Postmenopausal Estrogen Research Articles

302P - Factors associated with prolonged time to treatment failure with fulvestrant 500 mg in patients with postmenopausal estrogen receptor-positive advanced/metastatic breast cancer (JBCRG-C06; Safari): A subgroup analysis

302P - Factors associated with prolonged time to treatment failure with fulvestrant 500 mg in patients with postmenopausal estrogen receptor-positive advanced/metastatic breast cancer (JBCRG-C06; Safari): A subgroup analysis

난소절제 마우스에서 잔대 추출물의 인지능 개선 효과

Adenophora triphylla var. japonica extract has been reported to have estrogenic activity and beneficial effects in postmenopausal women requiring estrogen replacement therapy. This study investigated the effects of A. triphylla extract on cognitive function in ovariectomized mice. Water extracts fro...

Improved Prediction of Endoxifen Metabolism by CYP2D6 Genotype in Breast Cancer Patients Treated with Tamoxifen.

Purpose: Prediction of impaired tamoxifen (TAM) to endoxifen metabolism may be relevant to improve breast cancer treatment, e.g., via TAM dose increase. The polymorphic cytochrome P450 2D6 (CYP2D6) strongly determines an individual’s capacity for endoxifen formation, however, CYP2D6 phenotype assignments inferred from genotype widely differ between studies. Thus, we modeled plasma endoxifen predictability depending on variable CYP2D6 genotype groupings.Methods: CYP2D6 diplotype and metabolite plasma concentrations were assessed in 908 pre- and post-menopausal estrogen receptor (ER)-positive, TAM treated early breast cancer patients of Caucasian (N = 678), Middle-Eastern Arab (N = 77), and Asian (N = 153) origin. Robust coefficients of determination (R2) were estimated for endoxifen (E) or metabolic ratio endoxifen/desmethyl-TAM (E/DMT) as dependent and different CYP2D6 phenotype assignments as independent variables. Allele activity scores (ASs) were modified with respect to a reduced ∗10 allele activity. Predictability of endoxifen plasma concentrations above the clinical threshold of 5.9 ng/mL was investigated by receiver operating characteristic (ROC) analysis.Results: CYP2D6 diplotypes (N = 898) were strongly associated with E and E/DMT independent of age (P < 10-15). Across all ethnicities, 68–82% inter-patient variability of E/DMT was explained by CYP2D6 diplotype, while plasma endoxifen was predictable by 39–58%. The previously used codeine specific phenotype classification showed worse prediction for both endpoints particularly in Asians (median R2< 20%; P < 10-9). Downgrading of ∗10 activity slightly improved the explanatory value of metabolizer phenotype (P < 0.002). Endoxifen plasma concentrations above the clinical threshold of 5.9 ng/mL were achieved in 82.3% of patients and were predictable (96% sensitivity, 57% specificity) by CYP2D6 diplotypes with AS > 0.5, i.e., omitting PM/PM and PM/IM patients.Conclusion: The CYP2D6 explanatory power for active drug level assessment is maximized by TAM-specific phenotype assignments while a genotype cutoff that separates PM/PM and PM/IM from the remaining patients may improve clinical benefit via increased endoxifen concentrations.

Psoralen stimulates osteoblast proliferation through the activation of nuclear factor-κB-mitogen-activated protein kinase signaling.

Osteoporosis is a systemic skeletal disease that leads to increased bone fragility and susceptibility to fracture. Approximately 50% of postmenopausal women develop osteoporosis as a result of postmenopausal estrogen deficiency. To reduce fractures related to osteoporosis in women, previous studies have focused on therapeutic strategies that aim to increase bone formation or decrease bone resorption. However, pharmacological agents that aim to improve bone fracture susceptibility exhibit side effects. Current studies are investigating natural alternatives that possess the benefits of selective estrogen receptor modulators (SERMs) without the adverse effects. Recent studies have indicated that phytoestrogen may be an ideal natural SERM for the treatment of osteoporosis. In Chinese herbal medicine, psoralen, as the predominant substance of Psoralea corylifolia, is considered to be a phytoestrogen and is used as a remedy for osteoporosis. A number of studies have demonstrated the efficacy of psoralen in bone formation. However, the pathways and underlying molecular mechanisms that participate in psoralen-induced osteoblast formation are not well understood. In the present study, hFOB1.19 cells were treated with psoralen at different concentrations (0, 5, 10, 15 and 20 µM) for 0, 24, 36, 48 and 72 h, respectively. Reverse transcription-quantitative polymerase chain reaction and western blot assays were performed to detect glucose transporter 3 (GLUT3) expression. A cell counting kit-8 assay was used to analyze cell proliferation. In addition the effects of mitogen activated protein kinase inhibitors on extracellular signal-regulated kinase (ERK), phosphorylated (p)-ERK, p38, p-p38, c-Jun N-terminal kinase (JNK) and p-JNK expressions and cell proliferation were measured, as was the effect of nuclear factor (NF)-κB inhibitor on P65 and GLUT3 expressions and cell proliferation. The results indicated that psoralen stimulates hFOB1.19 cell proliferation in a dose-dependent manner (P<0.05). Phospho-ERK, p38 and JNK were markedly increased by psoralen compared with the control group (P<0.05), and the specific inhibitors of ERK (SCH772984), p38 (SB203580) and JNK (SP600125) reversed the stimulatory effects of psoralen on signal marker phosphorylation (P<0.05). The rate of psoralen-induced cell proliferation was significantly suppressed by inhibitors of ERK, JNK and p38 compared with psoralen treatment alone (P<0.05). In addition, psoralen stimulated osteoblast proliferation via the NF-κB signaling pathway. Therefore, the present findings suggest that psoralen may be a potential natural alternative to SERMs in the treatment of osteoporosis and fractures.

Abstract 4160: Impact of oral selective estrogen receptor degrader RAD1901 in preclinical models of endocrine sensitive/resistant breast cancer

Abstract Aromatase inhibitors (AI) are the mainstay for treatment of postmenopausal estrogen receptor positive (ER+) primary breast cancer (BC). However, many patients relapse whilst retaining a functional ER. The selective ER degrader (SERD) fulvestrant has been evaluated as a potential 2nd or 3rd line therapy for patients who relapse on AI treatment. Although exhibiting promising potential, its low bioavailability has limited its use to combination therapy in metastatic patients. Here, we assessed the efficacy of the orally available SERD, RAD1901, in a panel of BC cells with varying genetic backgrounds modelling patients both sensitive and resistant to AI therapy (LTED). Fulvestrant was used in parallel to allow relative responses to be compared. Cell proliferation assays in 2D and spheroids the presence of 0.01nM 17β-estradiol showed a concentration-dependent decrease in proliferation in response to RAD1901 and fulvestrant. GI50 values for RAD1901 in general were 10-fold higher than fulvestrant but equated to doses that are clinically achievable for RAD1901. Most importantly, RAD1901 effectively suppressed proliferation of two LTED models harbouring naturally occurring ESR1 mutations, MCF7 LTEDY537C (GI50 5nM) and SUM44-LTEDY537S (GI50 100nM). GI50 values of RAD1901 and fulvestrant showed similar reduction of ER, progesterone receptor (PGR) and cyclin D1 together with decreased phosphorylation of retinoblastoma (RB), concordant with cell cycle arrest. Furthermore, chromatin immunoprecipitation (ChIP) for ER in response to RAD1901 or fulvestrant showed a 70% reduction in recruitment of ER to TFF1, GREB1 and PGR promoters and concomitant reduction in mRNA expression of these genes. In MCF7-Arom cells, combination of letrozole with RAD1901 or fulvestrant showed enhanced antiproliferative effect compared to letrozole alone. The addition of RAD1901 to CDK4/6 inhibitor palbociclib or abemaciclib demonstrated additivity compared with monotherapy. In addition, RAD1901 effectively inhibited growth of palbociclib-resistant MCF7 LTED cells.These preclinical findings highlight the potential utility of RAD1901 as a potent drug in the treatment of ER+ BC. Combined with its bioavailability profile, RAD1901 warrants clinical testing versus fulvestrant after relapse on an AI, either alone or in combination with a CDK4/6 inhibitor. Citation Format: Sunil Pancholi, Joanna Nikitorowicz-Buniak, Ricardo Ribas, Nikiana Simigdala, Fiona Garner, Teeru Bihani, Stephen R. Johnston, Mitch Dowsett, Lesley-Ann Martin. Impact of oral selective estrogen receptor degrader RAD1901 in preclinical models of endocrine sensitive/resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4160. doi:10.1158/1538-7445.AM2017-4160

The correlation between estrogen and diabetic retinopathy of the postmenopasual patients

Objective To observe the correlation between postmenopausal estrogen levels and diabetic retinopathy (DR) in women. Methods Thirty-nine menopause female patients with type 2 diabetes mellitus and 17 menopause subjects (control group) were enrolled in this study. Control subjects aged from 53 to 82 years, with the mean age of (69.80±8.32) years. Diabetes mellitus patients aged from 56 to 84 years, with the mean age of (70.50±8.27) years; diabetes duration ranged from 3 to 23 years, with the average course of diabetes (11.40±7.97) years. DR diagnosis was according to the results of fundus fluorescein angiography, and thus the 39 patients were divided into DR group (19 patients) and non-DR (NDR) group (20 patients). There was no significant difference in age and menopause duration between the three groups (t=0.347, 0.485; P>0.05). There was significant difference in diabetes course (t=2.748, P<0.05). Compared with NDR group, fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) were significantly increased (t=6.130, 5.322, 4.574, 2.426, 4.033), high density lipoprotein cholesterol (HDL-C) was significantly lower (t=3.917), the difference was statistically significant (P<0.05). The level of estradiol (E2) was measured by radioimmunoassay. The differences of E2 levels between the three groups were compared. Logistic regression analysis was used to analyze the influencing factors of DR. Results The levels of E2 in control group, DR group and NDR group were (42.38±8.64), (21.49±9.81) and (32.72±10.51) pg/ml, respectively. The level of E2 in DR group was significantly lower than that in NDR group and control group (t=3.443, 10.110; P<0.05). Logistic regression analysis showed that the duration of diabetes mellitus [coefficients =0.166, odds ratio (OR)=1.181, P= 0.016], FBG (coefficients=1.162, OR=4.014, P=0.001), TC (coefficients=3.212, OR=10.820, P=0.002), TG (coefficients=1.649, OR=5.203, P= 0.030) and LDL-C (coefficients=1.605, OR= 4.976, P=0.003) were the risk factors for DR; E2 (coefficients=-0.100, OR=0.904, P=0.004) and HDL-C (coefficients=-4.460, OR=0.012, P=0.002) were the protective factors for DR. Conclusion The estrogen level of postmenopausal women have a certain correlation with the development of DR, it may be one of the protective factor of DR. Key words: Diabetic retinopathy/etiology; Estrogens; Menopause

Endocrine Therapy in the Current Management of Postmenopausal Estrogen Receptor-Positive Metastatic Breast Cancer.

Metastatic breast cancer (MBC) results in substantial morbidity and mortality for women afflicted with this disease. A majority of MBCs are hormone-responsive and estrogen receptor-positive, making endocrine therapy (ET) an integral component of systemic therapy. With a primary goal of minimizing the effects of estrogen on hormone-responsive MBC, ETs are among the first targeted treatments that aim to inhibit the influence of estrogen receptor activation on tumor proliferation. Several biochemical mechanisms have been the focus of drug development for treatment, including selective estrogen-receptor modulation, aromatase inhibition, and selective estrogen-receptor degradation. Treatments that exploit these mechanisms have improved survival and quality of life for women with MBC. However, in many cases, resistance to ET limits their effectiveness. Elucidation of the complex cellular signal cascades involved in the development of acquired resistance to ET and the interrelationship of growth factor signaling and estrogen responsiveness have characterized components of these pathways as attractive targets for drug development. Based on these insights and with the aim of overcoming hormone resistance, targeted therapies are emerging as useful treatments for MBC. This article reviews current endocrine treatments of MBC as well as recent and ongoing study of combination treatments and targeted therapies that interfere with cellular proliferation pathways as means of overcoming resistance. The Oncologist 2017;22:507-517 IMPLICATIONS FOR PRACTICE: This review provides medical oncologists and other oncology health care providers with a current understanding of the rationale for endocrine therapy in estrogen receptor-positive metastatic breast cancer and the efficacy and safety profile of available treatment options. Additionally, current concepts regarding the development of treatment resistance and the treatment strategies for overcoming resistance are discussed. Enhancing the current information and the understanding of these topics will assist clinicians in evaluating optimal treatment options for their patients.

Postmenopausal hormone therapy and Alzheimer disease: A prospective cohort study.

Objective:To explore the association between postmenopausal hormone therapy (HT) and Alzheimer disease (AD).Methods:Twenty-year follow-up data from the Kuopio Osteoporosis Risk Factor and Prevention study cohort were used. Self-administered questionnaires were sent to all women aged 47–56 years, residing in Kuopio Province starting in 1989 until 2009, every 5th year. Register-based information on HT prescriptions was available since 1995. Probable AD cases, based on DSM-IV and National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria, were identified from the special reimbursement register (1999–2009). The study population included 8,195 women (227 cases of incident AD).Results:Postmenopausal estrogen use was not associated with AD risk in register-based or self-reported data (hazard ratio/95% confidence interval 0.92/0.68–1.2, 0.99/0.75–1.3, respectively). Long-term self-reported postmenopausal HT was associated with reduced AD risk (0.53/0.31–0.91). Similar results were obtained with any dementia diagnosis in the hospital discharge register as an outcome.Conclusions:Our results do not provide strong evidence for a protective association between postmenopausal HT use and AD or dementia, although we observed a reduced AD risk among those with long-term self-reported HT use.

Abstract S1-10: Clinical implications of somatic mutations in post-menopausal early-stage estrogen receptor (ER)-positive HER2-negative breast cancer (BC): Results from the BIG 1-98 study

Abstract Background Next generation sequencing (NGS) has revealed that ER+/HER2- BCs have diverse somatic copy number and mutation profiles but thus far the clinical relevance of such findings is unknown. We characterized the molecular alterations in post-menopausal primary BC patients treated in the BIG 1-98 adjuvant letrozole and tamoxifen study and evaluated their associations with prognosis. Materials and Methods NGS was used to genotype DNA from archival primary tumor blocks for 286 cancer-related genes. From 2706 available eligible samples (confirmed ER+, excluding HER2-positivity or neoadjuvant treatment, adequate DNA quality/quantity), a case-cohort design selected 764 samples: all distant relapses and a stratified sampling of non-relapses after 8yr median follow-up. Mutation prevalence and associations with clinicopathological factors (CP) as well as distant recurrence-free interval (DRFS) were analyzed using weighted tests and Cox regression models, with sampling weights to represent the ER+/HER2-negative trial population. Multivariable analyses were adjusted for tumor size, nodal status, grade and age. Results NGS data was available from 538/764 samples (70%), there were 140 (26%) distant relapses. Median sequencing depth was 483x. There was a mean of 11 mutations (1-46) per sample, with 25% having 13 or more mutations and no tumors without a mutation. Overall 28 genes were altered at a frequency of &amp;gt;10%. The most commonly mutated genes were PIK3CA (49.3%), NCOR1 (27.2%), MAP3K1 (23.8%) TP53 (16.6%), CCND1 (17.8%) and GATA3 (17.1%). Alterations that were significantly associated with both Luminal B (Ki67 &amp;gt;14%) and grade 3 included TP53 mutations (p&amp;lt;0.001), FGFR1 (p=0.001) and MYC amplifications (p=0.004). Gene alterations that were significantly associated with shorter DRFS included TP53 (HR:2.16), ARID1A (HR:2.43), CHEK2 (HR:2.54), BRCA2 (HR:1.93), PTEN (HR:2.03), CCND1 (HR:1.82) and FGFR1 (HR:1.78). PIK3CA was significantly associated with lower risk of distant relapse (HR:0.64; 0.43-0.97). Increasing number of total mutations was significantly associated with shorter DRFS (HR:1.04; 95% CI 1.01-1.07; p=0.006). In the multivariable model adjusted for CP factors, ARID1A, BRCA2, CCND1, CHEK2 and PTEN remained independent for shorter DRFS. Greater than 90% of PIK3CA mutations co-existed with another alteration, most common being NCOR1 (29%), MAP3K1 (24%), CDH1 (16%), GATA3 (16%), TP53 (14%) and CCND1 (13%). Patients with a PIK3CA mutation had greater benefit with letrozole over tamoxifen monotherapy (HR 0.32; 0.13-0.8) than those without (HR:0.70; 0.33-1.48) (Pint=0.06). This effect was strongest in the subgroup of PIK3CA mutant patients who were CCND1 and TP53 wild-type (HR:0.24, 0.12-0.48; Pint=0.02) with only 1% relapsing at 5 years. Conclusion: For the first time, we report the prognostic relevance of oncogenic mutations in ER+/HER2- postmenopausal early-stage BCs from a clinical trial. Tumors with PIK3CA mutations derived greater benefit from letrozole over tamoxifen monotherapy, especially if wild-type for CCND1 and TP53. These findings could significantly improve prognostic risk classification and guide future clinical trials of targeted therapies in ER+/HER2- BCs. Citation Format: Loi S, Asher R, Lee CK, Luen S, Savas P, Kammler R, Dell'Orto P, Blasi OM, Demanse D, JeBailley L, Dolan S, Hackl W, Thuerlimann B, Viale G, Regan M, Colleoni MA. Clinical implications of somatic mutations in post-menopausal early-stage estrogen receptor (ER)-positive HER2-negative breast cancer (BC): Results from the BIG 1-98 study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S1-10.

Osteogenic differentiation potential of adipose-derived stem cells from ovariectomized mice.

Osteoporosis (OP) is a systemic disease caused by imbalance between bone resorption and bone formation, commonly resulting from post-menopausal oestrogen deficiency. Although osteogenic differentiation potential of adipose-derived stem cells (ASCs) has been demonstrated, the effect of OP on osteogenic differentiation of ASCs remains unclear. Here, our work has been designed to compare proliferative capacity and osteogenic differentiation ability of ASCs obtained from osteoporotic mice and normal control mice. Twenty 14-week-old female C57BL/6 mice were randomly divided into two groups: one, the ovariectomy (OVX) group (n=10), the other being the sham operated (Sham) group (n=10). ASCs and OP-ASCs were obtained from subcutaneous fat of female inguinal sites. Cells were passaged three times prior to subsequent experimentation. The xCELLigence system was used to monitor cell adhesion and proliferation. Mineralized nodules of differentiated ASCs and OP-ASCs were analysed using Alizarin red staining after osteogenic induction. Expressions of osteogenic-specific genes including osteopontin (Opn) and runt-related transcription factor 2 (Runx2) were assessed by real-time PCR and expression of bone-related proteins was detected by Western blotting. Numbers of cells in all groups increased steadily for 6days; rate of cell proliferation in the Sham group was found to be higher than in the OVX group after 48hours. Mineralized bone nodular structures were significantly more concentrated in the Sham group than in the OVX group by day 21, and mRNA levels of Runx2 in the OVX group were significantly lower than in the Sham group. Transcript levels of genes coding for Opn showed a similar pattern to those of Runx2. Western blot results indicated that protein expression levels of OPN and RUNX2 in the OVX group were lower than those in the Sham group, at each time point. These results indicated that the proliferative capacity and osteogenic potential of ASCs were significantly impaired in osteoporotic mice compared to normal controls. However, use of autologous transplantation of modified OP-ASCs for treatment of OP, or combination of composite scaffolds and modified OP-ASCs for repair of osteoporotic bone defects, can overcome shortcomings of other methods.

Pathomechanisms and management of osteoporotic pain with no traumatic evidence.

Introduction Osteoporosis is a pathological state with an unbalanced bone metabolism mainly caused by accelerated osteoporotic osteoclast activity due to a postmenopausal estrogen deficiency, and it causes some kinds of pain, which can be divided into two types: traumatic pain due to a fragility fracture from impaired rigidity, and pain derived from an osteoporotic pathology without evidence of fracture. We aimed to review the concepts of osteoporosis-related pain and its management. Methods We reviewed clinical and basic articles on osteoporosis-related pain, especially with a focus on the mechanism of pain derived from an osteoporotic pathology (i.e., osteoporotic pain) and its pharmacological treatment. Results Osteoporosis-related pain tends to be robust and acute if it is due to fracture or collapse, whereas pathology-related osteoporotic pain is vague and dull. Non-traumatic osteoporotic pain can originate from an undetectable microfracture or structural change such as muscle fatigue in kyphotic patients. Furthermore, basic studies have shown that the osteoporotic state itself is related to pain or hyperalgesia with increased pain-related neuropeptide expression or acid-sensing channels in the local tissue and nervous system. Traditional treatment for osteoporotic pain potentially prevents possible fracture-induced pain by increasing bone mineral density and affecting related mediators such as osteoclasts and osteoblasts. The most common agent for osteoporotic pain management is a bisphosphonate. Other non-osteoporotic analgesic agents such as celecoxib have also been reported to have a suppressive effect on osteoporotic pain. Conclusions Osteoporotic pain has traumatic and non-traumatic factors. Anti-osteoporotic treatments are effective for osteoporotic pain, as they improve bone structure and the condition of the pain-related sensory nervous system. Physicians should always consider these matters when choosing a treatment strategy that would best benefit patients with osteoporotic pain.

Biomarker Associations with Efficacy of Abiraterone Acetate and Exemestane in Postmenopausal Patients with Estrogen Receptor–Positive Metastatic Breast Cancer

Abiraterone may suppress androgens that stimulate breast cancer growth. We conducted a biomarker analysis of circulating tumor cells (CTCs), formalin-fixed paraffin-embedded tissues (FFPETs), and serum samples from postmenopausal estrogen receptor (ER)+ breast cancer patients to identify subgroups with differential abiraterone sensitivity. Patients (randomized 1:1:1) were treated with 1,000 mg/d abiraterone acetate + 5 mg/d prednisone (AA), AA + 25 mg/d exemestane (AAE), or exemestane. The biomarker population included treated patients (n = 293). The CTC population included patients with ≥3 baseline CTCs (n = 104). Biomarker [e.g., androgen receptor (AR), ER, Ki-67, CYP17] expression was evaluated. Cox regression stratified by prior therapies in the metastatic setting (0/1 vs. 2) and setting of letrozole/anastrozole (adjuvant vs. metastatic) was used to assess biomarker associations with progression-free survival (PFS). Serum testosterone and estrogen levels were lowered and progesterone increased with AA. Baseline AR or ER expression was not associated with PFS in CTCs or FFPETs for AAE versus exemestane, but dual positivity of AR and ER expression was associated with improved PFS [HR, 0.41; 95% confidence interval (CI), 0.16-1.07; P = 0.070]. For AR expression in FFPETs obtained <1 year prior to first dose (n = 67), a trend for improved PFS was noted for AAE versus exemestane (HR, 0.56; 95% CI, 0.24-1.33; P = 0.19). An AA pharmacodynamic effect was shown by decreased serum androgen and estrogen levels and increased progesterone. AR and ER dual expression in CTCs and newly obtained FFPETs may predict AA sensitivity. Clin Cancer Res; 22(24); 6002-9. ©2016 AACR.

Body mass index and menopausal disorders during menopause affect vasomotor symptoms of postmenopausal Japanese breast cancer patients treated with anastrozole: a prospective multicenter cohort study of patient-reported outcomes.

Adverse events related to endocrine therapies have a major impact not only on patients' quality of life but also on treatment discontinuation. Although vasomotor symptoms induced by aromatase inhibitors are frequently recognized, risk factors, especially for Japanese women, are not well reported. To identify risk factors for vasomotor symptoms of Japanese breast cancer patients treated with adjuvant anastrozole, we conducted a prospective cohort study based on patient-reported outcomes (PROs). For this prospective cohort study (SAVS-JP, UMIN000002455), 391 postmenopausal Japanese estrogen receptor-positive breast cancer patients who were treated with adjuvant anastrozole were recruited from 28 centers. The PRO assessment was obtained from a self-reported questionnaire at baseline, 3, 6, 9 and 12months between August 2009 and April 2012. Vasomotor symptoms, comprising hot flashes, night sweats, and cold sweats, were categorized into four grades (none, Grade 1: mild, Grade 2: moderate, Grade 3: severe). Pre-existing symptoms were only included if they had become worse than at baseline. Hot flashes, night sweats, and cold sweats at baseline were reported by 20.5, 15.1, and 8.2% of the patients, respectively, and new appearance or worsening of symptoms in comparison with baseline by 38.4, 29.3, and 28.7%, respectively. About 80% of newly occurring symptoms were Grade 1, and less than 5% were Grade 3. Vasomotor symptoms were reported by 201 out of 362 patients (55.5%) during the first year and the mean time to onset was 5.6months. Patients with vasomotor symptoms were significantly younger (mean 62.8years, range 38-86 vs 64.7years, range 37-84; p=0.02), had higher body mass index (BMI) (23.4kg/m2, range 15.8-39.9 vs 22.4kg/m2, range 15.8-34.9; p=0.01), had vasomotor symptoms sooner after menopause (12.4years, range 0-51 vs 15.1years, range 1-37; p=0.002), and had more menopausal disorders during menopause (63.3 vs 36.7%; p=0.002). Multivariate analysis showed that BMI [odds ratio (OR) 1.09 per unit of increase, 95% confidence interval (CI) 1.02-1.16; p=0.009] and experiencing menopausal disorders (OR 2.11, 95% CI 1.35-3.30; p=0.001) were significantly associated with vasomotor symptoms. High BMI and experiencing menopausal disorders at menopause were found to be significantly associated with the occurrence of vasomotor symptoms. These findings are expected to prove useful for the management of postmenopausal Japanese women treated with aromatase inhibitors.

Treatment with Aromatase Inhibitors in Postmenopausal Women with Breast Cancer and the Possibility of Influencing Side Effects

The third generation aromatase inhibitors (anastrozole, letrozole, exemestane) have become standard endocrine treatment for postmenopausal estrogen receptor - positive breast cancers in all settings (neoadjuvant, adjuvant, metastatic breast cancer), based on superiority to tamoxifen. Aromatase inhibitors interfere with the conversion of androgens into estrogens by blocking the enzyme aromatase resulting in low estradiol levels. Aromatase inhibitors are contraindicated in women with functional ovaries. Many premenopausal women develop amenorrhea after adjuvant chemoterapy. Aromatase inhibitors may promote recovery of ovarian function which could lead to therapeutic failure or even to unexpected pregnancy. Currently available measures to determine the menopausal status are conflicting. This paper focuses primarily on adverse effects of aromatase inhibitors which can lead to non-compliance or to discontinuation of treatment. Many side effects of aromatase inhibitors are related to estrogen deprivation. On the other hand as aromatase inhibitors lack estrogenic activity, they are not associated with serious adverse events typical for tamoxifen, such as endometrial cancer and thromboembolic disease. Aromatase inhibitors therapy is often associated with vasomotor symptoms (hot flashes), vaginal dryness, dyspareunia, bone loss, arthralgias and myalgias (musculoskeletal symptoms). Management of these side effects can lead to improved adherence and persistence with therapy.Key words: breast cancer - menopause - aromatase inhibitors - ovarian function recovery - adverse effectsThis work was supported by Czech Ministry of Health - RVO (MOÚ, 00209805).The author declares she has no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 10. 7. 2016Accepted: 3. 8. 2016.

Abstract P620: Aging Decreases Vascular GPER Expression and Function

Menopause accelerates the development of hypertension, arterial stiffness, end organ damage, and diastolic dysfunction. Postmenopausal hormone therapy relieves menopausal symptoms but promotes adverse cardiovascular outcomes, which may be due to aging-induced alterations in estrogen receptors. We previously published that GPER expression as well as agonist-induced vasorelaxation is decreased in mesenteric arteries from 12 month-old mRen2 female rats. We hypothesized that aging-induced GPER downregulation is present in other rodent species and strains as well. Aortas from young (2-3 months) and aged (11-23 months) C57BL/6 and BALB/c mice were lysed and immunoblotted for GPER protein. In addition, mesenteric arteries from C57BL/6 mice were mounted on a wire myograph and assessed for vasorelaxation in response to estrogen receptor agonists. We found a significant downregulation of GPER in aging aortas (3.1 ± 0.6 vs. 0.63 ± 0.42, P=0.016, N=4 per group). Moreover, we found that vasodilation to the GPER agonist G-1 was significantly attenuated in aging resistance arteries (22 ± 7.5% vs 58 ± 6.5%, P=0.023, N=2-4). Interestingly, vasodilation to the nonselective receptor agonist estradiol was not altered by aging (24 ± 10% vs. 32 ± 2.0%, P=0.23, N=2-4). In light of our previous findings in the rat vasculature, our data indicate that aging-induced decreases in vascular GPER expression and function are conserved across vascular beds and rodent species. We propose that aging-induced GPER downregulation switches the vascular benefits of postmenopausal estrogen therapy from positive to negative. Our future goal is to determine whether therapies that target GPER improve cardiovascular outcomes to protect the aging female population.

Association of obesity with serum estrogen level in postmenopausal women

Incidence of obesity among postmenopausal women is increasing throughout the world, leading to life threatening medical problem like cardiovascular diseases, type 2 diabetes mellitus. Estrogen deficiency that develops during menopause is likely the etiological factors for development of abdominal obesity. Increased incidence of cardiovascular diseases in postmenopausal women may be due to abdominal obesity caused by lower level of estrogen hormone. The study was carried out to observe the association of obesity with serum estrogen level in postmenopausal women. This cross sectional study was conducted in the Department of Physiology, Dhaka Medical College, Dhaka, during the period of January 2011 to December 2011. A total number of 90 female subjects were selected from different areas of Dhaka city. Among them, 60 postmenopausal women with age ranging from 50 to 60 years were taken as study group and 30 apparently healthy premenopausal women with age ranging from 20 to 30 years were included as control group for comparison. Waist circumference was measured and body mass index (BMI) was calculated in both groups. Serum estrogen level was estimated in order to assess the hormonal level of postmenopausal women. The value of waist circumference was higher in postmenopausal women than those of premenopausal women and result was statistically non significant. Body mass index value was significantly (p&lt;0.001) higher in postmenopausal women in comparison to those of premenopausal women. In postmenopausal women serum estrogen level was lower than premenopausal women and serum estrogen level showed negative correlation with waist circumference and body mass index values. All these correlations were statistically non significant. Present study revealed that there is association of obesity with serum estrogen level in postmenopausal women.Bangladesh Med J. 2016 May; 45 (2): 79-84

Evaluation of oral care to prevent oral mucositis in estrogen receptor-positive metastatic breast cancer patients treated with everolimus (Oral Care-BC): randomized controlled phase III trial

This is a randomized, multi-center, open-label, phase III study to evaluate the efficacy of professional oral care in preventing oral mucositis induced by everolimus in postmenopausal estrogen receptor-positive metastatic breast cancer. Patients will be randomized into professional oral care and control groups (1:1 ratio). All patients will receive everolimus with exemestane and will continue everolimus until disease progression. In the professional oral care group, patients will receive teeth surface cleaning, scaling and tongue cleaning before starting everolimus, and will continue to receive professional oral care weekly from oral surgeons throughout the 8 week treatment. In the control group, patients will brush their own teeth and gargle with 0.9% sodium chloride solution or water. The primary endpoint is the incidence of all grades of oral mucositis. Target accrual is 200 patients with a two-sided type I error rate of 5% and 80% power to detect 25% risk reduction.

Fracture healing in osteoporotic bone

As the world population rises, osteoporotic fracture is an emerging global threat to the well-being of elderly patients. The process of fracture healing by intramembranous ossification or/and endochondral ossification involve many well-orchestrated events including the signaling, recruitment and differentiation of mesenchymal stem cells (MSCs) during the early phase; formation of a hard callus and extracellular matrix, angiogenesis and revascularization during the mid-phase; and finally callus remodeling at the late phase of fracture healing.Through clinical and animal research, many of these factors are shown to be impaired in osteoporotic bone. Animal studies related to post-menopausal estrogen deficient osteoporosis (type I) have shown healing to be prolonged with decreased levels of MSCs and decreased levels of angiogenesis. Moreover, the expression of estrogen receptor (ER) was shown to be delayed in ovariectomy-induced osteoporotic fracture. This might be related to the observed difference in mechanical sensitivity between normal and osteoporotic bones, which requires further experiments to elucidate.In mice fracture models related to senile osteoporosis (type II), it was observed that chondrocyte and osteoblast differentiation were impaired; and that transplantation of juvenile bone marrow would result in enhanced callus formation. Other factors related to angiogenesis and vasculogenesis have also been noted to be impaired in aged models, affecting the degradation of cartilaginous matrixes and vascular invasion; the result is changes in matrix composition and growth factors concentrations that ultimately impairs healing during age-related osteoporosis. Most osteoporotic related fractures occur at metaphyseal sites clinically, and reports have indicated that differences exist between diaphyseal and metaphyseal fractures. An animal model that satisfies three main criteria (metaphyseal region, plate fixation, osteoporosis) is suggested for future research for more comprehensive understanding of the impairment in osteoporotic fractures. Therefore, a metaphyseal fracture or osteotomy that achieves complete discontinuity fixed with metal implants is suggested on ovariectomized aged rodent models.

Optimal endocrine therapy for breast cancer patients 45-50 years of age at diagnosis.

551Background: Aromatase inhibitors (AI) are superior to tamoxifen (TAM) in postmenopausal estrogen receptor positive (ER+) breast cancer patients. TAM is standard of care for premenopausal ER+ patients. The SOFT/TEXT trials showed, however, that ovarian function suppression combined with the AI exemestane significantly improves disease-free survival compared to TAM in premenopausal patients. Evidence on perimenopausal women at breast cancer diagnosis is scarce as they are usually excluded from studies. We therefore aim to provide evidence for the optimal treatment of ER+ breast cancer patients 45-50 years of age, using data from the population-based Netherlands Cancer Registry (NCR). Methods: All pre-menopausal Dutch women, without prior history of malignancy, diagnosed between 2004-2007 at age 45-50 years with an ER+, non-metastatic, primary invasive breast cancer for which they received chemotherapy and endocrine treatment, were identified through the NCR. Cox proportional hazards regression was used t...

The Intestinal Microbiome and Estrogen Receptor-Positive Female Breast Cancer.

The huge communities of residential microbes, including bacteria, viruses, Archaea, and Eukaryotes, that colonize humans are increasingly recognized as playing important roles in health and disease. A complex populous ecosystem, the human gastrointestinal (GI) tract harbors up to 10(11) bacterial cells per gram of luminal content, whose collective genome, the gut metagenome, contains a vastly greater number of individual genes than the human genome. In health, the function of the microbiome might be considered to be in dynamic equilibrium with the host, exerting both local and distant effects. However, 'disequilibrium' may contribute to the emergence of disease, including malignancy. In this review, we discuss how the intestinal bacterial microbiome and in particular how an 'estrobolome,' the aggregate of enteric bacterial genes capable of metabolizing estrogens, might affect women's risk of developing postmenopausal estrogen receptor-positive breast cancer. Estrobolome composition is impacted by factors that modulate its functional activity. Exploring variations in the composition and activities of the estrobolome in healthy individuals and in women with estrogen-driven breast cancer may lead to development of microbiome-based biomarkers and future targeted interventions to attenuate cancer risk.