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PubMedDate not supplied

Comparative cardiovascular effects of different progestins in menopause.

Progesterone receptors are present in the arterial wall and it is, therefore, likely that the arterial effects of progestins are mediated through progesterone receptors as well as through down-regulation of the estradiol receptor. Progestin therapy affects arterial function, as it can stabilize arteries in a state of vasomotor instability, but may also induce vasoconstriction of estrogenized vessels. Thus, the cardiovascular effects of progestins may influence the cardioprotective effect of estrogens. There has been some concern that a combined estrogen-progestogen therapy may attenuate some of estrogen's beneficial effects on cardiovascular health. This is a reflection of the past epidemiologic studies which have used primarily unopposed estrogen. The PEPI trial is the only large-scale, long-term study to compare directly the effects of different combined hormone replacement therapy regimens upon plasma lipids in healthy women. This study has shown that the adjunctive clinical impact of different progestogens on the beneficial effect of estrogen replacement therapy is trivial. It has never been proved that in normocholesterolemic women, e.g., those included in the PEPI trial, the increase in HDL reduces cardiovascular mortality or morbidity. Based on the results of PEPI, hormone replacement therapy has positive effects on key heart disease risk factors and endometrial tissue, and the magnitude of those effects does not differ significantly across the hormone replacement therapy regimens used. At present there are only few and inconclusive data available on the vascular effect of progestins in menopausal women. Some studies found that progestins reduced the beneficial effect of estrogens, while others did not. Our group has recently shown that different estrogen-progestin treatments have different effects upon vascular reactivity and that a careful selection of the progestin to be added to estrogen is of capital importance to preserve, or even enhance the positive vascular effects of estrogens. Few epidemiological studies have investigated the effect of adding a progestin to estrogen therapy upon cardiovascular mortality and morbidity, and all have suggested that hormone replacement therapy may be more effective than estrogen replacement alone in reducing cardiovascular events in primary prevention. The results of the recently published Heart and Estrogen/progestin Replacement Study (HERS) have added some critical data on the effect of hormone replacement therapy for secondary prevention in women with coronary artery disease. The study, however, is affected by several important methodological and statistical problems, which make its interpretation difficult and its conclusions useless for clinical practice. The results of the study should be evaluated with caution by physicians who give advice on hormone replacement therapy, and no woman should be taken off hormone replacement therapy because of HERS. Of importance, the results of HERS should not be used to suggest alternative forms of treatment, especially the selective estrogen receptor modulators (SERMs), for cardiovascular protection in postmenopausal women.

Adult↗
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↗
PubMed2005

Tissue-specific modulation of cyclooxygenase-2 (Cox-2) expression in the uterus and the v. cava by estrogens and phytoestrogens.

Cyclooxygenase 2 (Cox-2), an enzyme involved in prostaglandin production, is a key player in the development of pathologic changes, such as colorectal cancer, arteriosclerosis and thrombosis. In this study, we investigated the effects of estrogens, selective estrogen receptor modulators (SERMs), pure antiestrogens and phytoestrogens on the tissue-specific expression of Cox-2 in the uterus and the v. cava of ovariectomized female rats. Cox-2 expression could be detected in the uterine epithelium and in the endothelium of the v. cava. Cox-2 expression was time-dependently stimulated after administration of 17beta estradiol (E2) in the uterus. In the v. cava, E2 treatment resulted in a stimulated expression of the progesterone receptor (PR), a gene known to be regulated by E2, whereas Cox-2 was simultaneously down-regulated. Administration of the pure antiestrogen faslodex (Fas) had no effect on Cox-2 expression. In contrast, administration of tamoxifen (Tam) resulted in a decrease of Cox-2 expression in the v. cava but does not stimulate Cox-2 expression in the uterus. Interestingly, the same expression pattern of Cox-2 could be detected after dose-dependent administration of genistein (Gen). Here, down-regulation of Cox-2 could already be detected after administration of merely 0.5 mg/(kgBW) Gen, a dose where no effects on uterine weight were observed. In summary, our results demonstrate a reverse tissue-specific regulation of Cox-2 expression by estrogens in the v. cava and uterus indicating the existence of complex molecular mechanisms which have to be characterized in future studies. Remarkably, Tam and the phytoestrogen Gen, both share the ability to decrease the expression of Cox-2 in the v. cava without effecting its uterine expression. These observations may be of great importance with respect to potential beneficial or adverse effects of estrogens, SERMs and phytoestrogens on the cardiovascular tissue.

Animals↗
PubMed2005

Short-term effects of estrogen, tamoxifen and raloxifene on hemostasis: a randomized-controlled study and review of the literature.

INTRODUCTION: Estrogen therapy (ET), tamoxifen and raloxifene are associated with a two- to three-fold increased risk of venous thrombosis (VT); however, the mechanisms by which each drug increases venous thrombosis propensity are not fully understood. The objectives of this investigation were to compare the effects of these three treatments on hemostasis in a head to head randomized placebo-controlled trial. PATIENTS/METHODS: Ninety-four postmenopausal women were assigned to receive oral estrogen (conjugated equine estrogen [CEE] 0.625 mg, n=23), tamoxifen 20 mg (n=24), raloxifene 60 mg (n=24) or placebo (n=23) daily for 6 months. Blood samples were analyzed for procoagulant factors (prothrombin, factors VII [fVII], VIII [fVIII], IX [fIX] and XI [fXI], D-dimer and von Willebrand factor [vWf]), anticoagulant factors (antithrombin [AT], total and free protein S, protein C and activated protein C [APC] resistance) and fibrinolytic factors (thrombin activatable fibrinolysis inhibitor [TAFI] and plasminogen activator inhibitor-1 [PAI-1]), at baseline and at 6 months of treatment. RESULTS: Estrogen increased factor VII and D-dimer, and decreased antithrombin, total and free protein S and PAI-1. Changes with tamoxifen were distinct from estrogen with increases in factors VIII, IX, vWf and free protein S, and decreases in AT, total protein S, protein C and plasminogen activator inhibitor-1. Raloxifene produced similar effects as tamoxifen, but did not increase factor IX or decrease protein C. CONCLUSIONS: Estrogen, tamoxifen and raloxifene affected hemostasis favoring procoagulation and impairing anticoagulation. The biochemical effects of the selective estrogen receptor modulators (SERMs) were distinct from those of estrogen and differed only subtly from each other.

Biomarkers↗
PubMed2004

Treatment strategies for uterine leiomyoma: the role of hormonal modulation.

Uterine leiomyomas are the most common gynecological tumors and are a significant health concern for many women. Although the exact etiology of these tumors is unknown, epidemiological and experimental animal studies have established a role for ovarian hormones in the pathogenesis of this disease. Current treatment regimens for symptomatic tumors primarily require surgical intervention. However, a major emphasis of leiomyoma research involves understanding how hormones regulate tumor growth to target the hormonal dependence of these tumors with new therapeutic strategies. Gonadotropin-releasing hormone agonists that block hormone production and induce a hypoestrogenic milieu can be utilized as adjuvant therapy; however, these drugs do little to reduce tumor cellularity, and their negative impact on bone mineral density limits their use. Selective estrogen receptor modulators (SERMs) are nonsteroidal therapeutic agents that bind to the estrogen receptor and elicit tissue-specific estrogen agonist or antagonist effects. SERMs are effective in the treatment and prevention of breast cancer, and preclinical and clinical data suggest that these hormonal modulators may also be beneficial for the treatment of uterine leiomyomas. Continued efforts to understand the role of hormones in the development of this disease will allow the development of newer, less invasive treatment strategies, which will help minimize the negative impact of these tumors on women's health.

Estrogens↗
PubMed2004

Impact of the nuclear receptor coactivator AIB1 isoform AIB1-Delta3 on estrogenic ligands with different intrinsic activity.

The nuclear receptor coactivator amplified in breast cancer 1 (AIB1) and its more active isoform AIB1-Delta3 are overexpressed in breast cancer and preneoplastic breast tissue. However, the impact of these proteins on the transcriptional activity of natural estrogens or selective estrogen receptor modulators (SERMs) has not been determined. Here we show that AIB1-Delta3 causes a significant increase in the efficacy of 17beta-estradiol at both estrogen receptor-alpha (ER-alpha) and ER-beta in ovarian, breast and endometrial cancer cell lines. AIB1-Delta3 also significantly increased the efficacy of the natural estrogen genistein at both ER-alpha and ER-beta, whereas AIB1 had no effect on either the potency or efficacy of genistein at either receptor. The estrogenic efficacy of the partial agonist tamoxifen was significantly increased in all cell lines at ER-alpha by overexpression of AIB1-Delta3 both on transfected and endogenous estrogen responsive genes. In contrast, overexpression of AIB1 or AIB1-Delta3 had no effect on the potency or efficacy of the SERM raloxifene. We conclude that overexpression of the AIB1-Delta3 isoform will increase the estrogenicity of a variety of natural and pharmacologic compounds in tissues that develop hormone-dependent neoplasias and overexpression of these cofactors may be a contributing factor to the hormone-driven development of neoplasia and to antiestrogen resistance of breast cancers.

Breast Neoplasms↗
PubMed2001

Chemoprevention with antiestrogens: the beginning of the end for breast cancer. Daniel G. Miller Lecture.

In the 1960s, compounds known as nonsteroidal antiestrogens were identified as potential contraceptives, but the drugs caused the induction of ovulation in subfertile women. Tamoxifen and clomiphene were marketed for this indication. However, tamoxifen was advanced for the treatment of breast cancer in the 1970s through a close cooperation between the laboratory and the clinical trials community. The extensive use of long-term adjuvant tamoxifen has resulted in saving the lives of 400,000 women with breast cancer. Tamoxifen is a selective estrogen receptor modulator (SERM) that produces antiestrogenic actions in the breast but estrogen-like actions in bone and lowers serum cholesterol. These properties not only allowed the application of tamoxifen as the first chemopreventive in high-risk pre- and postmenopausal women but also the development of raloxifene to prevent osteoporosis with the potential to prevent breast cancer in postmenopausal women. The future development of SERMs holds the promise of preventing osteoporosis and coronary heart disease as well as breast and endometrial cancer.

Amino Acid Substitution↗
PubMed2004

Hormones and breast cancer.

The incidence of breast cancer in women varies with age, mammary gland mass and exposure to endogenous and exogenous hormones. Age is the single most important factor and if, as projected, 32% of women will be aged >60 years by 2050, world breast cancer incidence will exceed the current 10(6) per year. Hormonal influences that affect growth of the mammary gland increase the risk of breast cancer; for example earlier menarche and later menopause. Childbearing protects against later development of breast cancer, and breastfeeding further decreases the risk. The breast cancer risk declines more with increasing total duration of breastfeeding. Exposure to hormonal contraceptives has been evaluated in a combined reanalysis of data from 51 epidemiological studies. There is a small transient increase in the relative risk of breast cancer among users of oral contraceptives but, since use typically occurs at young ages when breast cancer is relatively rare, such an increase would have little effect on overall incidence rates. In contrast, exposure to menopause hormone treatment occurs when the baseline risk of breast cancer is higher, and epidemiological studies and randomized controlled trials consistently find an increase in breast cancer risk with exposure to combined estrogen and progestogen. Women with a family history of breast cancer in first degree relatives have an increased risk of breast cancer but there is no evidence to suggest that this differs according to a woman's use of oral contraceptives or menopause hormone treatment. Selective estrogen receptor modulators are useful in the treatment and/or prevention of breast cancer depending on the specific agonist or antagonist effects on estrogen target tissues.

Age Factors↗
PubMed2002

Vasomotor and vascular effects of hormone replacement therapy.

Cardiovascular risk factors impair endothelium-dependent vasodilation as well as other functions of the endothelium, thereby predisposing the patient to atherosclerosis and its overt clinical manifestations. Loss of endogenous estrogen also leads to reduced bioavailability of endothelium-derived nitric oxide. In premenopausal women, the impairment of endothelial function develops within 1 month of surgical ovariectomy and is reversed by the administration of exogenous 17 beta-estradiol. Exogenous estrogen administration restores endothelial function by enhancing nitric oxide synthesis through genomic and nongenomic mechanisms and by reducing oxidative stress and nitric oxide breakdown. The effect of progesterone on endothelial function is still under investigation. In animal studies, medroxyprogesterone acetate (MPA) counteracts estrogen's beneficial effects on endothelial function and on coronary plaque size. In humans, however, the addition of progesterone to estradiol does not appreciably attenuate estrogen-associated endothelium-dependent vasodilation. Secondary prevention trials with conjugated equine estrogen plus MPA have no proven benefit in reducing coronary events, progression of angiographic coronary atherosclerosis, or incidence of cerebrovascular events. This suggests that beneficial effects of estrogen on endothelial function are counterbalanced by detrimental effects, perhaps because of proinflammatory and prothrombotic actions. The selective estrogen receptor modulators are currently under investigation as agents that might retain the favorable, without possessing the unfavorable, effects of estrogen on the vascular system.

Animals↗
PubMed2002

Hormone replacement therapy trials: an update.

Recent randomized trials of hormone replacement therapy (HRT) in postmenopausal women are not consistent with the decrease in cardiovascular risk seen in observational studies of hormone therapy users compared with nonusers. Emerging evidence indicates that HRT use in some women with established coronary heart disease may be associated with prothrombotic effects or proinflammatory effects leading to adverse events. In healthy women, the decision to use HRT should be based primarily on noncardiac factors until more data becomes available that is relevant to this population. Several alternatives to HRT, including phytoestrogens and selective estrogen receptor modulators, have favorable effects on cardiovascular risk factors, but their impact on clinical outcomes remains to be determined.

Coronary Disease↗
PubMed2002

Prevention for the older woman. A practical guide to prevention and treatment of osteoporosis.

Osteoporosis causes approximately 1.5 million low-trauma fracture per year, and at all ages the incidence of fracture is higher in women than in men. Risk factors for osteoporotic fractures in postmenopausal women include family history of bone fracture, ethnicity, and weight < 127 pounds. Densitometry is used to diagnose osteoporosis and can be performed at intervals to monitor bone density during treatment. The older woman's diet should, in general, include 1,200 to 1,500 mg of calcium and 400 to 800 IU of vitamin D. Estrogens, bisphosphonates, selective estrogen receptor modulators, calcitonin, and exogenous parathyroid hormone are pharmacologic therapy options that can preserve and increase bone mass and reduce the risk of fracture.

Absorptiometry, Photon↗
PubMed2003

Functional aspects of estrogen neuroprotection.

Evidence that estrogen protects neurons against toxic/ ischemic insults or degenerative/aging processes is evident in a variety of in vitro and in vivo systems. However, a critical remaining question is: Does the demonstrated morphologic and neurochemical protection by estrogen lead to a preservation of brain function or an enhanced ability to recover? To date, little basic research is available on this issue. Cognition is a critical function that might provide a sensitive way to examine this question. As a first step, we present results showing that two chronic environmental insults, psychoactive drugs and stress, produce gender-specific responses in cognitive abilities. Specifically, females appear less sensitive than males to cognitive impairments following chronic exposure to these factors. Results are presented in male and female rats utilizing cognitive tests that assess visual (object recognition) and spatial memory (object placement and radial arm maze) following chronic amphetamine, methamphetamine, or daily restraint stress. Following regimes of chronic stress or amphetamine, males were impaired on these tasks while females were either unaffected, less affected, or enhanced in performance. These observations suggest that differences in circulating gonadal hormone levels between the sexes may contribute to the differential sensitivity of the sexes and provide endogenous neuroprotection for females. Surprisingly, ovariectomized females were still not impaired following a stress regimen that impaired males (21 d of daily restraint). These data taken together with neurochemical data on estrogen neuroprotective effects indicate that it is possible that neuroprotection by estrogen may result from hormone action both during sexual differentiation (organizational effect) and in adulthood (activational effect). These considerations and possible unwanted/untoward effects of chronic estrogen use are discussed in relation to the use of selective estrogen receptor modulators for chronic treatment of both males and females. In conclusion, although compelling evidence for neuroprotection by estrogen has been presented in anatomic and neurochemical studies, it is clear that the functional/ behavioral aspects need further investigation.

Animals↗
PubMedDate not supplied

Pharmacotherapeutics for osteoporosis prevention and treatment.

Osteoporosis is a silent disease that affects 10 million Americans; 80% of those affected are women. Although the disease is more common in postmenopausal Caucasian women, all ages and races are at risk. Osteoporosis can be a debilitating disease that can cause pain, fractures, depression, and social withdrawal. Signs of osteoporosis include kyphosis, loss of height, and protrusion of the abdomen. Because symptoms generally do not occur until after the disease has progressed, clinicians should include osteoporosis screening and preventative education as part of the regular gynecologic care. Diagnosis is typically made by a dual energy x-ray absorptiometry (DEXA) scan. Treatment consists of dietary and lifestyle changes, along with pharmacologic intervention. Although hormone therapy has been shown to be effective in preventing osteoporosis, the risks of long-term treatment with HRT are discussed. The following effective treatment options for women who have been diagnosed with the disease are discussed: bisphosphonates, calcitonin, and selective estrogen receptor modulators (SERMs). Because midwives regularly care for women of all ages, they are ideal candidates to provide women with preventative education, screening, counseling, and treatment.

Absorptiometry, Photon↗
PubMed1999

Status of aromatase inhibitors in relation to other breast cancer treatment modalities.

Aromatase is one of the key enzymes possibly linked with the perpetuation or even initiation of breast cancer. Modulation of its activity by the new generation inhibitors has resulted in increased responses and improved therapeutic ratio compared with those of parent aromatase inhibitors. More recent trials have shown promising results with regard to improved therapeutic ratio compared with what is seen with presently accepted second-line hormonal approaches. Present data and laboratory research indicate that new aromatase inhibitors have the potential to play an important role as adjuvants, and possibly in the prevention of human breast cancer. It is probable that it may be as adjuvants that their real therapeutic strength in terms of a beneficial impact on survival may be realized. The absence of estrogen agonist activity of new aromatase inhibitors on lipid and bone metabolism calls for more clinical studies having late mortality in breast cancer survivors as the ultimate outcome objective; in this regard, interaction of new aromatase inhibitors with new selective estrogen receptor modulators looks promising. Achievement of these outcomes, and understanding of interactions with other therapies, await the termination of present trials and the start of new initiatives.

Aminoglutethimide↗
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↗
PubMed2005

[Hormone resistance and its modulation in breast cancer].

Acquired hormone resistance is a reversible adaptative change of hormone-sensitive breast tumors promoting survival by changes in the balance and communication between estrogen receptor and growth factor signaling. The mechanisms of hormone resistance induced by various hormone therapies are different, however, their common feature is the dominance of growth factor signaling with the consequences of enhanced proliferation and decreased apoptosis. In case of tamoxifen or selective estrogen receptor modulator resistance, the agents' enhanced agonistic activity occurs. The increased expression of certain estrogen receptor coactivators may play an important role. The essential of hormone resistance after estrogen deprivation is estrogen hypersensitivity, which is a consequence of the enhanced activity of the membrane-associated estrogen receptor and its influence on the growth factor signaling. The integration of cell surface growth factor receptor or growth factor signal transduction blocking agents like tyrosine kinase, MAPK, mTOR, PI3K or farnesyl transferase inhibitors into hormone therapies may prevent or treat hormone resistance. The other possibility is to use the hormone therapies sequentially. A new promising agent is the pure antiestrogen fulvestrant which targets the estrogen receptor located in both the membrane or the nucleus. Also, estrogen therapy may revert hormone resistance. The use of predictive markers may promote treatment choice and indicate application of targeted therapies.

Breast Neoplasms↗
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↗
PubMed2000

Breast cancer chemoprevention.

Chemoprevention of breast cancer is a rapidly growing field. Chemoprevention was initiated with the development of the antiestrogen tamoxifen. A major clinical trial in the United States found that tamoxifen reduced the incidence of breast cancer by almost 50% in women at an increased risk for the disease. Although two European trials did not confirm these findings, the Food and Drug Administration found the American studies significant enough to approve tamoxifen for the delaying of breast cancer in women at high risk for the disease. However, adverse effects associated with tamoxifen include a minimally increased rate of endometrial cancer, cataracts, and strokes. Newer classes of antiestrogens, called selective estrogen receptor modulators (SERMs), are being investigated as potential chemopreventive agents. These SERMS, such as raloxifene, will hopefully provide some of the benefits of estrogen without its inherent risks. In addition, naturally occurring compounds and their analogues are also under investigation.

Adult↗