubMed2001

Phase I study of a third-generation selective estrogen receptor modulator, LY353381.HCL, in metastatic breast cancer.

PURPOSE: We conducted this phase I trial to determine the safety and toxicity profile of LY353381.HCl-a novel, potent, third-generation selective estrogen receptor modulator (SERM)-because this benzothiophene derivative demonstrated an SERM profile in preclinical studies. PATIENTS AND METHODS: We studied 32 patients with recurrent or metastatic breast cancer. Patients were treated in four cohorts with oral daily doses of 10, 20, 50, and 100 mg. Pharmacokinetic sampling was performed during the first 72 hours following the first dose on day 1 and during the 24 hours after the day 57 dose. Eligibility criteria included Eastern Cooperative Oncology Group performance status of 0 to 2; no significant major organ dysfunction; and at least 3 weeks elapsed since most recent hormonal therapy, chemotherapy, and estrogen replacement therapy. RESULTS: The median patient age was 56 years (range, 30 years to 76 years). The median number of prior chemotherapies for metastatic disease was one (range, zero to four), while the median number of prior hormone regimens for metastatic disease was two (range, zero to five). Receptor status was estrogen receptor (ER) positive and progesterone receptor (PR) positive, 19 patients; ER positive and PR negative, eight patients; ER positive and PR unknown, two patients; and ER and PR unknown, three patients. Dose-limiting toxicity was not observed. Treatment was well tolerated with mild to moderate hot flashes in 18 of 32 patients (56%) at all dose levels. Transvaginal ultrasound performed at baseline and after 12 weeks of treatment showed no endometrial thickening. Of the 32 patients evaluable for response, six patients had stable disease for at least 6 months with a median duration of 7.7 months (range, 6.2 months to 33.8 months). The pharmacokinetics of LY353381.HCl were generally linear with respect to time and studied dose range. CONCLUSION: As predicted in preclinical testing, daily oral LY353381.HCl is safe, is well tolerated at all tested dose levels, and may be clinically beneficial in patients with extensively pretreated metastatic breast cancer. Further studies with LY353381 to evaluate the efficacy in patients with or without prior exposure to tamoxifen and fewer overall prior regimens are under way.

Actuarial Analysis↗

PubMed2006

On-line formation, separation, and estrogen receptor affinity screening of cytochrome P450-derived metabolites of selective estrogen receptor modulators.

We have developed a fully automated bioreactor coupled to an on-line receptor affinity detection system. This analytical system provides detailed information on pharmacologically active metabolites of selective estrogen receptor modulators (SERMs) generated by cytochromes P450 (P450s). We demonstrated this novel concept by investigating the metabolic activation of tamoxifen and raloxifene by P450-containing pig and rat liver microsomes. The high resolution screening (HRS) system is based on the coupling of a P450-bioreactor to an HPLC-based estrogen receptor alpha (ERalpha) affinity assay. P450-derived metabolites of the SERMs were generated in the bioreactor, subsequently trapped on-line with solid phase extraction, and finally separated with gradient HPLC. Upon elution, the metabolites were screened on affinity for ERalpha with an on-line HRS assay. With this HRS system, we were able to follow, in a time-dependent manner, the formation of ERalpha-binding metabolites of tamoxifen and raloxifene. By analyzing the bioaffinity chromatograms with liquid chromatography-tandem mass spectrometry, structural information of the pharmacologically active metabolites was obtained as well. For tamoxifen, 15 active and 6 nonactive metabolites were observed, of which 5 were of primary, 10 of secondary, and 6 of an as yet unknown order of metabolism. Raloxifene was biotransformed in three primary and three secondary metabolites. MS/MS analysis revealed that three of the observed active metabolites of raloxifene were not described before. The present automated on-line HRS system coupled to a P450-containing bioreactor and an ERalpha-affinity detector proved very efficient, sensitive, and selective in metabolic profiling of SERMs.

Animals↗

PubMed2004

Selective estrogen receptor modulators prevent neointima formation after vascular injury.

Exploitation of estrogen's vasculoprotective properties in drug design is difficult due to its adverse effects on endometrium and breast. Selective estrogen receptor modulators (SERM) act as estrogen agonists in some tissues but are anti-estrogenic in others. We investigate here whether tamoxifen, raloxifene, and two novel SERMs, ospemifene and fispemifene, preserve estrogen's beneficial effects on the ovariectomized rat vascular wall, and correlate their effects with natural estrogen (17beta-E2) and a pure anti-estrogen ICI 182,780. All compounds dose-dependently (0.0025-25 mg/kg/day) inhibited neointimal thickening at 7 days after aorta denudation injury. At 28 days, tamoxifen and ospemifene (2.5 mg/kg/day) reduced intimal nuclei number and intimal area equal to 17beta-E2, while raloxifene and fispemifene had no effect. Replacing the drug at 14 days with vehicle did not induce any rebound effect at 28 days, and furthermore, resulted in a smaller neointima with raloxifene and fispemifene. 17beta-E2 and the SERMs also significantly enhanced reendothelialization. All compounds inhibited replication and all but fispemifene inhibited migration of vascular SMC and cells from cultured aortic explants in vitro. Finally, only 17beta-E2 increased the weight of the uterus above that of normal rats. Interestingly, ICI 182,780 also weakly inhibited neointima formation and SMC proliferation at 7 days, suggesting that non-estrogen receptor mediated effects may have also played a role. In conclusion, SERMs have beneficial estrogen agonist effects in the injured vascular wall through their regulation of vascular SMC function and reendothelialization. Early intervention is of particular importance in preventing the injury-response.

Animals↗

PubMed2001

LAS, a novel selective estrogen receptor modulator with chemopreventive and therapeutic activity in the N-nitroso-N-methylurea-induced rat mammary tumor model.

The N-nitroso-N-methylurea-induced rat mammary tumor model was used to conduct two types of studies: a prevention study designed to test the ability of the novel selective estrogen receptor modulator lasofoxifene (LAS) to inhibit the development of mammary tumors, and a treatment study designed to test the inhibitory effect of LAS on the growth of established tumors. The prevention study indicated that LAS markedly delayed the emergence of N-nitroso-N-methylurea-induced tumors to an extent similar to that obtained by the established antiestrogen tamoxifen (TAM). At the highest dose administered, both TAM and LAS reduced tumor incidence by 75% and total tumor number by 90% relative to the controls. LAS also reduced the multiplicity of tumors, i.e., the mean number of tumors per rat, and resulted in substantially smaller total tumor burden. In the treatment study, LAS significantly inhibited tumor growth compared with the controls. In addition, whereas none of the untreated tumors regressed completely over the experimental period, 40% of LAS-treated tumors regressed by >50% at the highest dose (10 mg/kg daily). The results of this study in a rat mammary tumor model indicate that LAS has both chemopreventive and chemotherapeutic effects quantitatively comparable with those of TAM.

Animals↗

PubMed2003

Selective estrogen receptor modulators.

Because of recent concerns about the long-term risks of estrogen replacement therapy in postmenopausal women, there is growing interest in a group of compounds known as selective estrogen receptor modulators (SERMs). The SERMs bind to estrogen receptors and have tissue-specific effects that allow them to function as estrogen agonists in some tissues and estrogen antagonists in other tissues. There are four SERMs currently marketed in the United States. These include the triphenylethylenes--clomiphene citrate (Clomid), tamoxifen, and toremifene--and the benzothiophene, raloxifene. Clomid is used primarily in the treatment of infertility. Tamoxifen is indicated for the treatment and prevention of breast cancer. It has an estrogen antagonist effect on breast tissue, but an estrogen-like effect on lipids, bone, and the endometrium. Toremifene has an antagonist/agonist profile similar to that of tamoxifen. Raloxifene is approved for the prevention of osteoporosis in postmenopausal women. It is thought to be an estrogen antagonist on the uterus and breast tissues and an estrogen agonist with respect to bone and serum lipids.

Bone and Bones↗

PubMed2004

The role of selective estrogen receptor modulators in the prevention of breast cancer: comparison of the clinical trials.

The role of estrogen in the development of breast cancer is well recognized, and the use of selective estrogen receptor modulators (SERMs) to reduce breast cancer risk continues to be evaluated. Tamoxifen is the only SERM approved for the reduction of breast cancer incidence in women at high risk. This approval was based on results from the Breast Cancer Prevention Trial. Although initial results from the Royal Marsden Hospital tamoxifen trial and Italian Tamoxifen Prevention Study did not show a similar overall effect of tamoxifen, recent updates from these two trials and initial results from the International Breast Cancer Intervention Study are consistent with a risk reduction effect of tamoxifen for estrogen-receptor-positive breast cancer. Raloxifene, approved for the prevention and treatment of postmenopausal osteoporosis, is another SERM being evaluated for breast cancer risk reduction. The recently completed Continuing Outcomes Relevant to Evista trial and the Raloxifene Use for The Heart trial, have breast cancer risk reduction as a primary end point. A third, ongoing trial, the Study of Tamoxifen and Raloxifene trial, is evaluating the relative efficacy and adverse event profile of these two agents in a population at high risk. The study populations of these raloxifene breast cancer prevention trials and the four tamoxifen prevention trials are quite diverse in terms of breast cancer risk. Completion of these trials will provide important information about the occurrence of invasive breast cancer in postmenopausal women and the efficacy of raloxifene for breast cancer risk reduction.

Adult↗

PubMed2004

Impact of the selective estrogen receptor modulator, raloxifene, on neuronal survival and outgrowth following toxic insults associated with aging and Alzheimer's disease.

The current study investigated the estrogen agonist-antagonist properties of the selective estrogen receptor modulator, raloxifene (Ral), on neuroprotection and neuronal markers of memory function. Low concentrations of raloxifene significantly reduced basal markers of membrane damage and had no deleterious effect on neuronal survival. However, high concentrations of raloxifene (1000-5000 ng/ml) induced a significant increase in markers of membrane damage and a significant decrease in neuronal survival. At subtoxic concentrations, raloxifene induced significant neuroprotection against beta amyloid(25-35)-, hydrogen peroxide- and glutamate-induced toxicity. Results of analyses to determine whether raloxifene acted competitively or synergistically with 17 beta-estradiol revealed that a postmenopausal level of 17 beta-estradiol exerted a significantly greater increase in neuronal survival against beta-amyloid- and glutamate-induced toxicity compared to 50 ng/ml raloxifene. The combined presence of raloxifene and 17 beta-estradiol was significantly neuroprotective against beta amyloid(25-35)- and glutamate-induced excitotoxicity but was significantly lower than 17 beta-estradiol alone while not significantly different than raloxifene alone. Morphologic analyses demonstrated that raloxifene significantly increased neuronal outgrowth of hippocampal neurons within a narrow dose range that was blocked by a glutamate NMDA receptor antagonist. Raloxifene did not promote the outgrowth of basal forebrain or cortical neurons. Results of this study indicate that raloxifene exerted partial estrogen agonist action in the absence of 17 beta-estradiol whereas in the presence of 17 beta-estradiol, raloxifene exerted a mixed estrogen agonist-antagonist effect.

Aging↗

PubMed2006

m-Carborane bisphenol structure as a pharmacophore for selective estrogen receptor modulators.

A series of m-carborane derivatives was prepared based upon the structures of antiestrogenic drugs and their activities were evaluated by estrogen receptor alpha (ERalpha) binding assay and transactivation assay using human breast cancer cell line, MCF-7 cells. The m-carborane bisphenol 5 exhibited about a thousand times more potent ER agonistic activity than the o-carborane bisphenol 11. The m-carborane bisphenol structure appears to be a favorable hydrophobic pharmacophore for the development of novel selective estrogen receptor modulators (SERMs).

Benzhydryl Compounds↗

PubMed2002

Estrogen and selective estrogen receptor modulator regulation of insulin-like growth factor binding protein 5 in the rat uterus.

Insulin-like growth factor (IGF) binding protein 5 (IGFPB-5) is abundant in the uterus and is implicated in the sex steroid-induced growth of this tissue. The purpose of this study was to investigate the potential for modulation of the action of IGFPB-5 at the uterus level in the rat by estrogen and selective estrogen receptor modulators (SERMs). One hundred and twenty adult rats, 2-3 months of age, were included. Among them 100 animals were ovariectomized 4 days prior to the use of drugs for 48 days. Rats were divided into six groups: non-ovariectomized (group 1); ovariectomized (group 2); and those receiving conjugated equine estrogens, 50 microg/day (group 3), tamoxifen 250 microg/day (group 4), raloxifene 3 mg/kg (group 5) and toremifene 2.5 mg/kg (group 6). Total RNA was isolated from the uterus and IGFBP-5 mRNA levels were assessed by the semiquantitative reverse transcription polymerase chain reaction (RT-PCR). Our results demonstrate that conjugated equine estrogens were able to up-regulate mRNA levels of the IGFBP-5 gene, while oophorectomy alone as well as associated with hormone therapy such as tamoxifen, raloxifene and toremifene resulted in down-regulation of uterine IGFBP-5 gene expression. The up-regulation of IGFBP-5 expression induced by estrogens suggests that, in vivo, the uterotrophic effects of estrogen replacement therapy are mediated, at least inpart, by the IGF pathways. On the other hand, the use of SERMs (tamoxifen, raloxifene and toremifene) was associated with severe down-regulation of this gene at the transcription level.

Animals↗

PubMed2003

Selective estrogen receptor modulators in chronic renal failure.

BACKGROUND: In addition to renal osteodystrophy, postmenopausal women on dialysis could be at risk of osteoporosis. Hormone replacement therapy (HRT) could have beneficial effects as well as potentially serious risks, especially in uremic women, due to the pharmacokinetics of estradiol in renal failure. Therapeutic alternatives, such as the selective estrogen receptor modulators (SERMs), have shown the benefits of estrogen on bone and serum lipid levels, without its adverse effects on the breast and endometrium, in nonuremic women. METHODS: Recent data on the effect of the SERM raloxifene in bone and lipid metabolism in osteoporotic postmenopausal women on dialysis is reviewed. Since the estrogen receptor (ER) gene has been suggested as a candidate marker for osteoporosis, we investigated whether ER polymorphism could have predicted the BMD response to raloxifene. RESULTS: Hemodialyzed women on raloxifene demonstrated increased trabecular bone mineral density (BMD) and decreased bone resorption markers. Similarly, LDL-cholesterol values dropped significantly. ER gene polymorphism analysis of baseline BMD parameters did not differ between PP/xx or Pp/Xx groups. Nevertheless, patients on raloxifene with PP/xx genotypes, but not those with Pp/Xx, showed a higher trabecular BMD after one year on treatment, suggesting that homozygous women for P or x alleles of the ER have a better BMD response to raloxifene. CONCLUSION: Raloxifene and, most likely, other SERMs, could represent a good alternative to HRT in postmenopausal uremic women.

Chronic Kidney Disease-Mineral and Bone Disorder↗