Effects Of Estrogen Research Articles

Intervening effects of progesterone combined with estradiol on streptozotocin-induced diabetes in ovariectomized mice and the underlying mechanisms

Background: Estrogen and progesterone are closely related to the occurrence of diabetes, and the progestogenic and estrogenic effects in the development of diabetes are related to their blood levels and the organism state, and it is not clear what effect their combination will be. The present study was to investigate the interaction between estrogen and progesterone in the development of diabetes mellitus. Methods: A model of type 1 diabetes mellitus（T1DM）was established in ovariectomized (OVX) mice by intraperitoneal injection of streptozotocin (STZ), and the levels of plasma glucose, insulin, C-peptide, progesterone, and estradiol, the changes of islet cells, the expressions of glucose transporter 4 (GLUT4), Glucokinase (Gck), Glucose-6-phosphatase (G-6-P) and phosphoenolpyruvate carboxylase (PCK) were detected after chronically injected different doses of progesterone and 17β-estradiol subcutaneously for 4 weeks. Results: Progesterone and 17β-estradiol could delay the occurrence of T1DM induced by STZ in ovariectomized mice, but there was no dose-response relationship; progesterone (2mg/kg) and 17β-estradiol (0.1mg/kg) injected separately or jointly could make the plasma concentration of estradiol and progesterone reaches the physiological dose range, which markedly inhibited the increase of the blood glucose induced by STZ, improved the glucose tolerance, protected islet cells, promoted C-peptide and insulin secretion, up-regulated skeletal muscle GLUT4 and liver Gck expressions, but significantly down-regulated the expressions of liver PCK and G-6-P mRNA. Conclusions: The physiological dose of progesterone combined with estradiol has certain synergistic effects in delaying the occurrence of diabetes, the mechanisms are probably related to the protection of islet cells, the promotion of insulin release, skeletal muscle glucose transport, and liver glucose metabolism.

Investigating the therapeutic potential of hesperidin targeting CRISP2 in intervertebral disc degeneration and cancer risk mitigation.

Intervertebral disc degeneration (IDD) can lead to disc herniation and spinal instability, sometimes requiring surgical intervention. Currently, estrogen has a potential protective effect on IDD, and estrogen is associated with an increased risk of some cancers, such as breast and endometrial cancer. Therefore, it is important to identify natural compounds that estrogen analogues treat IDD while reducing the risk of tumor development. This study aims to explore a natural metabolic treatment strategy by targeting CRISP2 with the natural compound Hesperidin to mimic the protective effects of estrogen on IDD and reduce the risk of tumor development. Microarray data from healthy volunteers and IDD patients were extracted from the Gene Expression Omnibus (GEO) database, and RNA sequencing and clinical data from various cancer types were analyzed. Differentially expressed genes (DEGs) were identified using the Bioconductor Limma package, followed by principal component analysis, volcano plot, and heatmap visualization. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, CIBERSORT and ssGSEA immune cell infiltration assessments, survival analysis, metabolite enrichment analysis, and molecular docking were performed. Hesperidin's interaction with CRISP2 was further validated through molecular docking and experimental studies. Hesperidin significantly reduced the expression of CRISP2, iNOS, and COX2 in IDD models, decreased reactive oxygen species (ROS) and apoptosis, and diminished inflammatory markers. CIBERSORT and ssGSEA analyses revealed a correlation between CRISP2 and immune cell infiltration. Survival analysis demonstrated that CRISP2 expression levels were associated with patient survival across various cancer types. Hesperidin was found to mimic estrogen's effects on IDD and reduce tumor progression. Cell culture and experimental validation confirmed Hesperidin's protective effects on nucleus pulposus cells (NPCs). Hesperidin, as a potential natural metabolic regulator, not only has therapeutic effects on IDD but may also synergize with estrogen therapy to promote spinal health without increasing cancer risk. This study presents a new clinical approach for IDD treatment and lays the foundation for further drug development and experimental research.

Effect of combined hormone replacement therapy on sympathetic nervous system function in postmenopausal women – A cross-sectional study

Background: There is an increased prevalence of cardiovascular and metabolic diseases in postmenopausal women. Estrogen plays an important role in the regulation of blood pressure (BP) and autonomic function. Various hormone therapies are widely used in postmenopausal women, especially combination therapy of low-dose estrogen and progesterone. Hormone therapy might be useful not only in alleviating menopausal symptoms but help in reducing cardiovascular risk factors and improving quality of life. Aims and Objectives: The aim of the study is to study the effect of combined estrogen and progesterone hormone therapy on BP and sympathetic overactivity in postmenopausal women. Materials and Methods: The study included two groups of 50 women each. Group I included postmenopausal women of age 45–55 years who were taking combined hormone therapy while Group II included postmenopausal women of the same age group who were not on any replacement therapy heart rate and BP in resting state was noted in both the groups. Sympathetic function assessment was done by performing cold pressor test, handgrip test, and BP response to standing on all the participants. Statistical analysis was done using the student’s t-test. Results: There was a statistically significant difference in resting heart rate, BP, and sympathetic function tests in both groups. Conclusion: There is a facilitatory role of combined estrogen and progesterone therapy in menopausal women in reducing BP and sympathetic system dysregulation.

Hormones and thrombosis: the dark side of the moon.

The main drawback of oral contraceptives (OC) and hormone replacement therapy (HRT) is an increased risk of venous and, to a lesser extent, arterial thrombosis. This narrative, case-based review describes the effect of available estrogens and progestogens on the hemostatic system and their potential impact on the risk of thrombosis. Clinical cases are used to illustrate different options for prescribing OC and HRT in the real-word. The aim is to offer discussion topics that could be helpful to guide the choice of different hormonal treatments over a woman's lifetime and in the presence of risk factors. We describe physio-pathological changes occurring during the administration of hormonal therapies. Furthermore, we analyze the risk of venous and arterial thrombosis associated with different products, routes of administration and additional risk factors. New hormonal preparations, such as estradiol combined with dienogest, as well as non-oral hormonal therapies, are suggested to decrease thrombotic risk significantly. The availability of many products and different routes of administration allow most women to safely use contraception, as well as HRT. We encourage careful counselling instead of inflexible or fearful behavior, as expanding options and choices will allow women to make the best decisions for their health.

A comparison of hyaluronic acid and estradiol treatment in vulvovaginal atrophy.

This study aims to compare the effects of vaginal estrogen and hyaluronic acid on vulvovaginal atrophy. This randomized controlled study included a total of 300 patients, with 150 patients in each group (Group E and Group H). The VHI score was determined based on a pre-treatment evaluation conducted by a gynecologist. After one month of receiving vaginal estrogen in Group E and vaginal hyaluronic acid in Group H, the patients were re-evaluated by their physicians. A statistically significant difference was found between the pre- and post-treatment VHI scores in Group E and Group H (p = 0.000; p = 0.000). No statistical difference was found between Group E and Group H in terms of treatment efficacy (p = 0.712). The pre- and post-treatment complaints of dryness, itching, dyspareunia, burning, and dysuria were found to be statistically significant in Group E and Group H (p = 0.000; p = 0.000; p = 0.000; p = 0.000; p = 0.000 in Group E, respectively) (p = 0.000; p = 0.000; p = 0.000; p = 0.000; p = 0.000 in Group H, respectively). No statistical difference was observed regarding dyspareunia, dysuria, and burning complaints (p = 0.632; p = 0.106; p = 0.128, respectively). However, hyaluronic acid was found to be significantly more effective for itching complaints (p = 0.002), while estrogen was found to be significantly more effective for dryness complaints (p = 0.012). Hyaluronic acid and estrogen were equally effective in vaginal treatment. Hyaluronic acid may be preferred for patients in whom hormonal therapy is contraindicated or for those who prefer non-hormonal therapy.

Combination of androgen and estrogen improves asthma by mediating Runx3 expression.

Objective: Asthma is a chronic heterogeneous airway disease, and imbalanced T-helper type 1 (Th1) and Th2 cell-mediated inflammation contribute to its pathogenesis. Although it has been suggested that androgen and estrogen were involved in development of asthma, the underlying mechanisms remained largely unclear. Studies have demonstrated that Runx3 could promote naive CD4+ T cells to differentiate into Th1 cells. Hence, our study aimed to explore the potential regulatory mechanism of androgen and estrogen on asthma via modulating Runx3. Methods: First, clinical assessments and pulmonary function tests were conducted on 35 asthma patients and 24 healthy controls. The concentrations of androgen, estrogen, and androgen estrogen ratios were assessed in peripheral blood samples of asthma patients and healthy controls. Then, a murine asthma model was established to explore the effects of estrogen and androgen (alone or in combination) on asthma. Third, an in vitro assay was used to explore the mechanism of combination of androgen and estrogen in asthma. Results: We observed decreased androgen and increased estrogen levels in asthma patients compared with healthy controls. In mice with experimental asthma, there were increased serum concentrations of estrogen and decreased serum concentrations of androgen, intervention with combination of androgen and estrogen alleviated airway inflammations, increased Runx3 expressions and elevated Th1 differentiation. In CD4+ T cells co-cultured with bronchial epithelial cells (BECs), treatment with androgen plus estrogen combination promoted Th1 differentiation, which was mitigated by Runx3 knockdown in BECs and enhanced by Runx3 overexpression. Conclusion: These findings suggest that androgen estrogen combination modulate the Th1/Th2 balance via regulating the expression of Runx3 in BECs, thereby providing experimental evidence supporting androgen and estrogen combination as a novel therapy for asthma.

Sacroiliitis in gout: Difficulties of diagnosis

Gout is the most common chronic autoinflammatory disease, the development of which is associated with persistent hyperuricemia caused by both environmental and genetic factors, which leads to the deposition of sodium monourate crystals in various tissues and organs of the human body. Gout is more common in men than in women of childbearing age, due to the uricosuric effect of estrogen, however, after menopause, the incidence of gout in women increases significantly. At the onset of the disease, the first metatarsophalangeal joint, ankle and knee joints are most often involved in the pathological process. However, there are isolated reports in the literature about a rare gout lesion of the axial skeleton, for example, the sacroiliac joint, in which the nature of the pain syndrome, magnetic resonance imaging, and X-ray picture can mimic spondyloarthritis. The article presents a rare case of damage to the axial skeleton in a 57-year-old patient with gout, manifested by acute inflammatory back pain and arthritis of the lower extremities.

Effects of estrogens in mitochondria: An approach to type 2 diabetes

<abstract> <p>Type 2 diabetes (T2D) is characterized by a state of hyperglycemia in the blood due to insulin resistance developed by organs such as muscle, liver, and adipose tissue. A common factor in individuals with T2D is mitochondrial dysfunction. Mitochondria are dynamic organelles responsible for energy and antioxidant metabolism in the cells. Estrogens, such as 17β-estradiol (E2), are steroid hormones that have shown a great capacity to regulate mitochondrial function and dynamics through estrogen receptors (ERs), modulating the expression of mitochondrial biogenesis-related genes and cell signaling mechanisms. The accumulation of reactive oxygen species, the low capacity for ATP synthesis, and morphological alterations are some of the mitochondrial processes impaired in T2D. Insulin signaling and secretion by pancreatic β-cells, ATP-dependent processes, are also altered in T2D. In this review, mitochondria were exposed as the central axis for the action of estrogens in individuals with T2D. Estrogens increased glucose uptake, insulin signaling, and mitochondrial bioenergetics, and decreased ectopic lipid accumulation in non-adipose tissues and oxidative stress, among other processes, in various preclinical and clinical models of diabetes. The development of strategies to target compounds to mitochondria could represent a novel therapeutic alternative to potentiate the effects of estrogens on this organelle in patients with insulin resistance and T2D.</p> </abstract>

Assessment of the application of atherosclerotic disease risk scores in the workplace

In occupational health activities in Japan, evaluating workers' fitness for work following health checkups is a primary task. Health checkups are used to identify workers at high risk of cerebrovascular and cardiovascular diseases and conduct fit-for-work evaluations. However, identifying high-risk individuals based on a single risk factor may overlook those with multiple risk factors who have a high risk of developing cerebrovascular and cardiovascular diseases. Presently, we aimed to investigate the atherosclerotic cardiovascular disease (ASCVD) risk score from a previous study by Hisayama (Hisayama study) and examine its use in the workplace. Baseline data from health checkups conducted in 2010 of 41,815 employees (men; 34,024, women; 7,791) aged 19-64 years without previous cerebrovascular or cardiovascular disease were analyzed. The relationship between baseline ASCVD risk scores and the incidence of ASCVD > 10 years (2011-2020) was examined using Cox regression analysis with hazard ratios (HR). Receiver operating curve (ROC) analysis was conducted to evaluate the model's performance and determine optimal cut-off values for the identification of high-risk individuals in the workplace. The 10-year incidence of ASCVD was 2.6% (men; 3.0%, women; 0.8%). In men, each 1% increase in ASCVD risk score was associated with a 1.5-fold increase in ASCVD incidence (HR; 1.46, 95% confidence interval [CI]; 1.42-1.51, p < .001), which was observed from age 30 and even after multivariate adjustment. In women, univariate analysis showed an association between increased ASCVD risk score and incidence (HR; 3.19, 95% CI; 2.10-4.85, p < .001); however, this was not significant after adjustment. ROC analysis identified 1.62% as the optimal cut-off (sensitivity; 58.6%, specificity; 71.9%, positive predictive value [PPV]; 5.2%). The ASCVD risk score is a useful tool for risk management and prevention in the workplace, particularly for men. In women, this association disappeared after age adjustment, possibly due to reduced estrogen effects with aging. Based on the ROC analysis, stratifying at ≥ 1.5% for intervention, ≥ 2.0% (top 20%) for "high risk," and ≥ 3.5% (PPV > 10%) for "extremely high risk" is advised. However, this study may have underestimated the risk levels; therefore, companies should adapt the use of ASCVD risk scores flexibly according to their circumstances.

The Effect of Estrogen on Anterior Cruciate Ligament Structure and Function: A Systematic Review

The Effect of Estrogen on Anterior Cruciate Ligament Structure and Function: A Systematic Review

Medicinal value of Phytoestrogens in Trigonella foenum-graecum L (Fenugreek) - Review

Trigonella foenum-graecum known as fenugreek, is a widely used spice and an abundant source of phytoestrogens. Fenugreek has a wide range of pharmacological effects, such as hypoglycemic, hypolipidemic, obesity, antioxidant activity, osteoporosis, anti-inflammatory, and antirheumatic effects. Phytoestrogens are one of the constituents of fenugreek. These are nonsteroidal compounds that resemble the structure of 17β -estradiol and can bind to the ERα and ERβ estrogen receptors. It acts as an estrogen receptor modulator, producing antiestrogenic and/or estrogenic effects. The protective effect was also apparent in the cellular architecture of the kidney, liver, and common carotid artery. Several beneficial effects are ascribed to the phytoestrogens present in fenugreek. In the present review, we focused on the medicinal values of phytoestrogens in fenugreek

Effects of Estrogen on Histomorphology Steroid-Induced Avascular Necrosis of Head of Femur in Male Rats

Objectives: To study the effects of estrogen administration on histomorphology of avascular necrosis of the femoral head in male rats. Study Design: Lab-based experimental study. Place and Duration of Study: Department of Anatomy, Army Medical College, National University of Medical Sciences, Rawalpindi (NUMS), in collaboration with the National Institute of Health Islamabad, (NIH) Pakistan from Aug to Nov 2021. Methodology: Thirty male Sprague Dawley rats, three months of age, weighing 200-300 gm, were selected. Rats were equally divided into three groups. Group-A served as a control group in which no intervention was made, and the rats were fed on a standard lab diet. Groups B and C served as experimental groups. In Groups B and C, avascular necrosis was induced by steroids for the first week of the study. Group C along with steroids also received tab estrogen by oral gavage for eight weeks, starting from the fifth week of the study till the twelfth week of the study. All the rats were sacrificed after the completion of the experimental period. The microscopic parameters like cortical thickness and percentage of the empty lacunae were counted. Results: Histomorphological changes were observed when the comparison was made between Group B, Control Group A, and Experimental Groups B and C with statistically significant results (p-value 0.001). Conclusion: Estrogen helps in fracture healing and shows improvement in cortical and trabecular strength. It has shown improvement in the cortical thickness measurement after avascular necrosis causes a decrease in the thickness.

Electrochemistry detection of estrogenic effect: Regulation of de novo purine synthesis and catabolism by gibberellin and fulvestrant

The estrogenic effect of plant growth regulators has been received little attention, which leads to the lack of relevant toxicity data. In this study, the estrogenic effect induced by gibberellin with ERα-dependent manner was found by E-screen and western blot methods, and the electrochemical signals of MCF-7 cells regulated by gibberellin and fulvestrant were investigated. The results showed that the electrochemical signals of MCF-7 cells were increased by gibberellin, while reduced by fulvestrant significantly, and displayed an extremely sensitive response to the effects of estrogenic effect induced by ERα agonist and antagonist. Western blot results showed that the expressions of phosphoribosyl pyrophosphate amidotransferase and hypoxanthine nucleotide dehydrogenase in de novo purine synthesis and adenine deaminase in catabolism were more effective regulated by gibberellin and fulvestrant, resulting in significant changes of the levels of guanine, hypoxanthine and xanthine in cells, and then electrochemical signals. The results provide a theoretical basis for the establishment of new electrochemical detection method of the estrogenic effect of plant regulators.

Effects of dietary soy content on cerebral artery function and behavior in ovariectomized female mice.

As females age, they transition through menopause, experiencing a decrease in estrogen and an increase in cardiovascular and neurodegenerative disease risk. Most standard rodent chows contain phytoestrogen-rich soybean meal, which can mimic the effects of estrogen. Understanding the impact of this soybean meal on vascular outcomes is crucial to proper experimental design. Thus, this study aimed to compare the effects of standard and soy-free chows on cerebral artery endothelial function and cognitive function in ovariectomized mice. Young female C57Bl/6J mice (n = 43; ∼6 mo) were randomly assigned to three groups: sham, ovariectomy (OVX), or ovariectomy on a diet containing soy (OVX + Soy). In posterior cerebral arteries, the OVX mice had a 27% lower maximal response to insulin compared with the sham mice. The OVX + Soy mice had a 27% greater maximal vasodilation to insulin compared with the OVX mice and there were no differences in vasodilation between the OVX + Soy and sham groups. The group differences in vasodilation were mediated by differences in nitric oxide bioavailability. The OVX + Soy mice also had greater insulin receptor gene expression in cerebral arteries compared with the OVX mice. However, no differences in aortic or cerebral artery stiffness were observed between groups. Interestingly, the OVX + Soy group scored better on nesting behavior compared with both sham and OVX groups. In summary, we found that ovariectomy impairs insulin-mediated vasodilation in cerebral arteries, but a diet containing soy mitigates these effects. These findings highlight the importance of considering dietary soy when performing vascular and behavioral tests in mice, particularly in females.NEW & NOTEWORTHY To properly design experiments, we must consider how variables like diet impact our outcomes, particularly the effects of soy on females. We found that cerebral artery vasodilation in response to insulin was impaired in ovariectomized female mice compared with intact shams. However, ovariectomized mice fed a soy diet had a preserved cerebral artery insulin-mediated vasodilation. These results highlight that the effects of diet on vascular function may explain inconsistencies found between studies.

Reduction in Nuclear Size by DHRS7 in Prostate Cancer Cells and by Estradiol Propionate in DHRS7-Depleted Cells.

Increased nuclear size correlates with lower survival rates and higher grades for prostate cancer. The short-chain dehydrogenase/reductase (SDR) family member DHRS7 was suggested as a biomarker for use in prostate cancer grading because it is largely lost in higher-grade tumors. Here, we found that reduction in DHRS7 from the LNCaP prostate cancer cell line with normally high levels of DHRS7 increases nuclear size, potentially explaining the nuclear size increase observed in higher-grade prostate tumors where it is lost. An exogenous expression of DHRS7 in the PC3 prostate cancer cell line with normally low DHRS7 levels correspondingly decreases nuclear size. We separately tested 80 compounds from the Microsource Spectrum library for their ability to restore normal smaller nuclear size to PC3 cells, finding that estradiol propionate had the same effect as the re-expression of DHRS7 in PC3 cells. However, the drug had no effect on LNCaP cells or PC3 cells re-expressing DHRS7. We speculate that separately reported beneficial effects of estrogens in androgen-independent prostate cancer may only occur with the loss of DHRS7/ increased nuclear size, and thus propose DHRS7 levels and nuclear size as potential biomarkers for the likely effectiveness of estrogen-based treatments.

SERM Therapy for patients of breast cancer and otherwise.

Madam, In Pakistan, the most frequently diagnosed cancer among females is breast cancer, where every year at least 90,000 women suffer from the disease [1]. This incidence is 2.5 times higher than that of Pakistan’s neighbouring countries and the highest in Asia[1]. The current treatments for breast cancer in the country are all invasive forms of therapy and include radiation therapy, chemotherapy, lymph node removal, and mastectomy. This letter aims to draw attention to a newer form of treatment for breast cancer known as selective estrogen receptor modulators (SERMs). Selective estrogen receptor modulators (SERMs) are synthetic molecules that provide a non-invasive therapy for breast cancer patients. Recent studies have proposed that the specificity of SERM’s mechanism of action and antiviral properties yield fruitful outcomes in treating covid-positive breast cancer patients [2], giving SERMs a significant advantage over former treatments such as radiation therapy or chemotherapy which reduce the body’s ability to fight infections. SERMs block the effects of estrogen on breast tissue, preventing cancer cells from dividing. They also act as an adjuvant in breast cancer therapy [3], suppressing secondary tumor formation. A recent study published in the Journal of Clinical Oncology showed significant benefits from two years of tamoxifen therapy in estrogen receptor- positive premenopausal patients of breast cancer [4]. On various other tissues, they act as estrogen, allowing for their use alongside other treatments for postmenopausal women to prevent bone loss and osteoporosis [3]. Despite SERM ‘s wide range of benefits in patients with breast cancer, it is not a fully recognized form of treatment for this population in Pakistan. Such hormonal therapy is only offered by a handful of high-end private-sector hospitals. This is attributed to a lack of research in this area due to various socio-economic factors. A limited choice of treatment for women with breast cancer in Pakistan results from fear of stigmatization and feminine sensitivity [5]. Attention should be brought to alternative therapies for breast cancer treatment to improve prognosis and help patients make the best possible shared decision-making choices.

Unveiling the connections: Chlorpyrifos and its association with breast cancer

Chlorpyrifos, a broad-spectrum insecticide categorized within the organophosphate family, is recognized for its potent inhibition of the enzyme Acetylcholinesterase (AChE), resulting in the manifestation of cholinergic syndrome in humans. Beyond its well-established toxicity in the central nervous system, recent studies have explored additional pathways through which this pesticide may adversely impact human health. Breast cancer, characterized by the uncontrolled proliferation of epithelial cells in the mammary gland, stands as the most diagnosed cancer in women and is a leading global cause of female cancer-related deaths. Chlorpyrifos, extensively employed worldwide for pest control in agriculture, domestic settings, and industries, has notably faced recent bans in the European Union, marking a significant regulatory shift. This bibliographical review aims to unravel the intricate mechanisms by which chlorpyrifos may contribute to the development of breast cancer. Collating findings from human studies, as well as in vitro and in vivo research spanning the past decade, the review sheds light on chlorpyrifos as a potent endocrine disruptor. It influences female sex hormones, exhibits estrogenic effects on breast cancer cells, and induces alterations in breast tissue. Additionally, chlorpyrifos acts as an agonist of Estrogen Receptor α(ERα) and Aryl hydrocarbon Receptor (AhR), contributing to cell proliferation, oxidative stress, and engaging epigenetic and angiogenic mechanisms. This comprehensive review underscores the compelling association between chlorpyrifos exposure and mammary cancer. It emphasizes the urgent need for further research on pesticide usage to mitigate potential adverse health consequences.

Safety Assessment of Hops as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of Humulus Lupulus (Hops) Extract (reported functions include antimicrobial agent and hair conditioning agent) and Humulus Lupulus (Hops) Oil (reported function is fragrance). The Panel reviewed the relevant data related to these ingredients. Because final product formulations may contain multiple botanicals, each containing the same constituents of concern, formulators are advised to be aware of these constituents and to avoid reaching levels that may be hazardous to consumers. For these ingredients, the Panel was concerned about the presence of 8-prenylnaringenin, β-myrcene, and quercetin in cosmetics, which could result in estrogenic effects, dermal irritation, and genotoxicity, respectively. Industry should use current good manufacturing practices to limit impurities and constituents of concern. The Panel concluded that Humulus Lupulus (Hops) Extract and Humulus Lupulus (Hops) Oil are safe in cosmetics in the present practices of use and concentration when formulated to be non-sensitizing.

The effects of sex hormones on the size of intestinal lipoproteins.

Larger intestinal lipoproteins are more likely to be retained longer in the intestinal wall, allowing more time for their fat to be hydrolyzed and subsequently taken up by the abdominal viscera. Since men generally accumulate more abdominal visceral fat than women, we sought to determine if males produce larger intestinal lipoproteins compared to females. Using the conscious lymph fistula mouse model, we discovered that the male mice indeed produced larger intestinal lipoproteins than the female mice when they were intraduodenally infused with lipid emulsion. We then employed our differentiated Caco-2 cell model with semipermeable membrane system to determine the effects of sex hormones on the size of intestinal lipoproteins. Lipoprotein size was quantitatively measured by calculating the ratio of triglycerides (TG)/Apolipoprotein B (ApoB) and by analyzing their transmission electron micrographs. Our studies showed that while there was no dose-dependent effect of estrogen and progesterone, testosterone significantly increased the size of lipoproteins. When these hormones were combined to resemble the physiological concentrations observed in males and the different ovarian cycle phases in premenopausal females, both the male and luteal groups had significantly larger lipoproteins than the ovulatory group; and the male group also had significantly larger lipoproteins than the follicular group. The ovulatory group secreted a significantly lower amount of TG than the male and luteal groups. ApoB was comparable among all these groups. These findings support our hypothesis that, through their testosterone effects, males are more likely to produce larger intestinal lipoproteins. Larger lipoproteins tend to remain longer in the intestinal wall and may facilitate fat uptake preferentially by the abdominal viscera. Our studies may partly explain why men are more prone to accumulating abdominal visceral fat, which is an independent predictor of mortality.

Portable NMR for the investigation of models of mammographic density ex vivo: Androgens antagonise the promotional effect of oestrogen

Background: Increased mammographic density (MD) is a strong and independent risk factor for breast cancer. Lifetime oestrogenic exposure is associated with increased MD, however androgenic effects on MD have not been widely investigated. Methods: We studied the effect of 17 β-oestradiol (E2) alone or in combination with an androgen receptor (AR) agonist ( 5 α-dihydrotestosterone [DHT]) or a selective AR modulator (Enobosarm), in modulating MD as measured via single-sided Portable NMR in a patient-derived explant (PDE) model of normal human mammary tissue. Results: We observed an upward trend in explants treated with E2 alone in 3/6 cases, an effect which appeared to be somewhat influenced by menopausal status. Co-treatment of E2 with the AR agonists DHT or Enobosarm however effected a downward trend in regards to MD. E2 significantly upregulated the ER regulated genes (ERGs) CELSR2 and AR, and the AR regulated genes SEC14L2 and GRPC5A, whereas E2 in combination with AR agonist Enobosarm downregulated ERGs SERPINA3, ATP6V1B1, TFF1 and PR regulated gene RANK. Only GREB1 and CLIC6 were upregulated by E2 and downregulated by the combination of E2 with Enobosarm. DHT + E2 exhibited no significant difference in expression of ER, AR or PR genes examined, compared with the effect of E2 alone. A negative trend was observed between ER protein levels and MD increase in PDEs. Since ER protein gets degraded upon hormone activation, this observation supports active ER signalling in the promotion of MD. Conclusions: Collectively, these findings supports the utility of single-sided Portable NMR for the measurement of MD in explanted human mammary tissue to detect MD change in response to exogenous hormone treatments. A mechanism through which activation of AR may reduce MD as a potential mechanism for reducing breast cancer risk associated to high MD is discussed.