Increased Serum Estradiol Levels Research Articles

Qixian granule inhibits ferroptosis in vascular endothelial cells by modulating TRPML1 in the lysosome to prevent postmenopausal atherosclerosis

Ethnopharmacological relevanceQiXian Granule (QXG) is an integrated traditional Chinese medicine formula used to treat postmenopausal atherosclerotic (AS) cardiovascular diseases. The previous studies have found that QXG inhibited isoproterenol (ISO)-induced myocardial remodeling. And its active ingredient, Icraiin, can inhibit ferroptosis by promoting oxidized low-density lipoprotein (xo-LDL)-induced vascular endothelial cell injury and autophagy in atherosclerotic mice. Another active ingredient, Salvianolic Acid B, can suppress ferroptosis and apoptosis during myocardial ischemia/reperfusion injury by reducing ubiquitin-proteasome degradation of Glutathione Peroxidase 4 (GPX4) and down-regulating the reactive oxygen species (ROS)- c-Jun N-terminal kinases (JNK)/mitogen-activated protein kinase (MAPK) pathway. Aim of the studyThe objective of this research was to assess the possible impact of QXG on atherosclerosis in postmenopausal individuals and investigate its underlying mechanisms. Materials and methodsFemale ApoE−/− mice underwent ovariectomy and were subjected to a high-fat diet (HFD) to establish a postmenopausal atherosclerosis model. The therapeutic effects of QXG were observed in vivo and in vitro through intraperitoneal injection of erastin, G-protein Coupled Estrogen Receptor (GPER) inhibitor (G15), and silent Mucolipin Transient Receptor Potential Channel 1 (TRPML1) adenovirus injection via tail vein. UPLC-MS and molecular docking techniques identified and evaluated major QXG components, contributing to the investigation of QXG's anti-postmenopausal atherosclerotic effects. ResultsQXG increased serum Estradiol levels, decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, which indicated QXG had estrogen-like effects in Ovx/ApoE−/− mice. Furthermore, QXG demonstrated the potential to impede the progression of AS in Ovx/ApoE−/− mice, as evidenced by reductions in serum triglycerides (TG), total cholesterol (TC), and low-density lipoprotein-cholesterol (LDL-C) levels. Additionally, QXG inhibited ferroptosis in Ovx/ApoE−/− mice. Notably, UPLC-MS analysis identified a total of 106 active components in QXG. The results of molecular docking analysis demonstrated that Epmedin B, Astragaloside II, and Orientin exhibit strong binding affinity towards TRPML1. QXG alleviates the progression of atherosclerosis by activating TRPML1 through the GPER pathway or directly activating TRPML1, thereby inhibiting GPX4 and ferritin heavy chain (FTH1)-mediated iron pendant disease. In vitro, QXG-treated serum suppressed proliferation, migration, and ox-LDL-induced MMP and ROS elevation in HAECs. ConclusionQXG inhibited GPX4 and FTH1-mediated ferroptosis in vascular endothelial cells through up-regulating GPER/TRPML1 signaling, providing a potential therapeutic option for postmenopausal females seeking a safe and effective medication to prevent atherosclerosis. The study highlights QXG's estrogenic properties and its promising role in combating postmenopausal atherosclerosis.

Sex differences in inflammation correlated with estrogen and estrogen receptor-β levels in azoxymethane/dextran sodium sulfate-induced colitis-associated colorectal cancer mice

Colorectal cancer (CRC) is a type of cancer that develops in the colon or rectum and is the second leading cause of cancer-related death worldwide. Several epidemiology studies have identified a significant sexual dimorphism in CRC, with women exhibiting a lower incidence rate and delayed onset compared to men. This study aims to investigate the sexual dimorphism in the inflammatory response in colitis-associated CRC and its relationship with estrogen and estrogen receptors. An azoxymethane (AOM)/dextran sodium sulfate (DSS) mouse model was used to induce colitis-associated CRC. Five-week-old male and female mice were randomly assigned into either the control group or the AOM/DSS CRC group, with 10 mice in each group. Colitis-associated CRC was induced by injecting AOM (10 mg/kg) and administering two-cycles of DSS treatment in the drinking water. The results revealed a significant decrease in colon length exclusively in the female group, indicating more severe colonic inflammation (P < 0.01). A significant interaction was identified between sex and AOM/DSS treatment in the female AOM/DSS group, with higher visceral fat weight compared to their male counterparts (P < 0.05). The female AOM/DSS group also exhibited elevated production of M1 macrophage-related pro-inflammatory cytokines, suggesting increased tumor-associated macrophage activity. Surprisingly, the male AOM/DSS group showed a marked increase in serum estradiol levels, while the female AOM/DSS group exhibited a decrease compared to the normal control group. Additionally, a notable upregulation of both estrogen receptor α and estrogen receptor β expression was observed in the colon tissues of the AOM/DSS groups compared to the normal control groups, with estrogen receptor β expression being particularly pronounced in females. Taken together, our findings suggest that a decline in endogenous estrogen and increased estrogen receptors potentially contribute to the pro-inflammatory response in early CRC by augmenting cytokine expressions associated with M1 macrophage polarization in females.

Association between serum estradiol levels and cognitive function in older women: a cross-sectional analysis.

Estradiol is a sex steroid hormone, which has been implicated in the pathogenesis of Alzheimer's disease and cognitive impairment. This cross-sectional study aimed to examine the relationship between serum estradiol levels and cognitive performance in older American women. Data were obtained from the National Health and Nutrition Examination Survey 2013-2014. A total of 731 women aged ≥60 years who met the inclusion criteria were included in this study. Serum estradiol levels were measured using the isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) method developed by the Centers for Disease Control and Prevention for routine analysis. All measured serum levels were further divided into three parts: T1, <3.68 pg./mL; T2, 3.68-7.49 pg./mL; T3, >7.49 pg./mL, and analyzed. Participants' cognitive abilities were tested using the Vocabulary Learning Subtest (CERAD), Animal Fluency Test (AFS), and digital symbol substitution test (DSST). Scores for each test were calculated based on the sample mean and standard deviation (SD). To examine the relationship between serum estradiol level tertiles and cognitive scores, multiple linear regression models were developed, controlling for race/ethnicity, education level, hypertension, diabetes, and insomnia. The mean age of the participants was 69.57 ± 6.68 years. The non-Hispanic whites were 78.95%, and those who had completed at least some college-level education were 60.62%. The mean BMI of the participants was 29.30 ± 6.79, and 10.85% had a history of smoking. Further, 73.41% did not have a history of alcohol consumption, and 63.03% had hypertension (63.03%). In addition, 81.81 and 88.3% did not have a history of diabetes mellitus and did not have sleep disorders, respectively. The mean serum estradiol level was 8.48 ± 0.77 pg./mL. Multivariate linear regression of the reference group consisting of participants in tertiles of serum estradiol levels revealed that one unit increase in serum estradiol levels increased DSST scores by 0.61 (0.87, 6.34) in the T3 group. However, no significant correlation was found in the CERAD and AFS tests. Participants with higher estradiol levels had higher DSST scores and better processing speed, sustained attention, and working memory, suggesting that serum estradiol may serve as a biomarker for cognitive decline in older women.

Serum Hormone Concentrations in Transgender Youth Receiving Estradiol

ObjectiveThis study aimed to evaluate the serum estradiol levels in gender-diverse youth to compare the efficacy of different estradiol routes in achieving therapeutic blood levels and suppressing serum testosterone levels. MethodsThis was a retrospective chart review of patients who initiated estradiol at an adolescent gender clinic between 2010 and 2019. Data on the route of estradiol administration and antiandrogen use (spironolactone or gonadotropin-releasing hormone agonist) were collected, and laboratory data were analyzed. Scatterplots were used to visualize the relationship between the estradiol dose and testosterone and estradiol laboratory values. ResultsA total of 118 patients were included, with a mean (standard deviation [SD]) age of 17.2 (1.6) years. The most common route of estradiol administration was oral only (62.7%), followed by transdermal only (23.7%), multiple routes excluding subcutaneous (8.5%), and any subcutaneous (5.1%). Notable variability was observed in the serum estradiol levels, with means (SDs) of 131.9 (120.4) pg/mL for those on oral estrogen 6 to 8 mg per day, 62.6 (40.3) pg/mL for those on transdermal estrogen 0.1 to 0.15 mg every 24 hours, and 53.6 (42.4) pg/mL for those on subcutaneous estradiol. In patients who received spironolactone, transdermal estradiol was associated with lower testosterone levels than estradiol administered orally or subcutaneously. ConclusionOral, transdermal, and subcutaneous administrations of estrogen all lead to increased serum estradiol levels and are effective for use in gender-affirming care for youth. Patients on transdermal estrogen tended to have lower serum estradiol levels but also had more suppression of serum testosterone levels.

Unraveling the mechanisms of Fenugreek seed for managing different gynecological disorders: steroidal saponins and isoflavones revealed as key bioactive metabolites

This study employed network pharmacology-based analysis and reverse molecular docking to investigate the molecular targets and pathways associated with gynecological disorders, particularly those related to steroidal hormones and their receptors, and the potential therapeutic effects of fenugreek (Trigonella foenum-graecum L.) constituents. The STITCH 5.0 database was utilized to identify potential molecular targets, and a compound-target network was constructed. The main targets associated with gynecological disorders included estrogen receptor beta (ESR2), estrogen-related receptor gamma (GPER1), oxytocin receptor (OXTR), progesterone receptor (PGR), prolactin receptor (PRLR), and several enzymes involved in sex hormone biosynthesis. Additionally, network topological analysis revealed that specific compounds, such as quercetin, luteolin, genistein, and vitexin, had significant interactions with the identified targets. Reverse molecular docking analysis confirmed the interactions between the identified compounds and target proteins where quercetin, luteolin, genistein, 4'-methylgenistein, trigoneoside IIB, diosgenin, and vitexin possessed the highest combined docking scores, indicating their multi-target nature. The results highlighted the potential of steroidal saponins, isoflavones, and flavones as active constituents of fenugreek with implications for lactation, reproductive processes, and estrogenic activity. The chemical profiling of saponin-enriched and flavonoid-enriched fractions using UPLC/MS/MS further supported the presence of these bioactive compounds. In an animal model study, the steroidal saponins-enriched fraction of fenugreek seed exhibited a significant increase in the body weight of lactating female rats and serum prolactin levels while the flavonoids-enriched fraction showed an increase in serum estradiol levels and improved the histological structure of ovaries.

Isoflavone and Antioxidant of Instant Cream Soup Made from Pumpkin and Tempeh and Their Active Compound in Ovariohysterectomy Rat-Induced Alzheimer's Disease.

Menopause period associated with brain function disorders can caused by decreasing estradiol levels and increasing oxidative stress in the body. Antioxidant agents are required to balance oxidative stress in the body. Instant cream soup made from pumpkin and tempeh is a supplementary food containing isoflavone and antioxidant agents. This study is aimed at analyzing the content of antioxidant level and isoflavones (genistein and daidzein) in instant cream soup and their effect on ovariohysterectomy (OVx) rats. Instant pumpkin cream soup with and without tempeh were subjected to isoflavone content and antioxidant analysis. Serum estradiol was analyzed using enzyme-linked immunosorbent assay. Liver concentration of malondialdehyde (MDA) and activities of superoxide dismutase (SOD) were measured by spectrophotometric methods. The study showed that the isoflavone content (genistein 370.86 g/100 g, daidzein 185.61 g/100 g) was only present in the pumpkin instant cream soup with tempeh (IPTS). IPTS has higher antioxidant levels (134.25 mg AEAC/100 g) than instant pumpkin cream soup without tempeh (IPS). In vivo study, experimental rats showed that OVx increased malondialdehyde (MDA) levels up to 5.85-6.07 nmol mL-1 as compared to control (4.47 nmol mL-1). Moreover, instant pumpkin cream soup with tempeh treatments significantly increased serum estradiol levels (2.37-3.63 μg) and superoxide dismutase (SOD) levels of 497.49-558.89 U mL-1. This study concluded that instant pumpkin cream soup and tempeh contained isoflavone and antioxidant, and it increased estradiol serum and SOD level.

Association of Vaginal Estradiol Tablet With Serum Estrogen Levels in Women Who Are Postmenopausal

Half of women who are postmenopausal have genitourinary discomfort after menopause. Recommended therapies include low-dose vaginal estrogen. Individuals with a history of breast cancer or venous thromboembolism may have concerns about the safety of this intervention. To compare serum estrogen concentrations with the use of vaginal estrogen, 10 μg, tablet vs placebo in women who are postmenopausal. This is a secondary, post hoc analysis of data from a randomized clinical trial of treatment for moderate to severe genitourinary syndrome in women who are postmenopausal. The study was conducted at Kaiser Permanente Washington Health Research Institute and the University of Minnesota from April 11, 2016, to April 23, 2017. Measurements and data analysis were performed from November 3, 2020, to September 23, 2022. Participants were randomly assigned to vaginal estradiol tablet (10 μg/d for 2 weeks and then twice weekly) plus placebo gel (3 times weekly) or dual placebo for 12 weeks. In this post hoc analysis, baseline and week 12 serum estradiol, estrone, and sex hormone-binding globulin (SHBG) concentrations were measured by a chemiluminescent assay. Week 12 values of the 3 analytes were compared by baseline participant characteristics. Linear models compared week 12 estradiol concentrations between treatment groups, adjusted for baseline characteristics. A total of 174 women, mean (SD) age 61 (4) years, were included. Those in the estrogen group (n = 88) were more likely to have higher geometric mean (SD) week 12 serum estradiol concentrations (4.3 [2.2 pg/mL]) than those in the placebo group (n = 86) (3.5 [2.1] pg/mL) (P = .01). Adjusted for pretreatment hormone concentrations, age, clinical site, and body mass index, assignment to the estrogen vs placebo treatment group was significantly associated with higher week 12 estradiol concentrations (23.8% difference; 95% CI, 6.9%-43.3%). Most (121 of 174 [69.5%]) participants had enrollment serum estradiol concentrations higher than 2.7 pg/mL. Of women starting treatment at estradiol levels lower than or equal to 2.7 pg/mL, 38.1% (8 of 21) in the estrogen group and 34.4% (11 of 32) in the placebo group had estradiol concentrations higher than 2.7 pg/mL after 12 weeks of study participation (P = .78). Treatment assignment was not associated with week 12 estrone or SHBG concentrations. In this secondary analysis of a randomized clinical trial, a significant, although small, increase in serum estradiol levels was noted after 12 weeks of vaginal estrogen administration. The clinical relevance of this small increase is uncertain. ClinicalTrials.gov Identifier: NCT02516202.

HLDF-6 peptides exhibit neuroprotective effects in the experimental model of preclinical Parkinson's disease

The mechanisms of the neuroprotective action of the hexapeptides HLDF-6 encoded by the amino acid sequence 41–46 of Human Leukemia Differentiation Factor and its homoserine derivative HLDF-6H were studied in an experimental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model of Parkinson's disease (PD). C57Bl/6 mice received two intraperitoneal injections of 18 mg/kg MPTP-HCl, with an interval of 2 hours. MPTP-induced motor dysfunction was assessed using horizontal grid test. Our data show that chronic intranasal administration of peptides (3 weeks, 300 μg/kg/day) restored normal levels of dopamine and improved its turnover rates in the striatum. Furthermore, peptide administration increased serum estradiol levels and led to a significant improvement in motor functions in MPTP-treated mice. Additionally, peptide treatment increased the levels of mRNA encoding neurotrophin BDNF, but normalized the levels of mRNA encoding the inflammatory mediators TGFβ1, IL1β and IFNγ in the brain. Collectively, our behavioral and biochemical studies demonstrate that HLDF-6 peptides have a therapeutic potential for treating PD. We propose that HLDF-6 peptides may exert their neuroprotective mechanism, at least in part, by normalizing estradiol levels and modulating the expression of key factors involved in neurotrophic support and neuroinflammation.

Changes in the Serum Levels of Estradiol and Changes in Expression of Estrogen Receptor Alpha in the Bone Tissue of Ovariectomized Wistar Rats

Estradiol is an estrogen steroid hormone and is produced basically within the follicles of the ovaries. The decrease in serum estrogens concentration at menopause disrupts the metabolic balance, changes the lipid profile leading to visceral obesity, which caused an increase in serum estradiol levels, through aromatase activity. Estrogen deficiency also is a reason for the development of osteoporosis.We investigated the serum estradiol levels and changes in bone alpha estrogen receptor expression in ovariectomized rats. For this purpose, we used 20 female Wistar rats at reproductive age - 2 months divided into 2 groups: group 1 (G1)-10 animals were ovariectomized and group 2 (G2)-10 of which were sham-operated. All animals of G1 showed weight gain compared to group G2. The results showed that the values of serum 17β-estradiol in rats of G1 statistically increased compared to G2 (p &lt;0.05). Immunohistochemical analysis revealed no difference in estrogen receptor expression between the both groups. Histomorphological analysis of femur from G1 showed the presence of pronounced osteoporosis. Ovariectomy led to the development of obesity, which caused an increase in serum estradiol levels, through aromatase activity, but this process did not prevent bone tissue from developing osteoporosis.

Chemotherapy Effect on Estradiol Levels in Patients with Triple-negative Breast Cancer: A Clinical Prospective Study from Indonesia

Research Background: This study aimed to scrutinize the chemotherapy’s effect on estradiol levels in patients with triple-negative breast cancer (TNBC) at low-resource country. Methods: This prospective analytic observational cohort study involved patients with TNBC who had undergone surgery and had never received chemotherapy or hormonal therapy before. Patients were checked for estradiol levels before and after chemotherapy. This study was conducted at the Surgical Oncology Department of Regional Public Hospital Dr. Moewardi, Surakarta Indonesia, from April 2020 to March 2021. Descriptive data were presented in a frequency table based on age, menopausal status, parity status, breastfeeding status, hormonal contraception, hormonal contraception duration, family history, stage, and histological grade. Differences in estradiol changes before and after chemotherapy (mean+sd) were then reported.&#x0D; Results: From a total of 23 patients, 21 patients (91.3%) experienced a decrease in estradiol levels, while two patients (8.7%) underwent an increase in serum estradiol levels after chemotherapy. The mean decrease was 11.57 pg/ml. The two samples that experienced an increase in estradiol levels had a mean increase of 16.5 pg/ml. There was a significant difference between estradiol levels before and after undergoing chemotherapy, with p-value=0.001.&#x0D; Conclusions: In this research, chemotherapy reduced estradiol levels in TNBC patients. Statistically significant reductions in estradiol levels were based on the disease stage.

P–465 Effect of letrozole over Ki–67 expression in breast cancer during controlled ovarian stimulation (COS) for fertility preservation (FP): case report

Abstract Study question Does concomitant letrozole administration during COS alter Ki–67 expression in women undergoing FP procedures before breast cancer surgery? Summary answer Concomitant letrozole administration during COS, even for a short period, can reduce Ki–67 expression in breast cancer. What is known already The biggest concern with COS in breast cancer patients is the increase in serum estradiol levels, caused by the development of multiple follicles simultaneously. This has always been a major hindrance to the use of traditional ovarian stimulation regimens in these patients, due to the large amount of evidence on the pathogenetic role of estrogen in breast cancer propagation. To limit the rise of estradiol during COS, most centers have adopted concomitant letrozole administration. Recently, some studies have reported changes in tumor pathology after letrozole administration, such as a significant fall in Ki–67 expression. Study design, size, duration Case report including 2 patients undergoing COS with concomitant letrozole administration for 12 days before breast cancer surgery. Participants/materials, setting, methods The first patient was a 28-year-old Caucasian woman with a breast biopsy showing an infiltrating ductal carcinoma in the upper external quadrant of the right breast. The second patient was a 33-year-old Caucasian woman with a diagnosis of infiltrating ductal carcinoma of the upper external quadrant of the left breast. Both patients underwent COS with concomitant letrozole administration 5 mg daily for 12 days. Ovarian stimulation was performed using a GnRH-antagonist random-start protocol. Main results and the role of chance In the first patient, Ki–67 expression in the initial biopsy was 55%. After completion of FP procedures, she underwent quadrantectomy with sentinel-lymphnode biopsy. In the final histopathological report Ki–67 expression fell to 25%. In the second patient, the first biopsy showed a Ki–67 expression of 30%, while after mastectomy it fell to 10%. Limitations, reasons for caution Only 2 patients were included in the study. Wider implications of the findings: COS is feasible before breast cancer surgery, as long as an adequate cancer biopsy with immunohistochemical evaluation has been collected. Cytological diagnosis is not enough to start FP procedures. Evaluation of biological parameters after letrozole administration could lead to underestimation of cancer proliferation rate and to inappropriate treatment strategies. Trial registration number NA

Leptin Modulates the mRNA Expression of Follicle Development Markers in Post-hatch Chicks in an Age-Dependent Manner.

Leptin is involved in regulating reproductive function in chickens, and the development of the leptin system is initiated during the early embryonic stage; however, whether leptin has a specific role in regulating the ovarian development in early post-hatch days is still not fully understood. This study investigated the expression of ovarian functional markers in growing juvenile chickens, along with the effects of leptin on gene expression in the hypothalamus–pituitary–gonadal (HPG) axis on specific ovarian-remodeling days. Leptin receptor (LEPR), follicle-stimulating hormone receptor (FSHR), and the mRNA expression of aromatase (CYP19A1) tended to increase with age in the ovaries of growing chicks. In the ovaries of 7-day-old chicks, intraperitoneally injected leptin significantly increased the mRNA expressions of LEPR, FSHR, and CYP19A1, and this resulted in the increased serum estradiol levels. However, leptin had no effect on hypothalamic LEPR, gonadotropin-releasing hormone 1 (GnRH1), or gonadotropin-inhibitory hormone (GnIH) mRNAs; however, in the pituitary gland, leptin significantly increased the mRNA expression of luteinizing hormone beta subunit (LHB) but had no effect on the mRNA expression of follicle-stimulating hormone beta subunit (FSHB). In 28-day-old chicks, hypothalamic and pituitary mRNAs were unaffected by leptin administration, except hypothalamic LEPR mRNA that was upregulated by a high dose of leptin. In the ovary, leptin dose-dependently decreased the mRNA expression of LEPR; low doses of leptin significantly increased the mRNA expression of FSHR, whereas high doses significantly decreased this expression; leptin did not affect the mRNA expression of CYP19A1; and high leptin doses significantly reduced the serum estradiol levels. Collectively, the results of this study show that leptin modulates ovarian development and folliculogenesis marker genes by primarily acting on ovaries on the specific ovarian-remodeling days in post-hatch chicks, which may alter folliculogenesis and ovarian development toward puberty in chicken.

OR29-03 The Effects of Hormone Therapy on Premature Ovarian Failure Following Allogenic Hematopoietic Stem Cell Transplantation: A Single-Center Experience

Background: With increasing survival rates after hematopoietic stem cell transplantation (HSCT), it has become important to evaluate methods of improving patients’ quality of life. Most female patients of childbearing age experience premature ovarian failure after transplantation, which results in decreased quality of life and an increase in fracture risk due to rapid bone loss. We analyzed the effects of hormone therapy (HT) on serum follicle stimulating hormone (FSH), serum estradiol, and bone mineral density (BMD) in young female HSCT recipients. Methods: This retrospective cohort study included 234 female patients who underwent allogenic HSCT between April 2009 and April 2018 at our center. The maximum age at the time of transplantation was 40 years, and patients were followed up for at least 3 years. Of the 734 patients who were initially screened, 360 patients aged <18 years and 8 who were transferred to another institution after transplantation were excluded from the study. There were 93 patients who died within 3 years of transplantation, while 30 were lost to follow-up, and 9 were followed-up for less than 3 years. Changes in hormone levels and BMD, according to HT regimen, were evaluated in 234 patients. Results: The mean age at transplantation was 30.47 ± 6.55 years. Out of 234 patients, 170 (72.6%) patients received HT, starting treatment at a mean of 15.1 ± 8.2 months after transplantation. A significant increase in estradiol level was observed in patients receiving HT (p < 0.001); no difference was observed between the 3 different types of HT regimen (p = 0.534). After 2 years of HT, BMD was significantly increased at all measurement sites: lumbar spine 5.8 ± 6.26% (p < 0.001), femoral neck 3.4 ± 17.78% (p = 0.037), total hip 2.1 ± 7.15% (p = 0.001). Again, there was no difference in changes between the HT regimens (p = 0.646 for lumbar spine, p = 0.840 for femoral neck, and p = 0.855 for total hip). These changes were significant even in patients with graft versus host disease (GVHD) or steroid exposure. Conclusion: In patients with premature ovarian failure following allogenic HSCT, HT effectively lowered serum FSH and increased serum estradiol levels. HT significantly increased BMD regardless of the history of GVHD or steroid exposure. These changes in hormones and BMD were independent of the HT regimen.

Chronic exposure to paroxetine or bupropion modulates the pubertal maturation and the reproductive system in female rats

Antidepressant drugs are globally used to treat several psychiatric disorders in pediatric patients and their prescription has continued to increase in recent years, especially among girls. In addition to its well-known metabolic and gastrointestinal side effects, antidepressants can cause sexual dysfunction in adults. However, the effects of the antidepressants on puberty onset and reproductive system remain unclear in children and adolescents. Therefore, the goal of this study is to examine the effects of chronic postnatal antidepressant drugs, paroxetine or bupropion, treatments on puberty onset and reproductive system components in female rats weaned at postnatal day (PND) 21. Female rats (n = 10 for each group) were exposed to vehicle (0.2 mL of saline), paroxetine (3.6 mg/kg in 0.2 mL of saline) or bupropion (17 mg/kg in 0.2 mL of saline) daily by oral gavage from the PND 21 to PND 90−93. Chronic paroxetine or bupropion treatments advanced the puberty onset, but the difference was statistically significant in only the paroxetine group. The exposure to bupropion significantly decreased the serum anti-Müllerian hormone (AMH) levels and luteinizing hormone (LH) levels. There were increases in serum estradiol levels by both antidepressant treatments and the significance was found in only the paroxetine group. Consistent with these results, histopathologic changes were observed in the ovary and uterus tissues taken from both antidepressant-treated rats. The obtained results of chronic postnatal exposure to paroxetine or bupropion may change the timing of puberty onset and lead to disruption of reproductive functions in females.

Ameliorative effects of quercetin on the preimplantation embryos development in diabetic pregnant mice.

Maternal diabetes adversely retards the development of preimplantation embryos. Quercetin is a flavonoid belonging to phytoestrogens family and may be useful in treatment of reproductive disorders. The aim of this study was investigation of the ameliorative effects of quercetin administration on preimplantation embryo development in diabetic pregnancy. Diabetic and healthy female mice were treated with 30 mg/kg/day quercetin 4 weeks before conception. Blastocysts were recovered at the 4th day of pregnancy for protein and mRNA expression changes. Plasma sex-steroid levels were also analyzed. Quercetin significantly decreased blood glucose levels in diabetic mice. Embryos retrieved from diabetic mice exhibited a considerable delay in morphological development. In diabetic mice with quercetin treatment, morphological distribution was shifted considerably to the well-developed stages. Serum estradiol level reduced in diabetic mice but, treatment with quercetin significantly increased serum estradiol level. While IGF1R, integrin αvβ3, and Cox2 mRNA expression in the blastocyst of diabetic mice decreased significantly, quercetin treatment caused increasing expression levels of these genes. Expression of the Caspase3 gene increased dramatically in the collected blastocysts from diabetic mice and reduced following quercetin treatment. Besides, the inactive β-catenin protein level in the blastocysts of diabetic mice was higher than that in normal mice, while treatment with quercetin decreased the level of inactive β-catenin protein in the blastocyst of diabetic mice. Quercetin protects preimplantation embryos from destructive effects of diabetes. The amelioration of sex hormones disturbance in early pregnancy may help to treat reproductive disorders in diabetic women. Quercetin can be considered as a novel solution to the improvement of reproductive disorders in the diabetic females.

Oncofertilité et cancer du sein

Over the past decades, progresses in oncology have improved the recovery rates after numerous malignant diseases, including breast cancer, that strike young adults in childbearing age. Quality of life of young cancer survivors has become a major issue. However, anticancer therapies can have a detrimental impact on fertility. It is now well-established that all patients should receive information about the fertility risks associated with their cancer treatment and the fertility preservation options available. These techniques aim to limit the negative impact of chemotherapy on the ovaries or to preserve gametes before treatment. Currently, oocyte or embryo freezing after controlled ovarian hyperstimulation represents the most effective method for preserving female fertility. Over the past years innovative protocols of ovarian stimulation have been developed to enable breast cancer patients to undergo oocyte or embryo cryopreservation irrespective of the phase of the cycle or without exogenous follicle-stimulating hormone related increase in serum estradiol levels. When controlled ovarian hyperstimualtion cannot be implemented, other techniques such as cryopreservation of ovarian cortex, in vitro maturation or the use of GnRH agonists may be proposed. However, it is important to inform patients that all these fertility preservation techniques do not represent a guarantee of pregnancy.

Succinate-Based Dietary Supplement for Menopausal Symptoms: A Pooled Analysis of Two Identical Randomized, Double-Blind, Placebo-Controlled Clinical Trials.

Background To evaluate the efficacy of a succinate-based dietary supplement (SBDS; Amberen) in symptomatic menopausal women using a larger sample size derived by pooling data from two identical trials. Methods Raw data were pooled from two identical randomized, multicenter, double-blinded, placebo-controlled, 90-day clinical trials. Women aged 42–60 years with mild to moderate vasomotor and psychosomatic menopausal symptoms were included (114 in the treatment group and 113 in the placebo group). Symptoms were assessed by the Greene Climacteric Scale and State-Trait Anxiety Inventory. Changes in body mass index, body weight, waist and hip circumferences, and plasma levels of follicle stimulating hormone, luteinizing hormone, estradiol, leptin, and apolipoproteins A1 and B were also evaluated. Results SBDS use resulted in significant improvements in several endpoints including alleviation of 16 of 21 menopausal symptoms (p ≤ 0.05, Greene Scale) and a decrease in anxiety (p < 0.0001, State-Trait Anxiety Inventory) when compared to placebo. Significant reductions were observed in weight, body mass index, and waist and hip circumferences in the supplement cohort. Evaluation of physiological parameters showed a significant increase in serum estradiol levels compared to baseline (p < 0.0001) among users of the SBDS. Levels of follicle stimulating hormone and luteinizing hormone decreased slightly in both groups, without significant differences between the groups. Leptin levels decreased with statistical significance in the SBDS cohort compared to placebo (p=0.027). For those with initial leptin concentrations above the reference range, leptin decreased significantly in the SBDS group compared to the baseline (p < 0.0001) and to placebo (p=0.027). Conclusions The pooled analysis reaffirms the outcomes from the individual trials. A nonhormonal, succinate-based dietary supplement is shown to relieve menopausal symptoms when compared to a placebo regimen in a randomized, double-blinded clinical trial.

Prenatal metformin treatment improves ovarian function in offspring of obese rats.

Maternal obesity causes a wide range of impairment in offspring, such as metabolic and reproductive dysfunctions. We previously demonstrated that female offspring of obese rats have increased serum estradiol levels during early postnatal life, probably because of decreased hepatic cytochrome P450 3A2 levels, which could lead to early onset of puberty and polycystic ovary condition in adulthood. Using metformin during pregnancy and nursing to improve the metabolic status of obese mothers could prevent the sequence of events that lead to an increase in postnatal serum estradiol levels in female offspring and, hence, reproductive dysfunction. We found that metformin prevented an increase in serum estradiol levels at postnatal day 14 in female offspring of obese mothers, which was associated with a restoration of hepatic cytochrome P450 3A2 levels to control values. Treatment using metformin could not prevent advanced puberty, but we observed that the number of antral follicles, follicular cysts and multi-oocyte follicles returned to control values in the female offspring of obese mothers treated with metformin. We also observed an increase in the levels of norepinephrine and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol in the ovaries, indicating increased sympathetic activity in female offspring induced by an obesogenic uterine environment. We found that this effect was prevented by metformin administration. From the results of this study, we concluded that metformin administration to obese mothers during pregnancy and nursing partially prevents ovarian dysfunction in female offspring during adulthood.

Maternal lipopolysaccharide exposure results in glucose metabolism disorders and sex hormone imbalance in male offspring.

An adverse intrauterine environment may be an important factor contributing to the development of type 2 diabetes in later life. The present study investigated the longitudinal effects of maternal lipopolysaccharide (LPS) exposure during the third trimester on glucose metabolism and sex hormone balance in the offspring. Pregnant mice were intraperitoneally injected with LPS (50 μg/kg) daily from gestational day (GD) 15 to GD17. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were assessed at postnatal day (PND) 60 and PND120. Sex hormones, their receptors, and metabolic enzymes (aromatase) were measured in male offspring at different phases of development (PND14: juvenile; PND35: adolescence; PND60: adulthood; and PND120: middle age). LPS-exposed male offspring exhibited glucose intolerance and insulin resistance by GTT and ITT at middle age, accompanied by an increase in fasting blood glucose and reductions in serum insulin levels and hepatic phosphorylated (p) -AKT/AKT ratio. However, glucose intolerance and insulin resistance were not observed in LPS-exposed female offspring. Maternal LPS exposure upregulated hepatic aromatase proteins and mRNA levels in male offspring at all time points. At adolescence, the testosterone/estradiol ratio (T/E2) was markedly reduced in LPS-exposed male offspring. Moreover, maternal LPS exposure significantly increased hepatic estrogen receptor (ER) α expressions and decreased hepatic androgen receptor (AR) expressions in male offspring. At adulthood, maternal LPS exposure increased serum estradiol levels, decreased serum testosterone levels and elevated hepatic ERβ expressions in male offspring. In conclusion, maternal LPS exposure upregulated aromatase expressions, followed by a reduction in the T/E2 ratio and an alteration in sex hormone receptor activity, which might be involved in the development of glucose metabolism disorders in middle-aged male offspring. This study provides a novel clue and direction to clarify the pathogenesis of maternal infection-related diabetes in male offspring.

Effects of exposure to tembotrione during gestation on serum oestradiol and testosterone levels in neonatal rats

Tembotrione is a selective, triketone herbicide used for post-emergence weed control in corn. Some pesticides may act as endocrine disrupting chemicals because of their strong potential to bind to oestrogen and androgen receptors and change sex hormone status in males and females. Especially vulnerable groups are foetuses, infants and children in puberty. We investigated the effects of tembotrione exposure during gestation on oestradiol and testosterone levels in female and male neonatal Wistar rats at doses relevant to real human exposure. Pregnant Wistar rats were exposed orally to 0.0004 mg/kg b.w./day and 0.0007 mg/kg b.w./day of tembotrione each day during the entire gestation period. After delivery, blood samples of newborn rats were collected and oestradiol level was measured in female and testosterone level in male serum by enzyme- linked immunosorbent assay (ELISA). We observed significantly increased serum oestradiol levels in female neonatal rats at 0.0007 mg/kg b.w./day. Similarly, significantly increased serum testosterone levels in male neonatal rats at 0.0004 mg/kg b.w./day were recorded. We also found a statistically significant difference between testosterone levels in male neonatal rats exposed to 0.0004 mg/kg b.w./day and 0.0007 mg/kg b.w./day. Our findings suggest that exposure to tembotrione during intrauterine development disturbs sexual hormone levels both in female and male neonatal rats. This may lead to different adverse health consequences later in adulthood. This work was financially supported by Project No. 8366 funded by the Croatian Science Foundation.