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PubMed2001

Capitalizing on the complexities of estrogen receptor pharmacology in the quest for the perfect SERM.

The term Selective Estrogen Receptor Modulators (SERMs) has been used of late to describe a group of pharmaceuticals that manifest estrogen receptor (ER) agonist activity in some tissues, but that oppose estrogen action in others. Whereas the name describing this class of drugs is new, the concept is not. Indeed, compounds exhibiting tissue-selective ER agonist/antagonist properties have been around for nearly 40 years. What is new is the idea that it may be possible to capitalize on the paradoxical activities of these drugs and develop them as treatments for estrogenopathies where it is desirable to direct therapy to a specific estrogen-responsive target organ. This realization has provided the impetus for research in this area and has pushed the development and clinical use of this class of drugs. The objective of this review is to describe how the medical need for SERMs arose and how recent studies of the mechanism of action of the currently available drugs are paving the way for the development of novel drugs with improved selectivity.

Amino Acid Sequence↗
PubMed2004

Pilot study evaluating the pharmacokinetics, pharmacodynamics, and safety of the combination of exemestane and tamoxifen.

PURPOSE: We conducted a pilot study assessing the effects of the selective estrogen receptor modulator, tamoxifen, on the pharmacokinetics, pharmacodynamics, and safety of the steroidal, irreversible aromatase inhibitor (AI), exemestane, when the two were coadministered in postmenopausal women with metastatic breast cancer. EXPERIMENTAL DESIGN: Patients with documented or unknown hormone receptor sensitivity were eligible. Patients received oral exemestane at 25-mg once daily. Starting day 15, oral tamoxifen at 20-mg once daily, was added. We measured plasma concentrations of exemestane, estrone, estrone sulfate, and estradiol after 14 days of exemestane monotherapy and after approximately 4 weeks of combination therapy. The incidence and severity of adverse events were assessed by physical examination and patient reporting. RESULTS: We treated 18 patients. All had received prior chemotherapy and/or hormonal therapy, eight and six, respectively, with single-agent selective estrogen receptor modulators or irreversible aromatase inhibitors; no hormonal therapy was given within 30 days of study entry. Plasma exemestane concentrations and estrone, estrone sulfate, and estradiol suppression were unchanged after approximately 4 weeks of tamoxifen coadministration. All drug-related adverse events were grades 1 or 2; none was unexpected. Although not a formal study end point, antitumor activity was noted, with two partial responses and four cases of stable disease among 17 evaluable patients after a 9-month median follow-up (range, 2.5-19 months). CONCLUSIONS: This pilot study provides evidence that coadministration of tamoxifen does not affect exemestane pharmacokinetics or pharmacodynamics and that the combination is well-tolerated and active. Further clinical investigation is warranted.

Administration, Oral↗
PubMed2003

[SERMs and uterus].

The uterus is one of the target organs of sexual steroids synthesized in the ovary. Estrogen is known to stimulate cell proliferation in the endometrium while progesterone has an anti-estrogenic secretory effect on this tissue. Renewed interest in the action of new anti-estrogenic agents on the uterus has arisen over the last decade, but not simply in order to achieve new therapeutic strategies for the prevention or cure of uterine tumors. New compounds were developed for their action on other tissues such as the breast, but it rapidly became clear that they were a source of uterine disease. A clear example is tamoxifen which has a powerful anti-estrogenic effect on breast tissue. It was hoped however that this compound, which behaves either like an antagonist or an agonist, depending on the target tissue, could have an anti-estrogenic effect on the uterus and on the contrary an agonistic estrogenic protective effect on bony and vascular tissue. This approach progressively led to the development of SERMs (Selective Estrogen Receptor Modulators), non-steroidal compounds modulating the action of estrogens. The first member of this new pharmaceutical class was raloxifen, marketed in France under the brand name Evista, which has an estrogenic effect on vertebral bone, warranting its authorization for use in patients with vertebral osteoporosis with or without fracture. Raloxifen thus has a beneficial estrogenic effect, at least on trabecular bone, and an anti-estrogenic effect on the uterus and breast. The goal today is to continue the development of new compounds in the SERM family with well targeted, and well understood, agonistic and/or antagonistic actions on different body tissues.

Estrogen Antagonists↗
PubMed2003

Nongenomic activity and subsequent c-fos induction by estrogen receptor ligands are not sufficient to promote deoxyribonucleic acid synthesis in human endometrial adenocarcinoma cells.

Estrogen 17beta-estradiol (E2) rapidly modulates several signaling pathways related to cell growth, preservation, and differentiation. The physiological role of these nongenomic effects with regard to downstream outcomes, and the relationship with transcriptional estrogen activity are unclear. Furthermore, the ability of selective estrogen receptor modulators (SERMs) to trigger nongenomic actions is largely unknown. To determine whether estrogen receptor (ER) ligands exert nongenomic activity in endometrial adenocarcinoma cells, and whether this activity affects transcription and DNA synthesis, we challenged human Ishikawa cells with E2 or partial ER agonists 4-hydroxytamoxifen (OHT) and raloxifene (ral). Serum-starved Ishikawa cells exposed for 5 min to 0.1 nM E2 showed induced phosphorylation of MAPK (ERK1/2). Ral and 4-OHT each at 1 nM also stimulated ERK in a rapid transient manner. E2 and 4-OHT induced proto-oncogene c-fos mRNA expression in Ishikawa cells within 30 min, but ral had no effect. In contrast to nongenomic action, only E2 stimulated expression of an estrogen response element (ERE)-driven luciferase (LUC) reporter gene. To examine DNA synthesis, [(3)H]-thymidine incorporation was measured in serum-starved cultures exposed to E2 or partial agonists for 2 d. E2 at 1 nM stimulated thymidine uptake in an ERK-dependent manner, but 1 nM 4-OHT, 1 nM ral, and 0.1-nM concentrations of E2 had no significant effects. Taken together, these data indicate that both nongenomic and direct transcriptional ER effects are likely required to promote DNA synthesis.

Adenocarcinoma↗
PubMed2000

Complete and selective estrogenic effects on lipids and cardiovascular disease.

Observational studies have shown a protective effect of estrogen replacement on risk of cardiovascular disease in postmenopausal women. The estrogen protection is thought to be mediated by mechanisms acting at different levels, including a beneficial effect on plasma lipid concentrations. Selective estrogen receptor modulators (SERM) share with estrogen the ability to reduce plasma levels of atherogenic lipoproteins like low-density lipoproteins and lipoprotein(a). The recent publication of the first randomized, placebo-controlled trial of estrogen/progestin replacement (HERS), which failed to show a reduced number of cardiovascular events in women randomized to estrogen treatment as compared with placebo, has cast some doubts on the protective role of estrogen. Other large randomized studies on the effect of estrogen and other compounds with estrogenic activity (eg, SERM) on cardiovascular disease risk are currently underway and will provide more definite answers to both clinicians and postmenopausal women.

Arteriosclerosis↗
PubMedDate not supplied

Mammographic changes associated with raloxifene and tibolone therapy in postmenopausal women: a prospective study.

OBJECTIVE: The prolonged use of estrogen therapy is associated with a slightly increased risk of breast cancer. Alternative therapies that are effective in the prevention of menopause, having associated morbidities but no unwanted effects, are of primary interest in the pharmacologic research. The aim of this study was to evaluate the effect of two alternative to estrogens drugs, the selective estrogen receptor modulator raloxifene and the tissue-specific tibolone, on the mammographic appearance of the breast. DESIGN: The study group comprised 131 postmenopausal women aged 41 to 67 years. The women were at least 2 years postmenopausal, free of climacteric symptoms, and at the time of entry to the study had not had therapy for at least 9 months. Women with risk factors for osteoporosis or cardiovascular disease were allocated either to tibolone (n = 56) or raloxifene (n = 48) therapy. Women with no risk factors and women who either did not qualify for or denied treatment (n = 27) served as controls. The study duration was 12 months. Women received a baseline mammogram before commencing therapy and a repeat mammogram at the end of the study period. Mammogram findings were classified according to the modified Wolfe criteria by two expert radiologists. RESULTS: No difference was identified between groups with respect to baseline characteristics associated with breast cancer risk. Similarly, no difference was detected between groups concerning the modified Wolfe classification of baseline mammographic findings. In the tibolone group, 10.7% of the women showed an increase in breast density in the 12-month reevaluation. The respective figure in the raloxifene group was 6.3%, whereas no woman in the control group showed an increase in breast density. Differences in the increase in breast density between groups did not, however, reach statistical significance. Accordingly, 10.7% of women in the tibolone group and 18.8% of women in the raloxifene group exhibited involutionary changes in the repeat mammogram, whereas 25.9% of women in the control group revealed a decrease in breast density in the 12-month examination. The percentages were not significantly different between groups. CONCLUSIONS: Breast density as shown by mammography was stable in a majority of patients and changed in a minority of cases for both tibolone and raloxifene. In most patients, these drugs are not likely to interfere with mammogram interpretation. Larger long-term studies are needed to confirm the impact of prolonged tibolone or raloxifene administration on mammography.

Adult↗
PubMedDate not supplied

Postmenopausal hormonal support: discontinuation of raloxifene versus estrogen.

OBJECTIVE: To determine possible differences in continuation among women initiating treatment with the selective estrogen receptor modulator raloxifene, versus those initiating treatment with estrogen-containing regimens. DESIGN: A pharmacy prescription database search for refill patterns. The study subjects were members of Kaiser Foundation Health Plan, a large health maintenance organization; 1,394 women age >or=60 years who filled index prescriptions for either raloxifene (n = 331) or systemic estrogens (n = 1,063) between April 1998 and March 1999. The main outcome measure was discontinuation based on prescription refill patterns through December 2000. RESULTS: At 24 months, the probabilities of discontinuing were 56% for women starting raloxifene compared to 72% for women starting estrogens. The likelihood of discontinuation was significantly less among women starting raloxifene than among those starting estrogen (hazard ratio = 0.75; 95% confidence interval = 0.64-0.88). Adjustments for age and prescriber specialty did not affect the risk. CONCLUSIONS: We conclude that discontinuation of estrogen by women well beyond the age of menopause is high; more than two-thirds discontinue within 2 years of starting. Women starting therapy with raloxifene are 25% percent less likely to discontinue their medication than those starting estrogen, providing some promise that long-term benefits of raloxifene may be more easily achieved than those of estrogen.

Aged↗
PubMedDate not supplied

[Large clinical trials for osteoporosis].

The prevention and treatment of osteoporosis are now a necessary goal because of the aging of the population and the social and economic costs of fracture complications. The publication of guidelines by registration agencies during the last 10 years has provided precise rules for evaluating new drugs designed for the prevention and treatment of postmenopausal osteoporosis. The benefit of combination treatment with calcium and vitamin D in osteoporotic patients has clearly been proven, especially among the oldest patients, but results of prospective studies designed for the prevention of fracture risk are conflicting. In the Fracture Intervention Trial (FIT), treatment with alendronate 10 mg/day reduces the risk of vertebral fracture by 48% and increases bone mineral density (BMD) in patients with vertebral fractures. In the Vertebral Efficacy with Risedronate Therapy Multi-National (VERT-MN) and VERT-NA (North America) studies, treatment with risedronate 5 mg/day reduces the risk of vertebral fracture by 49% and 41%, respectively. Risedronate 5 mg daly for 3 years leads to an increase in BMD. The Prevent Recurrence Of Osteoporotic Fractures (PROOF) study has shown a significant decrease in the risk of vertebral fracture in patients treated with calcitonin 200 IU. However, numerous criticisms of the methodology of this study design have been identified. Selective estrogen receptor modulators could act as agonists or antagonists of estrogens, depending on the target tissue. In the Multiple Outcomes of Raloxifene Evaluation (MORE) study, treatment with raloxifene reduces the risk of vertebral fracture by 50% in patients without prevalent vertebral fracture and by 30% in patients with prevalent vertebral fracture. PTH treatment leads to an increase in BMD and reduces the risk of vertebral fracture by 65%. Strontium ranelate has a novel mechanism of action (stimulation of bone synthesis and decrease in bone resorption), and administration of 2 g daily has a proven positive effect, leading to an increase in bone mass among women with osteoporosis. This effect was especially evident in the Spinal Osteoporosis Therapeutic Intervention phase III (SOTI) study, in which a significant decrease in the incidence of vertebral fracture of 41% over 3 years has been shown. Thus, effective therapeutic strategies now enable improved treatment of postmenopausal osteoporosis. However, this condition is still poorly diagnosed and not all patients are correctly treated. Preventing the occurrence of the first fracture should remain the prime concern.

Calcitonin↗
PubMed1998

Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women.

CONTEXT: Raloxifene is a selective estrogen receptor modulator that has estrogen-agonistic effects on bone and estrogen-antagonistic effects on breast and uterus. OBJECTIVE: To identify the effects of raloxifene on markers of cardiovascular risk in postmenopausal women, and to compare them with those induced by hormone replacement therapy (HRT). DESIGN: Double-blind, randomized, parallel trial. SETTING: Eight sites in the United States. PARTICIPANTS: 390 healthy postmenopausal women recruited by advertisement. INTERVENTION: Participants were randomized to receive 1 of 4 treatments: raloxifene, 60 mg/d; raloxifene, 120 mg/d; HRT (conjugated equine estrogen, 0.625 mg/d, and medroxyprogesterone acetate, 2.5 mg/d); or placebo. MAIN OUTCOME MEASURES: Change and percent change from baseline of lipid levels and coagulation parameters after 3 months and 6 months of treatment. RESULTS: At the last visit completed, compared with placebo, both dosages of raloxifene significantly lowered low-density lipoprotein cholesterol (LDL-C) by 12% (P < .001), similar to the 14% reduction with HRT (P < .001). Both dosages of raloxifene significantly lowered lipoprotein(a) by 7% to 8% (P < .001), less than the 19% decrease with HRT (P<.001). Raloxifene increased high-density lipoprotein-2 cholesterol (HDL2-C) by 15% to 17% (P < .05), less than the 33% increase with HRT (P < .001). Raloxifene did not significantly change high-density lipoprotein cholesterol (HDL-C), triglycerides, or plasminogen activator inhibitor-1 (PAI-1); whereas HRT increased HDL-C by 11% and triglycerides by 20%, and decreased PAI-1 by 29% (for all, P < .001). Raloxifene significantly lowered fibrinogen by 12% to 14% (P < .001), unlike HRT, which had no effect. Neither treatment changed fibrinopeptide A or prothrombin fragment 1 and 2. CONCLUSIONS: Raloxifene favorably alters biochemical markers of cardiovascular risk by decreasing LDL-C, fibrinogen, and lipoprotein(a), and by increasing HDL2-C without raising triglycerides. In contrast to HRT, raloxifene had no effect on HDL-C and PAI-1, and a lesser effect on HDL2-C and lipoprotein(a). Further clinical trials are necessary to determine whether these favorable biochemical effects are associated with protection against cardiovascular disease.

Aged↗
PubMedDate not supplied

Comparison of tamoxifen and testosterone propionate in male rats: differential prevention of orchidectomy effects on sex organs, bone mass, growth, and the growth hormone-IGF-I axis.

Testis dysfunction can weaken bone and reduce muscle mass as well as impair sexual function. Testosterone (T) therapy has useful effects on sex organs, bone, and muscle in T-deficient males, but prostate concerns can preclude T use in some men. Although estrogens or other drugs can protect bone in men, gynecomastia makes estrogens unappealing, and other drugs may also be undesirable in some cases. Selective estrogen receptor modulators (SERMs) inhibit estrogen-evoked sex organ growth but mimic estrogen effects on bone and cholesterol and are advantageous for some women. SERMs may also be useful in men who must avoid androgens. As a preclinical test of this idea, tamoxifen (a SERM) and testosterone propionate (TP, a classic androgen) were compared for their efficacy in preventing varied effects of orchidectomy (ORX) in adult male rats. ORX led to ventral prostate and seminal vesicle atrophy and decreases in somatic growth, proximal tibia bone mineral density (BMD), and serum growth hormone (GH) and insulin-like growth factor I (IGF-I). ORX also increased anterior pituitary glandular kallikrein, serum cholesterol, and body temperature. Pituitary prolactin (PRL) content was unaltered. ORX effects on sex organs, somatic growth, IGF-I, cholesterol, body temperature, and pituitary kallikrein were prevented by TP at 1 mg/kg (3 doses per week), but BMD and GH were unresponsive. ORX effects on BMD and GH were prevented by TP at 10 mg/kg, but this dose evoked supraphysiologic increases in sex organs and PRL, failed to restore somatic growth, and further reduced IGF-I. Tamoxifen (1 mg/kg daily) prevented ORX effects on BMD, GH, and cholesterol without altering basal or TP-induced sex organ growth and further reduced IGF-I and somatic growth. Tamoxifen did not alter basal PRL but blocked increases caused by TP at 10 mg/kg. In summary, tamoxifen prevented ORX effects on bone and cholesterol in male rats without affecting sex organs or PRL and might be useful for men who must avoid androgens. Unexpectedly, a TP dose that replicated testis effects on sex organs and other targets had no effect on BMD or GH, and a larger TP dose that restored BMD and GH was worse at replicating normal male physiology. In addition, correlation/regression results suggested that the GH-IGF-I axis contributes to changes in BMD.

Animals↗
PubMed1998

Role of IRS-1 signaling in insulin-induced modulation of estrogen receptors in breast cancer cells.

Cross-talk between steroid hormones and polypeptide growth factors regulates the growth of hormone-responsive breast cancer cells. For example, in the MCF-7 human breast cancer cell line, insulin up-regulates estrogen receptor (ER) content and binding capacity. Since the insulin receptor (IR) substrate 1 (IRS-1) is one of the core signaling elements transmitting mitogenic and metabolic effects of insulin, we investigated whether IRS-1 is also required for the insulin-induced function of the ER. The effects of insulin on the ER were compared in MCF-7 cells and MCF-7-derived cell lines with decreased levels (by approximately 80%) of IRS-1 due to the expression of IRS-1 antisense RNA. The severe IRS-1 deficiency in MCF-7 cells was associated with (1) reduced mitogenic response to 20 ng/ml insulin and 10% calf serum (CS), but not to 1 nM estradiol (E2); (2) loss of insulin-E2 synergism; (3) up-regulation of ER protein expression and binding capacity; and (4) loss of insulin-induced regulation of ER tyrosine phosphorylation. In conclusion, the data confirm the existence of the IR-ER cross-talk and suggest that IRS-1-dependent signaling may contribute to the negative regulation of the ER expression and function in MCF-7 cells.

Breast Neoplasms↗
PubMed1994

Progesterone modulation of estrogen receptors in microdissected regions of the rat hypothalamus.

One mechanism whereby progesterone opposes the regulatory actions of estrogen in the brain may include the down-regulation of estrogen receptors. A previous study has shown a small decrease in estrogen binding in the combined preoptic area-hypothalamic area in response to progesterone treatment. To determine if this effect is region specific, gonadectomized/adrenalectomized (GDX/ADX) estrogen-treated female rats were administered a single injection of progesterone (5.0 mg, sc) or a silastic capsule containing crystalline progesterone. Control animals were treated identically but without progesterone exposure. Animals were killed 24 or 72 h after initiating progesterone treatment and estrogen binding was measured in cytosol and cell nuclear extracts of the anterior pituitary, mediobasal hypothalamus (MBH), and preoptic area. A significant effect of progesterone injection on nuclear estrogen binding was observed in the MBH at 24 h. This effect had subsided by 72 h. No effect was observed when progesterone was administered in a continuous fashion. To further examine the regional specificity of the progesterone effect and to determine if males were similarly affected, nuclear-bound estrogen receptors were measured in microdissected brain regions from male and female estrogen-treated GDX/ADX rats treated with 5.0 mg progesterone or vehicle 24 h before sacrifice. A significant decrease in estrogen binding was found in the ventromedial nucleus of the female but not the male. A significant effect of progesterone treatment was found in the periventricular preoptic area of the male.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗
PubMed1989

Modulation of estrogen receptor and epidermal growth factor receptor mRNAs by phorbol ester in MCF 7 breast cancer cells.

Previous studies have demonstrated an inverse relationship between estrogen receptor (ER) and epidermal growth factor receptor (EGF-R) gene expression in human breast cancer cells. This relationship was further investigated in MCF 7 cells treated with 12-O-tetradecanoylphorbol-13-acetate (TPA). Exposure to 10 nM TPA resulted in a time-dependent increase in EGF-R mRNA, first apparent at 3 h and maximal between 9 and 24 h. There was a concomitant fall in ER mRNA with a maximum decline to 15-20% of control between 12 and 24 h. Although EGF-R mRNA levels declined between 24 and 72 h, both EGF-R mRNA and EGF-R binding remained above control levels and this was accompanied by a sustained depression of ER mRNA. These data support the view that ER and EGR-R gene expression is inversely regulated in human breast cancer and describe for the first time an inhibitory effect of a phorbol ester on steroid hormone receptor gene expression.

Breast Neoplasms↗
PubMed1985

Expression and modulation of estrogen receptors in human breast cancer.

Estrogen receptors have been traced at the tissue level in premalignant and malignant changes of human mammary gland by an immunoperoxidase technique using a monoclonal antibody against the receptor protein. Proliferative premalignant cells show an increased and homogeneous expression of the estrogen receptor by this technique; it seems that a constitutive expression of the receptor may play a role in the promotional carcinogenetic process. Moreover, infiltrating tumors show a striking heterogeneity in the cellular expression of estrogen receptor, which seems related to differentiation level.

Antibodies, Monoclonal↗
PubMed1978

Influence of bromoergocryptine on estrogen-modulated prolactin receptors of mouse mammary gland.

Modulation of specific binding of prolactin to murine mammary gland as a response to treatment with various doses of estradiol benzoate (EB) was studied. Measurements of serum and pituitary levels of prolactin were also carried out simultaneously. Estradiol benzoate at a dose of 5 microgram significantly increased the binding of 125I-labelled rat prolactin (rPRL) to mammary gland concomitant with increased serum prolactin levels in ovariectomized mice. Administration of bromoergocryptine along with EB resulted in decreased serum prolactin levels as well as binding of prolactin to breast tissue. It thus appears that the influence of estradiol on binding of prolactin to mammary gland is mediated primarily via its property of enhancing serum prolactin concentration apart from its possible direct effect at the target tissue level.

Animals↗
PubMed1988

Modulation of estrogen receptors by phorbol diesters in human breast MCF-7 cell line.

Treatment of MCF-7 cells with 12-O-tetradecanoylphorbol 13-acetate (TPA) results in an inhibition of cell proliferation and a reduction in the number of estrogen receptors (ER), shown by binding studies and immunoassay. The decrease in ER concentration induced by phorbol ester derivatives parallels their growth inhibitory effect. Moreover, the estrogen receptor of TPA-resistant RPh4 cells (which are insensitive to the antiproliferative and morphological effects of TPA) is not affected by TPA treatment. The reduction in ER concentration appear to be a specific phenomenon since it contrasted with the 2-fold increase in total cell protein content which included an increase in progesterone receptor (PgR). We also found that addition of TPA does not affect estrogen induction of PgR.

Binding, Competitive↗
PubMed2006

Modulation of estrogen receptor transactivation and estrogen-induced gene expression by ormeloxifene-a triphenylethylene derivative.

The study was aimed to investigate the interaction of D,L-ormeloxifene (Orm), a triphenylethylene and its hydroxy derivative with estrogen receptor subtypes alpha and beta, its influence on ERE-driven transcriptional activation and progesterone receptor expression. In competitive binding experiments using human recombinant ERalpha and ERbeta, Orm showed interaction with both ER subtypes, with more selectivity and higher affinity towards ERalpha (8.8%) as compared to ERbeta (3%). In case of 7-hydroxy derivative, the relative binding affinity for both ERs was enhanced several folds. Orm showed lower Ki, i.e. higher affinity for ERalpha (250 nM) than for ERbeta (750 nM). It was observed that Orm promoted the formation of ER-ERE complexes in uterine tissue extract whereas its hydroxy derivative showed inhibitory effects. Transient co-transfection assay in COS-1 cells using ERE-luciferase reporter construct, revealed that Orm showed estrogenic response whereas its hydroxy-derivative was potent antiestrogen at ERalpha at transcription level. In immature rats, Orm (2 mg/kg) was associated with less increase in uterine weight and in luminal epithelial cell height than E2 or Tam. Orm also induced the expression of PR mRNA but the expression level was significantly less than estradiol treated group. These results suggest that ER-ERE complexes formed under the influence of 7-hydroxy Orm appear to be transcriptionally less effective hence antagonizing the E2-regulated gene expression in this target tissue.

Animals↗