Long-term use of clomiphene in male macroprolactinomas with persistent hypogonadism.

BACKGROUND: Men with macroprolactinoma can present persistent hypogonadism despite normoprolactinemia achieved with clinical and/or neurosurgical treatment. Usually, testosterone replacement therapy is indicated. Nevertheless, although off-label, clomiphene citrate (CC), a selective estrogen receptor modulator, has also been used, mainly when fertility is an issue. The aim of this study is to evaluate the effectiveness of CC in recovering the gonadal axis in men with macroprolactinoma, with or without hyperprolactinemia, and evaluate its safety as a long-term therapy. METHODS: This is a retrospective study including 10 men with macroprolactinoma on cabergoline treatment and persistent hypogonadism. All patients received initially 50 mg/d of CC. RESULTS: The median age at diagnosis of prolactinomas was 34 (range, 26-60) years old. All patients were treated with cabergoline at a median maximum dose of 2 (1-7) mg/week, with a median time of treatment of 8.5 (2-15) years. Prolactin was still above the normal range when CC was introduced only in two patients. The mean duration of CC therapy was 3.2 (±2.8) years. Prolactin levels maintained stable (p = 0.252) and testosterone increased (p = 0.027) significantly on CC therapy. Tumor size remained stable. Eight patients (80%) maintained testosterone above 300 ng/dL and were classified as responders. Three responders succeeded in using a lower dose of CC and one of them completed withdrawal CC and maintained eugonadism. There were no side effects or safety concerns reported. CONCLUSION: CC should be seen as a safe treatment option for men with macroprolactinoma and persistent hypogonadism.

Design and Characterization of Maltoheptaose-b-Polystyrene Nanoparticles, as a Potential New Nanocarrier for Oral Delivery of Tamoxifen.

Tamoxifen citrate (TMC), a non-steroidal antiestrogen drug used for the treatment of breast cancer, was loaded in a block copolymer of maltoheptaose-b-polystyrene (MH-b-PS) nanoparticles, a potential drug delivery system to optimize oral chemotherapy. The nanoparticles were obtained from self-assembly of MH-b-PS using the standard and reverse nanoprecipitation methods. The MH-b-PS@TMC nanoparticles were characterized by their physicochemical properties, morphology, drug loading and encapsulation efficiency, and release kinetic profile in simulated intestinal fluid (pH 7.4). Finally, their cytotoxicity towards the human breast carcinoma MCF-7 cell line was assessed. The standard nanoprecipitation method proved to be more efficient than reverse nanoprecipitation to produce nanoparticles with small size and narrow particle size distribution. Moreover, tamoxifen-loaded nanoparticles displayed spherical morphology, a positive zeta potential and high drug content (238.6 ± 6.8 µg mL-1) and encapsulation efficiency (80.9 ± 0.4 %). In vitro drug release kinetics showed a burst release at early time points, followed by a sustained release profile controlled by diffusion. MH-b-PS@TMC nanoparticles showed higher cytotoxicity towards MCF-7 cells than free tamoxifen citrate, confirming their effectiveness as a delivery system for administration of lipophilic anticancer drugs.

Tamoxifen and meglumine antimoniate combined therapy in cutaneous leishmaniasis patients: a randomised trial.

OBJECTIVES: There is a clear need for new strategies of leishmaniasis treatment. This work was conducted to evaluate the efficacy of the co-administration of tamoxifen and meglumine antimoniate (SbV ) in a phase II pilot clinical trial in localised cutaneous leishmaniasis patients. METHODS: A randomised controlled pilot clinical trial was conducted to evaluate the efficacy and safety of oral (40 mg/day for 20 days) or topical tamoxifen (0.1% tamoxifen citrate for 20 days) combined with meglumine antimoniate (20 mg SbV /kg/day for 20 days) vs. a standard SbV protocol (20 mg/kg/day for 20 days) for the treatment of cutaneous leishmaniasis. Primary outcome was complete epithelisation of the lesion 6 months after the end of treatment. Secondary outcomes were lesion healing 2 months after the end of treatment and frequency and severity of adverse events. RESULTS: A total of 38 subjects were included in the trial, 15 were treated with standard SbV and 23 with the combination of tamoxifen and SbV . Of the patients treated with the co-administration scheme, 12 received tamoxifen orally and 11 were treated with topical tamoxifen. Tamoxifen administered by the oral or topical routes was well tolerated. Cure rates 6 months after the end of treatment per intention to treat were 40% in the group treated with the standard SbV scheme, and 36.4% and 58%, respectively, for groups treated with SbV plus topical or oral tamoxifen. CONCLUSIONS: In the doses and schemes used in this study, co-administration of oral tamoxifen and SbV resulted in higher cure rates in comparison with the standard scheme of treatment, although not to statistically significant levels.

Morphological and morphometric analysis of the effects of intralesional tamoxifen on keloids.

The aim of this study was to evaluate the effect of intralesional tamoxifen on keloids, particularly on the concentration of fibroblasts, dermal inflammatory infiltrate, and collagen degeneration. A prospective study was carried out to evaluate keloids in 13 patients of both genders pre- and post-treatment with intralesional tamoxifen. Two samples of keloid lesions were obtained by 4-mm punch biopsies during the study: the first at the time of diagnostic confirmation of keloid and the other eight weeks later at the end of intralesional tamoxifen treatment. The biopsy samples were placed in 10% buffered formalin for HE staining and morphological and morphometric study. The degree of collagen fiber reduction and inflammatory infiltration were analyzed. Student's t-test was used for statistical analysis of the mean number of fibroblasts before and following tamoxifen treatment ( P < 0.05). The degree of collagen fiber reduction and inflammatory infiltration were absent before treatment and present in 100% of cases after treatment, while the mean number of fibroblasts was significantly lower after intralesional tamoxifen treatment ( P < 0.0001). We conclude that intralesional administration of tamoxifen promoted an inflammatory stimulus and collagen fiber reduction as well as a significant reduction in the number of fibroblasts that produce collagen. Impact statement Effective treatment of keloid that is a commonly recurrent dermatosis is very difficult, even after standard treatment. Standard treatment consists of partial resection of the lesion (shaving excision), in addition to local corticosteroid injection. Therefore, there is interest in alternative forms of topical treatment, e.g., selective estrogen receptor modulators, particularly tamoxifen has demonstrated in vitro studies to be a promising drug. Nevertheless, there is scarcity of publications on the effects of intralesional tamoxifen on keloids have been found, leading us to the conception of the present study. In this study, tamoxifen has proven to be an interesting alternative drug for the topical treatment of keloid, allowing us to conclude that the intralesional application of tamoxifen in keloids promotes a variable but ever-present inflammatory stimulus, associated with intense reduction of collagen fiber, in addition to a significant decrease in the number of fibroblasts that produce collagen and are involved in disease maintenance.

Clinical investigation of RAD1901, a novel estrogen receptor ligand, for the treatment of postmenopausal vasomotor symptoms: a phase 2 randomized, placebo-controlled, double-blind, dose-ranging, proof-of-concept trial.

OBJECTIVE: The aim of the study was to assess the efficacy and safety of RAD1901, an oral estrogen receptor ligand, for the treatment of moderate-to-severe vasomotor symptoms of menopause. METHODS: This was a randomized, placebo-controlled, double-blind, dose-ranging, proof-of-concept trial. Postmenopausal women with a minimum of 7 moderate-to-severe, diary-reported hot flashes per day, or 50 per week, were randomized to one of five blinded dose groups (0 [placebo], 10, 25, 50, or 100 mg RAD1901 daily for 28 d). Efficacy endpoints included frequency and severity of hot flashes over 4 weeks of treatment. RESULTS: One hundred participants were randomized across the five treatment regimens. The frequency of moderate-to-severe hot flashes decreased in all groups over the treatment period (mean percent change from baseline at 4 wk, -54.1%, -77.2%, -51.8%, -53.8%, and -67.0% for placebo, 10, 25, 50, and 100 mg groups). The response in the 10 mg group was significantly different from placebo at 4 weeks (P = 0.024). No other dose group was significantly different from placebo. There were no statistically significant differences in severity of hot flashes between placebo and any dose group. Treatment was well tolerated; most treatment-emergent adverse events were mild to moderate in severity. CONCLUSIONS: Daily treatment with 10 mg RAD1901 over 4 weeks resulted in a statistically significant reduction in the frequency of moderate-to-severe hot flashes compared with placebo, with an acceptable safety profile. Further clinical trials are warranted to investigate RAD1901's utility as a potential treatment for vasomotor symptoms.

Eficacia y seguridad de fulvestrant en pacientes con cáncer de mama metastásico con receptores hormonales positivos, no tributarios a quimioterapia, que ha progresado a inhibidores de aromatasa no esteroideos / Efficacy and safety of fulvestrant in patients with metastatic breast cancer with hormone receptor positive, non-tributary to chemotherapy, who has progressed to non-steroidal aromatase inhibitors

INTRODUCCIÓN: Antecedentes: El presente informe expone la evaluación de eficacia y seguridad del uso de fulvestrant en el manejo de pacientes post-menopáusicas, con diagnóstico de cáncer de mama metastásico con receptores hormonales positivos, progresivo a inhibidores de aromatasa no esteroideos con control de enfermedad visceral y de partes blandas con quimioterapia basada en taxanos con toxicidad limitante (i.e., no tributarios a quimioterapia sistémica). Aspectos Generales: El cáncer de mama es el tipo de cáncer que se diagnostica con mayor frecuencia entre mujeres a nivel mundial. En el Perú, del total de cánceres reportados entre los años 2006 a 2011, el cáncer de mama fue el tercer tipo de cáncer más frecuente en toda la población (10.3%) y el segundo tipo de cáncer más frecuente entre mujeres (16.6%). Aproximadamente 34 de cada 100 mil mujeres al año es diagnosticada con cáncer de mama, con una tasa de mortalidad de 14 por cada 100 mil mujeres diagnosticadas. El cáncer de mama metastásico es la principal causa de muerte dentro de los pacientes con cáncer de mama. Más del 90% de pacientes con cáncer de mama muere por metástasis. Tecnologia Sanitaria de Interés: Fulvestrant (nombre comercial Faslodex), es una terapia antiestrogénica de tipo SERDs. Esta terapia está indicada para el tratamiento de cáncer de mama metastásico con receptores estrogénicos positivos en mujeres post-menopáusicas que han progresado luego de terapia antiestrogénica. Fulvestrant disminuye la actividad de los receptores de estrógeno, presenta actividad anti-proliferativa, induce apoptosis, no posee actividad agonista de estrógeno y carece de resistencia cruzada con otras terapias antiestrogénicas, tales como los SERMs. METODOLOGIA: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de fulvestrant para el tratamiento de cáncer de mama con receptores estrogénicos positivos metastásico, en pacientes no tributarios a quimioterapia, que han progresado a inhibidores de aromatasa no esteroideos. Esta búsqueda se realizó utilizando los meta-buscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline) y Health Systems Evidence. RESULTADOS: Sinopsis de la Evidencia: Se realizó la búsqueda bibliográfica y de evidencia científica hasta Junio 2016 para el sustento del uso de fulvestrant en el tratamiento de cáncer de mama positivo a receptores hormonales metastásico, en pacientes no tributarios a quimioterapia que han progresado a inhibidores de aromatasa no esteroideos. Se presenta la evidencia\r\ndisponible según el tipo de publicación priorizada en los criterios de inclusión (i.e., GP, ETS, RS y ECA fase III). CONCLUSIONES: El presente documento evaluó la evidencia científica publicada hasta Julio del 2016 para el uso fulvestrant en mujeres post-menopáusicas con cáncer de mama metastásico con receptores hormonales positivos que han progresado a tratamientos previos con inhibidores de aromatasa no esteroideos. Existen pacientes con cáncer de mama metastásico con receptores hormonales positivos que progresan a terapia hormonal estándar con inhibidores de aromatasa no esteroideos, en quienes la quimioterapia no está indicada, dejando limitadas alternativas para su tratamiento. En la actualidad, el Petitorio Farmacológico de EsSalud cuenta con exemestano, un inhibidor de aromatasa esteroideo, por lo tanto es necesario probar que fulvestrant es una alternativa superior a exemestano en relación a los desenlaces considerados en el presente dictamen. Fulvestrant, es una alternativa de terapia hormonal se segunda línea. Sin embargo, esta no ha probado ser mejor que exemestano para ninguno de los desenlaces de interés, a pesar de ello, el costo de este medicamento es considerablemente elevado en relación al que actualmente se encuentra en el petitorio farmacológico de EsSalud. El Instituto de evaluación de Tecnologías en Salud e Investigación (IETSI) no aprueba el uso de fulvestrant para el tratamiento endocrino de cancer de mama con receptores hormonales positivos metastásico en mujeres post-menopaúsicas no tributarias a quimioterapia que han progresado a terapia con inhibidores de aromatasa no esteroideos.

Evaluation of Ki-67 antigen expression in the vaginal epithelium of castrated female rats treated with raloxifene and tamoxifen: a comparative study.

OBJECTIVE: The aim of this study was to evaluate the effects of raloxifene and tamoxifen on Ki-67 antigen expression in the vaginal epithelium of castrated rats. MATERIAL AND METHODS: Thirty-nine virgin, adult, castrated female Wistar-Hannover rats were randomly divided into three groups: Group I (control, n = 13), Group II (raloxifene, n = 13) and Group III (tamoxifen, n = 13). After confirmation of their hypoestrogenic state, the rats were given 0.5 ml of propylene glycol (vehicle), 750 µg of raloxifene or 250 µg of tamoxifen, respectively, by gavage, for 30 days. On the 31st day, the rats were euthanized and their vaginas removed and fixed in 10% buffered formalin for of Ki-67 immunohistochemical evaluation. Data were analyzed using Levene's test and Tukey's method (p < 0.05). RESULTS: Mean Ki-67 expression in groups I, II and III was 27 ± 2.6, 32.3 ± 1.9 and 43.7 ± 3.5, respectively. In Group III (tamoxifen), there was a greater proportion of stained cells compared to Groups I and II (p < 0.0003), with no statistically significant difference between Groups I and II (p = 0.3626). CONCLUSIONS: The present results show that tamoxifen significantly increased cell proliferation in the vaginal epithelium of the castrated rats and no difference between the raloxifene and control groups.

Tamoxifen antagonizes the effects of ovarian hormones to induce anxiety and depression-like behavior in rats.

The effects of tamoxifen (TAM) on anxiety and depression-like behavior in ovariectomized (OVX) and naïve female rats were investigated. The animals were divided into Sham-TAM, OVX-TAM, Sham and OVX groups. Tamoxifen (1 mg/kg) was administered for 4 weeks. In the forced swimming test, the immobility times in the OVX and Sham-TAM groups were higher than in the Sham group. In the open field, the numbers of central crossings in the OVX and Sham-TAM groups were lower than the number in the Sham group, and the number of peripheral crossings in the OVX group was lower than the number in the Sham group. In the elevated plus maze, the numbers of entries to the open arm among the animals in the Sham-TAM and OVX groups were lower than the number in the Sham group, while the number of entries to the open arm in the OVX-TAM group was higher than the number in the OVX group. It was shown that deletion of ovarian hormones induced anxiety and depression-like behavior. Administration of tamoxifen in naïve rats led to anxiety and depression-like behavior that was comparable with the effects of ovarian hormone deletion. It can be suggested that tamoxifen antagonizes the effects of ovarian hormones. It also seems that tamoxifen has anxiolytic effects on ovariectomized rats.

Risk-benefit profiles of women using tamoxifen for chemoprevention.

BACKGROUND: Tamoxifen has been US Food and Drug Administration-approved for primary prevention of breast cancer since 1998 but has not been widely adopted, in part because of increased risk of serious side effects. Little is known about the risk-benefit profiles of women who use chemoprevention outside of a clinical trial. We examined characteristics associated with initiation and discontinuation of tamoxifen for primary prevention of breast cancer within a large cohort of women with a first-degree family history of breast cancer. METHODS: This research was conducted within The Sister Study, a cohort of 50884 US and Puerto Rican women age 35 to 74 years enrolled from 2003 to 2009. Eligible women were breast cancer-free at enrollment and had a sister who had been diagnosed with breast cancer. Participants reported tamoxifen use, ages started and stopped taking tamoxifen, and total duration of use at enrollment. We identified 788 tamoxifen users and 3131 nonusers matched on age and year of enrollment who had no history of contraindicating factors (stroke, transient ischemic attack, cataract, endometrial or uterine cancer). Characteristics associated with tamoxifen initiation were evaluated with multivariable conditional logistic regression. All statistical tests were two-sided. RESULTS: Based on published risk-benefit indices, 20% of women who used tamoxifen had insufficient evidence that the benefits of tamoxifen outweigh the risk of serious side effects. After 4.5 years, 46% of women had discontinued tamoxifen. CONCLUSIONS: While the majority of women who used tamoxifen for primary prevention of breast cancer were likely to benefit, substantial discontinuation of tamoxifen before five years and use by women at risk of serious side effects may attenuate benefits for breast cancer prevention.

Evaluation of the measurement model and clinically important differences for menopause-specific quality of life associated with bazedoxifene/conjugated estrogens.

OBJECTIVE: This study aims to confirm the factor structure of the Menopause-Specific Quality of Life (MENQOL) questionnaire by using confirmatory factor analysis (CFA) and to determine whether improvements in menopause-specific health-related quality of life (HRQOL) observed with bazedoxifene (BZA)/conjugated estrogens (CE) relative to placebo are clinically meaningful. METHODS: Postmenopausal women with seven or more moderate to severe hot flushes per day (or ≥50 per wk) received BZA 20 mg/CE 0.45 mg, BZA 20 mg/CE 0.625 mg, or placebo for 12 weeks. HRQOL and treatment satisfaction were evaluated using the MENQOL questionnaire and the Menopause Symptoms Treatment Satisfaction Questionnaire, respectively. The structure of the MENQOL questionnaire was evaluated using CFA. To estimate clinically important differences (CIDs) in HRQOL, we used a repeated-measures model to estimate changes in MENQOL domain and total scores using Menopause Symptoms Treatment Satisfaction Questionnaire items as anchors. RESULTS: The CFA model fits the MENQOL data (Bentler's comparative fit index >0.9). CID estimates ranged from 0.5 to 1.2 for the MENQOL domains and total score. Change from baseline in MENQOL vasomotor domain score for BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg compared with placebo was greater than the estimated CID, as were changes in MENQOL physical domain and total scores for BZA 20 mg/CE 0.625 mg compared with placebo. CONCLUSIONS: CFA confirms the factor structure of the MENQOL questionnaire. Treatment with BZA/CE provides clinically meaningful improvements in HRQOL in a population of postmenopausal women with bothersome vasomotor symptoms.

Changes in bone mineral density are correlated with bone markers and reductions in hot flush severity in postmenopausal women treated with bazedoxifene/conjugated estrogens.

OBJECTIVE: A post hoc exploratory analysis was conducted to examine correlations between changes in bone density, bone markers, and hot flushes after the treatment of postmenopausal women with bazedoxifene (BZA)/conjugated estrogens (CE). METHODS: In a 2-year phase 3 study, 3,397 postmenopausal women were randomized to BZA 10 mg/CE 0.45 mg, BZA 20 mg/CE 0.45 mg, BZA 40 mg/CE 0.45 mg, BZA 10 mg/CE 0.625 mg, BZA 20 mg/CE 0.625 mg, BZA 40 mg/CE 0.625 mg, raloxifene 60 mg, or placebo. In this analysis, bone density changes at 2 years were compared with baseline levels of the bone markers serum C-telopeptide and osteocalcin. Correlations between changes in bone density and changes in 12-week hot flush composite scores in symptomatic women were also analyzed. RESULTS: Treatment with BZA 20 mg/CE 0.45 mg or BZA 20 mg/CE 0.625 mg increased lumbar spine bone density more in women with higher bone resorption and formation, categorized by baseline levels of C-telopeptide and osteocalcin (P < 0.001, both BZA/CE doses). With placebo, larger decreases in lumbar spine bone density were seen in the highest tertile of serum C-telopeptide. There was no correlation between changes in total hip bone density and baseline bone markers. There were significant correlations between percent change in hot flush score at week 12 and percent changes in lumbar spine (r = -0.31, P = 0.006) and total hip (r = -0.23, P = 0.044) bone densities at month 24. CONCLUSIONS: With 2-year BZA/CE treatment, women with larger increases in lumbar spine and total hip densities also have higher baseline bone markers. Early reductions in hot flush score (12 wk) are predictive of long-term increases in bone density (24 mo).

Effects of tamoxifen and raloxifene on body and uterine weights of rats in persistent estrus.

PURPOSE: To evaluate the change in body and uterine weights of rats in persistent estrus, a model developed to mimic polycystic ovary syndrome treated with selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene. METHODS: Sixty Wistar-Hannover rats induced by a single subcutaneous dose of 1.25 mg testosterone propionate were divided into three groups of 20 animals: Group I (placebo); Group II (tamoxifen, 250 microg/day) and Group III (raloxifene, 750 microg/day). At 90 days of life, the treatment began for 30 consecutive days, in which the animals were weighed weekly. On the 31st day, the animals were sacrificed and the uterus removed. Data were analyzed statistically by analysis of variance and by the Tukey-Kramer multiple comparisons test (p<0.05). RESULTS: Means of body and uterine weights (g) after treatment were: 227.3+/-2.20 and 0.40+/-0.01; 185.3+/-2.45 and 0.25+/-0.01; 186.4+/-2.20 and 0.27+/-0.01 in Groups I, II and III, respectively (p<0.001). There was no statistical difference between groups II and III for body and uterine weight (p=0.727 and p=0.646, respectively). CONCLUSION: The present results indicate that, at the doses and during the time of treatment used, both tamoxifen and raloxifene reduce in a similar way the body and uterine weights of rats in persistent estrus showing a possible antiestrogenic effect of SERMs under high levels of estrogens.

Estrogens plus raloxifene on endometrial safety and menopausal symptoms--semisystematic review.

OBJECTIVE: The aim of this study was to summarize the evidence of endometrial safety and quality of life assessment in postmenopausal women taking raloxifene (RLX) + estrogens (E). METHODS: Clinical studies reporting RLX + E were identified using Medline and LILACS and through reviewing reference lists of highly significant publications. Articles published in Portuguese, Spanish, and English from the past 10 years were considered. RESULTS: Six corresponding clinical trials were identified. Different estrogen formulations, doses, and routes were used. The primary outcome of the selected studies also differed. Most of the studies found a benefit profile on RLX + E on women's quality of life, satisfaction with the treatment, and vaginal dryness. Some studies showed an increased endometrial thickness after 3 months of treatment. Most biopsies revealed benign endometrial proliferation; only two women experienced endometrial hyperplasia, both of them after 24 weeks of treatment. CONCLUSIONS: There are only a few clinical trials that evaluated endometrial safety and quality of life with RLX + E in postmenopausal women. The benefits shown on quality of life and endometrial safety are not certified. Larger studies are deemed necessary to define the better estrogen form and to evaluate the safety and efficacy of long-term use of RLX + E.

Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up.

BACKGROUND: Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast-cancer recurrence and death. Therefore, trials assessing endocrine therapies for this patient population need extended follow-up. We present an update of efficacy outcomes in the Breast International Group (BIG) 1-98 study at 8·1 years median follow-up. METHODS: BIG 1-98 is a randomised, phase 3, double-blind trial of postmenopausal women with hormone receptor-positive early breast cancer that compares 5 years of tamoxifen or letrozole monotherapy, or sequential treatment with 2 years of one of these drugs followed by 3 years of the other. Randomisation was done with permuted blocks, and stratified according to the two-arm or four-arm randomisation option, participating institution, and chemotherapy use. Patients, investigators, data managers, and medical reviewers were masked. The primary efficacy endpoint was disease-free survival (events were invasive breast cancer relapse, second primaries [contralateral breast and non-breast], or death without previous cancer event). Secondary endpoints were overall survival, distant recurrence-free interval (DRFI), and breast cancer-free interval (BCFI). The monotherapy comparison included patients randomly assigned to tamoxifen or letrozole for 5 years. In 2005, after a significant disease-free survival benefit was reported for letrozole as compared with tamoxifen, a protocol amendment facilitated the crossover to letrozole of patients who were still receiving tamoxifen alone; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting (IPCW) are used to account for selective crossover to letrozole of patients (n=619) in the tamoxifen arm. Comparison of sequential treatments to letrozole monotherapy included patients enrolled and randomly assigned to letrozole for 5 years, letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years. Treatment has ended for all patients and detailed safety results for adverse events that occurred during the 5 years of treatment have been reported elsewhere. Follow-up is continuing for those enrolled in the four-arm option. BIG 1-98 is registered at clinicaltrials.govNCT00004205. FINDINGS: 8010 patients were included in the trial, with a median follow-up of 8·1 years (range 0-12·4). 2459 were randomly assigned to monotherapy with tamoxifen for 5 years and 2463 to monotherapy with letrozole for 5 years. In the four-arm option of the trial, 1546 were randomly assigned to letrozole for 5 years, 1548 to tamoxifen for 5 years, 1540 to letrozole for 2 years followed by tamoxifen for 3 years, and 1548 to tamoxifen for 2 years followed by letrozole for 3 years. At a median follow-up of 8·7 years from randomisation (range 0-12·4), letrozole monotherapy was significantly better than tamoxifen, whether by IPCW or intention-to-treat analysis (IPCW disease-free survival HR 0·82 [95% CI 0·74-0·92], overall survival HR 0·79 [0·69-0·90], DRFI HR 0·79 [0·68-0·92], BCFI HR 0·80 [0·70-0·92]; intention-to-treat disease-free survival HR 0·86 [0·78-0·96], overall survival HR 0·87 [0·77-0·999], DRFI HR 0·86 [0·74-0·998], BCFI HR 0·86 [0·76-0·98]). At a median follow-up of 8·0 years from randomisation (range 0-11·2) for the comparison of the sequential groups with letrozole monotherapy, there were no statistically significant differences in any of the four endpoints for either sequence. 8-year intention-to-treat estimates (each with SE ≤1·1%) for letrozole monotherapy, letrozole followed by tamoxifen, and tamoxifen followed by letrozole were 78·6%, 77·8%, 77·3% for disease-free survival; 87·5%, 87·7%, 85·9% for overall survival; 89·9%, 88·7%, 88·1% for DRFI; and 86·1%, 85·3%, 84·3% for BCFI. INTERPRETATION: For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by letrozole monotherapy when compared with tamoxifen montherapy. Sequential treatments involving tamoxifen and letrozole do not improve outcome compared with letrozole monotherapy, but might be useful strategies when considering an individual patient's risk of recurrence and treatment tolerability. FUNDING: Novartis, United States National Cancer Institute, International Breast Cancer Study Group.

SERMs in the prevention and treatment of postmenopausal osteoporosis: an update.

Selective estrogen receptor modulators (SERMs) have the ability to bind the estrogen receptor (ER) and are known to confer ER agonist or antagonist effects depending on the target tissue. A number of newer SERMs, including bazedoxifene, lasofoxifene and ospemifene, are currently under clinical development for the prevention and treatment of postmenopausal osteoporosis and for other indications. Although the possibility of developing a single agent that has all of the desired characteristics of an ideal SERM seems to be unlikely, progress in the clinical development of SERMs targeted to the ER suggests that these newer compounds may have attributes that represent an improvement relative to existing SERMs. A new approach to menopausal therapy is the tissue selective estrogen complex or the pairing of a selective estrogen receptor modulator with estrogens. Further investigation will help to clarify relative benefits/risks of novel SERMs in development within specific indications.

SERMs in the prevention and treatment of postmenopausal osteoporosis: an update / SERMs na prevenção e no tratamento da osteoporose pós-menopausa: uma atualização

Selective estrogen receptor modulators (SERMs) have the ability to bind the estrogen receptor (ER) and are known to confer ER agonist or antagonist effects depending on the target tissue. A number of newer SERMs, including bazedoxifene, lasofoxifene and ospemifene, are currently under clinical development for the prevention and treatment of postmenopausal osteoporosis and for other indications. Although the possibility of developing a single agent that has all of the desired characteristics of an ideal SERM seems to be unlikely, progress in the clinical development of SERMs targeted to the ER suggests that these newer compounds may have attributes that represent an improvement relative to existing SERMs. A new approach to menopausal therapy is the tissue selective estrogen complex or the pairing of a selective estrogen receptor modulator with estrogens. Further investigation will help to clarify relative benefits/risks of novel SERMs in development within specific indications.

Moduladores seletivos do receptor do estrogênio (SERMs) têm a habilidade de se ligar ao receptor de estrogênio (ER) e são conhecidos por conferir um efeito agonista ou antagonista sobre o tecido-alvo. Um número de novos SERMs, incluindo bazedoxifeno, lasofoxifeno e ospemifeno, está atualmente em desenvolvimento clínico para prevenção e tratamento da osteoporose pós-menopausa e para outras indicações. Embora a possibilidade de desenvolver um simples agente que tenha todas as características desejadas de um SERM ideal parece ser pouco provável, esses novos SERMs apresentam propriedades que indicam uma melhora em relação aos SERMs existentes. Uma nova opção terapêutica é o uso do complexo estrogênico do tecido seletivo ou a associação do SERM com estrogênios. Novos estudos ajudarão a rastrear os riscos e benefícios dos novos SERMs em desenvolvimento dentro das suas indicações específicas.

Raloxifene effects on thyroid gland morphology in ovariectomized rats.

We aimed to analyze the effects of raloxifene and estrogen on thyroid gland morphology of ovariectomized rats. Raloxifene treatment led to effects similar to those of estrogen on thyroid glands from ovariectomized rats, so that both were able to normalize the changes detected after ovariectomy.

Ação do raloxifeno no endométrio / Raloxifene effects on endometrium

O raloxifeno é uma droga relativamente nova quando consideramos seus efeitos colaterais. Efeitos adversos podem se manifestar muito tempo após o início do uso ou ter uma incidência tão pequena, que somente anos de acompanhamento permitiriam sua identificação. O raloxifeno tem sido associado com a redução da incidência de câncer de mama após 2 a 3 anos de tratamento, além de mostrar um efeito positivo na densidade óssea e no perfil lipídico. Os principais inconvenientes ao seu uso são uma maior incidência de fogachos e de tromboembolismo venoso, embora haja meios de diminuir a incidência do primeiro. A grande maioria dos estudos em humanos mostrou uma grande segurança em nível endometrial, mesmo quando o raloxifeno foi usado em doses acima da comumente recomendada, que é de 60 mg/dia. Poucos são os estudos que mostram algum efeito negativo do raloxifeno no útero, sendo geralmente com pequeno número de participantes e com baixo nível de evidência. Nota-se que o raloxifeno é seguro em pacientes na pós-menopausa e sem patologias uterinas, fazendo parte do arsenal terapêutico contra a osteoporose. Porém, devemos estar atentos para possíveis efeitos negativos no endométrio, principalmente em longo prazo.

Nonproliferative epithelial alteration and expression of estrogen receptor and Ki67 in the contralateral breast of women treated with tamoxifen for breast cancer.

The aim of study was to evaluate the frequency of nonproliferative epithelial alteration and expression of Ki67 and estrogen receptors (ER) in patients using tamoxifen. Forty-four women were selected who had been taking 20mg of tamoxifen daily for at least 12 months for adjuvant treatment of breast cancer. The women underwent core biopsy in the contralateral breast into an area of highest fibroglandular mammographic density. Fragments were analyzed by immunohistochemistry for monoclonal antibody Ki67 and ER, and histopathologic analysis. It was verified that 82% of the patients presented nonproliferative epithelial alteration, 70% were ER-negative, and all had low Ki67 expression. There was no association between duration of tamoxifen therapy, patient age, mammographic density, and presence of nonproliferative alteration (P>0.05). In conclusion, tamoxifen for more than a year showed a high frequency of nonproliferative epithelial alteration and low expression of Ki67 and ER in the normal breast tissue, consistent with low cell proliferation.

Procoagulant state after raloxifene therapy in postmenopausal women.

OBJECTIVE: To investigate the effects of raloxifene on the hemostatic system in postmenopausal women. DESIGN: A prospective longitudinal study. SETTING: Outpatient clinic of the Faculty of Medicine of Ribeirão Preto, Brazil. PATIENT(S): Sixteen postmenopausal women aged 56.8 +/- 5.9 years (mean +/- SD). INTERVENTION(S): Raloxifene hydrochloride (60 mg once daily) was administered orally for a period of 6 months. MAIN OUTCOME MEASURE(S): Plasma activities of coagulation factors (II, V, VII, VIII, IX, X, XI, XII, and fibrinogen), prothrombin-derived fragment 1+2, and activated protein C (APC) sensitivity ratio were measured at baseline and after 1, 3, and 6 months of treatment. RESULT(S): Factor VIII activity increased by 17.1% and 26.9% at 3 and 6 months of treatment, respectively, compared with baseline. Factor XI and FXII activities significantly increased by 10.9% and 43.1%, respectively, after 6 months compared with baseline. A significant reduction of APC sensitivity ratio also was observed after 6 months of treatment. CONCLUSION(S): A procoagulant state characterized by increased factor VIII, XI, and XII plasma levels and by reduced APC sensitivity was observed after raloxifene therapy in post-menopausal women.