Reduced Estrogen Levels Research Articles

Current Evidence on the Impact of Diet, Food, and Supplement Intake on Breast Cancer Health Outcomes in Patients Undergoing Endocrine Therapy

Background/Objectives: The most common type of breast cancer (BRC) in women is estrogen/progesterone receptor positive. First-line treatment includes endocrine therapy, either with aromatase inhibitors or tamoxifen to reduce estrogen levels. Among the side effects produced by this treatment, aromatase inhibitor-induced arthralgia is the most common, affecting the patients’ overall health and quality of life (QoL). The objectives here were to evaluate interventions examining the impact of modified diets, supplements, and/or some food components on health outcomes in BRC patients undergoing endocrine therapy. Methods: The literature search was performed in PubMed, Scopus, and Web of Science from June 2024, as well as manually, through the end of November 2024. The search was limited to studies of women diagnosed with estrogen/progesterone-receptor-positive BRC with selected articles reporting interventions with diet, food, or supplement intake and examining the relevant health outcomes. Studies not focusing on BRC patients undergoing endocrine therapy or not including specific health outcomes were excluded. Results: The search uncovered 1028 studies; after the removal of duplicates, abstracts, and irrelevant studies, 53 were closely examined, with 26 evaluated and presented here. The outcomes were changes in bone and body composition, cardiovascular disease risks, inflammation, and QoL. Conclusions: The examined evidence suggests that adherence to dietary patterns such as the Mediterranean or a low-fat diet, and a higher intake of fruits and vegetables were beneficial for various outcomes. Additionally, supplementation with some foods/components (dried plum, red clover) contributed to improving/maintaining bone and body composition, especially in overweight/obese patients. Supplementation with vitamin D or omega-3 improved lipid and angiogenic parameters and QoL. Although these results are promising, the effects of each supplement/food cannot be summarized due to the diverse nature of study designs, patients, and supplement dosages. Further studies are needed to explore the effects of specific nutritional interventions (including the newest, like fasting-mimicking diets and whole-grain cereal diets) on various health outcomes in BRC survivors during endocrine therapy, and to derive universal recommendations.

Relationship Between Estrogen and Idiopathic Mandibular Condylar Resorption: A Systematic Literature Review

Background and Objectives: Pain in the TMJ is the second most common in the orofacial region. The objective of this systematic review was to assess whether a decrease in estrogen levels increases the risk of idiopathic condylar resorption by reviewing relevant literature and evidence. Material and Methods: This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A comprehensive search was performed in the PubMed (Medline), Science Direct (Elsevier), and Web of Science electronic databases. Results: The initial database search identified a total number of 453 studies. After applying the selection criteria, 36 articles were selected for a full-text analysis, and nine studies involving 1105 patients were included in the systematic review. According to the Newcastle–Ottawa Scale (NOS), two of the included articles were graded as being of “Moderate” quality and one was of “Fair” quality. After evaluating the rest of the articles according to the AXIS tool for cross-sectional studies, we generally found that the reliability is moderate. The results show that the decrease in estrogen promotes the occurrence of inflammation in the temporomandibular joint, and some sources mention that it increases the occurrence of idiopathic joint resorption, but we did not establish a complete correlation between the level of estrogen and idiopathic joint resorption. Conclusions: This systematic review indicates that there is no evidence suggesting that fluctuations in estrogen levels contribute to idiopathic mandibular condylar resorption, but reduced estrogen levels can be associated with chronic pain in the temporomandibular joint.

Depot-specific adiposity changes in ovariectomized mice on high-fat diet

Ovariectomized (OVX) mice serve as a key model for studying postmenopausal metabolic changes, particularly obesity, as they mimic the hormonal state of postmenopausal women. However, our understanding remains limited regarding how hormonal and dietary factors affect different adipose tissues. Furthermore, precise documentation of experimental procedures and their effects on specific adipose tissue depots is essential for reproducible translational research. This study investigated depot-specific adiposity development in OVX mice fed a high-fat diet (HFD), focusing on how reduced estrogen levels and dietary intervention affect distinct fat depots. We composed subcutaneous and visceral white adipose tissue (WAT) depots from sham-operated (Sham) and OVX female C57BL/6JJcl mice on a regular diet (RD) and high-fat diet (HFD) for 20 weeks. OVX mice on HFD gained significantly more weight than Sham controls. Adiposity increased in abdominal subcutaneous WAT (sWAT) and perirenal WAT (prWAT) of OVX mice, but not in mesenteric WAT (mWAT). Analysis of adipose tissue morphology revealed that OVX mice exhibited enlarged adipocyte cross-sectional areas under low estrogen (E2) conditions, suggesting enhanced adipogenesis in an estrogen-deficient state. These findings suggest that low estrogen condition accelerated adiposity, in a tissue site-dependent manner.

Sex Hormones and Common Abnormalities Encountered in the Acute Medicine Units

Hypogonadism is a reduction in sperm count and/or testosterone level (male) and amenorrhoea and reduction in estrogen level (female). Primary hypogonadism refers to testicular or ovarian pathology with raised levels of FSH and LH, while secondary hypogonadism refers to a disease in hypothalamic-pituitary axis leading to a deficiency in gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus or FSH/LH or inadequately normal levels from the pituitary gland. Common causes of secondary hypogonadism are mass lesion in pituitary gland leading to gonadotrophins and growth hormones deficiencies mainly with preservation of more vital hormones like ACTH and TSH and hyperprolactinemia which suppresses gonadotropin secretion. Other acquired causes of secondary hypogonadism are like causes of hypopituitarism.

Combine Surgery and In Vitro Fertilization (IVF) in Endometriosis-Related Infertility: When and Why.

Endometriosis is a chronic, estrogen-dependent inflammatory disease characterized by the presence of endometrial tissue outside the uterus, causing pelvic pain and infertility. Infertility arises mainly due to inflammatory mediators in the peritoneal fluid, contributing to local hypoestrogenism, which appears to exacerbate chronic inflammation and sensitize pelvic nerves. Local hypoestrogenism within endometriotic lesions contrasts with the systemic estrogen-dependent nature of the disease. This localized reduction in estrogen levels, resulting from an altered hormonal response, can contribute to the altered immune response and inflammation characteristic of endometriosis, potentially exacerbating tissue damage, promoting fibrosis, adhesions, and endometrioma formation that distort pelvic anatomy, and affecting fertility. Chronic pelvic pain and dyspareunia further complicate conception in affected women. In vitro fertilization (IVF) and laparoscopic surgical excision of endometriotic lesions are the two primary management options for endometriosis-related infertility, although current data provide limited guidance on when to prefer one approach over the other. It is generally accepted that treatment strategies must be individualized according to the patient's wishes, symptomatology, age and the preferences of the woman and the couple. Timely intervention and structured follow-up for symptomatic women wishing to conceive may maximize conception rates within two years post-surgery, while minimizing the need for repeated interventions, which should be avoided. On the other hand, first-line IVF is particularly viable in cases of unoperated deep infiltrating endometriosis in asymptomatic women, or for those ineligible for or opposed to surgery. This review aims to evaluate the most recent data on endometriosis-related infertility to identify evidence-based key points that can enhance tailored management in clinical practice.

Vulvovaginal Atrophy Following Treatment for Oncogynecologic Pathologies: Etiology, Epidemiology, Diagnosis, and Treatment Options.

Vulvovaginal atrophy, characterized by the thinning of vaginal mucosa typically resulting from reduced estrogen levels, is frequently exacerbated by oncogynecologic treatments such as chemotherapy, hormonal therapy, radiotherapy, or surgery. This condition significantly impacts the quality of life for cancer survivors, leading to persistent discomfort, heightened infection risk, and negative effects on sexual function and self-esteem. Despite being a relatively common complication, vulvovaginal atrophy is not always discussed before the start of treatment. Treatments typically mirror those used for natural menopause; however, efficacy and safety data specific to this population are limited due to the exclusion of these patients from clinical trials. A major safety concern is the risk of hormone-sensitive cancer recurrence associated with estrogen therapy, which drives a preference for non-hormonal alternatives. Newer treatments, such as laser therapy, radiofrequency, and vaginal injections, show promise with minimal side effects and hormone-independent mechanisms, though efficacy data varies, highlighting the need for further research. This narrative review explores the epidemiology, risk factors, diagnosis, and management of vulvovaginal atrophy after the treatment for oncogynecologic disorders.

Influence of the Onset of Menopause on the Risk of Developing Alzheimer's Disease.

Menopause is a natural phase marked by the permanent cessation of menstrual cycles, occurring when the production of reproductive hormones from the ovaries stops for at least 12 consecutive months. Studies have suggested a potential connection between menopause and a heightened risk of developing Alzheimer's disease (AD), underscoring the significant role of reduced estrogen levels in the development of AD. Estrogen plays a crucial role in brain metabolism, influencing energy metabolism, synaptic plasticity, and cognitive functions. The cognitive benefits associated with hormone replacement therapy (HRT) are believed to be linked to estrogen's neuroprotective effects, either through direct action on the brain or indirectly by improving cardiovascular health. Extensive literature supports the positive impact of estrogen on brain cells. While the physiological effects of estrogen on the brain have not been consistently replicated in clinical trials, further research is crucial to provide more definitive recommendations to menopausal patients regarding the influence of HRT on AD. This review aims to comprehensively explore the interplay between menopause and AD, as well as the potential of HRT to mitigate cognitive decline in post-menopausal individuals.

Ovariectomy exacerbates the disturbance of excitation- inhibition balance in the brain of APP/PS-1/tau mice.

The prevalence of Alzheimer's disease (AD) is significantly gender-differentiated, with the number of female AD patients far exceeding that of males, accounting for two-thirds of the total prevalence. Although postmenopausal AD mice have been shown to have more prominent pathologic features and memory impairments than normal AD mice, the relevant molecular mechanisms leading to these outcomes have not been well elucidated. In the present study, we used the disturbance of excitation-inhibition balance in the postmenopausal brain as an entry point to explore the link between estrogen deficiency, disorders of the glutamatergic-GABAergic nervous system, and memory impairment. Wild-type (WT) mice and APP/PS1/tau (3 × Tg-AD) mice (10 months old) were randomly divided into four groups: WT+Sham group, WT+OVX group, 3 × Tg-AD+Sham group and 3 × Tg-AD+OVX group. Ovariectomy (OVX) was performed in the WT+OVX group and the 3 × Tg-AD+OVX group, and sham surgery was performed in the WT+Sham group and the 3 × Tg-AD+Sham group. The learning and memory ability and the anxiety and depression-like behavior changes of mice were evaluated by behavioral experiments, and the association between estrogen-estrogen receptors pathway and glutamatergic/GABAergic nervous system and female AD was evaluated by neurochemical experiments. In WT and 3 × Tg-AD mice, OVX resulted in impaired learning and memory abilities and anxiety and depression-like behaviors; reduced estrogen levels and downregulated the expression of estrogen receptors; upregulated the expression of amyloid-β, amyloid precursor protein, presenilin 1, and p-tau; upregulated the expression of Bcl-2-associated X protein and downregulated the expression of B-cell lymphoma-2, promoting cell apoptosis; reduced the number of neuronal dendrites and downregulated the expression of postsynaptic density protein-95; more importantly, OVX increased brain glutamate levels but downregulated the expression of N-methyl-D-aspartate receptor-2B, excitatory amino acid transporter 1, excitatory amino acid transporter 2, γ-aminobutyric acid receptor-A and γ-aminobutyric acid receptor-B. Our results suggested that OVX-induced estrogen-estrogen receptors pathway disruption caused learning and memory impairment and anxiety and depression-like behaviors, upregulated the expression of AD pathological markers, promoted apoptosis, destroyed neuronal structure, and most importantly, caused glutamatergic/GABAergic nervous system disorders.

Reviewing the recurrence rates in stage I-III HR or ER positive breast cancer in obese patients given multi-modal weight loss plan post-treatment with aromatase inhibitors.

15 Background: Aromatase inhibitors (AIs) in the treatment of endocrine recepter positive breast cancer stages I-III, poses significant challenges in the management of obesity. Obesity is not only associated with an increased risk of breast cancer incidence but also with higher rates of cancer recurrence and poorer treatment outcomes. Moreover, the use of AIs, while effective in reducing estrogen levels and preventing ER or HR positive breast cancer recurrence, may exacerbate weight gain and metabolic disturbances in obese individuals. Weight management strategies have experienced increased attention in breast cancer survivors in recent years, especially overweight or obese individuals. Novel data makes it possible to infer that obesity management activities and multimodal programs that incorporate dietary counseling and physical activity can reduce recurrence rates. Methods: Participants in this study were individuals with Stage I-III endocrine receptor positive breast cancer who had completed adjuvant therapy and had a BMI in the 40s or 50s, increasing risk of recurrence. Eligible patients were identified based on the start date for endocrine therapy. High-risk patients were then assigned to either the intervention or control group. Those in the intervention group received access to a dietician, along with informational pamphlets on physiology and weight loss strategies. Additionally, they were offered discounts to certain gyms or provided free access to fitness facilities. Both intervention and control groups were briefed about the study, with those in the intervention group encouraged to utilize the provided resources for weight management. Results: The evidence from our study will underscore the potential benefits of multimodal weight loss interventions in overweight or obese breast cancer survivors, particularly in improving anthropometric outcomes and enhancing overall quality of life. Conclusions: While the studies included in our analysis demonstrated reductions in body weight, BMI, and waist circumference, as well as improvements in quality of life measures, there remains a notable gap in understanding the impact of these interventions on breast cancer recurrence rates, especially in the context of endocrine-positive breast cancer treated with Aromatase Inhibitors (AIs).

The Effect of Flavonoids of Phaleria macrocarpa Fruit Extract on Aortic Diameter Mice Menopause Model

Menopause is a phase experienced by women with an age range of 45-55 years. Menopause is a condition where menstruation stops for a minimum of 12 consecutive months due to the decline in ovarian function, leading to a reduction in estrogen levels. A decrease in estrogen can lead to impaired fat metabolism resulting in atherosclerosis. This study aimed to illustrate the influence of flavonoid extract derived from Phaleria Macrocarpa on the enlargement of the aorta's diameter of mice with a menopause condition. The method of this study is a genuine experimental laboratory setting with a research design of a Randomized Post Test Only Control Group setting. Using 32 female mice divided into 6 groups: K- (without ovariectomy and flavonoid extract Phaleria Macrocarpa), K + (ovariectomy without treatment), P1 (ovariectomy + dose 3.75 mg/mice/day), P2 (ovariectomy + dose 7.5 mg/mice/day), P3 (ovariectomy + dose 11.25 mg/mice/day), and P4 (ovariectomy + dose 15 mg/mice/day). Administration of flavonoid extract Phaleria Macrocarpa was carried out for 14 days. Data analysis using statistical analysis. The results showed that in a post-hoc test, namely the administration of Phaleria macrocarpa flavonoid extract at a dose of 11.25 mg/mice/day and 15 mg/mice/day showed that it could increase the dilation of the aortic diameter of mice model menopause. The study concludes that the flavonoid fruit extract from Phaleria Macrocarpa has the ability to increase the width of the aorta in mice with a menopause condition. In future studies, it is recommended to investigate various variables in order to identify the factors that contribute to the narrowing of the aorta. Additionally, it is suggested to perform further research specifically focusing on women going through menopause.

Abstract PO4-02-01: Characterization of immune and malignant cell evolution upon treatment pressure with aromatase inhibitors in locally advanced estrogen positive breast cancer

Abstract Background Aromatase inhibitors (AIs) are commonly used in the management of estrogen receptor-positive (ER+) breast cancer, as they effectively reduce estrogen levels which inhibits tumor growth and recurrence. In postmenopausal women with ER+ breast cancer, aromatase inhibitors are increasingly used in selected patients as neoadjuvant therapy to reduce the tumor burden before surgery and to improve overall treatment outcomes. Clinical trial The NEOLETEXE trial aimed to treat postmenopausal patients with locally advanced breast cancer. It was a neoadjuvant, randomized, open-label, intra-patient, cross-over, single-center phase II clinical trial. Most patients presented large T3/T4 tumors and/or N2/N3 involvement. Patients were randomly assigned to receive neoadjuvant therapy with either letrozole (2.5 mg daily) or exemestane (25 mg daily) for 3 months followed by a cross-over to the alternative AI for another 3 months followed by surgery. A total of 102 patients were enrolled in the NEOLETEXE trial. Aim of the study We aim at using single-cell analyses at different time points of treatment, to characterize evolutionary trajectories of cancer and immune cells in 23 patients from the NEOLETEXE trial. Methods Tumor biopsies taken before treatment (baseline) at crossover (after 3 months) and end of neoadjuvant therapy (after 6 months), were analyzed by single-cell RNA (scRNA), T cell receptor (TCR), and B cell receptor (BCR) sequencing. The data were first processed using cellRanger and the Seurat package. Results The main cell types found in tumors were identified through clustering of the scRNA data. We then focused on the epithelial cells to first distinguish between the normal and malignant epithelial cells using the InferCNV algorithm. For each patient, the analysis of inferred copy number events allowed to elucidate the genetic background of clones resistant or sensitive to aromatase inhibitors. This analysis unveiled the evolutionary dynamics of tumor heterogeneity during treatment. We next examined CD4, CD8, NK cells, and macrophages, using RNA velocity and diffusion pseudotime using CellRank and scVelo to delineate the differentiation trajectories of immune cell types. Conclusions We created a detailed map that provides a high-resolution view of the diverse cell types present in tumor biopsies from the NEOLETEXE trial. We characterize the impact of therapies on the evolutionary dynamics of both cancer and immune cells. Our analyzes sought insights into the underlying factors that contribute to the sensitivity and resistance to aromatase inhibitors. Citation Format: Leonard Schmiester, Salim Ghannoum, Marie Fongård, Marius Bjørnstad, Knut Selsås, Stephanie Geisler, Manouchehr Seyedzadeh, Unn-Cathrin Buvarp, Torben Lüders, Diether Lambrechts, Marianne Lyngra, Arnoldo Frigessi, Vessela Kristensen, Jürgen Geisler, Xavier Tekpli. Characterization of immune and malignant cell evolution upon treatment pressure with aromatase inhibitors in locally advanced estrogen positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-02-01.

Infertility in POMC-deficient mice

The pro-opiomelanocortin (POMC) gene is expressed in the hypothalamus and pituitary and its product is cleaved into several peptides including the melanocyte stimulating hormones (α, β, or γ-MSH), adrenocorticotropic hormone (ACTH), and beta-endorphin. Alpha-MSH is involved in regulating appetite, sexual behavior, and melanin, while ACTH regulates secretion of glucocorticoids from the adrenal cortex. Humans who have a POMC mutation either produce an abnormally short version of POMC or are missing the protein completely and therefore lack these hormones. This has biological consequences including red hair and fair skin, early-onset obesity (due to severe hyperphagia), and potentially hypothyroidism, hypogonadism, and infertility. Many of these same effects are seen with mice containing this deficiency. We are interested in studying infertility through a mouse model of hypothalamic-specific POMC-deficiency. These mice also experience early-onset obesity and infertility. Estradiol is a key reproductive hormone that is essential for fertility. POMC deficiency may lead to hypogonadism, which can cause low levels of estrogen so we hypothesize that POMC-deficient mice have reduced estrogen levels, which may contribute to their infertility. To test this hypothesis, we will measure estrogen levels in POMC-deficient mice at different stages of the estrus cycle using an estradiol ELISA kit. We expect the POMC-deficient mice to have lower estrogen levels than control mice. We also plan to use liquid chromatography mass spectrometry (LC-MS) to measure estrogen levels. Before collecting the blood samples, vaginal cell samples are obtained and viewed under a microscope to analyze the ratio of cells and determine which stage the females were in—proestrus, estrus, metestrus, or diestrus. Blood samples are then collected into 1.5 mL microcentrifuge tubes with 10 microliters of 0.5 M EDTA to prevent blood clotting. After blood is collected, it is centrifuged at 2,000 g for 20 minutes at 4 degrees Celsius. The plasma is then stored at -80 degrees Celsius until analysis. Based on preliminary results we expect the POMC deficient mice to have reduced estrogen and/or altered levels throughout the cycle. So far, our results have indicated that POMC-deficient female mice have abnormal estrus cycles and also reduced uterine weights. The conclusions from this study will help us understand more about the causes of infertility in POMC-deficient mice, which may also lead to greater understanding on how to treat humans with infertility due to a POMC mutation. Support for this research was provided by IRACDA grant NIHK12GM111725 to Z.T. and UVU Scholarly Activities Grant to A.G. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract LB394: Tumor evolution upon treatment pressure with aromatase inhibitors in locally advanced estrogen receptor positive breast cancer

Abstract BackgroundAromatase inhibitors (AIs) are commonly used in the management of estrogen receptor-positive (ER+) breast cancer as they effectively reduce estrogen levels which inhibits tumor growth and recurrence. Aromatase inhibitors are increasingly used in selected patients as neoadjuvant therapy. Clinical trialThe NEOLETEXE is a neoadjuvant, randomized, open-label, intra-patient, cross-over, single-center phase II clinical trial, aimed to treat postmenopausal patients with locally advanced breast cancer. Most patients presented large T3/T4 tumors and/or N2/N3 involvement. Patients were randomly assigned to neoadjuvant therapy with either letrozole (2.5 mg daily) or exemestane (25 mg daily) for 3 months followed by a cross-over to the alternative AI for another 3 months followed by surgery. A total of 102 patients were enrolled in the NEOLETEXE trial. Aim of the studyWe aimed to compare clones derived from bulk exome sequencing with single-cell analyses at DNA and RNA level from the same tumors at different time points of treatment in order to characterize evolutionary trajectories of cancer and immune cells in 23 patients at scRNA level and 16 patients at scDNA level from the NEOLETEXE trial. MethodsTumor biopsies taken before treatment (baseline) at crossover (after 3 months) and end of neoadjuvant therapy (after 6 months), were analyzed by single-cell DNA (MissionBio) and scRNA (10xGenomics), T cell receptor (TCR), and B cell receptor (BCR) sequencing. Results We employed the The Mission Bio Tapestri Platform, which enables targeted scDNAseq of nuclei isolated from fresh frozen tumor tissue using microfluid droplet technology. A custom panel of 497 amplicons covering 528 sequence variants was designed to study treatment response selected by the following criteria: 1) Up to 10 mutations from each sublonal clusters defined by analysing 32 samples (3 time points) from 11 NeoLetExe patients with whole exome sequencing (WES) data prioritizing mutations in genes part of the Cancer Gene Census (COSMIC), 2) known mutations covering all chromosomes to enable CNV analysis and 3) “Hand-picked” mutations with significance for breast cancer (e.g. hotspot ESR1 mutations). We performed SNV and CNV analysis and reconstruction of mutational lineages with user developed tools. On average, 81% of the clusters defined by WES was validated by scDNAseq and copy number profiles matching between the two data sets. Fishplot with variants defining cell clusters in WES using data from scDNAseq show clonal development during treatment.The scRNA analyses revealed cell types were identified through clustering of the scRNA data. We focused on the epithelial cells to first distinguish between the normal and malignant epithelial cells using the InferCNV algorithm. We next examined CD4, CD8, NK cells, and macrophages, using RNA velocity and diffusion pseudotime using CellRank and scVelo to delineate the differentiation trajectories of immune cell types. Conclusions We created a detailed map that provides a high-resolution view of the diverse clones and cell types present in tumor biopsies from the NEOLETEXE trial. We characterize the impact of therapies on the evolutionary dynamics of both cancer and immune cells. Our analyzes sought insights into the underlying factors that contribute to the sensitivity and resistance to aromatase inhibitors. Citation Format: Vessela N. Kristensen, Grethe I. Alnaes, Patrik Vernhoff, Leonard Schmiester, Salim Ghannoum, Marie Fongaard, Paal M. Bjornstad, Knut Selsaas, Stephanie Geisler, Manouchehr Seyedzadeh, Unn-Cathrin Buvarp, Torben Luders, Diether Lambrechts, Marianne Lyngra, Arnoldo Frigessi, Xavier Tekpli, Jurgen Geilser. Tumor evolution upon treatment pressure with aromatase inhibitors in locally advanced estrogen receptor positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB394.

Aromatase Inhibitors and Plasma Lipid Changes in Postmenopausal Women with Breast Cancer: A Systematic Review and Meta-Analysis.

Background: Women are typically diagnosed with estrogen receptor-positive breast cancer around the postmenopausal period when declining estrogen levels initiate changes in lipid profiles. Aromatase inhibitors (AI) are used to prevent the progression of cancer; however, a further reduction in estrogen levels may have detrimental effects on lipid levels, which was our working hypothesis. Methods: Our meta-analysis was conducted on the lipid profiles of postmenopausal breast cancer patients at baseline and at different treatment time points. Results: We identified 15 studies, including 1708 patients. Studies using anastrozole (ANA), exemestane (EXE), letrozole (LET), and tamoxifen (TMX) were involved. Subgroup analyses revealed that 3- and 12-month administrations of LET and EXE lead to negative changes in lipid profiles that tend to alter the lipid profile undesirably, unlike ANA and TMX. Conclusions: Our results suggest that, despite statistically significant results, EXE and LET may not be sufficient to cause severe dyslipidemia in patients without cardiovascular comorbidities according to the AHA/ACC Guideline on the Management of Blood Cholesterol. However, the results may raise the question of monitoring the effects of AIs in patients, especially those with pre-existing cardiovascular risk factors such as dyslipidemia.

Sharing the multidisciplinary clinical approach to peri- and postmenopausal women: A Delphi consensus among Italian gynecologists, endocrinologists, and cardiologists for an integrated and optimal approach to clinical practice.

The critical phase of perimenopausal period is marked by a reduction in estrogen levels, leading to various clinical issues (vasomotor and neurodegenerative symptoms, increased osteoporosis risk and cardiovascular risk). These complex clinical scenarios pose challenges to clinicians in providing the right support for diagnosis and treatment. A group of Italian cardiologists, endocrinologists, and gynecologists conducted a survey among expert colleagues to assess consensus on controversial issues and best practices for screening and treating peri- and postmenopausal women. The Delphi methodology was used to analyze responses from a qualitative expert panel comprising 25 cardiologists, 25 endocrinologists, and 25 gynecologists, selected nationwide. Two consecutive questionnaires were proposed between February and May 2023. Agreement among experts was assessed following the Delphi method as developed by the RAND Corporation. The results of this Delphi Consensus have been shared by the leading scientific societies: Italian Society of Cardiology, Italian Society of Endocrinology, Italian Society of Gynecology and Obstetrics, and Italian Hospital Obstetricians Gynecologists Association. The experts highlighted comorbidities and hormone deprivation as crucial clinical problems to be evaluated in perimenopausal women, requiring investigation from cardiovascular and endocrinologic perspectives to assess cardiovascular risk, involving the use of BMI, standard blood samples, endocrine-metabolic tests, and lifestyle assessment, particularly in women with higher cardiovascular and metabolic risks candidates for hormone replacement therapy (HRT). The experts also agreed on the benefits of HRT in improving lipid metabolism and reducing insulin resistance, thereby mitigating the metabolic risks associated with menopause. However, this therapy should be tailored considering individual women's comorbidities and thrombotic risk.

Mechanobiochemical bone remodelling around an uncemented acetabular component: influence of bone orthotropy.

Mechanical loosening of an implant is often caused by bone resorption, owing to stress/strain shielding. Adaptive bone remodelling elucidates the response of bone tissue to alterations in mechanical and biochemical environments. This study aims to propose a novel framework of bone remodelling based on the combined effects of bone orthotropy and mechanobiochemical stimulus. The proposed remodelling framework was employed in the finite element model of an implanted hemipelvis to predict evolutionary changes in bone density and associated orthotropic bone material properties. In order to account for variations in load transfer during common daily activities, several musculoskeletal loading conditions of hip joint corresponding to sitting down/up, stairs ascend/descend and normal walking were considered. The bone remodelling predictions were compared with those of isotropic strain energy density (SED)-based, isotropic mechanobiochemical and orthotropic strain-based bone remodelling formulations. Although similar trends of bone resorption were predicted by orthotropic mechanobiochemical (MBC) and orthotropic strain-based models across implanted acetabulum, more volume (10-20%) of bone elements was subjected to bone resorption for the orthotropic MBC model. Higher bone resorption (75-85%) was predicted by the orthotropic strain-based and orthotropic MBC models compared to the isotropic MBC and SED-based models. Higher bone apposition (35-160%) across the implanted acetabulum was predicted by the isotropic MBC model, compared to the SED-based model. The remodelling predictions indicated that a reduction in estrogen level might lead to an increase in bone resorption. The study highlighted the importance of including mechanobiochemical stimulus and bone anisotropy to predict bone remodelling adequately.

Role of Platelet-Rich Plasma in Genitourinary Syndrome of Menopause.

The genitourinary syndrome of menopause (GSM) encompasses a range of symptoms linked to the genitourinary tract stemming from the reduction in estrogen levels following menopause. These symptoms may endure throughout a woman's lifetime. Platelet-rich plasma (PRP), known for its capacity to induce angiogenesis and the restoration effects of growth factors, has been widely employed in various disorders, including GSM. This article aims to comprehensively review the existing literature on the utilization of PRP for managing GSM. The search was executed in electronic databases, specifically PubMed, Scopus, and Google Scholar, up until April 2023. Eligible studies were meticulously chosen for inclusion in this systematic review. PRP emerges as a viable alternative for addressing vaginal atrophy, exhibiting favorable outcomes. Notably, it can be considered for patients with contraindications to hormonal therapy. However, the available body of evidence supporting the use of PRP for GSM remains limited. PRP presents itself as a promising agent, offering a patient-friendly, cost-effective alternative modality. To establish the efficacy of PRP in treating GSM definitively, future randomized trials are imperative.

The effects of treadmill exercise on brain angiogenesis in ovariectomized rats.

Menopause is associated with vascular dysfunction attributed to reduced estrogen levels. Exercise has been proposed to promote angiogenesis and vascular dysfunction. However, studies of brain angiogenesis during menopause are limited. We analyzed the effects of exercise on angiogenesis-related factors in menopausal rat model. Twenty-week-old female Sprague-Dawley rats (N = 18) were randomly divided into a normal control group (N, n = 6), an ovariectomized control group (OVX, n = 6), and an ovariectomy + exercise group (OVX-EX, n = 6). Treadmill exercises were conducted in the OVX-EX group for 8 weeks (15-60 m/min, 1 h/day, and 5 days/week). The current study showed that the expression of angiogenesis-related factors (platelet-derived growth factor subunit A, B, vascular endothelial growth factor, angiopoietin 1, and angiopoietin 2) significantly decreased in the cortex of the OVX group. However, these factors were significantly restored in the cortex of the OVX-EX group after 8 weeks of treadmill exercise. In summary, estrogen deficiency causes vascular dysfunction by inhibiting the expression of angiogenesis-related factors. However, exercise can restore angiogenesis-related factors in OVX rats. Exercise eventually prevents vascular dysfunction in the brain and may help prevent cognitive dysfunction in menopausal women.

Cholesterol Levels, Hormone Replacement Therapy, and Incident Dementia among Older Adult Women.

Previous studies revealed that hormone replacement therapy (HRT) probably has a protective effect for preventing dementia in post-menopausal women. However, the results were still controversial. The association between cholesterol levels and incident dementia in older women is not fully understood either. We conducted a retrospective analysis on a cohort of non-demented women aged older than 50 years, which was registered in the History-based Artificial Intelligence Clinical Dementia Diagnostic System database from September 2015 to August 2021. We followed this cohort longitudinally to examine the rates of conversion to dementia. Using a Cox regression model, we investigated the impact of the quartile of total cholesterol (TC) levels on incident dementia, adjusting for age, sex, education, neuropsychiatric symptoms, neuropsychological assessments, HRT, as well as various vascular risk factors and medications. We examined a cohort of 787 participants, comprising 539 (68.5%) individuals who did not develop dementia (non-converters). Among these non-converters, 68 individuals (12.6%) were treated with HRT. By contrast, there were 248 (31.5%) who did develop dementia (converters). Among the converters, 28 individuals (11.3%) were treated with HRT. The average follow-up durations were 2.9 ± 1.5 and 3.3 ± 1.6 years for non-converters and converters, respectively. Compared to the lowest quartile of TC levels (<153), the hazard ratios (HR) for converting to dementia were 0.61, 0.58, and 0.58 for the second (153-176), third (177-201), and highest (>201) quartiles, respectively (all p < 0.05). However, the low-density lipoprotein cholesterol (LDL-C) level and HRT did not alter the rate of conversion to dementia. In conclusion, the lowest quartile of TC increased incident dementia in post-menopausal women without dementia; however, HRT did not contribute to conversion to dementia. Some studies suggest that post-menopausal women who have reduced estrogen levels might have an increased risk of Alzheimer's disease if they also have high cholesterol. Nonetheless, the evidence is inconclusive, as not all studies support this finding. The "Lower LDL-C is better" strategy for preventing cardiac vascular disease should be re-examined for the possible serial adverse effects of new onset dementia due to very low cholesterol levels.

Icariin inhibits hypertrophy by regulation of GPER1 and CaMKII/HDAC4/MEF2C signaling crosstalk in ovariectomized mice

Icariin (ICA), a flavonoid phytoestrogen, was isolated from traditional Chinese medicine Yin Yang Huo (Epimedium brevicornu Maxim.). Previous studies reporting the cardioprotective effects of ICA are available; however, little is known about the impact of ICA on cardioprotection under conditions of reduced estrogen levels. This study aimed to provide detailed information regarding the antihypertrophic effects of ICA in ovariectomized female mice. Female mice were subjected to ovariectomy (OVX) and transverse aortic constriction and then orally treated with ICA at doses of 30, 60 or 120 mg/kg/day for 4 weeks. Morphological assessments, echocardiographic parameters, histological analyses, and immunofluorescence were performed to evaluate cardiac hypertrophy. Cardiomyocytes from mice or rats were stimulated using phenylephrine, and cell surface and hypertrophy markers were tested using immunofluorescence and qPCR. Western blotting, qPCR, and luciferase reporter gene assays were used to assess the expression of proteins and mRNA and further investigate the proteins related to the G-protein coupled estrogen receptor (GPER1) and CaMKII/HDAC4/MEF2C signaling pathways in vivo and in vitro. ICA blocks cardiac hypertrophy induced by pressure overload in OVX mice. Additionally, we demonstrated that ICA activated GPER1 and inhibited the nuclear export or promoted the nuclear import of histone deacetylase 4 (HDAC4) through regulation of phosphorylation of calmodulin-dependent protein kinase II (CaMKII) and further improved the repression of myocyte enhancer factor-2C (MEF2C). ICA ameliorated cardiac hypertrophy in OVX mice by activating GPER1 and inhibiting the CaMKII/HDAC4/MEF2 signaling pathway.