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PubMed2000

Identification of selective estrogen receptor modulators by their gene expression fingerprints.

Clinical studies have shown that estrogen replacement therapy (ERT) reduces the incidence and severity of osteoporosis and cardiovascular disease in postmenopausal women. However, long term estrogen treatment also increases the risk of endometrial and breast cancer. The selective estrogen receptor (ER) modulators (SERMs) tamoxifen and raloxifene, cause antagonistic and agonistic responses when bound to the ER. Their predominantly antagonistic actions in the mammary gland form the rationale for their therapeutic utility in estrogen-responsive breast cancer, while their agonistic estrogen-like effects in bone and the cardiovascular system make them candidates for ERT regimens. Of these two SERMs, raloxifene is preferred because it has markedly less uterine-stimulatory activity than either estrogen or tamoxifen. To identify additional SERMs, a method to classify compounds based on differential gene expression modulation was developed. By analysis of 24 different combinations of genes and cells, a selected set of assays that permitted discrimination between estrogen, tamoxifen, raloxifene, and the pure ER antagonist ICI164384 was generated. This assay panel was employed to measure the activity of 38 compounds, and the gene expression fingerprints (GEFs) obtained for each compound were used to classify all compounds into eight groups. The compound's GEF predicted its uterine-stimulatory activity. One group of compounds was evaluated for activity in attenuating bone loss in ovariectomized rats. Most compounds with similar GEFs had similar in vivo activities, thereby suggesting that GEF-based screens could be useful in predicting a compound's in vivo pharmacological profile.

Animals↗
PubMed2003

Effect of reproductive hormones and selective estrogen receptor modulators on mood during menopause.

Periods of intense hormonal fluctuations have been associated with heightened prevalence and exacerbation of underlying psychiatric illness, particularly the occurrence of premenstrual dysphoria, puerperal depression and depressive symptoms during perimenopause. It has been speculated that sex steroids such as estrogens, progestogens, testosterone and dehydroepiandrosterone (DHEA) exert a significant modulation of brain functioning, possibly through interactions with various neurotransmitter systems. It is therefore intuitive that abrupt alterations of these hormones would interfere with mood and behaviour. On the other hand, accumulating data suggest that hormonal interventions may also promote relief or even remission of depressive symptoms, as already demonstrated in studies with patients experiencing postpartum depression and perimenopausal depressive disorders. The extent to which perimenopause, alone, may increase the risk for depression is unclear. However, existing data strongly suggest that some women are particularly vulnerable to developing significant physical and psychological disturbances when entering perimenopause. This article reviews the effect of sex hormones and selective estrogen receptor modulators (SERMs) on mood among peri- and postmenopausal women. There are preliminary, though promising, data on the use of estradiol (particularly transdermal estradiol) to alleviate depression during perimenopause, use of a combination of estrogens and selective serotonin reuptake inhibitors for depression during the postmenopausal period, and the use of testosterone to improve psychological well-being and increase libido among women with induced menopause. Further studies would help to better delineate the usage of hormones as an antidepressant strategy (monotherapy or augmenting treatment) for peri- and postmenopausal women. A brief review of some nonhormonal interventions for the treatment of menopause-related symptoms that may significantly affect a woman's quality of life is also presented. There are some preliminary data suggesting the efficacy of antidepressants for the treatment of hot flushes; existing data on diet supplements and herbal products have shown more mixed results.

Affect↗
PubMed2001

Molecular identification of potential selective estrogen receptor modulator (SERM) like properties of phytoestrogens in the human breast cancer cell line MCF-7.

Numerous epidemiologic studies revealed that ethnic populations with higher dietary intake of phytoestrogens have the lowest incidence for breast cancer. The molecular mechanisms which may be responsible for this cancer protective action of phytoestrogens are so far only barely characterised. There are some hints that phytoestrogens may act like selective estrogen receptor modulators (SERMs) on the breast. For this reason we have investigated potential SERM-like properties of the phytoestrogens daidzein (Dai), coumestrol (Cou), and genistein (Gen) in the human breast cancer cell line MCF-7. Effects of these substances on progesterone (PR) and estrogen receptor alpha (ER) mRNA expression and estrogen receptor alpha protein levels were studied in comparison to estradiol (E2) and the synthetic SERMs raloxifene (Ral) and faslodex (ICI 182 780). PR mRNA expression was up-regulated after administration of Cou, whereas treatment with Dai and Gen induced only a faint increase. ER mRNA expression was down-regulated by Cou but not affected by Dai and Gen. The content of ER protein in the breast cancer cells was strongly decreased by Gen, only a faint reduction could be observed following administration of Cou, whereas administration of Dai slightly increases ER protein levels. In summary and in comparison to the effects observed after administration of E2, Ral, and ICI it turned out that Cou shows molecular properties which are very similar to an estrogen receptor agonist like E2, whereas the molecular properties of Gen are comparable to the SERMs ICI and Ral. These results clearly indicate that phytoestrogens differ significantly in regard to their molecular action on breast cancer cells and can be subdivided into distinct functional categories.

Blotting, Western↗
PubMed2005

Endometrial effects of bazedoxifene acetate, a novel selective estrogen receptor modulator, in postmenopausal women.

OBJECTIVE: To assess the endometrial effects of bazedoxifene acetate in healthy postmenopausal women. METHODS: The endometrial effects of bazedoxifene 2.5, 5.0, 10, 20, 30, and 40 mg/d were evaluated in a 2-part, 6-month, double-blind, randomized, active- and placebo-controlled study among a total of 497 healthy postmenopausal women. Conjugated estrogens (0.625 mg)/medroxyprogesterone acetate (2.5 mg) served as the active control. Patients underwent transvaginal ultrasonography to measure double-wall endometrial thickness and endometrial biopsy at baseline and at 6 months of treatment. The incidence of amenorrhea was assessed from self-reported daily diaries. RESULTS: Bazedoxifene treatment at 2.5-20 mg/d resulted in mean changes from baseline in endometrial thickness that were no different than those seen with placebo treatment. Changes in endometrial thickness for the bazedoxifene 30 and 40 mg groups were significantly smaller than for placebo. The change from baseline in endometrial thickness was significantly and inversely related to dose (P < or = .001). None of the endometrial biopsy specimens demonstrated endometrial hyperplasia. Subjects in the 2.5-20 mg bazedoxifene groups experienced amenorrhea rates of 57-74%, comparable with the 59% seen in placebo. Over 90% of subjects treated with bazedoxifene 30 or 40 mg/d were amenorrheic at 6 months. CONCLUSION: Bazedoxifene at dosages up to 40 mg/d was well tolerated and did not stimulate the endometrium. The significant decreases in endometrial thickness and decreased uterine bleeding observed with doses of 30 and 40 mg/d as compared with placebo suggest endometrial antagonism, representing a novel characteristic not previously associated with any selective estrogen receptor modulator.

Adult↗
PubMed2003

Tamoxifen, a selective estrogen receptor modulator, reduces ischemic damage caused by middle cerebral artery occlusion in the ovariectomized female rat.

Previous work has demonstrated that physiological concentrations of 17beta-estradiol can protect the female rat brain against middle cerebral artery occlusion (MCAO)-induced ischemic damage. The present study examined whether therapeutic doses of the clinically relevant selective estrogen receptor modulator (SERM), tamoxifen, can similarly protect the female rat brain against ischemic stroke damage. Adult female rats were bilaterally ovariectomized and implanted subcutaneously with either a placebo or tamoxifen time-release pellet (0.1, 0.8 or 2.4 mg/kg/day). One week later, the animals underwent permanent MCAO to assess the protective ability of the different tamoxifen doses on brain infarct size. As expected, MCAO produced a large infarct ( approximately 53%) of the affected cerebral hemisphere in placebo (control) animals. The 0.1 mg/kg/day dose of tamoxifen did not exhibit any significant protective effects, however; the 0.8 and 2.4 mg/kg/day doses of tamoxifen, which are in the therapeutic range, dramatically reduced infarct of the affected cerebral hemisphere ( approximately 70% reduction) as compared to the controls. The reduction of infarct size was primarily due to protection of two major structures, the cerebral cortex and striatum. Laser Doppler analysis further revealed that tamoxifen had no significant effect on cerebral blood flow either before or after MCAO, suggesting that tamoxifen protection is independent of cerebral blood flow changes. Further studies showed that tamoxifen pellets implanted at the time of MCAO did not reduce infarct size, suggesting that pretreatment with tamoxifen is necessary to observe a protective effect. These studies suggest that clinically important SERMs may have an additional unrecognized beneficial effect of protection of the female brain.

Animals↗
PubMed2006

Emerging selective estrogen receptor modulators: special focus on effects on coronary heart disease in postmenopausal women.

Menopause, regardless of age at onset, is associated with a marked increase in coronary heart disease (CHD) risk. On the basis of epidemiological studies that demonstrated mainly positive effects of postmenopausal hormone therapy on CHD as well as on risk markers of CHD, it has been suggested that CHD could be prevented in postmenopausal women with long-term hormone therapy. However, since the publications of the Heart and Estrogen/progestin Replacement Study and the Women's Health Initiative trial, prescription of hormone therapy for the prevention of CHD has become controversial. Major efforts have been made to identify alternatives for hormone therapy. Compounds suggested have included selective estrogen receptor modulators (SERMs), which represent a class with a growing number of compounds that act as either estrogen receptor agonists or antagonists in a tissue-specific manner. This pharmacological profile may offer the opportunity to dissociate favourable estrogenic effects on the bone and cardiovascular system from unfavourable stimulatory effects on the breast and endometrium. Two SERMs presently on the market are tamoxifen and raloxifene. The only data available regarding the effects of tamoxifen on cardiovascular events in postmenopausal women are from breast cancer trials. These trials found fewer fatal myocardial events in women randomly assigned to tamoxifen compared with women assigned to placebo. Raloxifene is a second-generation SERM that has been shown to prevent osteoporotic fractures, is safe for the endometrium and holds high promise for the prevention of breast cancer. The effect of raloxifene on CHD is still uncertain. On the basis of the MORE (Multiple Outcomes of Raloxifene Evaluation) trial, raloxifene may offer some protection to women with CHD or to those who are at high risk of CHD. Proof that raloxifene reduces the risk of CHD requires a clinical trial with hard clinical endpoints. Such a study is currently underway. Next-generation SERMs taken into clinical development include idoxifene, droloxifene, ospemifene, arzoxifene, acolbifene/EM-800, levormeloxifene, lasofoxifene, bazedoxifene and HMR 3339. The aim is to find a compound with the ideal profile, that is, alleviation of climacteric symptoms and prevention of osteoporotic fractures, but without an adverse effect on the breast and endometrium, and no negative effect or even a beneficial effect on the cardiovascular system and the brain. Currently, limited data are available with regard to these next-generation SERMs and CHD. Nevertheless, some of these novel agents provide arguments for continuing the search for an ideal SERM.

Animals↗
PubMed2005

A new selective estrogen receptor modulator, CHF 4227.01, preserves bone mass and microarchitecture in ovariectomized rats.

UNLABELLED: A new SERM, CHF 4227.01, given to 6-month-old female rats immediately after ovariectomy, preserved bone mass and bone microarchitecture without affecting uterus weight. It also decreased serum cholesterol and fat mass in estrogen-deficient rats. INTRODUCTION: We tested the effect of a new benzopyran derivative, CHF 4227.01, with selective estrogen receptor modulator (SERM) activity on bone mass and biomechanics in ovariectomized (OVX) female rats in comparison with 17alpha-ethinylestradiol (EST), raloxifene (RLX), and lasofoxifene (LFX). MATERIALS AND METHODS: Four doses of CHF 4227.01 (0.001, 0.01, 0.1, and 1 mg/kg body weight [bw]/day) were administered in OVX animals daily by gavage 5 days/week for 4 months. EST was administered at a dose of 0.1 mg/kg bw/day, whereas RLX and LSX were administered at doses of 1 and 0.1 mg/kg bw/day, respectively, by gavage. In one group (Sham), rats were operated but the ovaries not removed; another OVX group was treated only with placebo. RESULTS AND CONCLUSIONS: Treatment with CHF 4227.01 (1.0 and 0.1 mg/kg bw), EST (0.1 mg/kg bw), LFX (0.1 mg/kg bw), or RLX (1.0 mg/kg bw) prevented bone loss on the lumbar spine and the proximal femur assessed in vivo by DXA. Volumetric BMD obtained by pQCT ex vivo confirmed protection from bone loss in the spine and proximal femur among rats treated with CHF 4227.01. This effect was associated with strong inhibition of bone resorption both histologically and biochemically. Furthermore, CHF 4227.01 preserved trabecular microarchitecture, analyzed by muCT, and maintained biomechanical indices of bone strength in the spine and proximal femur, effects also observed for RLX, whereas LSX was less protective of microarchitecture. CHF 4227.01 treatment did not affect uterine weight, prevented the increase in body weight and fat mass seen in OVX animals, and decreased serum cholesterol to below the average of intact animals. In conclusion, CHF 4227.01 exhibits a promising therapeutic and safety profile as a new SERM on both skeletal and extraskeletal outcomes.

Absorptiometry, Photon↗
PubMed2001

Regulation of human cbfa1 gene transcription in osteoblasts by selective estrogen receptor modulators (SERMs).

Cbfa1, a transcription factor critical for bone formation, plays a key role in osteoblast recruitment and differentiation. We have cloned and characterized a 3.0 KB 5'-flanking region of the human cbfa1 gene isolated from a P1 human genomic library. DNA sequencing revealed several known canonical nuclear transcription factor binding sites, including two AP1 and six OSE2 binding sites in the proximal promoter region. Although no estrogen (E2)-response element (ERE) binding sites were identified, E2 has been shown to regulate gene activity via AP1 promoter sites. We examined the effect of selective estrogen receptor modulators (SERMs) on human cbfa1 gene promoter activity using cell-based luciferase reporter transcriptional assays. Three characterized SERMs, tamoxifen, raloxifene, and ICI 178,180, all upregulated cbfa1-luciferase (cbfa1Luc) gene activity 5- to 10-fold in a dose-dependent manner. This effect was mediated by both ER alpha and ER beta. Mutational analysis demonstrated that the minimal promoter region for basal of SERM-activated transcription was mapped to adjacent AP1-like and OSE2 binding sites within -93 and +7 of the transcription start condon. Further, electrophoretic mobility shift assays (EMSAs) demonstrate that ICI 178,180 increased binding of AP1 and OSE2 site by ER alpha and cbfa1, respectively. These studies suggest that SERMs can modulate bone-specific cbfa1 gene expression in a human osteosarcoma cell line.

Base Sequence↗
PubMed2005

Genistein derivatives as selective estrogen receptor modulators: sonochemical synthesis and in vivo anti-osteoporotic action.

Genistein derivatives were synthesized from genistein through a facile sonochemical approach in high yields. The bioassay was performed on ovariectomized (OVX) rats in terms of bone mineral density (BMD) and the weight of bone ash (WBA) to lead to the discovery of eight novel genistein-based selective estrogen receptor modulators. Attention to the structure-activity relationship disclosed that the newly introduced 2-hydroxyethylthio scaffolds were essential for the anti-osteoporotic activity. Moreover, the anti-osteoporotic action of genistein, deprivable by methylation, could be restored and enhanced by subsequent sulfonation. The most promising compound was 4',5,7-tri[3-(2-hydroxyethylthio)propoxy]isoflavone, displaying 24% (or 8%) increment in BMD and 31% (or 11%) increase in WBA of the femora relative to those discerned with the OVX (or genistein) group. Acute toxicity test showed that none of the active compounds was acutely toxic.

Alkaline Phosphatase↗
PubMed2003

Selective estrogen receptors modulators in the prevention and treatment of postmenopausal osteoporosis.

Raloxifene, the first of the second-generation of SERMs to be widely available, represents a significant improvement over tamoxifen. It prevents postmenopausal bone loss and reduces the incidence of vertebral fractures and of new breast cancer cases in osteoporotic patients without stimulating the endometrium. The suggestion that raloxifene could have a beneficial effect on cardiovascular disease in high-risk patients needs to be confirmed in prospective study. Selective estrogen receptors modulators represent a new and promising class of agents for the management of postmenopausal women with a scope that goes far beyond the prevention and treatment of osteoporosis. The observations that estrogens may play a role in bone metabolism of men and that SERMs prevent bone loss and induce a decrease in total serum cholesterol without affecting the prostate in orchidectomized male rats raises the possibility that they also may be of interest for the treatment of elderly men.

Aged↗
PubMed2004

Hormone replacement therapy, selective estrogen receptor modulators, and tissue-specific compounds: cardiovascular effects and clinical implications.

In industrialized countries, coronary heart disease (CHD) is not only the leading cause of death in women but of disability as well. Menopause, regardless of age at onset, is associated with a marked increase in CHD risk. Based on epidemiologic studies demonstrating mainly positive biologic effects of hormone replacement therapy (HRT) on CHD risk factors and outcomes, earlier recommendations decreed that most, if not all, postmenopausal women should be treated with long-term HRT. Recent randomized controlled trials with clinical CHD endpoints have shown that previously held dicta may not be accurate. Selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene are alternatives to HRT. SERMs represent a growing class of compounds that act as either estrogen receptor agonists or antagonists in a tissue-selective manner. This pharmacologic profile may offer the opportunity to dissociate favorable cardiovascular effects of estrogen from unfavorable stimulatory effects on the breast and endometrium. The only data available regarding the effects of tamoxifen on cardiovascular events in postmenopausal women are from breast cancer trials. They showed fewer fatal myocardial events in women randomly assigned to tamoxifen compared with women assigned to placebo. Raloxifene is a so-called second-generation SERM. It seems clear that raloxifene increases bone mineral density, has no effect on the endometrium, and holds high promise for the prevention of breast cancer. The effect of raloxifene on cardiovascular disease is uncertain. On the basis of the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene may offer some protection to women with cardiovascular disease or to those who are at high risk. Proof that raloxifene reduces the risk of CHD requires a clinical trial with hard clinical endpoints. Such a study is currently underway. Clinical trials have demonstrated that the synthetic 19-nortestosterone derivative tibolone reduces climacteric complaints and prevent osteoporosis without causing menstrual bleeding. Tibolone lowers lipoprotein(a), fibrinogen, and plasminogen activator inhibitor-1 levels and improves glucose tolerance, insulin sensitivity, and endothelial function; however, it also lowers high-density lipoprotein cholesterol by >20%. The long-term impact of tibolone on the risk of CHD is not known and needs to be studied.

Aging↗
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↗
PubMed1988

Physiological implications of estrogen receptor modulation by 2,3,7,8-tetrachlorodibenzo-p-dioxin.

The interactions of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with hormones and hormone receptors have important implications for TCDD toxicity. Evidence suggests that TCDD modulates receptors for glucocorticoids, prolactin, thyroxine, low density lipids, epidermal growth factor, and estrogens. Estrogen receptor modulation and the animal's physiological responses to this modulation appear to be particularly important effects and can explain much of the toxicity observed in TCDD-treated animals. Susceptibility of different species to TCDD correlates with their steroid glucuronidation capacity. Because of the close interactions and interdependent regulation of hormonal systems, other hormones may have a similar role in TCDD toxicity.

Animals↗
PubMed2001

Effects of estrogen and selective estrogen receptor modulators on hemostasis and inflammation: potential differences among drugs.

Postmenopausal hormone replacement therapy (HRT), tamoxifen, and raloxifene all share an increase of about three-fold in the risk of venous thromboembolism (VTE). Currently, it is thought that HRT transiently increases the risk of myocardial infarction (MI), followed by subsequent reduction in risk, at least among women with established coronary heart disease. Raloxifene and tamoxifen are not known to share this apparent clinical effect. Study of hemostasis and inflammation factors, as surrogate end points, can be useful to form hypotheses concerning the pathophysiology related to clinical effects of these agents. Data presented here suggest differences among these agents that might relate to differences in clinical outcomes. From the vascular perspective, future studies need to focus on interactions of treatment with these biochemical parameters and their genetic correlates in order to define low- or high-risk subgroups for intervention with these therapies.

Estrogen Receptor Modulators↗
PubMed2006

Future perspectives of selective estrogen receptor modulators used alone and in combination with DHEA.

Breast cancer is the most frequently diagnosed and the second cause of cancer death in women, thus making breast cancer a most feared disease. Since breast cancer metastasizes early and it is unlikely that improvements in the treatment of metastatic disease could permit a cure in most cases in the foreseeable future, it is clear that prevention is essential in order practically to eliminate deaths from breast cancer. Tamoxifen is the only selective estrogen receptor modulator (SERM) currently registered for use in breast cancer prevention; the tamoxifen versus raloxifene study should indicate the efficacy of this compound compared with raloxifene. The recent benefits of aromatase inhibitors over tamoxifen indicate the advantages of a blockade of estrogens more complete than the one achieved with tamoxifen, a SERM having some estrogenic activity in the mammary gland and an even higher estrogenic action in the uterus. However, it is unlikely that the general estrogen ablation achieved with aromatase inhibitors will be acceptable for the long-term use required for prevention. It is thus important to develop SERMs with highly potent and pure antagonistic activity in the mammary gland and uterus while possessing estrogen-like activity in tissues of particular importance for women's health, namely the bones and the cardiovascular system. However, it is expected that a SERM alone will not meet all the requirements of women's health at the postmenopause when ovarian estrogen secretion has ceased and peripheral formation of androgens and estrogens from DHEA by intracrine mechanisms is decreased by 60% or more. One possibility is to combine a SERM with DHEA, a precursor of sex steroids that permits, somewhat like SERMs, tissue-specific formation of androgens and/or estrogens according to the level of expression of the steroidogenic and steroid-inactivating enzymes. DHEA could thus compensate for the important loss of androgens that accompanies aging and could also permit sex steroid formation and action in the brain while breast cancer prevention would be achieved by the SERM.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

The selective estrogen receptor modulator 4-hydroxy tamoxifen induces G1 arrest and apoptosis of multiple myeloma cell lines.

Multiple myeloma (MM) is an incurable hematological malignancy for which new therapeutic strategies should be envisaged. The selective estrogen receptor modulator (SERM), 4-hydroxy tamoxifen (4-OHTam), in the range of 1 to 10 micro M, was able to impair the cell proliferation of MM cell lines. This was achieved by blocking cells at the G1 phase of the cell cycle and by inducing apoptosis. This cellular response was observed in five out of six tested cell lines, all five expressing both alpha and beta estrogen receptor forms. No modifications of Bcl-2, Bcl-X, and Bax levels were observed, as well as no changes in Pi3K/Akt and JAK/STAT pathways that are often constitutively active in these cells. The signalization of 4-OHTam-induced cell death needs further investigation.

Apoptosis↗
PubMed2001

Effects of a new selective estrogen receptor modulator (MDL 103,323) on cancellous and cortical bone in ovariectomized ewes: a biochemical, histomorphometric, and densitometric study.

The aims of this study performed in ewes were: (1) to confirm in this animal model the effects on bone of ovariectomy (OVX) alone or associated with Lentaron (L), a potent peripheral aromatase inhibitor, used to amplify the effects of OVX and (2) to evaluate the effects of a new selective estrogen receptor modulator (SERM; MDL 103,323) on bone remodeling. Thirty-nine old ewes were divided into five groups: sham (n = 7); OVX (n = 8); OVX + L (n = 8); OVX + L + MDL; 0.1 mg/kg per day (n = 8); and OVX + L + MDL 1 mg/kg per day (n = 8). The animals were treated for 6 months. Biochemical markers of bone turnover (urinary excretion of type 1 collagen C-telopeptide [CTX], serum osteocalcin [OC], and bone alkaline phosphatase [BAP]) were measured each month. Bone biopsy specimens were taken at the beginning and after death at the end of the experiment. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) on the lumbar spine and femur. OVX induced a significant increase in biochemical markers. This effect was the highest after 3 months for CTX (+156% vs. sham) and after 4 months for OC and BAP (+74% and +53% vs. sham, respectively). L tended to amplify the effect of OVX on OC and BAP. OVX induced significant increases in the porosity, eroded, and osteoid surfaces in cortical bone but no effect was observed in cancellous bone. MDL treatment reduced the bone turnover as assessed by bone markers, which returned to sham levels as well as histomorphometry both in cortical and in cancellous bone. Cancellous osteoid thickness decreased by 27% (p < 0.05), mineralizing perimeter by 81% (p < 0.05), and activation frequency by 84% (p < 0.02) versus OVX + L. Femoral and spinal BMD were increased by MDL and tended to return to the sham values. The effects of OVX on bone turnover were different on cortical and cancellous bone. These effects on cortical bone were reflected by changes in biochemical markers. MDL markedly reduces bone turnover and increases BMD suggesting that this new agent may prevent postmenopausal bone loss.

Alkaline Phosphatase↗