scholarly journals The Role of Ovarian Sex Steroids in Metabolic Homeostasis, Obesity, and Postmenopausal Breast Cancer: Molecular Mechanisms and Therapeutic Implications

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Viroj Boonyaratanakornkit ◽  
Prangwan Pateetin
Keyword(s):  
Breast Cancer ◽  
Postmenopausal Women ◽  
Molecular Mechanisms ◽  
Ovarian Function ◽  
Postmenopausal Breast Cancer ◽  
Cellular Metabolism ◽  
Obese Women ◽  
Therapeutic Implications ◽  
Estrogen Production ◽  
Increased Risk

Obese postmenopausal women have an increased risk of breast cancer and are likely to have a worse prognosis than nonobese postmenopausal women. The cessation of ovarian function after menopause results in withdrawal of ovarian sex steroid hormones, estrogen, and progesterone. Accumulating evidence suggests that the withdrawal of estrogen and progesterone causes homeostasis imbalances, including decreases in insulin sensitivity and leptin secretion and changes in glucose and lipid metabolism, resulting in a total reduction in energy expenditure. Together with a decrease in physical activity and consumption of a high fat diet, these factors significantly contribute to obesity in postmenopausal women. Obesity may contribute to breast cancer development through several mechanisms. Obesity causes localized inflammation, an increase in local estrogen production, and changes in cellular metabolism. In addition, obese women have a higher risk of insulin insensitivity, and an increase in insulin and other growth factor secretion. In this review, we describe our current understanding of the molecular actions of estrogen and progesterone and their contributions to cellular metabolism, obesity, inflammation, and postmenopausal breast cancer. We also discuss how modifications of estrogen and progesterone actions might be used as a therapeutic approach for obesity and postmenopausal breast cancer.

scholarly journals Uric Acid Mediated the Association between BMI and Postmenopausal Breast Cancer Incidence: A Bidirectional Mendelian Randomization Analysis and Prospective Cohort Study

2021 ◽  
Author(s):  
Yue Feng ◽  
Mengying Li ◽  
Yansen Bai ◽  
Guyanan Li ◽  
Xiulong Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Uric Acid ◽  
Postmenopausal Women ◽  
Mendelian Randomization ◽  
Breast Cancer Incidence ◽  
Elevated Serum ◽  
Postmenopausal Breast Cancer ◽  
Genome Wide Association Studies ◽  
Increased Risk

Abstract Background: The observational epidemiological studies have reported the associations of high body mass index (BMI) with elevated serum uric acid (UA) level and increased risk of postmenopausal breast cancer. However, whether UA is causally induced by BMI and functioned in the BMI-breast cancer relationship remains unclear. Methods: To elucidate the causality direction between BMI and serum UA, the bidirectional Mendelian randomization (MR) analyses were performed by using summarized data from the largest Asian genome-wide association studies (GWAS) of BMI and UA carried out in over 150,000 Japanese populations. Then, a total of 19,518 postmenopausal women from the Dongfeng-Tongji (DFTJ) cohort (with a mean 8.2-year follow-up) were included and analyzed on the associations of BMI and serum UA with incidence risk of postmenopausal breast cancer by using multivariable Cox proportional hazard regression models. Mediation analysis was further conducted among DFTJ cohort to assess the intermediate role of serum UA in the BMI-breast cancer association.Results: In the bidirectional MR analyses, we observed that genetically determined BMI was causally associated with elevated serum UA [β(95%CI)=0.225(0.111, 0.339), P<0.001], but not vice versa. In the DFTJ cohort, each standard deviation (SD) increment in BMI (3.5 kg/m2) and UA (75.4 μmol/L) was associated with a separate 24% and 22% increased risk of postmenopausal breast cancer [HR(95%CI)= 1.24(1.07, 1.44) and 1.22(1.05, 1.42), respectively]. More importantly, serum UA could mediate 16.9% of the association between BMI and incident postmenopausal breast cancer.Conclusions: The current findings revealed a causal effect of BMI on increasing serum UA and highlighted the mediating role of UA in BMI-breast cancer relationship. Controlling the serum level of UA among overweight postmenopausal women may help to decrease their incident risk of breast cancer.

scholarly journals Interactions Between Adiponectin-Pathway Polymorphisms and Obesity on Postmenopausal Breast Cancer Risk Among African American Women: The WHI SHARe Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Gina E. Nam ◽  
Zuo-Feng Zhang ◽  
Jianyu Rao ◽  
Hua Zhou ◽  
Su Yon Jung
Keyword(s):  
Breast Cancer ◽  
African American ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
African American Women ◽  
Postmenopausal Women ◽  
Genetic Variants ◽  
Postmenopausal Breast Cancer ◽  
Serum Adiponectin ◽  
Increased Risk

BackgroundA decreased level of serum adiponectin is associated with obesity and an increased risk of breast cancer among postmenopausal women. Yet, the interplay between genetic variants associated with adiponectin phenotype, obesity, and breast cancer risk is unclear in African American (AA) women.MethodsWe examined 32 single-nucleotide polymorphisms (SNPs) previously identified in genome-wide association and replication studies of serum adiponectin levels using data from 7,991 AA postmenopausal women in the Women’s Health Initiative SNP Health Association Resource.ResultsStratifying by obesity status, we identified 18 adiponectin-related SNPs that were associated with breast cancer risk. Among women with BMI ≥ 30 kg/m2, the minor TT genotype of FER rs10447248 had an elevated breast cancer risk. Interaction was observed between obesity and the CT genotype of ADIPOQ rs6773957 on the additive scale for breast cancer risk (relative excess risk due to interaction, 0.62; 95% CI, 0.32–0.92). The joint effect of BMI ≥ 30 kg/m2 and the TC genotype of OR8S1 rs11168618 was larger than the sum of the independent effects on breast cancer risk.ConclusionsWe demonstrated that obesity plays a significant role as an effect modifier in an increased effect of the SNPs on breast cancer risk using one of the most extensive data on postmenopausal AA women.ImpactThe results suggest the potential use of adiponectin genetic variants as obesity-associated biomarkers for informing AA women who are at greater risk for breast cancer and also for promoting behavioral interventions, such as weight control, to those with risk genotypes.

Endocrine Treatment of Breast Cancer: Current Perspectives, Future Directions

2017 ◽  
Vol 8 (03) ◽  
Author(s):  
Tazia Irfan ◽  
Mainul Haque ◽  
Sayeeda Rahman ◽  
Russell Kabir ◽  
Nuzhat Rahman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Ovarian Function ◽  
Premenopausal Women ◽  
New Drugs ◽  
Effective Control ◽  
Endocrine Treatment ◽  
Estrogen Production ◽  
Hormone Sensitive

Breast cancer remains one of the major causes of death in women, and endocrine treatment is currently one of the mainstay of treatment in patients with estrogen receptor positive breast cancer. Endocrine therapy either slows down or stops the growth of hormone-sensitive tumors by blocking the body’s capability to yield hormones or by interfering with hormone action. In this paper, we intended to review various approaches of endocrine treatments for breast cancer highlighting successes and limitations. There are three settings where endocrine treatment of breast cancer can be used: neoadjuvant, adjuvant, or metastatic. Several strategies have also been developed to treat hormone-sensitive breast cancer which include ovarian ablation, blocking estrogen production, and stopping estrogen effects. Selective estrogen-receptor modulators (SERMs) (e.g. tamoxifen and raloxifene), aromatase inhibitors (AIs) (e.g. anastrozole, letrozole and exemestane), gonadotropin-releasing hormone agonists (GnRH) (e.g. goserelin), and selective estrogen receptor downregulators (SERDs) (e.g. fulvestrant) are currently used drugs to treat breast cancer. Tamoxifen is probably the first targeted therapy widely used in breast cancer treatment which is considered to be very effective as first line endocrine treatment in previously untreated patients and also can be used after other endocrine therapy and chemotherapy. AIs inhibit the action of enzyme aromatase which ultimately decrease the production of estrogen to stimulate the growth of ER+ breast cancer cells. GnRH agonists suppress ovarian function, inducing artificial menopause in premenopausal women. Endocrine treatments are cheap, well-tolerated and have a fixed single daily dose for all ages, heights and weights of patients. Endocrine treatments are not nearly as toxic as chemotherapy and frequent hospitalization can be avoided. New drugs in preliminary trials demonstrated the potential for improvement of the efficacy of endocrine therapy including overcoming resistance. However, the overall goals for breast cancer including endocrine therapy should focus on effective control of cancer, design personalized medical therapeutic approach, increase survival time and quality of life, and improve supportive and palliative care for end-stage disease.

Aromatase Inhibitors for the Treatment of Breast Cancer: A Journey from the Scratch

2020 ◽  
Vol 20 (17) ◽  
pp. 1994-2004 ◽  
Author(s):  
Pooja Ratre ◽  
Keerti Mishra ◽  
Amit Dubey ◽  
Amber Vyas ◽  
Akhlesh Jain ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Treatment ◽  
Postmenopausal Women ◽  
Aromatase Inhibitors ◽  
3D Structure ◽  
Postmenopausal Breast Cancer ◽  
Breast Cancer Treatment ◽  
Third Generation ◽  
Breast Cancer Chemotherapy

Background: Estrogens are essential for the growth of breast cancer in the case of premenopausal as well as in postmenopausal women. However, most of the breast cancer incidences are reported in postmenopausal women and the concurrent risk surges with an increase in age. Since the enzyme aromatase catalyses essential steps in estrogen biosynthesis, Aromatase Inhibitors (AIs) are effective targeted therapy in patients with Estrogen Receptor positive (ER+) breast cancer. AIs are more effective than Selective Estrogen Receptor Modulators (SERMs) because they block both the genomic and nongenomic activities of ER. Till date, first, second and third-generation AIs have been approved by the FDA. The third-generation AIs, viz. Letrozole, Anastrozole, Exemestane, are currently used in the standard treatment for postmenopausal breast cancer. Methods: Data were collected from Medline, PubMed, Google Scholar, Science Direct through searching of keywords: ‘aromatase’, ‘aromatase inhibitors’, ‘breast cancer’, ‘steroidal aromatase inhibitors’, ‘non-steroidal inhibitors’ and ‘generations of aromatase inhibitors’. Results: In the current scenario of breast cancer chemotherapy, AIs are the most widely used agents which reveal optimum efficacy along with the least side effects. Keeping in view the prominence of AIs in breast cancer therapy, this review covered the detailed description of aromatase including its role in the biosynthesis of estrogen, biochemistry, gene expression, 3D-structure, and information of reported AIs along with their role in breast cancer treatment. Conclusion: AIs are the mainstream solution of the ER+ breast cancer treatment regimen with the continuous improvement of human understanding of the importance of a healthy life of women suffering from breast cancer.

scholarly journals Effects of Tamoxifen and Raloxifene on Memory and Other Cognitive Abilities: Cognition in the Study of Tamoxifen and Raloxifene

2009 ◽  
Vol 27 (31) ◽  
pp. 5144-5152 ◽  
Author(s):  
Claudine Legault ◽  
Pauline M. Maki ◽  
Susan M. Resnick ◽  
Laura Coker ◽  
Patricia Hogan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cognitive Function ◽  
Postmenopausal Women ◽  
Cognitive Abilities ◽  
Cognitive Aging ◽  
Cognitive Test ◽  
Domain Specific ◽  
Estrogen Receptor Modulators ◽  
Increased Risk ◽  
The One

Purpose To compare the effects of two selective estrogen receptor modulators, tamoxifen and raloxifene, on global and domain-specific cognitive function. Patients and Methods The National Surgical Adjuvant Breast and Bowel Project's Study of Tamoxifen and Raloxifene (STAR) study was a randomized clinical trial of tamoxifen 20 mg/d or raloxifene 60 mg/d in healthy postmenopausal women at increased risk of breast cancer. The 1,498 women who were randomly assigned in STAR were age 65 years and older, were not diagnosed with dementia, and were enrolled onto the Cognition in the Study of Tamoxifen and Raloxifene (Co-STAR) trial, beginning 18 months after STAR enrollment started. A cognitive test battery modeled after the one used in the Women's Health Initiative Study of Cognitive Aging (WHISCA) was administered. Technicians were centrally trained to administer the battery and recertified every 6 months. Analyses were conducted on all participants and on 273 women who completed the first cognitive battery before they started taking their medications. Results Overall, there were no significant differences in adjusted mean cognitive scores between the two treatment groups across visits. There were significant time effects across the three visits for some of the cognitive measures. Similar results were obtained for the subset of women with true baseline measures. Conclusion Tamoxifen and raloxifene are associated with similar patterns of cognitive function in postmenopausal women at increased risk of breast cancer. Future comparisons between these findings and patterns of cognitive function in hormone therapy and placebo groups in WHISCA should provide additional insights into the effects of tamoxifen and raloxifene on cognitive function in older women.

Obesity and oocyte quality: Significant implications for ART and Emerging mechanistic insights

2021 ◽  
Author(s):  
Macarena B Gonzalez ◽  
Rebecca L Robker ◽  
Ryan D Rose
Keyword(s):  
Pregnancy Complications ◽  
Maternal Obesity ◽  
Ovarian Function ◽  
Polycystic Ovary ◽  
Live Birth Rate ◽  
Oocyte Quality ◽  
Reproductive Age ◽  
Developmental Competence ◽  
Obese Women ◽  
Increased Risk

Abstract The prevalence of obesity in adults worldwide, and specifically in women of reproductive age, is concerning given the risks to fertility posed by the increased risk of type 2 diabetes, metabolic syndrome and other non-communicable diseases. Obesity has a multi-systemic impact in female physiology that is characterized by the presence of oxidative stress, lipotoxicity, and the activation of pro-inflammatory pathways, inducing tissue-specific insulin resistance and ultimately conducive to abnormal ovarian function. A higher body mass is linked to Polycystic Ovary Syndrome, dysregulated menstrual cycles, anovulation, and longer time to pregnancy, even in ovulatory women. In the context of ART, compared to women of normal BMI, obese women have worse outcomes in every step of their journey, resulting in reduced success measured as live birth rate. Even after pregnancy is achieved, obese women have a higher chance of miscarriage, gestational diabetes, pregnancy complications, birth defects, and most worryingly, a higher risk of stillbirth and neonatal death. The potential for compounding effects of ART on pregnancy complications and infant morbidities in obese women has not been studied. There is still much debate in the field on whether these poorer outcomes are mainly driven by defects in oocyte quality, abnormal embryo development or an unaccommodating uterine environment, however the clinical evidence to date suggests a combination of all three are responsible. Animal models of maternal obesity shed light on the mechanisms underlaying the effects of obesity on the peri-conception environment, with recent findings pointing to lipotoxicity in the ovarian environment as a key driver of defects in oocytes that have not only reduced developmental competence but long-lasting effects in offspring health.

scholarly journals Angiogenic Abnormalities in Diabetes Mellitus: Mechanistic and Clinical Aspects

2019 ◽  
Vol 104 (11) ◽  
pp. 5431-5444 ◽  
Author(s):  
Gian Paolo Fadini ◽  
Mattia Albiero ◽  
Benedetta Maria Bonora ◽  
Angelo Avogaro
Keyword(s):  
English Language ◽  
Molecular Mechanisms ◽  
Evidence Synthesis ◽  
Clinical Manifestations ◽  
Vascular Complications ◽  
Peripheral Circulation ◽  
Clinical Aspects ◽  
Therapeutic Implications ◽  
Diabetes Onset ◽  
Increased Risk

Abstract Context Diabetes causes severe pathological changes to the microvasculature in many organs and tissues and is at the same time associated with an increased risk of coronary and peripheral macrovascular events. We herein review alterations in angiogenesis observed in human and experimental diabetes and how they contribute to diabetes onset and development of vascular complications. Evidence Acquisition The English language medical literature was searched for articles reporting on angiogenesis/vasculogenesis abnormalities in diabetes and their clinical manifestations, mechanistic aspects, and possible therapeutic implications. Evidence Synthesis Angiogenesis is a complex process, driven by a multiplicity of molecular mechanisms and involved in several physiological and pathological conditions. Incompetent angiogenesis is pervasive in diabetic vascular complications, with both excessive and defective angiogenesis observed in various tissues. A striking different angiogenic response typically occurs in the retina vs the myocardium and peripheral circulation, but some commonalities in abnormal angiogenesis can explain the well-known association between microangiopathy and macroangiopathy. Impaired angiogenesis can also affect endocrine islet and adipose tissue function, providing a link to diabetes onset. Exposure to high glucose itself directly affects angiogenic/vasculogenic processes, and the mechanisms include defective responses to hypoxia and proangiogenic factors, impaired nitric oxide bioavailability, shortage of proangiogenic cells, and loss of pericytes. Conclusions Dissecting the molecular drivers of tissue-specific alterations of angiogenesis/vasculogenesis is an important challenge to devise new therapeutic approaches. Angiogenesis-modulating therapies should be carefully evaluated in view of their potential off-target effects. At present, glycemic control remains the most reasonable therapeutic strategy to normalize angiogenesis in diabetes.

Hormone replacement therapy in women with breast cancer. Do the risks outweigh the benefits?

1996 ◽  
Vol 14 (3) ◽  
pp. 997-1006 ◽  
Author(s):  
J A Roy ◽  
C A Sawka ◽  
K I Pritchard
Keyword(s):  
Breast Cancer ◽  
Replacement Therapy ◽  
Postmenopausal Women ◽  
Hormone Replacement ◽  
Risks And Benefits ◽  
Previous Diagnosis ◽  
Increased Risk ◽  
History Of ◽  
Expected Benefits ◽  
Meta Analyses

PURPOSE To review critically the literature regarding effects of estrogen replacement therapy (ERT)/combined estrogen and progesterone replacement therapy (HRT) on the risk of breast cancer and on other health risks and benefits in postmenopausal women, with a focus on risks and benefits in women with a previous diagnosis of breast cancer. METHOD A literature search was conducted using Medline, Cancerline, and the bibliographies of reports published as of March 1995. All five published meta-analyses that examined the risk of breast cancer in relation to ERT/HRT in otherwise healthy women were critically reviewed. All known reports of women with a history of breast cancer given ERT/HRT subsequent to diagnosis and additional reports regarding the benefits of ERT/HRT were also reviewed. RESULTS None of the five meta-analyses demonstrated a significantly increased risk of developing breast cancer in ever users compared with never users of ERT/HRT. Current use may be associated with a small increased risk. This increased risk should be balanced by the expected benefits of ERT/HRT on quality of life, bone metabolism, and cardiovascular function. Preliminary information does not suggest a major detrimental effect of ERT/HRT in women with a previous diagnosis of breast cancer, but these reports include few women with limited follow-up data. There are no randomized trials in women with a previous diagnosis of breast cancer. CONCLUSION In healthy postmenopausal women, the benefits associated with ERT/HRT outweigh the risks. In women with a previous diagnosis of breast cancer, the balance of risks and benefits should be explored in randomized controlled trials.

Effectiveness of adjuvant chemotherapy in combination with tamoxifen for node-positive postmenopausal breast cancer patients.

1997 ◽  
Vol 15 (4) ◽  
pp. 1385-1394 ◽  
Author(s):  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Disease Free Survival ◽  
Postmenopausal Breast Cancer ◽  
Breast Cancer Patients ◽  
Node Positive ◽  
Increased Risk ◽  
Node Positive Disease ◽  
Er Positive ◽  
Risk Of Relapse

PURPOSE Adjuvant tamoxifen has been shown to reduce relapse and mortality among node-positive post-menopausal breast cancer patients. The value of adding chemotherapy to tamoxifen is controversial. PATIENTS AND METHODS Between July 1986 and April 1993, 1,266 postmenopausal breast cancer patients with node-positive disease were randomly assigned to receive one of four adjuvant therapy regimens: (A) tamoxifen alone for 5 years; (B) tamoxifen plus three courses of early cyclophosphamide, methotrexate, and fluorouracil (CMF) on months 1, 2, and 3; (C) tamoxifen plus delayed single courses of CMF on months 9, 12, and 15; (D) tamoxifen plus early and delayed CMF on months 1, 2, 3, 9, 12, and 15. The two-by-two factorial design allowed two direct comparisons: early CMF (B and D) versus no early CMF (A and C), and delayed CMF (C and D) versus no delayed CMF (A and B). Estrogen receptor (ER) status was known for all patients and was used to stratify the randomization. A total of 1, 212 patients (96%) were eligible and assessable. The median follow-up duration was 60 months. RESULTS The results of the two-by-two factorial comparisons were as follows: (1) early CMF added to tamoxifen significantly improved 5-year disease-free survival (DFS; 64% v 57%; hazards ratio [HR], 0.79; 95% confidence interval [CI], 0.66 to 0.95; P = .01); and (2) delayed CMF added to tamoxifen did not improve DFS (5-year DFS, 61% v 60%; HR, 0.97; 95% CI, 0.81 to 1.17; P = .77). For patients with ER-positive tumors, the addition of CMF, either early or delayed or both, reduced the relative risk of relapse by 22% to 36%. In contrast, for patients with ER-negative tumors, tamoxifen with delayed CMF was associated with a nonsignificant increased risk of relapse (HR, 1.27; 95% CI, 0.92 to 1.76; P = .15). CONCLUSION Postmenopausal patients with node-positive breast cancer should be offered combination chemotherapy in addition to tamoxifen. Tamoxifen should not be initiated before CMF, as this might be detrimental, especially for patients with ER-negative tumors.

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