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PubMed1999

Risks versus benefits in the clinical application of aromatase inhibitors.

Third-generation aromatase inhibitors are able to reduce circulating plasma estrogen concentrations in postmenopausal women to below detectable limits and significantly inhibit aromatase, the enzyme responsible for estrogen synthesis, in normal breast tissue and breast tumors. Their role in the treatment of advanced breast cancer is well established and their use in adjuvant therapy is currently being explored. On the basis of these trials, evaluation of these inhibitors in the prevention of breast cancer may be appropriate. Aromatase inhibitors have non-specific toxic side effects including (but not limited to): asthenia, headache, nausea, peripheral edema, fatigue, vomiting and dyspepsia. In addition, certain endocrinological side effects in postmenopausal women are notable, namely hot flushes and vaginal dryness. In advanced breast cancer, these side effects result in treatment withdrawal in few (<4%) women. Of concern, however, are the potential long-term endocrinological side effects in women receiving treatment as first-line adjuvant therapy or in sequence or combination with tamoxifen or other selective estrogen receptor modulators (SERMs). Current studies of adjuvant treatments for breast cancer in healthy women are carefully evaluating, in addition to general toxicities, the effects on bone, lipid metabolism, cardiovascular risk, quality of life and menopausal symptoms. Careful evaluation of all-cause morbidity and mortality is necessary to plan trials and justify long-term use of aromatase inhibitors in the treatment or prevention of breast cancer in healthy women.

Anticarcinogenic Agents↗
PubMed2005

Regulation of osteoblastic phenotype and gene expression by hop-derived phytoestrogens.

Certain plant-derived compounds show selective estrogen receptor modulator (SERM) activity and may therefore be an alternative to the conventional hormone replacement therapy, which prevents osteoporosis but is also associated with an increased risk of breast and endometrial cancers. In the current study, we tested the effects of the hop-derived compounds 8-prenylnaringenin, 6-prenylnaringenin, xanthohumol and isoxanthohumol (1) to modulate markers of differentiation and gene expression in osteoblasts and (2) to regulate proliferation in MCF-7 breast cancer cells. Additionally, we analyzed the ER-binding affinities of these hop compounds as well as the ER-mediation of their effects. Bone-forming activity and ER-subtype specificity were investigated by measuring alkaline phosphatase (AP) activity in hFOB/ERalpha cells and regulation of gene transcription for AP, interleukin-6, pS2 and von Willebrand factor (VWF) in U-2 OS/ERalpha and U-2 OS/ERbeta cells. Our results demonstrate that AP, pS2 and VWF mRNA levels are significantly increased by the compounds in an estrogen-like manner via both ERalpha and ERbeta, while IL-6 is down-regulated in U-2 OS/ERalpha cells. Consistently, AP enzymatic activity is up-regulated by all compounds in hFOB/ERalpha9 cells. Depending on their concentration, all compounds show proliferative effects in MCF-7 cells. Except for 8-PN the hop constituents display an ERbeta-preference. Reversal of estrogen-specific AP-induction in Ishikawa cells indicates an ER-regulated mechanism. Finally, the flavonoids display cytotoxic effects only at high concentrations (> or =10(-4)M). In summary, we have demonstrated for the first time that specific phytoestrogen compounds found in hop extracts exert estrogen-like activities on bone metabolism. Regarding a potential for use in osteoporosis-prevention therapy, the dosage of a phytoestrogen, which is taken, will play an important role concerning a desired in vivo profile.

Adult↗
PubMed1998

LY353381 x HCl: an improved benzothiophene analog with bone efficacy complementary to parathyroid hormone-(1-34).

LY353381 x HCl is a benzothiophene analog that is structurally related to raloxifene with potent selective estrogen receptor modulator activity in the ovariectomized rat model of postmenopausal osteoporosis. The effects of LY353381 x HCl on bones, body weight, and uterine weight were evaluated in 7-month-old rats with osteopenia that was induced by ovariectomizing animals for 1 month before initiation of treatment with several agents individually, in combination, or in sequence. LY353381 x HCl was administered daily by itself for 90 days, in combination with the amino-terminal fragment of PTH-(1-34) (PTH) for 90 days, or sequentially after PTH when PTH was discontinued after 45 days of treatment. Additionally, comparisons were made of animals treated with PTH alone, 17alpha-ethynyl estradiol alone, equine estrogens (Premarin) alone, raloxifene alone, or combinations of PTH and equine estrogens or raloxifene. Ovariectomy induced increases in the rate of bone turnover and body weight while decreasing bone mineral density, bone mineral content, bone strength, trabecular bone volume, trabecular thickness, trabecular number, and uterine weight. LY353381 x HCl at 0.01-1 mg/kg had marginal effects on body weight and no effect on uterine weight compared with those in ovariectomized controls, in contrast to 17alpha-ethynyl estradiol or equine estrogens. LY353381 x HCl prevented further bone loss due to ovariectomy in tibia, femora, and lumbar vertebra, like 17alpha-ethynyl estradiol but unlike equine estrogens. LY353381 x HCl prevented the resorption of trabecular bone spicules, like 17alpha-ethynyl estradiol, but inhibited bone formation activity to a lesser extent than 17alpha-ethynyl estradiol. In this model, 17alpha-ethynyl estradiol appeared to be more efficacious after 3 months of treatment than equine estrogens in the proximal tibia metaphysis, suggesting efficacy differences between metabolites of 17beta-estradiol in bone. PTH at 10 microg/kg had no effect on body weight or uterine weight, but significantly increased bone mass to beyond those in sham-operated controls, baseline controls, and groups receiving other individual treatments at both axial and appendicular sites. The combination of LY353381 x HCl and PTH increased bone mass at a faster rate and to a greater extent than PTH alone or the combinations of equine estrogens/PTH and raloxifene/PTH at trabecular bone sites. The LY353381 x HCl/PTH combination improved bone mass and quality beyond any agent alone in regions enriched for cancellous bone, but was not significantly better than PTH alone on cortical bone. Additionally, when PTH was discontinued at 45 days, LY353381 x HCl prevented the rapid loss of bone observed in controls. Therefore, LY353381 x HCl appears to be useful by itself, in combination, or in sequence with PTH to replace lost bone in postmenopausal women.

Animals↗
PubMed2005

Evaluation of hormone replacement therapy.

Hormone Replacement Therapy (HRT), once considered as the gold standard of treatment of menopausal symptoms and osteoporosis, introduced about seventy years ago still continuing with lot of controversies. Menopause, a transitional period of women's life, is not an illness when oestrogen level falls leading to its consequences. Results of earlier observational studies showed beneficial effects of HRT including cardiovascular protection. But all recent randomized controlled trials have failed to prove these positive effects, rather increases the cardiovascular risk and breast cancer. Women's Health Initiative(WHI), one of the recent randomized controlled trials was stopped prematurely in 2002 due to unfavorable risk-benefit ratio. HRT is not the only way of treating the menopausal symptoms and other consequences of estrogen deficiency. There are suitable alternatives without bearing the risk of HRT. Vasomotor symptoms with hot flushes and sweating experienced by about 75 percent of menopausal women can be treated with alternatives like phyto-estrogens, selective estrogen receptor modulators (SERMs), clonidine, selective serotonin reuptake inhibitors, acupuncture, exercise, behavioral therapy etc. HRT is no longer considered as the first line of treatment of postmenopausal osteoporosis. It can be treated with alternatives like regular weight bearing exercise, balanced calcium rich diet, maintaining weight, avoidance of bone robbers, (like excess alcohol, caffeine, smoking), use of SERMs etc. Use of HRT should be individualized and rationalized considering its risks and benefits.

Breast Neoplasms↗
PubMed1999

An expanding landscape. Osteoporosis. Treatment options today.

Choices for osteoporosis therapy have expanded within the past 5 years. This article provides an overview of currently available therapy options. Exogenous estrogen can prevent and treat osteoporosis and is available in several delivery routes. Calcitonin is also designed to reduce bone loss in osteoporosis. Bisphosphonates such as alendronate prevent bone resorption by inhibiting osteoclasts and causing increased osteoclast cell death. Raloxifene is a selective estrogen receptor modulator and is the newest osteoporosis medication on the market. It may also have beneficial effects on breast cancer risk. All postmenopausal women should obtain 1,000 mg to 1,500 mg of calcium and 400 IU to 800 IU of vitamin D every day--regardless of any prescription therapy regimen for osteoporosis. They should also perform weight-bearing exercise, such as walking, for 20 to 30 minutes every day or for 1 hour three times a week.

Aged↗
PubMed2003

Uncoupling of 5-HT1A receptors in the brain by estrogens: regional variations in antagonism by ICI 182,780.

Previously we have shown that 17beta-estradiol (in vivo and in vitro) rapidly decreases the function of serotonin(1A) (5-HT(1A)) receptors, allowing us to hypothesize that 17beta-estradiol accomplished this via activation of a membrane estrogen receptor. Hippocampus and frontal cortex obtained from ovariectomized rats were incubated with 17beta-estradiol or bovine serum albumin (BSA)-estradiol in the presence or absence of the estrogen receptor (ER) antagonist ICI 182,780. Membranes were prepared to measure R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding (a measure of 5-HT(1A) receptor coupling and function). In both hippocampus and frontal cortex, 17beta-estradiol and BSA-estradiol (50 nM) decreased R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding. ICI 182,780 blocked the effect of both the estrogens in hippocampus, but only the effect of 17beta-estradiol in frontal cortex. Due to the inability of ICI 182,780 to block the effects of BSA-estradiol in frontal cortex, similar experiments were performed using the selective estrogen receptor modulator tamoxifen as the agonist. Tamoxifen (100 nM and 1 microM) decreased R(+)8-OH-DPAT-stimulated [(35)S]GTPgammaS binding. ICI 182,780 (1 microM) blocked the ability of tamoxifen to decrease 5-HT(1A) receptor coupling in the hippocampus, but not in the frontal cortex. Taken together, these data support the existence of a pharmacologically distinct ER in hippocampus vs. frontal cortex that might be responsible for rapid uncoupling of 5-HT(1A) receptors.

Animals↗
PubMed2002

Chemoprevention of prostate cancer: current status and future directions.

Prostate cancer chemoprevention can be described as the administration of natural products and pharmaceutical agents that inhibit one or more steps in the natural history of prostatic carcinogenesis. The principle components of the chemoprevention strategy are closely connected to this natural history and include: (a) agents and their molecular targets; (b) strategic intermediate endpoint biomarkers (IEBs) and their critical pathways; (c) cohorts identified by genetic and acquired risk factors and (d) efficient designs that combine these elements into a cohesive clinical trial. The primary goal is to find effective noncytotoxic agents that modulate the promotion and progression from normal epithelium to dysplasia to high-grade prostatic intraepithelial neoplasia (HGPIN) to locally invasive cancer and metastatic disease. Another important target for chemoprevention is to modulate progression to clinically aggressive disease and to maintain an androgen-sensitive clinical state and delay the emergence of androgen resistance. There is a rationale for use of antiandrogens as the lead class, e.g., 5 alpha receptor inhibitors (5ARI), for chemoprevention of prostate cancer. Nevertheless, the desire to improve the therapeutic index, achieve synergy (5ARI may have only modest anticancer effects) and prevent the emergence of drug (androgen) resistance provide incentives for developing other effective agents and combinations. The availability of more than a dozen classes of noncytotoxic pharmaceutical and natural products already in clinical development create many opportunities for rational combination therapy. Several agent classes have a pharmacodynamic basis for combination with antiandrogens including antiproliferatives, selective estrogen receptor modulators (SERMs), proapoptotic antioxidant micronutrients and selective cyclo-oxygenase (COX)-2 inhibitors. Many other rational pharmacodynamic combinations without antiandrogens are feasible. It is anticipated that in the future, a selective COX-2 inhibitor may be combined with other agent classes such as proapoptotic antioxidant micronutrients, receptor tyrosine kinase modulators, antiangiogenic modulators, antiproliferative/differentiating agents, NFkappaB modulators, IGF-1 modulators and other novel proapototic nonsteroidal drugs. A novel target for rational combinations is the hypermethylation of GST-PI leading to functional silencing of this key anticarcinogen defense enzyme in precursors (HGPIN) and prostate cancer. Factorial designs are well suited for evaluating the individual and combined effects of each agent in a single trial design. There are a number of moderate to high-risk cohorts and clinical models of primary and secondary prevention that can be employed in both short-term developmental (translational) trials for proof of biologic activity and in intermediate sized longer-term chemoprevention trials for proof of efficacy against prostate cancer. Strategic IEBs are needed to more efficiently monitor short-term biologic activity and validate efficacy. The emergence of new powerful tools such as gene chip cDNA microarrays for multiplex gene expression profiling and proteomic analysis of tissue based and secreted proteins will accelerate the identification of new molecular targets, strategic endpoints, cohorts at risk and the design of rational combination trials.

Anticarcinogenic Agents↗
PubMed2005

Aromatase inhibitors for the treatment and prevention of breast cancer.

In a review of current information on aromatase inhibitors (AIs) and their use in breast cancer treatment and prevention, published reports were obtained through a Medline search. Tamoxifen, a selective estrogen receptor modulator, is approved for use in metastatic breast cancer (MBC), the adjuvant treatment of breast cancer, and the prevention of breast cancer in women at high risk. The 50% reduction in breast cancer incidence seen with tamoxifen is significant for women at increased risk but is accompanied by notable toxicities such as thrombotic events and endometrial cancer. Therefore, the development of other effective agents with less toxicity would be a major advance in breast cancer prevention. Aromatase inhibitors, recently approved for the treatment of MBC and in the adjuvant setting, are proving to be slightly more effective than tamoxifen therapy. These drugs, approved for use in only postmenopausal women, inhibit the enzyme aromatase and thereby lower circulating functional estrogen. To date, the most concerning side effect of these agents is an increase in fracture rate. Compared with tamoxifen, thrombotic events and endometrial cancer rates are much lower. Ongoing data from the Arimidex, Tamoxifen, Alone or in Combination trial continue to favor anastrozole over tamoxifen in the reduction of primary contralateral breast cancers. This information has prompted breast cancer chemoprevention trials with AIs. Although tamoxifen is the gold standard for prevention therapy, results of ongoing studies may indicate a role for AIs in the prevention of breast cancer.

Adult↗
PubMed1998

The estrogen receptor's involvement in osteoblasts' adaptive response to mechanical strain.

The estrogen receptor's role in bone cells' response to mechanical strain was investigated by studying the effect of the estrogen receptor modulators ICI 182, 780 and tamoxifen on the proliferation of primary cultures of rat long bone-derived osteoblasts stimulated by the independent and combined effects of 17beta-estradiol, mechanical strain, and the mitogens basic fibroblast growth factor (bFGF), truncated insulin-like growth factor (tIGF)-I and tIGF-II, and epidermal growth factor (EGF). 17Beta-estradiol (10(-10) M to 10(-8) M) increased [3H]thymidine incorporation equally in cells from males and females, as did a single period of cyclical strain in the plastic strips onto which the cells had been seeded (peak strain 3,400 microepsilon, 600 cycles, 1 Hz). At 10(-8) M, neither ICI 182,780 nor tamoxifen had any effect on basal [3H]thymidine incorporation in these cells, but both compounds prevented their proliferative responses to 10(-8) M 17beta-estradiol. Tamoxifen eliminated and ICI 182,780 substantially reduced the proliferation stimulated by strain. 17Beta-estradiol partially rescued the strain-related response from the effect of tamoxifen but not that of ICI 182,780. Both tamoxifen and ICI 182,780 reduced proliferation stimulated by 10(-8) M EGF but had no effect on that by 10(-7) M bFGF or tIGF-I and tIGF-II. That both ICI 182,780 and tamoxifen, which in other tissues act as estrogen antagonists, should reduce osteoblast proliferation stimulated by 17beta-estradiol and EGF, but not that by FGF or the IGFs, was expected since the mitogenic effects of estrogen and EGF involve the estrogen receptor, whereas those of FGF and the IGFs do not. That these compounds should prevent osteoblasts' proliferative response to strain suggests that strain also stimulates mitogenesis by a mechanism involving the estrogen receptor. If this is so, bones' reduced ability to maintain their structural strength after the menopause could be explained by less effective strain-related (re)modeling when estrogen is absent and, among other changes, the estrogen receptor could be down-regulated.

Animals↗
PubMed2000

Preventing fractures in postmenopausal women with osteoporosis. A review of recent controlled trials of antiresorptive agents.

The evidence from randomised, controlled trials of the ability of antiresorptive treatments to reduce the risk of fractures in postmenopausal women with osteoporosis is reviewed and summarised. The aminobisphosphonates, alendronic acid and risedronic acid, and the selective estrogen receptor modulator raloxifene have all been shown to reduce the incidence of radiographic vertebral fractures. Only alendronic acid and risedronic acid have been shown to reduce the incidence of non-spine fractures in women with postmenopausal osteoporosis. There is evidence of antifracture efficacy for calcium plus vitamin D, primarily in a nursing home setting or in people with low intakes of these nutrients. Furthermore, since both the placebo and active treatment groups received calcium and vitamin D in most controlled trials of antiresorptive agents, it appears that the other agents provide benefits beyond those of calcium and vitamin D alone. There is insufficient published evidence from randomised controlled trials to convincingly support the antifracture efficacy of other agents, including calcitonin, estrogen and etidronic acid, at this time. Data from observational studies suggest, however, that estrogen and etidronic acid may have antifracture efficacy in this population.

Calcitonin↗
PubMed2002

[Review of risk factors for breast cancer--what's new?].

Breast cancer is the most common malignancy in women and constitutes 18% of all cancers in women. Female gender, age and country of birth are the strongest determinants of disease risk. Family history and mutations in tumor suppressor genes BRCA1 and BRCA2 are important correlates of lifetime risk. Genetic polymorphisms associated with estrogen synthesis and metabolism are viewed as major factors in breast cancer prevalence in specific populations. Atypical hyperplasia and ductal/lobular carcinoma in situ although uncommon, are considered as pre-malignant conditions as well as markers for invasive breast cancer. Lately, increased bone density and high breast tissue density on mammogram in postmenopausal women have been reported in association with increased risk of breast carcinoma, probably attributable to increased levels of endogenous estrogen. Serum estrogen levels are higher in breast cancer cases as compared with controls. Current use of oral contraceptives and prolonged, current or recent use of postmenopausal hormonal replacement therapy are also considered as risk factors for breast cancer. Tamoxifen and raloxifene, selective estrogen receptor modulators, were shown to reduce breast cancer risk among high-risk women. Various nutrients were evaluated for their possible effect on breast cancer risk but further studies are needed. High socioeconomic status is found to be associated with increased risk of breast malignancy for as yet unestablished reasons. Studying breast cancer risk factors and further research into the molecular etiology of the disease will enable early diagnosis and detection of high-risk women and ultimately improve prognosis.

Breast Neoplasms↗
PubMed2006

Effect of concurrently coadministered drugs on the pharmacokinetic/pharmacodynamic profile of centchroman, a nonsteroidal oral contraceptive, in rats.

INTRODUCTION: Centchroman (international nonproprietary name: ormeloxifene) is a nonsteroidal selective estrogen receptor modulator, oral contraceptive, anticancer and antiosteoporotic agent that is intended for long-term use by women. In view of the vast clinical applications and interactions of steroidal oral contraceptives with commonly used therapeutic agents, the interaction potential of certain concomitantly administered therapeutic agents was investigated in terms of postcoital contraceptive efficacy (pharmacological) and the pharmacokinetic profile of centchroman in female Sprague-Dawley rats. The coadministered drugs used in the study were ciprofloxacin, cefixime, amoxicillin, metronidazole, amlodipine, atenolol, theophylline, metformin, pioglitazone and glibenclamide. MATERIALS AND METHODS: The pharmacological activity of centchroman was evaluated in sperm-positive female rats at 1.5 mg/kg, with or without coadministered drugs. Rats were sacrificed on Day 10 postcoitus, and autopsy was performed to check for the presence or absence of implantations. The estrogenic and antiestrogenic activities of centchroman were evaluated in immature ovariectomized rats. Pharmacokinetic interaction was studied in normal female rats with or without coadministered drugs. Serum samples were taken over 120 h and analyzed using a validated high-performance liquid chromatography method to generate the pharmacokinetic profile of centchroman. Pharmacokinetic parameters were estimated using noncompartmental analysis, and the results were compared. RESULTS: In pharmacological interaction studies, centchroman alone showed a 100% success rate when given alone or in the presence of coadministered drugs. The only exception was amoxicillin coadministration, with 66% rats in the group showing resorbed implantations. Further investigation with amoxicillin in ovariectomized immature rats indicates no alteration in the estrogenic and antiestrogenic profiles of centchroman. In pharmacokinetic interaction studies, most of the therapeutic agents affected the rate and extent of absorption of centchroman. In other pharmacokinetic parameters, clearance (CL) remained unchanged; however, there was decrease in bioavailability (F) and volume of distribution (V(d)) in some situations. CONCLUSIONS: The results indicate that there is no direct link between the altered pharmacokinetics of centchroman and the failure of pharmacological effect. The pharmacological interaction with amoxicillin could not be explained on the basis of alteration in the estrogenic and antiestrogenic activities of centchroman, indicating that different mechanisms are involved. The findings, however, suggest that amoxicillin coadministration may result in pharmacological interaction with centchroman and that caution should be taken in clinical practice.

Amoxicillin↗
PubMed2003

Estrogenic effects of toremifene and tamoxifen in postmenopausal breast cancer patients.

Intrinsic estrogenicities of the selective estrogen receptor modulators (SERMs) toremifene 60 mg daily or 200 mg daily and tamoxifen 20 mg daily (TOR60, TOR200 and TAM20) were compared in a randomized clinical study in postmenopausal women with advanced breast cancer. The study was open label in three parallel groups. Variables for analysis were serum follicle stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin (SHBG), estradiol (E2), antithrombin III (AT III), aspartate aminotransferase (ASAT) and vaginal cytology. Clinical efficacy and safety have been reported earlier. A total of 648 patients were randomized (221 to TOR60, 212 to TOR200 and 215 to TAM20). Sera were available for the analysis from 148, 165 and 156 and for vaginal cytology from 98, 93 and 86 patients, respectively. All treatment regimens showed tissue-specific and dose-dependent estrogen agonist effect. In the primary measure of in vivo estrogenicity, effect on hypothalamus-pituitary-axis, all three treatment regimens decreased serum FSH (p < 0.001). TOR200 was more potent than the two other treatments (p < 0.05), but surprisingly, TAM20 was more estrogenic than TOR60 (p < 0.001). As could be expected in postmenopausal women, the treatments had no effect on mean serum E2 concentrations and decrease of serum LH was similar to that of FSH. Estrogenic effect on the liver was seen as dose-dependent increase of SHBG with statistically significant differences between the treatment groups (p < 0.001). Trends of transient ASAT elevations in TOR200 group (p = 0.07) and in all treatment groups AT III decrease (p = 0.1) were seen in the beginning of the treatment. TOR60 or TAM20 did not have an effect on mean ASAT values, and AT III decreased in TAM20 group more than in the two other groups (p = 0.1 compared to TOR60 and p < 0.05 compared to TOR200). Estrogenic effects on vaginal superficial cells were higher in TOR60 and TOR200 groups when compared to TAM20 (p < 0.05). Toremifene and tamoxifen had tissue-specific and partially dose-dependent estrogenic effects in hypothalamus-pituitary-axis, in the liver and in the vaginal epithelium of postmenopausal women. In some tissues tamoxifen 20 may be more estrogenic than toremifene 60 mg/day.

Aged↗
PubMed2004

Genistein inhibits expressions of NADPH oxidase p22phox and angiotensin II type 1 receptor in aortic endothelial cells from stroke-prone spontaneously hypertensive rats.

Phytoestrogens are considered to be natural selective estrogen receptor modulators exerting antioxidant activity and improving vascular function. However, the mechanisms responsible for their antioxidative effects remain largely unknown. This study tested the hypothesis that genistein may provide significant endothelial protection by antioxidative effects through attenuating NADPH oxidase expression and activity. The results showed that genistein suppressed the expressions of the p22phox NADPH oxidase subunit and angiotensin II (Ang II) type 1 (AT1) receptor in a concentration- and time-dependent manner in aortic endothelial cells from stroke-prone spontaneously hypertensive rats examined by Western blot analysis. Treatment with genistein also remarkably reduced the Ang II-induced superoxide by the reduction of nitroblue tetrazolium, inhibited nitrotyrosine formation, and attenuated endothelin-1 production by ELISA via the stimulation of Ang II. However, when cells were pretreated with ICI-182780, an estrogen-receptor antagonist, at a concentration of 50 micromol/l for 30 min and then co-incubated with ICI-182780 and genistein for 24 h, the inhibitory effect of genistein was not blocked. In contrast, the inhibitory effect of genistein treatment was partially reversed by 30-min pretreatment of endothelial cells with GW9662, a peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist. Genistein thus appears to act as an antioxidant at the transcription level by the downregulation of p22phox and AT1 receptor expression. Our data also showed that the PPARgamma pathway was involved, at least in part, in the inhibitory effect of genistein on the expression of p22phox and AT1 receptors. The endothelial-protective effects of phytoestrogen may contribute to improvement of cardiovascular functions.

Angiotensin II↗
PubMed2000

Hormonal Therapy and Chemoprevention.

Hormone replacement therapy (HRT) can increase the quality as well as the length of life, but a prolonged use can also increase the risk of breast cancer. The combination of HRT and a selective estrogen receptor modulator (SERM) such as tamoxifen may retain the benefits while reducing the risks of either agent. A post hoc analysis of the Italian Tamoxifen Prevention Study showed a borderline significant reduction of breast cancer among women who were on HRT continuously and tamoxifen as compared with continuous HRT users who received placebo. Recent studies suggest that the standard dose of tamoxifen may be reduced to one-quarter (i.e., 10 mg every other day) without loss of its beneficial biological effects. Since the endometrial effect of tamoxifen seems to be both dose and time dependent, a dose reduction could substantially reduce the risk of endometrial cancer while retaining its preventive efficacy. On the other hand, the addition of HRT containing progestins could also minimize the risk of endometrial cancer associated with tamoxifen. Moreover, estrogen should reduce the incidence of vasomotor and urogenital symptoms, which are a major reason for tamoxifen withdrawal in prevention studies. Notably, in the National Surgical Adjuvant Breast Project (NSABP) P-1 trial, women ages 50 or younger had no increased incidence of adverse events, including endometrial cancer and venous thromboembolic events. One possible explanation for the lack of toxicity in premenopause is the presence of adequate circulating estrogen levels which prevent tamoxifen to act as an estrogen agonist at these target tissues. Moreover, data from the current Italian tamoxifen prevention trial indicate that the compliance was substantially higher for de novo and current HRT users as compared to women who never received HRT during the study. The combination of HRT and tamoxifen at low doses could thus reduce the risks and side effects while retaining the benefits of either agent.

Journal Article↗
PubMed2001

Constructive interactions among nutrients and bone-active pharmacologic agents with principal emphasis on calcium, phosphorus, vitamin D and protein.

Current and emerging bone active pharmacologic agents are capable of producing substantial gains in bone mass. However, nutrition must be adequate if this potential is to be realized. Calcium and vitamin D supplementation, for example, have both been demonstrated to augment substantially the skeletal response to estrogen therapy in postmenopausal women. The bisphosphonates and selective estrogen receptor modulator (SERMs) have all been tested only in the context of supplemental calcium and vitamin D. Therefore, it cannot be assumed that these bone active agents would be effective in the absence of these nutrients. Adequate protein intake has also been demonstrated to protect bone mass in the elderly and to improve recovery from osteoporotic fractures. Phosphorus intake, less extensively studied, may be more important than currently recognized, particularly in elderly individuals living alone, eating little meat, and receiving anti-osteoporosis treatment agents.

Adaptation, Physiological↗
PubMed2000

Phytoestrogens as hormone replacement therapy: an evidence-based approach.

Postmenopausal women have sought nonestrogen alternatives to hormone replacement in order to avoid possible risks and side effects of the therapy. Selective estrogen receptor modulators have been developed to tailor therapy to a specific risk/benefit profile that will best fit the patient. More women have looked to phytoestrogens, such as the isoflavones found in the soy plant, to tailor their menopausal therapy in a "natural" way. This review examines the evidence regarding the risks and benefits of isoflavones as hormone replacement therapy. Controlled trials have shown a reduction in postmenopausal hot flashes when subjects' diets were supplemented with soy. There is less evidence for a benefit in vaginal dryness symptoms. Furthermore, dietary supplementation also appears to lower total and low-density lipoprotein cholesterol in hypercholesterolemic subjects. A synthetic isoflavone, ipriflavone, has been shown in controlled trials to prevent postmenopausal bone loss, though there is much less evidence that soy isoflavones will accomplish this goal. Finally, although unopposed estrogen replacement may promote breast and endometrial cancer, there is no evidence that phytoestrogens will do the same. In contrast, great interest has been taken in the potential cancer-protective effects of phytoestrogens, though prospective evidence in postmenopausal women is not available. Although data regarding the use of isoflavone extracts are incomplete, dietary supplementation with soy foods appears to be a safe and possibly beneficial option for postmenopausal women.

Journal Article↗
PubMed1998

A practical guide to prescribing hormone replacement therapy.

Over the past 20 years there has been increasing interest in the menopause and hormone replacement therapy (HRT). More recently, postmenopausal HRT has been seen as a specific treatment for symptoms in the short term and preventative therapy in the long term. Women must be counselled regarding the risks and benefits of HRT according to the best available evidence. The patient should also be actively involved in the decision regarding HRT therapy, which should then improve patient compliance. Generally, an appropriate regimen of HRT can be formulated for the majority of patients. Progestogen should be added to therapy in women with an intact uterus in a cyclical or continuous regimen. The management of common estrogenic and progestogenic adverse effects is important in improving compliance. At present, new drugs are being developed for the management of the menopause (selective estrogen receptor modulators and phytoestrogens). Obviously, further research will be necessary to determine whether these drugs have advantages over regular HRT. By offering postmenopausal women HRT an attempt is made to optimise their physical and psychological well-being. However, HRT is not without adverse effects, the most worrying of which is the possible increase in breast cancer risk with long term use. However, with patient education efforts, treatment regimens acceptable to both patient and practitioner can be initiated; in this regard, the aim of the practitioner should be to help the menopausal woman make the decision which is the most appropriate for her.

Contraindications↗