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Results for “Selective Estrogen Receptor Modulators”

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PubMed2005

Hormone replacement therapy in postmenopausal women: breast tissue perfusion determined with MR imaging--initial observations.

PURPOSE: To use magnetic resonance (MR) imaging to evaluate tissue perfusion in the normal breast parenchyma of postmenopausal women with current or recent hormone replacement therapy (HRT). MATERIALS AND METHODS: The study was approved by the institutional subcommittee on human studies, and informed consent was obtained from all patients prior to MR imaging. Sixty postmenopausal women (age range, 44-77 years) were grouped according to HRT received: estrogen replacement therapy (ERT) (n = 13), combined (estrogen and progesterone) replacement therapy (CRT) (n = 16), selective estrogen receptor modulator (SERM) therapy (n = 8), and no (hormone replacement) therapy (NT) (n = 23). MR imaging with a 1.5-T magnet was performed by using gradient-echo and dynamic contrast material-enhanced echo-planar pulse sequences before and after gadopentetate dimeglumine injection. Precontrast T1 relaxation times were measured, after which extraction-flow product (EFP) maps were calculated with a multicompartmental model. Analysis of variance was performed. RESULTS: Age did not significantly differ between the groups (P > .3). Women receiving ERT or CRT at the time of MR imaging had higher EFP values (7.3 mL . 100 g(-1) . min(-1)+/- 2.6 and 7.1 mL . 100 g(-1) . min(-1)+/- 3.8, respectively) than did women receiving NT (4.4 mL . 100 g(-1) . min(-1)+/- 2.1) (P = .012 and P = .008, respectively) or SERM therapy (3.9 mL . 100 g(-1) . min(-1)+/- 1.1) (P = .015 and P = .013, respectively). Women who ended ERT or CRT 1-47 months before MR examination had lower EFP values than did women with current ERT or CRT and had higher EFP values than did women receiving NT or SERM therapy (6.2 mL . 100 g(-1) . min(-1)+/- 2.4 and 5.9 mL . 100 g(-1) . min(-1)+/- 3.8, respectively), but the observed differences were not significant (P > .1). Differences in T1 between all groups were not significant (P > .5). CONCLUSION: Higher breast tissue perfusion is observed in postmenopausal women receiving HRT.

Adult↗

PubMed2002

Glycolysis as a metabolic marker in orthotopic breast cancer, monitored by in vivo (13)C MRS.

Enhanced glycolysis represents a striking feature of cancers and can therefore serve to indicate a malignant transformation. We have developed a noninvasive, quantitative method to characterize tumor glycolysis by monitoring (13)C-labeled glucose and lactate with magnetic resonance spectroscopy. This method was applied in MCF7 human breast cancer implanted in the mammary gland of female CD1-NU mice and was further employed to assess tumor response to hormonal manipulation with the antiestrogen tamoxifen. Analysis of the kinetic data based on a unique physiological-metabolic model yielded the rate parameters of glycolysis, glucose perfusion, and lactate clearance in the tumor, as well as glucose pharmacokinetics in the plasma. Treatment with tamoxifen induced a twofold reduction in the rate of glycolysis and of lactate clearance but did not affect the other parameters. This metabolic monitoring can thus serve to evaluate the efficacy of new selective estrogen receptor modulators and may be further extended to improve diagnosis and prognosis of breast cancer.

Animals↗

PubMed2005

Differential effects of 17beta-estradiol and raloxifene on VSMC phenotype and expression of osteoblast-associated proteins.

Several studies demonstrate an association between osteoporosis and arterial calcific disease, both of which being common in elderly women. Estradiol and raloxifene, a selective estrogen receptor modulator, prevent bone loss in postmenopausal women. Little is known regarding how these agents affect arterial calcification. The aim of this study was to determine whether or not 17beta-estradiol and raloxifene reduced vascular smooth muscle cell (VSMC) differentiation and expression of bone-associated proteins during phosphate-induced calcification in vitro. Aortic VSMC were cultured from adult, gonadally intact, and ovariectomized (OVX) female pigs. Calcifying medium was added, and cells were treated with solvent (control), 17beta-estradiol (E(2)), or raloxifene. Extent of calcification and phenotypic expression of bone-associated proteins [matrix gla protein (MGP), osteoprotegerin (OPG), and bone sialoprotein (BSP)] were examined at 3-day intervals over 2 wk. Calcium content increased in all groups but was greater in VSMC derived from intact compared with OVX animals. E(2) reduced calcification and preserved a contractile phenotype. Expression of OPG significantly decreased with time; this decrease was significantly greater in VSMC derived from OVX compared with gonadally intact pigs. E(2) and raloxifene preserved expression of OPG only in VSMC from intact pigs. Expression of MGP increased significantly with time and was not affected by E(2) or raloxifene treatments. E(2) treatment significantly inhibited synthesis of BSP in cells from both groups. In conclusion, E(2) slows differentiation of VSMC induced by excess phosphate. Effectiveness of raloxifene to preserve expression of bone cell-associated proteins depends on the hormonal status of the tissue donor.

Animals↗

PubMed2006

Development and therapeutic options for the treatment of raloxifene-stimulated breast cancer in athymic mice.

PURPOSE: Selective estrogen receptor modulators (SERM) are used for the treatment and prevention of breast cancer (tamoxifen) and osteoporosis (raloxifene). Mechanisms of tamoxifen-resistance in breast cancer are incompletely understood but current research is focused on crosstalk between growth factor receptors and the estrogen receptor alpha (ERalpha) pathway. There is increasing clinical use of raloxifene for the treatment of osteoporosis, but the widespread use of this SERM will have consequences for the treatment of breast cancer in raloxifene-exposed women. EXPERIMENTAL DESIGN: We took the strategic step of developing a raloxifene-resistant tumor (MCF-7RALT) model in vivo and investigating the mechanisms responsible for resistance. RESULTS: MCF-7RALT tumors exhibited phase I SERM resistance, growing in response to SERMs and 17beta-estradiol. Epidermal growth factor receptor/HER1 and HER2/neu mRNAs were increased in MCF-7RALT tumors. The HER2/neu blocker, trastuzumab, but not the epidermal growth factor receptor blocker, gefitinib, decreased the growth of MCF-7RALT tumors in vivo. Consequently, trastuzumab decreased prosurvival/proliferative proteins: phospho-HER2/neu, total HER2/neu, phospho-Akt (protein kinase B), glycogen synthetase kinase-3, cyclin D1, and the antiapoptotic protein X chromosome-linked inhibitor of apoptosis, whereas increasing the proapoptotic protein, caspase-7, in raloxifene-treated MCF-7RALT tumors. Interestingly, ERalpha protein was overexpressed in untreated MCF-7RALT tumors and hyperactivated in cells derived from these tumors. Only fulvestrant completely inhibited the growth and ERalpha activity of MCF-7RALT tumors. The coactivator of ERalpha, amplified in breast cancer-1 protein was modestly increased in the raloxifene-treated MCF-7RALT tumors and increased both basal and estradiol-induced activity of ERalpha in cells derived from the MCF-7RALT tumors. CONCLUSIONS: These results suggest that overexpression and increased activity of HER2/neu might be responsible for the development of raloxifene-resistant breast cancer. The results also suggest that increased expression of basal activity of ERalpha could contribute to the hypersensitivity of MCF-7RALT tumors in response to estradiol because only fulvestrant blocked growth and ERalpha activity.

Animals↗

PubMed2006

Treatment-related osteoporosis in men with prostate cancer.

The intended therapeutic effect of gonadotropin-releasing hormone (GnRH) agonists is hypogonadism, a major cause of acquired osteoporosis in men. Consistent with this observation, GnRH agonists increase bone turnover and decrease bone mineral density, a surrogate for fracture risk. Large claims-based analyses and other retrospective studies provide compelling evidence that GnRH agonists increase risk of clinical fractures. Estrogens play a central role in homeostasis of the normal male skeleton, and estrogen deficiency rather than testosterone deficiency seems to be primarily responsible for the adverse skeletal effects of GnRH agonists. In randomized controlled trials, bisphosphonates (pamidronate and zoledronic acid) and selective estrogen receptor modulators (raloxifene and toremifene) increased bone mineral density in GnRH agonist-treated men. Two ongoing large randomized placebo-controlled studies will prospectively define fracture outcomes in men with prostate cancer and assess the efficacy of novel pharmacologic interventions (AMG162, toremifene) during GnRH agonist treatment.

Antineoplastic Agents↗

PubMed2005

[Aromatase inhibitors in the adjuvant therapy of breast cancer].

Breast cancer is a hormone-sensitive cancer and in most post-menopausal women hormone receptor positive. The hormone receptor status is a highly valid predictive marker of responsiveness to endocrine therapy. The standard adjuvant therapy in patients with hormone-receptor-positive breast cancer is the selective estrogen receptor modulator tamoxifen. Third-generation aromatase inhibitors are accepted as a treatment option for metastatic breast cancer. However, results from recent studies show also a benefit of this type of drugs for disease-free survival with fewer adverse reactions in the adjuvant therapy. Therefore a new therapeutic field opens for the use of 3rd-generation aromatase inhibitors. This will lead to an expansion of the indication, but the question of modality -- up-front, switch or extended therapy -- remains to be resolved.

Antineoplastic Agents, Hormonal↗

PubMed2005

Effects of resveratrol, raloxifene, tibolone and conjugated equine estrogen on vaginal squamous cell maturation of ovariectomized rats.

OBJECTIVE: The effects of estrogen replacement therapy, selective estrogen receptor modulators, or tibolone on vaginal squamous cell maturation in postmenopausal women are not well established. Resveratrol (3,5,4'-trans-trihydroxystilbene) has been shown to bind the estrogen receptor in rat uteri. The aim of this study was to cytologically evaluate vaginal smears from ovariectomized rats treated with resveratrol, raloxifene, tibolone and conjugated equine estrogen, and to compare each drug with regard to vaginal epithelial maturation. MATERIAL AND METHODS: Forty-two bilaterally ovariectomized Wistar albino rats were equally randomized into 6 groups: (1) control sham-operated rats; (2) ovariectomized rats administered 0.1% ethanol; (3) ovariectomized rats administered resveratrol at a dose of 5 mg/kg/day p.o.; (4) ovariectomized rats administered conjugated equine estrogen (CEE) at a dose of 0.1 mg/kg/day p.o.; (5) ovariectomized rats administered tibolone at a dose of 0.25 mg/kg/day p.o., and (6) ovariectomized rats administered raloxifen at a dose of 1 mg/kg/day p.o. Administration of drugs started 5 days after bilateral ovariectomy and continued for 35 days. After 35 days of treatment a vaginal smear was obtained from each rat. Smears were stained with the usual Papanicolaou method, and observed with a light microscope by an experienced cytopathologist. Cytological grading was made according to the extent of parabasal, intermediate, superficial and anuclear squamous cells. RESULTS: Ovariectomized rats had lower scores for superficial and anuclear cells when compared to sham-operated rats (p < 0.05). The CEE group had higher scores for superficial and anuclear cells than those of the ovariectomized, raloxifene and tibolone groups (p < 0.05). The resveratrol-treated rats had higher scores for superficial cells but lower scores for parabasal cells than ovariectomized rats (p < 0.05). The raloxifene and tibolone groups had the same scores for intermediate, superficial and anuclear cells but lower scores for parabasal cells compared to ovariectomized rats. CONCLUSION: The results of our study suggest that resveratrol offsets the reduction in vaginal stratification generally observed after oophorectomy.

Animals↗

PubMed2006

Differential protective properties of estradiol and tamoxifen against methamphetamine-induced nigrostriatal dopaminergic toxicity in mice.

Mechanisms implicated in protective potential of estrogens are poorly understood. Tamoxifen, a selective estrogen receptor modulator (SERM), presents a neuroprotective effect against methamphetamine (MA)- and methoxy-phenyltetrahydropyridine (MPTP)-induced toxicity when used alone but abolishes estrogen's positive effects when combined with this hormone. In order to understand tamoxifen's protective properties, the present study compared it to estradiol on several markers of dopaminergic neurons to achieve a relatively comprehensive comparison between these two agents. Estradiol benzoate (E) or tamoxifen were used at different concentrations (E: 1, 10 or 40 microg; tamoxifen: 12.5, 125 or 500 microg) 24 h prior to a MA injection in ovariectomized CD-1 mice. The effects of the lesion and treatments were studied on striatal dopamine (DA) concentrations, dopamine and monoamine vesicular transporters (DAT and VMAT2), and preproenkephalin (PPE) mRNA levels. Both treatments, at all concentrations, prevented the MA-induced decrease of striatal DA concentrations and VMAT2 binding. Only E was able to prevent loss of DAT binding in the lateral striatum and to attenuate the MA-induced increase in striatal PPE mRNA levels (at 1 or 40 microg). Therefore, in this paradigm, E and tamoxifen differentially modulated MA-induced neuronal damages. While both treatments prevented the DA decrease, E protected more efficiently other dopaminergic parameters suggesting that overall E is more effective than tamoxifen as a neuroprotectant of the nigrostriatal dopaminergic system.

Animals↗

PubMed1999

Both raloxifene and estrogen reduce major cardiovascular risk factors in healthy postmenopausal women: A 2-year, placebo-controlled study.

Currently raloxifene, a selective estrogen receptor modulator, is being investigated as a potential alternative for postmenopausal hormone replacement to prevent osteoporosis and cardiovascular disease. We compared the 2-year effects of raloxifene on a wide range of cardiovascular risk factors with those of placebo and conjugated equine estrogens (CEEs). Analyses were based on 56 hysterectomized but otherwise healthy postmenopausal women aged 54. 8+/-3.5 (mean+/-SD) years who entered this double-blind study and who were randomly assigned to raloxifene hydrochloride 60 mg/d (n=15) or 150 mg/d (n=13), placebo (n=13), or CEEs 0.625 mg/d (n=15). At baseline and after 6, 12, and 24 months of treatment, we assessed serum lipids, blood pressure, glucose metabolism, C-reactive protein, and various hemostatic parameters. Compared with placebo, both raloxifene and CEEs lowered the level of low density lipoprotein cholesterol by 0.53 to 0.79 mmol/L (all P<0.04) and lowered, at 24 months, the level of fibrinogen by 0.71 to 0.86 g/L (all P<0.05). The effects of raloxifene and CEEs did not differ significantly. In contrast to raloxifene, from 6 months on CEEs increased high density lipoprotein cholesterol by 0.25 to 0.29 mmol/L and reduced plasminogen activator inhibitor-1 antigen by 30.6 to 48.6 ng/mL (all P<0.02 versus both placebo and raloxifene). CEEs transiently increased C-reactive protein by 1.0 mg/L at 6 months (P<0.05 versus placebo) and prothrombin-derived fragment F1+2 by 0. 79 nmol/L at 12 months (P<0.001 versus placebo). Finally, from 12 months on, CEEs increased triglycerides by 0.33 to 0.56 mmol/L (all P<0.05 versus both placebo and raloxifene). Our findings suggest that in healthy postmenopausal women, raloxifene and estrogen monotherapy have similar beneficial effects on low density lipoprotein cholesterol and fibrinogen levels. These treatments differ, however, in their effects on high density lipoprotein cholesterol, triglycerides, and plasminogen activator inhibitor-1 and possibly in their effects on prothrombin fragment F1+2 and C-reactive protein.

Biomarkers↗

PubMed2001

Tamoxifen effects on endothelial function and cardiovascular risk factors in men with advanced atherosclerosis.

BACKGROUND: Tamoxifen and its analogues act as selective estrogen receptor modulators (SERMs) in women, with estrogen-like activities on some plasma cardiovascular risk factors (eg, lipoproteins). Effects of SERMs on men with coronary artery disease (CAD) have not been reported. METHODS AND RESULTS: Thirty-one men with angiographically proven CAD were recruited; 16 were treated with tamoxifen (40 mg/d) for 56 days, and 15 were untreated. All the CAD patients were medicated with aspirin and an HMG-CoA reductase inhibitor for >/=6 weeks before entering the study. Ten men with angina-like symptoms but normal coronary arteries by angiography (NCA group) were also treated with tamoxifen. Blood samples were collected at days -7, 0, 7, 14, 21, 28, and 56 of treatment. Endothelium-dependent flow-mediated dilatation (ED-FMD) of the brachial artery was measured by high-resolution ultrasound at 5 visits. Tamoxifen caused an increase in %ED-FMD maximal at 28 days in the CAD group (2.1+/-0.3% to 7.5+/-0.7%; P<0.0001) and the NCA group (3.8+/-0.4% to 7.9+/-1.0%; P<0.0001), with no significant change in the untreated group. Tamoxifen also caused decreases in several plasma cardiovascular risk factors, including total cholesterol, triglycerides, lipoprotein(a), and fibrinogen. Except for the triglyceride response, these effects were similar to those reported for postmenopausal women treated with tamoxifen. CONCLUSIONS: Tamoxifen substantially increased ED-FMD in men with CAD who were taking conventional medication. Together with the effects on risk factors, the data strongly support clinical evaluation of SERMs for the treatment of men with CAD.

Aged↗

PubMed1997

Raloxifene inhibits aortic accumulation of cholesterol in ovariectomized, cholesterol-fed rabbits.

BACKGROUND: The beneficial effect of long-term hormone replacement therapy in terms of a decreased risk of cardiovascular disease is now generally accepted. Raloxifene, a selective estrogen receptor modulator, has demonstrated hypolipidemic properties while leaving the endometrium unstimulated. METHODS AND RESULTS: For our study of the effects of raloxifene on atherosclerosis, 75 rabbits were ovariectomized and treated with either raloxifene, 17beta-estradiol, or placebo; 25 rabbits were sham operated and treated with placebo. After 45 weeks, the raloxifene group had two thirds of the aortic atherosclerosis, as evaluated by the cholesterol content of the proximal inner part of the aorta, found in the placebo group (placebo, 577+/-55.1 nmol/mg protein; raloxifene, 397+/-53.6 nmol/mg protein; P<.05); the estrogen group had one third of the aortic atherosclerosis in the placebo group (estrogen, 177+/-32.1 nmol/mg protein; P<.001). The sham-operated group (473+/-59.6 nmol/mg protein) was not significantly different from placebo. These effects were only partly explained by the changes in serum lipids and lipoproteins, and treatment with both estrogen and raloxifene independently predicted the response in aorta cholesterol. Because plasma levels of total raloxifene were low relative to clinical values in postmenopausal women, dose-response data for raloxifene are required. CONCLUSIONS: Our findings indicate that raloxifene hydrochloride has a potentially important antiatherogenic effect, analogous to that observed with estrogen in this model.

Animals↗

PubMedDate not supplied

Depression, estrogen, and the Women's Health Initiative.

This clinical observation report compares hormone use and clinical presentation in a series of middle-aged depressed women before and after publication of the Women's Health Initiative. Depressed women over age 40 seen at a general hospital academic women's affective disorders practice 6 months before and after publication of the Women's Health Initiative were compared for medication changes, hormone therapy, lifetime depressive episodes, time since last episode, time to depression recurrence after hormone cessation, symptoms, and treatment response. More women stopped hormone therapy and reported onset of depression within 3 weeks of hormone discontinuation after than before publication of the Women's Health Initiative. Depression in most women responded to reinstitution of estrogen or initiation or increase in antidepressant dose. Discontinuation of hormone therapy appears to be associated with the rapid recurrence of depression in some women with a history of depression. Randomized controlled trials in middle-aged depressed women of estrogen or a selective estrogen receptor modulator as monotherapy or as an augmentation agent are urgently needed.

Depression↗

PubMed2006

Evaluation of 227 drugs for in vitro inhibition of cytochrome P450 2B6.

Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of drugs such as bupropion, efavirenz, propofol, and selegiline, among others. More than 200 commonly prescribed drugs and other xenobiotics were examined for their ability to inhibit CYP2B6-mediated bupropion hydroxylase activity. Thirty compounds were found exhibiting greater than 50% inhibition at 30 microM. Inhibitors of CYP2B6 were identified from a wide variety of therapeutic classes. The 2 platelet aggregation inhibitors, clopidogrel and ticlopidine, were both identified as potent inhibitors (IC50 = 0.0206 and 0.149 microM, respectively). Other inhibitors (IC50 < 1 microM) included clotrimazole, itraconazole, sertraline, and raloxifene. These in vitro data were used along with clinical pharmacokinetic information in the prediction of potential drug-drug interactions that could occur by inhibition of CYP2B6. Although few drugs tested are expected to cause drug interactions, clopidogrel and ticlopidine were identified as being of concern as potential inhibitors of clinical relevance. These findings are discussed in context to potential drug interactions that could be observed between these agents and drugs for which CYP2B6 is involved in metabolism.

Algorithms↗

PubMed2004

The HORIZON Recurrent Fracture Trial: design of a clinical trial in the prevention of subsequent fractures after low trauma hip fracture repair.

OBJECTIVE: To present the novel design of a trial testing the safety and efficacy of a yearly bisphosponate, zoledronic acid, in preventing new clinical fractures in patients with recent low trauma hip fracture repair. RESEARCH DESIGN AND METHODS: Randomized, placebo-controlled, triple-blind study. One hundred and fifteen clinical centers worldwide are recruiting approximately 1714 subjects aged 50 years and over (no upper age limit, median age of enrolled subjects to date 79 years) who have undergone surgical repair of a low trauma hip fracture in the preceding 90 days. Patients will be assigned at random to an intervention group (5 mg zoledronic acid intravenously yearly) or a control group (placebo infusion yearly). Both groups receive a loading dose of Vitamin D2 or D3 IM or orally, followed by 800-1200 IU Vitamin D and 1000-1500 mg elemental calcium orally on a daily basis. Concomitant therapy with calcitonin, hormone replacement therapy, selective estrogen receptor modulators, tibolone, and external hip protectors are allowed. MAIN OUTCOME MEASURES: The primary endpoint is subsequent skeletal fractures as adjudicated by a clinical endpoints committee blinded to intervention status. Secondary outcomes include delayed hip fracture healing, changes in bone mineral density, and health resource utilization. Subjects will be recruited over a 3-4 year period and will be followed until 211 primary endpoints are accrued and adjudicated. CONCLUSIONS: This randomized clinical trial is novel among osteoporosis therapies as it (1). targets hip fracture patients, a previously understudied group, and (2). uses only clinically evident fractures as the primary outcome. Ethical and practical considerations in studying this frail population are discussed.

Bone Density↗

PubMed2005

Emerging concepts in osteoporosis and bone strength.

OBJECTIVE: Osteoporosis is a systemic skeletal disorder characterized by compromised bone strength and increased fracture risk. The factors that contribute to bone strength include bone mineral density (BMD) and bone quality, which encompasses factors such as bone turnover, microarchitecture, mineralization, and geometry. The objective of this paper was to review the factors that contribute to bone strength and osteoporosis. RESEARCH DESIGN: A MEDLINE search of English language journals between 1 January 1995 and 1 March 2005 was conducted using the term 'osteoporosis' combined with 'bone strength' or 'bone quality'. Reference lists of pivotal studies and reviews were also examined. Studies were otherwise not excluded on the basis of quality or size, the aim being to present an overview of research conducted to date on osteoporosis and bone strength. RESULTS: While there is a relationship between BMD and fracture risk, evidence suggests that BMD measurements reflect only 1 component of bone strength. For example, small changes in BMD produced by osteoporosis treatments do not fully explain the reductions in fracture risk observed after initiation of therapy, and substantial fracture risk reduction is observed before peak increases in BMD are achieved. In addition to their effects on BMD, anti-resorptive therapies for osteoporosis (i.e., bisphosphonates, selective estrogen receptor modulators, calcitonin, and estrogen) produce positive effects on bone turnover, microarchitecture, and/or mineralization, all of which can contribute to the reductions in fracture risk observed with these agents. Anabolic agents such as teriparatide also appear to have beneficial effects on bone strength independent of bone mass. New, non-invasive, high-resolution imaging methods, such as magnetic resonance imaging and computed tomography, may offer a comprehensive assessment of bone quality in the future. CONCLUSIONS: The development of clinical tools that assess bone quality independent of BMD will be essential to advance our assessment of fracture risk and response to osteoporosis treatment.

Bone Density↗

PubMed2006

Effects of tamoxifen on vaginal blood flow and epithelial morphology in the rat.

BACKGROUND: Tamoxifen, a selective estrogen receptor modulator with both estrogenic and anti-estrogenic activity, is widely used as adjuvant therapy in breast cancer patients. Treatment with tamoxifen is associated with sexual side effects, such as increased vaginal dryness and pain/discomfort during sexual activity. There have been limited investigations of the effect of tamoxifen on estrogen-dependent peripheral genital arousal responses. The objective of this study was to investigate the effects of tamoxifen on vaginal physiology in the rat. METHODS: Female Sprague-Dawley rats were subjected to sham surgery or bilateral ovariectomy. After 2 weeks, sham-operated rats were implanted with subcutaneous osmotic infusion pumps containing vehicle (control) or tamoxifen (150 microg/day). Ovariectomized rats were similarly infused with vehicle. After an additional 2 weeks, vaginal blood flow responses to pelvic nerve stimulation were measured by laser Doppler flowmetry and vaginal tissue was collected for histological and biochemical assay. RESULTS: Tamoxifen treatment did not change plasma estradiol concentrations relative to control animals, while ovariectomized rats exhibited a 60% decrease in plasma estradiol. Tamoxifen treatment caused a significant decrease in mean uterine weight, but did not alter mean vaginal weight. Vaginal blood flow was significantly decreased in tamoxifen-infused rats compared to controls. Similar to ovariectomized animals, estrogen receptor binding was increased and arginase enzyme activity was decreased in tamoxifen-infused rats. However, different from control and ovariectomized animals, the vaginal epithelium in tamoxifen-infused rats appeared highly mucified. Periodic acid-Schiff staining confirmed a greater production of carbohydrate-rich compounds (e.g. mucin, glycogen) by the vaginal epithelium of tamoxifen-infused rats. CONCLUSION: The observations suggest that tamoxifen exerts both anti-estrogenic and pro-estrogenic effects in the vagina. These physiological alterations may eventually lead to vaginal atrophy and compromise sexual function.

Journal Article↗

PubMed2005

Patterns of reduced nipple aspirate fluid production and ductal lavage cellularity in women at high risk for breast cancer.

INTRODUCTION: Nipple aspiration is a noninvasive technique for obtaining breast fluids from the duct openings of the nipple for the evaluation of abnormalities associated with breast cancer. Nipple aspirate fluid (NAF) can be elicited from 48 to 94% of healthy women, and its production has been linked to an increased relative risk for breast cancer development. NAF production has been used in studies to guide the selection of ducts for ductal lavage, a procedure in which ducts are cannulated and flushed with saline to collect cells. In a previous multicenter trial to evaluate intraductal approaches in women at high-risk for breast cancer, NAF production was observed in 84% of the subjects. However, we observed a significantly lower proportion of fluid-yielding subjects in a similar series of high-risk women. The purpose of the present study was to identify variables associated with this reduction. METHOD: Nipple aspiration was performed on 33 high-risk women (defined as having a 5-year Gail model index of more than 1.7, a personal or family history of breast cancer, and/or a BRCA1 or BRCA2 germline mutation) to identify ductal orifices for lavage procedures. Lavage was performed on all fluid-yielding ducts and on nine non-fluid-yielding ducts. RESULTS: Fluid-yielding ducts were identified in 12 of 33 (36%) of the subjects in the present series, compared with 16 of 19 (84%) of the subjects undergoing identical procedures at our facility during a multicenter trial (P = 0.001). Reduced NAF yields were associated with postmenopausal status (P = 0.02), BRCA germline mutations (P = 0.004), and risk reduction therapies, including bilateral salpingo-oophorectomy (BSO) and/or selective estrogen receptor modulators (SERMs; P = 0.009). All nine (100%) of the ductal lavage specimens collected from non-fluidyielding ducts were acellular, in comparison with 3 of 13 specimens from fluid-yielding ducts (P < .001). CONCLUSION: Analysis of high-risk women in the present series revealed patterns of reduced NAF production and ductal lavage cellularity compared with a previous multicenter trial. The present series included more BRCA-positive women, many of whom had undergone BSO and/or were using SERMs. Our data suggest that endocrine mechanisms associated with these risk-reducing therapies may be related to patterns of diminished breast fluid production.

Adult↗

PubMed2004

Prevention of breast cancer by recapitulation of pregnancy hormone levels.

At the present time, the only approved method of breast cancer prevention is use of the selective estrogen receptor modulator (SERM) tamoxifen. Many breast cancers are driven to grow by estrogen, and tamoxifen exploits this by blocking estrogen action at the estrogen receptor. A counter-intuitive and controversial approach to breast cancer prevention is administration of estrogen and progestin at an early age to achieve pregnancy levels. This approach is supported by the fact that breast cancer incidence is halved by early (< or = 20 years of age) full-term pregnancy. Moreover, it has been demonstrated in rodent models that mimicking the hormonal milieu can effectively prevent carcinogen-induced mammary cancer. In this issue of Breast Cancer Research Rajkumar and colleagues use the rodent model to further define the timing and type of hormonal therapy that is effective in preventing mammary carcinogenesis. Clearly, application of this approach in humans may be difficult, but the potential benefit is intriguing.

Animals↗