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PubMed2003

Extragonadal synthesis of sex steroids: intracrinology.

All androgens and estrogens in post-menopausal women are synthesized locally in peripheral target tissues by tissue-specific steroidogenic enzymes according to the intracrine process. The importance of the intracrine or peripheral formation of sex steroids is illustrated by the success of aromatase inhibitors and antiestrogens in the prevention and treatment of breast cancer in post-menopausal women. On the other hand, a large series of problems are associated with the deficiency of sex steroids accompanying menopause and the decreased secretion of DHEA, osteoporosis being the best defined example. In this context, an important observation is that women at menopause are not only deprived from ovarian estrogens but are also lacking androgens due to the marked decrease of DHEA. In order to achieve a more physiological and tissue-specific hormone replacement therapy, DHEA, in combination with a SERM (selective estrogen receptor modulator) having pure antiestrogenic activity in the mammary gland and uterus could possibly meet the most important needs of women at menopause, namely control of hot flushes and, most importantly, prevent breast cancer, uterine cancer, ovarian cancer and osteoporosis with a potential improvement of cognitive functions and memory and prevention of Alzheimer's disease.

Adult↗
PubMed2002

Raloxifene treatment increases plasma levels of beta-endorphin in postmenopausal women: a randomized, placebo-controlled study.

OBJECTIVE: To evaluate the effect of the selective estrogen receptor modulator raloxifene hydrochloride (Evista, Eli Lilly and Company, Indianapolis, IN) on plasma levels of beta-endorphin, and to determine whether beta-endorphin levels and menopausal symptoms are related. DESIGN: A randomized, double-blind, placebo-controlled pilot study. SETTING: Endocrinology outpatient department. PATIENT(S): Forty postmenopausal women. INTERVENTION(S): The women received raloxifene, 60 mg/d, or placebo for 3 months. A questionnaire on climacteric symptoms was administered before and after treatment. MAIN OUTCOME MEASURE(S): Circulating levels of beta-endorphin, climacteric symptom score, and correlation with beta-endorphin levels. RESULT(S): Raloxifene treatment significantly increased levels of beta-endorphin and did not significantly affect climacteric symptoms, with the exception of worsening vasomotor symptoms. No significant relation was seen between plasma levels of beta-endorphin and climacteric symptoms. CONCLUSION(S): Raloxifene modulates plasma levels of beta-endorphin without concomitantly relieving climacteric symptoms, as seen with hormone replacement therapy.

Aged↗
PubMedDate not supplied

Treatment of ductal carcinoma in situ of the breast: review of recent advances and future prospects.

Ductal carcinoma in situ (DCIS) is a heterogeneous disease characterized by noninvasive clonal proliferation of malignant epithelial cells arising from the mammary ducts and terminal ductal-lobular units. Its reported incidence is rising due to the wide adoption of screening mammography. The combination of nuclear grade and presence of necrosis is currently the best predictor of biological behavior. Approximately 25-50% of DCIS lesions progress to invasive disease if left untreated. The treatment options for DCIS include total mastectomy with or without immediate breast reconstruction (IBR), local excision (LE) plus adjuvant radiotherapy (RT), and LE alone. Total mastectomy is associated with lowest rates of local recurrence and breast cancer-specific mortality. If IBR is considered, then skin-sparing mastectomy (SSM) combined with autologous myocutaneous flap reconstruction can achieve excellent cosmesis without compromising local control. The role of adjuvant radiotherapy (RT) after LE remains controversial. Three recent randomized controlled trials have demonstrated that adjuvant RT after LE of localized DCIS significantly reduces the incidence of local recurrence. However, these trials did not identify any subgroups of patients where RT could be safely omitted and were criticized for lack of emphasis on standardized and meticulous tissue processing and pathological evaluation. Retrospective studies indicate that RT can be safely omitted after adequate LE (margin width > or = 1 cm) of small (< 15 mm), non-high grade DCIS not associated with necrosis. The role of tamoxifen in the treatment of DCIS continues to evolve. Formal axillary dissection is not appropriate for DCIS; however, the potential role of the sentinel node biopsy (SNB) in selected high-risk cases requires further evaluation. Areas of ongoing and future research include the potential role of third-generation aromatase inhibitors and third- and fourth-generation selective estrogen receptor modulators in women with hormone-sensitive DCIS; the potential role of cyclo-oxygenase type 2 inhibitors in DCIS treatment and prevention; the value of magnetic resonance and nuclear medicine imaging; and the clinical relevance of gene expression profiling, proteomics, radiofrequency or LASER ablation and mammary ductoscopy in the management of DCIS.

Breast Neoplasms↗
PubMed2002

[Hormone replacement therapy in peri- and postmenopause. Routine use is not indicated].

Hormone replacement therapy (HRT) with estrogens (in non-hysterectomized women with estrogens and progestins) during the peri- and postmenopausal period has been widely applied for many years. On the basis of new data, HRT is currently being critically reviewed. HRT administered for up to 5 years to treat climacteric hot flashes, mood changes and sleep disturbances continues to be advocated and is largely safe. When HRT is used for longer periods, as required for the prevention of osteoporosis, a possible increase in the relative risk for breast cancer must be considered. Correctly applied in combination with an adequate dose of progestins, HRT can avoid an increase in the endometrial cancer risk. HRT is no longer recommended for secondary prevention of cardiovascular disease, and its use in primary prevention has not been convincingly demonstrated. The hoped-for efficacy of HRT in the prevention of Alzheimer's disease has not been confirmed by the data. Selective estrogen receptor modulators (e.g. Raloxifene) and biphosphonates are efficacious drugs for the prevention and treatment of osteoporosis. For women at risk of developing cardiovascular disease, changes in lifestyle, lipid-lowering drugs (statins), blood pressure control, use of acetylsalicylic acid, among others, have well-documented efficacy in primary and secondary prevention.

Alzheimer Disease↗
PubMed2005

[SERMs: an update for clinicians].

With the successful manipulation by molecular pharmacological technology of the estrogenic properties of selective estrogen receptor modulators (SERMs) that are highly organ- and tissue-specific, SERMs have now become available for the management of osteoporosis, as they did for breast cancer earlier. This presentation focuses on raloxifene (RLX), a second-generation SERM and an agent of interest to clinicians engaged in the management of osteoporosis on a day-to-day basis. RLX is a unique agent, in that it exhibits similar but distinct effects on bone metabolism from those of estrogen. RLX also appears to exert milder inhibitory effects on bone resorption than bisphosphonates (BPs), another class of antiresorptive agents, while ample evidence suggests that RLX compares favorably with BPs in preventing a variety of non-traumatic fractures.

Animals↗
PubMed2005

Seladin-1 as a target of estrogen receptor activation in the brain: a new gene for a rather old story?

Experimental evidence indicates that estrogen exerts neuroprotective effects. According to the fact that Alzheimer's disease (AD) is more common in post-menopausal women, estrogen treatment has been proposed. However, the beneficial effect of estrogen or selective estrogen receptor modulators (SERMs) in preventing or treating AD is a controversial issue, which will be summarized in this review. Recently, a novel gene, named selective AD indicator-1 (seladin-1), has been isolated and found to be down-regulated in brain regions affected by AD. Seladin-1, which is considered the human homolog of the plant protein DIMINUTO/DWARF1, confers protection against beta-amyloid-mediated toxicity and from oxidative stress and is an effective inhibitor of caspase 3 activity, a key mediator of apoptosis. This review will present the up-to-date findings regarding seladin-1 and DIMINUTO/DWARF1. In addition, the possibility that seladin-1 may be a downstream effector of estrogen receptor activation in the brain, based on our recent experimental findings using a human fetal neuronal model, will be addressed.

Alzheimer Disease↗
PubMed2002

Effects of ospemifene (FC-1271a) on uterine endometrium, vaginal maturation index, and hormonal status in healthy postmenopausal women.

OBJECTIVE: Selective estrogen receptor modulators (SERMs) are drugs that exhibit both estrogen agonistic and antagonistic effects that are tissue-specific. Ospemifene (FC-1271a) is a novel SERM compound, which has been shown in animal models to have estrogen-like effects on bone and the cardiovascular system, while having antiestrogen-like effects in uterus and breast. In this study, we investigated the effects of ospemifene on the uterine endometrium, vaginal maturation index and hormonal status in healthy postmenopausal women. METHODS: The study was conducted as a double-blind, placebo-controlled phase I study, where 40 healthy postmenopausal women volunteers were randomized to receive daily oral doses of ospemifene either 25, 50, 100 or 200 mg or placebo for 12 weeks. Vaginal ultrasonography and endometrial biopsy were performed and vaginal maturation index determined at baseline and at 12 weeks' visit. Serum concentrations of estradiol, luteinizing hormone, follicle stimulating hormone (FSH), sex-hormone binding globulin (SHBG), parathyroid hormone and prolactin were determined from samples taken at baseline, at 4 days and at 4, 12, and 16 weeks' visits. Climacteric symptoms were assessed using 12 visual analogue scales (VAS) at baseline and at the end of the study. RESULTS: No clinically significant changes were seen in endometrial thickness at any dose level. Ospemifene exerted a very weak estrogenic effect on endometrial histology. On the other hand, it induced a clear estrogenic effect on vaginal epithelium. Among the endocrine parameters only FSH and SHBG showed significant dose dependent changes; FSH decreased and SHBG increased during the treatment. In general, ospemifene was well tolerated. The 25 and 50 mg doses tended to reduce climacteric symptoms, but no statistically significant differences were observed between different doses of ospemifene and placebo. The highest dose level (200 mg) induced more subjective adverse reactions, especially hot flushes, than lower doses. CONCLUSION: Our study suggests that a safe and well tolerated dose of ospemifene for potential clinical use may be between 25 and 100 mg. Further studies are needed to substantiate the results of this Phase I pilot study.

Administration, Oral↗
PubMed2000

17beta-estradiol, but not raloxifene, decreases thrombomodulin in the antithrombotic protein C pathway.

Raloxifene is a nonsteroidal selective estrogen receptor modulator (SERM) that mimics the effects of estrogen on some plasma lipids and may have direct effects on the vascular wall. The objective of this study was to determine the effects of 17beta-estradiol, raloxifene, and LY139,478 (a related benzothiophene SERM) on the anticoagulant protein C pathway. In human vascular endothelial cells activated with interleukin-1 (IL-1), we demonstrated decreased thrombomodulin-dependent protein C activation. 17beta-estradiol reduced the anticoagulant properties of both unstimulated and IL-1-activated endothelial cells by decreasing thrombomodulin expression. In contrast, raloxifene and LY139,478 enhanced the anticoagulant properties of both unstimulated and IL-1-activated endothelial cells through upregulation of thrombomodulin. Regulation of the protein C pathway via thrombomodulin on vascular endothelium may be a novel mechanism by which SERMs could potentially confer cardioprotective effects and reduce the thrombotic risk associated with HRT in compromised patients.

Cells, Cultured↗
PubMed2002

[Estrogen replacement therapy: for whom, why and how?].

Symptoms may appear during the perimenopause, but it is often difficult to treat them at that time. Progestins are used to treat abnormal bleeding. Low dose hormone replacement therapy (HRT) or oral contraception are often used also. HRT can be used to maintain the bone density even in elderly women. Nevertheless, the treatment is often not taken for sufficient time. In order to improve compliance, a number of low dose HRT have been developed. For most patients these medications will preserve the bone mass, but data showing a fracture protection are missing. The exact role of HRT on cardiovascular pathologies is controversial. Observational data indicated a protective effect on atherosclerosis. But randomised studies contradicted these results: the latest randomised trial involving a continuous combined regimen of estrogen and progestin reported an increased risk in cardiovascular events as compared to placebo. It is still possible that estrogen decreases atheromatosis but that it increases the risk of thrombosis. SERM (Selective Estrogen Receptor Modulators) have agonistic and antagonistic proprieties to estrogens on selective tissues. They have a proven protective effect on bone and possibly also on cardiovascular system. Nevertheless, the risk of thrombosis seems to be similar to that of estrogens. The risk of breast cancer seems to be increased in long term HRT users but this subject is also controversial since discordant results have been reported. Furthermore, breast cancer mortality in HRT users seems to be lower than in non users.

Breast Neoplasms↗
PubMed2002

[Effects and safety of SERM in animal study].

SERM (estrogen receptor modulator) has the different effects of both estrogen agonist and antagonist depending on the organs. Raloxifene has been developed as a medicine for the treatment of postmenopausal osteoporosis, which reduces bone loss by suppressing bone resorption after ovariectomy (estrogen agonist for bone), while not increasing the proliferation of uterine endometrium or estrogen sensitive mammary cancer (estrogen antagonist for uterus or mamma).

English Abstract↗
PubMed2004

Non-classical regulation of estrogen receptor-alpha by ICI182,780.

Estrogen receptor-alpha (ER alpha) regulates transcription through a number of molecular mechanisms. Two mechanisms by which ER alpha acts directly in the nucleus have emerged: (1) in classical ER alpha action, estrogen-bound receptor binds estrogen response elements (ERE) and regulates promoters by recruiting coactivators or corepressors to DNA; (2) non-classical action is not dependent on ER alpha binding to EREs; its mechanism is not as clearly defined as classical action. In many instances, non-classical action is mediated by tethering of ER alpha to other DNA-binding proteins, facilitating recruitment of coregulators to transcription regulatory sequences. In some cell types, non-classical stimulation can be enhanced by antagonists and repressed by agonists of ER alpha. Here, we show that non-classical action of ER alpha in 293 cells occurs in a wide range of enhancers and enhancer binding proteins. ER alpha stimulates AP-1 elements, cyclic AMP response elements (CRE), and serum response elements (SRE) in the presence of the antiestrogen ICI182,780. Further, in the presence of ICI182,780, ER alpha stimulates activation domains of Jun, ATF-2, Elk, and CRE-binding protein (CREB). Non-classical ER alpha regulation described here does not appear to be sensitive to point mutations which affect classical and tethered ER alpha action; moreover, in our experiments, non-classical action is uniquely sensitive to nuclear transport inhibition by leptomycin B. Because ICI182,780 appears to affect multiple and diverse transcriptional systems, our results are likely explained by ER alpha-dependent modulation of common components of the transcriptional machinery and may not be completely explained by tethering of ER alpha to specific transcription factors.

Cell Line↗
PubMed2004

A review of adjuvant hormonal therapy in breast cancer.

Breast cancer is the most common carcinoma diagnosed in women today excluding non-melanoma skin cancers. It has been well documented that estrogen plays a critical role in its development and is a major target for treatment. For many years, tamoxifen has been the gold standard for adjuvant hormonal therapy in breast cancer patients. With newer products targeting different mechanisms to suppress estrogen production, patients now have many decisions regarding their care. Agents such as luteinizing hormone releasing hormone (LHRH) agonists can suppress ovarian function in premenopausal patients and have been shown to be as effective and even better than chemotherapy (CMF--cyclophosphamide, methotrexate, fluorouracil-containing regimens) in certain patient populations. Tamoxifen continues to be an option as well as toremifene, a similar selective estrogen receptor modulator. With the advent of newer third generation aromatase inhibitors (anastrozole, letrozole and exemestane) toxicities have been documented to be less and in some cases they are more efficacious than the standard, tamoxifen. This article reviews the current data regarding ovarian suppression, ovarian suppression plus tamoxifen, tamoxifen, toremifene, anastrozole, letrozole, and exemestane in the treatment of adjuvant hormonal-sensitive breast cancer.

Antineoplastic Agents, Hormonal↗
PubMed1999

[New developments in the hormonal treatment of breast cancer in postmenopausal women].

Nowadays the role of the hormonotherapy in the treatment of breast cancer in postmenopausal women is well established. The benefit of tamoxifen is demonstrated in the adjuvant setting as well as in the treatment of advanced breast cancer. After tamoxifen failure the hormonosensitive patients can be offered a second and a third hormonal treatment. The developments of new hormonotherapies recently or shortly put at the disposal of oncologists, such as new antiestrogens or selective estrogen receptors modulators (SERM), new steroidal and nonsteroidal aromatase inhibitors and antiprogestins are reviewed as well as the recent data on the use of tamoxifen in the primary prevention of breast cancer. The principal characteristics and the potential therapeutic uses of these agents are reviewed in the treatment and prevention of breast cancer in postmenopausal patients.

Anticarcinogenic Agents↗
PubMed2000

Managing menopause.

Many women will spend one third of their lifetime after menopause. A growing number of options are available for the treatment of menopausal symptoms like vasomotor instability and vaginal atrophy, as well as the long-term health risks such as cardiovascular disease and osteoporosis that are associated with menopause. Currently, hormone replacement therapy (estrogen with or without progestin) is the primary treatment for the symptoms and long-term risks associated with menopause. However, recent evidence calls into question the protective effect of estrogen on cardiovascular disease risk. The association of risk for breast cancer with estrogen replacement therapy also has not been fully clarified. In addition, many women cannot or choose not to take hormones. For treatment of osteoporosis and heart disease, pharmacologic choices include antiresorptive agents such as bisphosphonates and calcitonin, and estrogens or selective estrogen receptor modulators such as raloxifene. In addition, complementary options that include vitamins, herbal treatments, exercise and other lifestyle adaptations are gaining increased interest. The growing number of choices and questions in this area emphasizes the need to individualize a treatment plan for each woman to meet her specific needs.

Aged↗
PubMed2003

Endocrine therapy of advanced disease: analysis and implications of the existing data.

Endocrine therapy remains an important approach to the treatment of metastatic breast cancer because of its effectiveness and excellent tolerability. In the last 10 years, a number of new endocrine therapies have been introduced. These include the luteinizing hormone-releasing hormone agonists, which produce menopausal changes in premenopausal women; the aromatase inhibitors, which prevent production of estrogen in postmenopausal women; and the estrogen receptor down-regulator fulvestrant (Faslodex), which is effective in postmenopausal women whose tumors have progressed following response to other selective estrogen receptor modulators. The endocrine cascade for the treatment of premenopausal women with metastatic disease now involves the concurrent or sequential combination of a luteinizing hormone-releasing hormone analogue and tamoxifen, whereas the cascade for the treatment of postmenopausal women can begin with tamoxifen followed by an aromatase inhibitor or with an aromatase inhibitor followed by tamoxifen. The optimal cascade following the use of an aromatase inhibitor and tamoxifen in postmenopausal women remains unclear, but fulvestrant and megestrol acetate or the use of an aromatase inactivator (exemestane) following an aromatase inhibitor are all available options with some activity. Over the next few years, clinical trials will clarify the optimal sequence of endocrine therapy for postmenopausal women. The use of estrogen and progesterone receptor status to select for endocrine therapy is undeniably crucial. HER2/neu overexpression may also predict response to endocrine therapy, but this remains controversial.

Antineoplastic Agents, Hormonal↗
PubMed2006

Effects of genistein on angiotensin-converting enzyme in rats.

Genistein (4,5,7-trihydroxyisoflavone), a phytoestrogen with selective estrogen receptor modulator properties, has received a great deal of attention over the last few years because of its potentially preventive roles against cardiovascular diseases. However, the precise molecular mechanisms for this modulation are not fully elucidated. In this study, we investigated (both in vivo and in vitro) the relationship between genistein and the changes of angiotensin-converting enzyme (ACE) in rat aortic endothelial cells (RAECs), serum and tissue (aorta). ACE expression was assessed by the immunofluorescence and the reverse transcriptase-polymerase chain reaction (RT-PCR) assay. Serum and tissue ACE activity was detected with a commercial kit. Genistein exhibited a concentration-dependent inhibitory effect on the expression of ACE, particularly at higher concentrations (24.70+/-1.20 at 100microM, P<0.01, and 18.22+/-0.92 at 200microM, P<0.01 compared with the control group 50.49+/-5.19). The estrogen receptor blocker tamoxifen at 100microM attenuated this effect of genistein. The extracellular signal-regulated kinase 1/2 (ERK1/2) blocker PD98059 also markedly inhibited this effect. The observations in vivo were highly consistent with the data in RAECs. These results indicate that genistein inhibits the expression of ACE via estrogen receptor and subsequently ERK1/2 signaling pathway in RAECs. Our results suggest that the down-regulation of ACE with a consequent change in the circulating levels of angiotensin II (Ang II), vasorelaxant angiotensin-(1-7) [Ang-(1-7)] and bradykinin plays an important role in cardiovascular effects of genistein through the ERK1/2 pathway.

Animals↗
PubMed2003

An approach to postmenopausal osteoporosis treatment: a case study review.

PURPOSE: To review and discuss the clinical evaluation and therapeutic options for a postmenopausal woman with osteoporosis. DATA SOURCES: Review of scientific literature, practice guidelines, and a case study. CONCLUSIONS: To prevent and treat postmenopausal osteoporosis, women should be encouraged to perform weight-bearing exercise, to not smoke, and to optimize calcium and vitamin D intake through diet and supplements. Drug regimens are effective and well tolerated in postmenopausal women with osteoporosis. IMPLICATIONS FOR PRACTICE: Drugs currently approved by the U.S. Food and Drug Administration for the treatment of postmenopausal osteoporosis include the bisphosphonates risedronate and alendronate; the selective estrogen receptor modulator, raloxifene; and intranasal calcitonin-salmon spray. Bisphosphonates have demonstrated the most impressive fracture risk reduction in prospective clinical trials of women with postmenopausal osteoporosis. Risedronate has consistently demonstrated significant reductions in vertebral fracture risk at 1 year and in vertebral and nonvertebral fracture risk at 3 years. Alendronate has demonstrated significant reductions in vertebral and nonvertebral fracture risk after 3 years.

Aged↗
PubMed2003

Ligand-induced regulation of ERalpha and ERbeta is indicative of human breast cancer cell proliferation.

Two estrogen receptors (ER), ERalpha and ERbeta, are expressed in breast cancer but their role in treatment response is unclear. The overall objective of this study was to determine if the presence of ERbeta protein in breast cancer cell lines is an indicator of a poor prognosis based on cell proliferation. In addition, we determined the effect of estradiol (E2) and selective estrogen receptor modulators (SERMs), such as tamoxifen and genistein, on ERalpha and ERbeta protein regulation, to help in the understanding of the mechanism behind their role in modulating cell proliferation. Using western blot and immunofluorescence analysis, the ER positive cell lines, MCF-7 and T47D, were found to contain both ERalpha and ERbeta, and thus were used as model systems. E2 and genistein, which increased cell proliferation in both cell lines, induced an up regulation of ERbeta in both cell lines. This suggests that an estrogenic response in breast cancer cells is indicated by an increase in ERbeta expression. Tamoxifen decreased cell proliferation in both cell lines, while up regulating ERalpha in both cell lines, suggesting that antiestrogenic response is indicated by an increase in ERalpha expression. Although a change in the ERalpha/ERbeta ratio may play a role in the effect seen in cell proliferation, this study indicates that ERbeta is a poor prognosticator of cell proliferation in breast cancer and that ERalpha is a positive prognosticator of responsiveness to antiestrogen treatment.

Antineoplastic Agents↗