Weight Loss Differentially Impacts Sex Hormones in Women and Men with Type 2 Diabetes: Look AHEAD Sex Hormone Study.

BACKGROUND: Despite sex differences in T2D, few studies have examined the role of sex hormones. We sought to assess the impact of weight loss, the cornerstone of T2D management, on sex hormone levels. METHODS: This was an ancillary study to the Look AHEAD (Action for Health In Diabetes) Study (n=850 postmenopausal females, n=890 males, with T2D and BMI ≥25 kg/m2). We measured total testosterone (T), estradiol (E2) and sex hormone binding globulin (SHBG) and calculated bioavailable T (bioT). We examined the effect of the intensive lifestyle intervention (ILI) on hormone changes, whether changes were mediated by waist circumference and sex differences in treatment effect. RESULTS: The baseline mean age was 60 years with a higher proportion of Black females (21%) vs. males (9%) and higher mean BMI in females vs. males (36.3 vs. 34.8 kg/m2). At year 1 in females, ILI decreased E2 by 15% and bioT by 13% and increased SHBG by 21%. At year 1 in males, ILI did not change E2 levels, but increased T by 14% and increased SHBG by 18%. The effect was attenuated over 4 years, there were statistically significant sex differences in treatment effect and change in waist circumference due to ILI at year 1 was a significant mediator of sex hormone changes. CONCLUSION: Weight loss in T2D resulted in sex hormone changes, which varied by sex and were mediated by changes in WC. Changes in sex hormone due to weight loss in T2D should be considered in the context of an individual's health risks, including cardiovascular, bone health, menopausal symptoms and cognition.

Hormonal profiles and biomarkers leading to parturition in cattle.

This study aimed to understand the physiological mechanisms regulating parturition and to identify potential biomarkers to predict onset of birth. Additionally, we compared hormone profiles between cows with shorter and longer gestation lengths. Twenty-eight days before due date until 3d postpartum, cows (n = 18) were blood sampled daily. Circulating concentrations were measured for progesterone (P4) and estradiol (E2) by RIA, testosterone, prostaglandin F2α metabolite (PGFM), cortisol, pregnancy-specific protein B (PSPB) by ELISA and lactate concentrations by colorimetric assay. At end of gestation, P4 decreased from d-14 to d-4 (from 3.6 to 1.4 ng/mL), most likely from rapid loss of placental P4 production (64% of decline in 24 h). A second rapid decrease in P4 to undetectable concentrations was observed from d-2 to parturition (from 1.4 to 0.1 ng/ml; most likely luteal origin) corresponding to increase in PGFM from d-2 to parturition (249.7 to 2868.4 pg/mL). Estradiol and PSPB increased ~8-fold from ~13d before parturition with acute rise in E2 but not PSPB (45% vs 13% in first 24 h). Testosterone decreased slightly during the same period. Cortisol and lactate increased only at calving. Comparison of cows with shorter vs longer gestation, when data were normalized to parturition day, a difference was detected in circulating E2 and PGFM patterns, but not P4 and PSPB. Thus, the first significant hormonal changes associated with parturition begin at d-14 with E2 and PSPB as two clear biomarkers of impending parturition. Cows with shorter and longer gestation had hormonal differences indicative of identifiable earlier placental maturation.

Are natural estrogens used in contraception at lower risk of venous thromboembolism than synthetic ones? A systematic literature review and meta-analysis.

Background: Venous thromboembolism (VTE) poses a significant global health challenge, notably exacerbated by the use of combined oral contraceptives (COCs). Evidence mainly focuses on the type of progestogen used in COCs to establish the increased risk of VTE with less data assessed on the type of estrogen used. This meta-analysis aims to assess the risk of VTE associated with COCs containing synthetic estrogens like ethinylestradiol (EE) versus natural estrogens like estradiol (E2). Methods: A systematic review and meta-analysis was conducted following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Literature searches were performed in December 2023 in MEDLINE and EMBASE to identify clinical studies comparing the VTE risk between COCs containing synthetic versus natural estrogens. Studies were selected through rigorous screening, and data extraction followed standardized protocols, with statistical analyses employing a random effects model. Results: The search yielded five relevant studies, involving over 560,000 women/time, demonstrating a significant 33% reduction in VTE risk among users of natural estrogen-based COCs compared to synthetic estrogen-based COCs (OR 0.67, 95% CI 0.51-0.87). Stratification analyses using adjusted hazard ratios (HR) of the main observationnal studies showed a 49% reduced VTE risk of E2-based pills compared to EE in association with levonorgestrel. Discussion and conclusion: Despite the longstanding use of EE-based COCs, emerging evidence supports a lower thrombotic risk associated with natural estrogens. This meta-analysis substantiates the lower VTE risk associated with natural estrogen-based COCs compared to synthetic alternatives, advocating for a re-evaluation of contraceptive guidelines to prioritize patient safety and reduce thrombotic risks.

Molecularly Imprinted Polymers Electrochemical Sensing: The Effect of Inhomogeneous Binding Sites on the Measurements. A Comparison between Imprinted Polyaniline versus nanoMIP-Doped Polyaniline Electrodes for the EIS Detection of 17ß-Estradiol.

Molecularly imprinted polymers (MIPs) are synthetic receptors made by template-assisted synthesis. MIPs might be ideal receptors for sensing devices, given the possibility to custom-design selectivity and affinity toward a targeted analyte and their robustness and ability to withstand harsh conditions. However, the synthesis of MIP is an inherently random process that produces a statistical distribution of binding sites, characterized by a variety of affinities. This is verified both for bulk MIP materials and for MIP's thin layers. In the present work, we aimed at assessing the effects of inhomogeneous versus homogeneous imprinted binding sites on electrochemical sensing measurements, and the possible implications on the sensor's performance. In the example of an Electrochemical Impedance Spectroscopy (EIS) sensor for the 17ß-estradiol (E2) hormone, the scenario of inhomogeneous binding sites was studied by modifying electrodes with an E2-MIP polyaniline (PANI) thin layer, called the "Imprinted PANI layer". In contrast, the condition of discrete and uniform binding sites was epitomized by electrodes modified with a thin PANI layer purposedly doped with E2-MIP nanoparticles (nanoMIPs), which were referred to as "nanoMIP-doped PANI". The behaviors of the two EIS sensors were compared. Interestingly, the sensitivity of the nanoMIP-doped PANI was almost twice with respect to that of the imprinted PANI layer, strongly suggesting that the homogeneity of the binding sites has a fundamental role in the sensor's development. The nanoMIP-doped PANI sensor, which showed a response for E2 in the range 36.7 pM-36.7 nM and had a limit of detection of 2.86 pg/mL, was used to determine E2 in wastewater.

Novel self-powered sandwich type Aptamer sensor for estrogen detection assisted with peroxidase mimic Cu-MOF.

A novel self-powered and flexible enzymatic biofuel cell (EBFC)-based aptasensor was developed for the sensitive and selective detection of 17 ß-estradiol (E2). A flexible polyvinyl alcohol (PVA)-tannic acid­carbon nanotube/reduced graphene oxide (PTCR) substrate was modified with gold nanoparticles (AuNPs) and thiolated aptamer 1 (Apt1) to yield Apt1@AuNPs/PTCR. A copper-based metal-organic framework (Cu-MOF) with peroxidase mimicking activity was employed to anchor glucose oxidase (GOD) and Apt2, forming the Cu-MOF@GOD/Apt2 tag. When E2 was recognized by Apt1, the anchored E2 quantitatively recognized Cu-MOF@GOD/Apt2 to create a Cu-MOF@GOD/Apt2-E2-Apt1 sandwich structure for glucose oxidation to generate electrical power. Increased E2 concentrations enhanced Cu-MOF@GOD/Apt2 capture and amplified the electrical signal. The electrical power increased linearly as the E2 concentration increased from 1.0 pM to 1.0 nM. The sensor was successfully applied to various food samples and blood serum detection. This work promoted the application of novel self-powered biosensors for food safety analysis.

An ultrasensitive dual-mode stagey for 17ß-estradiol assay: Photoelectrochemical and colorimetric biosensor based on a WSe2/TiO2-modified electrode coupled with nucleic acid amplification.

BACKGROUND: The abuse of 17ß-estradiol(E2) has aroused wide concern in environmental and biomedical fields, which severely affects the endocrine function of human and animals. Therefore, an ultrasensitive and accurate assay of E2 is critically important. Traditional chromatography or immunoassay techniques exhibited good sensitivity and selectivity, but expensive instruments and antibodies may pose cost and stability issues, as well as difficulties in meeting on-site detection requirements. Ultrasensitive, reliable, and on-site detection of E2 at trace level remains a challenge. Hence, developing a simple, ultrasensitive assay to simultaneously achieve accurate detection and rapid visual analysis of E2 is extremely crucial. RESULTS: We developed a versatile dual-mode photoelectrochemical (PEC) and colorimetric biosensor based on isothermal nucleic acid amplification strategy for the ultrasensitive and accurate detection of E2. The method modified titanium dioxide (TiO2) with tungsten selenide (WSe2) nanoflowers to synthesize WSe2/TiO2 heterostructures as a substrate for signal amplification and nanoprobe modification. Isothermal nucleic acid amplification strategy has been proven to be a powerful tool for strong signal amplification. The presence of a target triggered the nucleic acid amplification reaction, and produced a large amount of tDNA that competed with G-quadruplex immobilized on the electrode surface. The remaining G-quadruplex/hemin catalyzed the 4-chloro-1-naphthol (4-CN) to form biocatalytic precipitation (BCP) and ABTS-H2O2 chromogenic reaction, thus, the dual-mode platform was capable of achieving PEC-colorimetric ultrasensitive detection based on the catalytic activity of G-quadruplex/hemin DNAzyme. Within optimal conditions, the dual-mode biosensor exhibited a remarkable detection limit as low as 0.026 pM. SIGNIFICANCE: Benefiting from the superior performance of WSe2/TiO2 and the power signal amplification of isothermal nucleic acid amplification strategy, this aptasensor achieved the ultrasensitive detection of E2. The independent transmission paths of photoelectrochemical and colorimetric provide mutual support and flexible switching, significantly enhancing the overall sensitivity and accuracy of the detection strategy, which can meet the needs for E2 precise quantification and rapid on-site detection.

Sex Hormone Trajectories and Association to Outcomes After Out-of-Hospital Cardiac Arrest.

BACKGROUND: Outcomes and susceptibility to out-of-hospital cardiac arrest (OHCA) are known to differ by sex, yet little is known about changes in sex hormones after OHCA. We sought to determine the trajectory of sex hormones after OHCA and their association to survival and neurological outcome. METHODS: Plasma samples were collected from those that survived to hospital admission at four time points (1, 6, 24, and 48 hours) and estrone, estradiol, progesterone, and testosterone concentrations were quantified via liquid chromatography-mass spectrometry. Trends in hormones were plotted over time by sex and outcomes. The association between sex, hormone levels with survival and neurological outcome (cerebral performance category 1-2 indicating good outcome and 3-5 for poor outcome) were determined using generalized estimating equation models. RESULTS: Of the 94 OHCA patients, 50 were males and 44 females, with a mean age of 61.3 (+15.7) years. Despite older age and lower BCPR in females compared to males, females had higher proportion of good neurological outcome compared to males. Over the 48 hours, estrone increased, testosterone decreased, and estradiol and progesterone remained flat. Survivors had lower levels of estrone at all time points but only at early time points for estradiol, progesterone and testosterone. Lower estrone level predicted survival at discharge, even after adjusting for time, sex, age, and hormones independently (ß=-3.38, 95% CI= -5.71, -0.85). Females had better neurological scores compared to males after adjusting for estrone (ß=1.27, 95% CI= 0.01, 2.53) and estradiol (ß=2.92, 95% CI= 1.13, 4.70). CONCLUSIONS: Survivors and those with favorable neurological outcome had lower trend in estrone. The sex hormone estrone, present in both males and females, may be a predictor of survival. When adjusted for estrogens, female sex had better neurological recovery compared to males. The difference in neurological outcome by sex is not explained by estrogens. However, these finding open the door for exploration of other sex-specific pathways in resuscitation after OHCA.

Interaction of a caffeine overdose with clinical doses of contraceptive ethinyl estradiol in a young woman.

Aim: The overdose of caffeine, a cytochrome P450 1A2 probe, in young women has become a problem. The aim of this study was to evaluate possible drug interactions between intentionally overdosed caffeine (12 g) and oral contraceptive doses of ethinyl estradiol prescribed to a young woman in a suicide attempt. Methods: The serum concentrations of caffeine in the patient and the time-dependent ethinyl estradiol inhibition of caffeine oxidation in vitro were evaluated. Results: The serum concentration of caffeine 4 h after overdose was 136 µg/mL; from the data obtained between 4 and 28 h after overdose, the half-life was estimated to be 33 h, which is many times larger than the normal value. Prescribed ethinyl estradiol prolonged caffeine elimination in vivo and inhibited paraxanthine formation, as evidenced by the low serum concentrations. In human liver microsomes, ethinyl estradiol (50 nM) inhibited half of caffeine N 3 -demethylation. Pre-incubation of human liver microsomes with ethinyl estradiol resulted in a powerful time-dependent inhibitory effect on caffeine N 3 -demethylation in human liver microsomes. Conclusion: These results suggest that a prescription history of contraceptives at clinical doses may have a strong effect on the pharmacokinetics of overdosed caffeine in young women, resulting in dangerous drug interactions.

Variations in volume; Breast size in trans women in relation to timing of testosterone suppression.

CONTEXT: Breast development is an important outcome for trans women receiving gender affirming hormone therapy (GAHT). Limited breast development has been reported, possibly because of testosterone exposure during puberty. The impact of puberty suppression (PS) on breast development is unclear. OBJECTIVE: To investigate the impact of PS and timing of PS prior to GAHT on breast volume and satisfaction. DESIGN: Cross-sectional study. SETTING: Tertiary gender identity clinic. PARTICIPANTS: 60 trans women (aged 17-57 years) after 4.5±1.7 years of GAHT were included of whom 23 initiated PS early in puberty (Tanner stage G2-3), 17 late in puberty (Tanner stage G4-5), and 20 started GAHT in adulthood without prior PS. MAIN OUTCOME MEASURES: Breast volume measured with a 3D scanner and breast satisfaction measured with a questionnaire. Comparisons of breast volumes were adjusted for fat percentage. RESULTS: Median breast volume was 115ml (IQR 68; 203), i.e. bra cup-size

The Effect of Statin Treatment on Synaptogenesis in the Hippocampus.

Deranged lipid homeostasis has been implicated in neurodegenerative diseases. Cholesterol reducing compounds such as statins have received special attention for the possibility that they may be able to ameliorate or prevent cognitive loss associated with neurodegeneration. However, there is much dissension concerning the actual effect of statins on cognitive function. The aim of this study is to investigate the effects of pitavastatin on hippocampal synaptogenesis because the hippocampus is crucial for memory formation. We also evaluated the effects of pitavastatin on local hippocampal estrogen synthesized in the hippocampus itself and its effect on Brain-Derived Neurotrophic Factor (BDNF). Using a hippocampal cell line, H19-7, we found that hippocampal neurons exposed to pitavastatin demonstrate a significant reduction in the synaptic marker postsynaptic density protein 95 (psd-95). The pitavastatin treated neurons also exhibited decreased production of local estrogen and their expression of BDNF mRNA was decreased. These results suggest that statins reduce the ability of hippocampal neurons to form synapses by restricting the production of local estrogen. Because neural connections in the hippocampus are crucial for memory formation, our findings implicate statins as medications that may compromise cognitive function.

Laparoscopic bilateral salpingo-oophorectomy for recurrent ovarian endometriotic cysts in a woman taking adjuvant tamoxifen for breast cancer: A case report.

The case report describes the management of endometriotic cysts in a woman taking adjuvant tamoxifen. A diagnosis of endometriosis was made at the age of 38, and the condition was initially managed with a low-dose estrogen-progestogen combination; the patient then switched to dienogest at the age of 45. Following a diagnosis of breast cancer at the age of 46, dienogest was stopped and adjuvant tamoxifen treatment started. After 4 months the patient was diagnosed with bilateral ovarian cysts and underwent laparoscopic bilateral salpingo-oophorectomy. Endometriosis was diagnosed in both ovaries on histopathological examination. This case report describes progression of endometriosis in a tamoxifen user.

Association of serum uric acid with male sexual hormones and erectile dysfunction: a bidirectional 2-sample Mendelian randomization analysis.

Background: Observational studies indicated that serum uric acid (SUA) was associated with male sexual hormones and erectile dysfunction (ED). However, their relationship was still heterogeneous. Aim: This study conducted 2-sample univariate mendelian randomization (UVMR) and multivariate mendelian randomization (MVMR) to explore the causal relationship between SUA and sexual hormones as well as ED. Methods: Genetic variants associated with SUA were derived from the UK Biobank database (N = 437 354). Outcomes from the IEU Open GWAS and summary data sets were sexual hormones (sex hormone-binding globulin [SHBG], testosterone, estradiol [E2], follicle-stimulating hormone, luteinizing hormone) and ED, with 3301 to 625 650 participants. UVMR analysis primarily utilized the inverse variance weighted method, complemented by MVMR analysis. Thorough sensitivity analyses were carried out to ensure the reliability of results. Moreover, mediation analysis was conducted to estimate the mediated effect between SUA and outcomes. Outcomes: The primary outcomes included results of UVMR and MVMR analysis and mediation analysis, along with sensitivity analyses involving the Cochran Q test, the MR Egger intercept test, leave-1-out analysis, and the MR-PRESSO method (mendelian randomization pleiotropy residual sum and outlier). Results: UVMR analysis revealed that an elevated SUA level could decrease levels of SHBG (ß = -0.10, P = 1.70 × 10-7) and testosterone (ß = -0.10, P = 5.94 × 10-3) and had a positive causal effect on ED (odds ratio, 1.10; P = .018). According to reverse mendelian randomization results, increased levels of SHBG (ß = -0.06, P = 4.82 × 10-4) and E2 (ß = -0.04, P = .037) could also reduce SUA levels. As shown by MVMR analysis, SUA had a negative effect on SHBG and testosterone levels (P < .05), while the significant causal relationship between SUA and ED disappeared. Furthermore, SHBG mediated 98.1% of the effect of SUA on testosterone levels. Results of other mendelian randomization analyses were not statistically significant. No pleiotropy was found by sensitivity analysis in this study. Clinical Implications: Given the causal relationship between SUA and sexual hormones, we must focus on SUA and E2 levels in men, especially patients with hypogonadism and ED. Strengths and Limitations: This study evaluated the causal effect of SUA on male sexual hormones and ED genetically for the first time, clarifying the common biases in observational studies and confirming the negative relationship between SUA and testosterone level. Limitations include a population based on European ancestry, some crossover of the samples, and unobserved confounding factors. Conclusion: Genetic studies provide evidence for the causal relationship between SUA and male sexual hormones (SHBG, testosterone, E2), while the relationship between SUA and ED should be further evaluated.

Attentional bias to alcohol-related cues: effects of menstrual cycle phase and sex differences.

RATIONALE: A recent study by our group found that women displayed greater attentional bias to alcohol-related cues during the late versus early follicular phase in both sober and intoxicated states, suggesting a greater risk of excessive drinking among women during this phase. Changes in attentional bias as a function of menstrual cycle phase raise questions about potential sex differences in the relative consistency by which women and men display attentional bias to alcohol over time. OBJECTIVES: The present study tested sex differences in attentional bias to alcohol by comparing the change in women's attentional bias from early to late follicular phase to that observed in men over the same period. METHODS: Twenty-five men and 25 women aged 21-32 participated in a placebo-controlled study examining sex differences in the rewarding properties of alcohol. Participants completed measures of attentional bias to alcohol-related cues during two sessions following both 0.6 g/kg alcohol and placebo. Test sessions occurred one week apart, and for female participants coincided with the early and late follicular phases. RESULTS: Men consistently displayed attentional bias to alcohol-related cues across sessions under both doses. By contrast, women showed attentional bias only during the late follicular phase, at a magnitude greater than that observed in men, and persistent under both doses. CONCLUSIONS: These findings highlight the potential role of sex and menstrual cycle phase in sensitizing drinkers to rewarding properties of alcohol-related cues. Men's motivation to drink may remain relatively consistent, whereas women may be most motivated during the late follicular phase.

17ß-Estradiol reduces inhibitory synaptic currents in entorhinal cortex neurons through G protein-coupled estrogen receptor-1 activation of extracellular signal-regulated kinase.

Estrogens are believed to modulate cognitive functions in part through the modulation of synaptic transmission in the cortex and hippocampus. Administration of 17ß-estradiol (E2) can rapidly enhance excitatory synaptic transmission in the hippocampus and facilitate excitatory synaptic transmission in rat lateral entorhinal cortex via activation of the G protein-coupled estrogen receptor-1 (GPER1). To assess the mechanisms through which GPER1 activation facilitates synaptic transmission, we assessed the effects of acute 10 nM E2 administration on pharmacologically isolated evoked excitatory and inhibitory synaptic currents in layer II/III entorhinal neurons. Female Long-Evans rats were ovariectomized between postnatal day (PD) 63 and 74 and implanted with a subdermal E2 capsule to maintain continuous low levels of E2. Electrophysiological recordings were obtained between 7 and 20 days after ovariectomy. Application of E2 for 20 min did not significantly affect AMPA or NMDA receptor-mediated excitatory synaptic currents. However, GABA receptor-mediated inhibitory synaptic currents (IPSCs) were markedly reduced by E2 and returned towards baseline levels during the 20-min washout period. The inhibition of GABA-mediated IPSCs was blocked in the presence of the GPER1 receptor antagonist G15. GPER1 can modulate protein kinase A (PKA), but blocking PKA with intracellular KT5720 did not prevent the E2-induced reduction in IPSCs. GPER1 can also stimulate extracellular signal-regulated kinase (ERK), a negative modulator of GABAA receptors, and blocking activation of ERK with PD90859 prevented the E2-induced reduction of IPSCs. E2 can therefore result in a rapid GPER1 and ERK signaling-mediated reduction in GABA-mediated IPSCs. This provides a novel mechanism through which E2 can rapidly modulate synaptic excitability in entorhinal layer II/III neurons and may also contribute to E2 and ERK-dependent alterations in synaptic transmission in other brain areas.

Associations between estradiol and hyperuricemia and the mediating effects of TC, TG, and TyG: NHANES 2013-2016.

Objectives: To explore the relationship between estradiol (E2) and the incidence of hyperuricemia (HUA) in adult women and to explore whether glucolipid metabolism disorders play a mediating role in mediating this relationship. Methods: A total of 2,941 participants aged 20-65 years were included in the National Health and Nutrition Examination Survey (NHANES) 2013-2016. Multivariate logistic regression analysis was performed to evaluate the correlations of E2 with HUA. Multivariate linear regression analysis was performed to evaluate the associations between E2 and triglyceride (TG), total cholesterol (TC), and the triglyceride-glucose index (TyG). The restricted cubic spline (RCS) model was used to further explore the association between E2 and HUA and between TG, TC, and TyG and HUA. Mediation analyses were performed to examine whether TC, TG, and TyG mediated the relationship between E2 and HUA. Results: After adjusting for covariates, logistic regression revealed that ln(E2) was significantly associated with HUA in the female subgroup (p = 0.035) and that the incidence of HUA tended to increase with decreasing ln(E2) (p for trend = 0.026). Linear regression showed that E2 was significantly associated with TC (p = 0.032), TG (p = 0.019), and TyG (p = 0.048). The RCS model showed that ln(E2) was linearly correlated with the incidence of HUA (p-overall = 0.0106, p-non-linear = 0.3030). TC and TyG were linearly correlated with HUA (TC: p-overall = 0.0039, p-non-linear = 0.4774; TyG: p-overall = 0.0082, p-non-linear = 0.0663), whereas TG was non-linearly correlated with HUA. Mediation analyses revealed that TC, TG, and TyG significantly mediated the relationship between ln(E2) and HUA (TC, indirect effect: -0.00148, 7.5%, p = 0.008; TG, indirect effect: -0.00062, 3.1%, p = 0.004; TyG, indirect effect: -0.00113, 5.6%, p = 0.016). Conclusion: In conclusion, this study demonstrated that compared with women aged 20-45 years, women aged 45-55 years and 55-65 years had lower E2 levels and a greater incidence of HUA. E2 levels and the incidence of HUA were negatively associated in female individuals but not in male individuals. In addition, TC, TG, and TyG, which are markers of glucolipid metabolism, played a mediating role in the association between E2 and HUA.

Casein kinase 1α mediates estradiol secretion via CYP19A1 expression in mouse ovarian granulosa cells.

BACKGROUND: Casein kinase 1α (CK1α), expressed in both ovarian germ and somatic cells, is involved in the initial meiosis and primordial follicle formation of mouse oocytes. Using in vitro and in vivo experiments in this study, we explored the function and mechanism of CK1α in estrogen synthesis in mice ovarian granulosa cells. METHODS: A CK1α knockout (cKO) mouse model, targeted specifically to ovarian granulosa cells (GCs), was employed to establish the influence of CK1α on in vivo estrogen synthesis. The influence of CK1α deficiency on GCs was determined in vivo and in vitro by immunofluorescence analysis and Western blot assay. Transcriptome profiling, differentially expressed genes and gene functional enrichment analyses, and computation protein-protein docking, were further employed to assess the CK1α pathway. Furthermore, wild-type female mice were treated with the CK1α antagonist D4476 to elucidate the CK1α's role in estrogen regulation. RESULTS: Ovarian GCs CK1α deficiency impaired fertility and superovulation of female mice; also, the average litter size and the estradiol (E2) level in the serum of cKO female mice were decreased by 57.3% and 87.4% vs. control mice, respectively. This deficiency disrupted the estrous cycle and enhanced the apoptosis in the GCs. We observed that CK1α mediated the secretion of estradiol in mouse ovarian GCs via the cytochrome P450 subfamily 19 member 1 (CYP19A1). CONCLUSIONS: These findings improve the existing understanding of the regulation mechanism of female reproduction and estrogen synthesis. TRIAL REGISTRATION: Not applicable.

Endocrine-Disrupting Effects of Transplacental and Translactational Exposure to Tembotrione on Hormone Status in Wistar Rat Offspring at Different Developmental Stages: A Pilot Study.

Green agronomy promotes the implementation of natural and naturally derived substances in crop protection. In the present study, we evaluated the endocrine-disrupting potential of the allelopathic herbicide tembotrione in Wistar rats by studying the hormone status of offspring from the treated dams. Three doses of tembotrione (0.0004, 0.0007, and 4.0 mg/kg b.w./day) have been administered to dams during gestation and/or lactation. In the serum of newborn, weaning, and pubertal female and male offspring, 17ß-estradiol and testosterone were determined using enzyme-linked immunosorbent assay. A decrease in 17ß-estradiol and testosterone was observed in female and male weaning and pubertal offspring exposed to all doses of tembotrione during gestation and lactation. In weaning offspring exposed only during lactation, 17ß-estradiol dropped significantly after exposure to the two lower doses and testosterone after exposure to the lowest dose of tembotrione. The greatest effect was observed at the lowest dose of tembotrione. In newborns, we observed increased 17ß-estradiol after exposure to two lower doses of tembotrione and significantly increased testosterone after exposure to the lowest dose. The highest dose of tembotrione decreased 17ß-estradiol significantly in newborn females. The obtained results suggest that tembotrione might be considered a pro-estrogenic or estrogen agonistic compound under the exposure conditions applied in this investigation.

ARE/Nrf2 Transcription System Involved in Carotenoid, Polyphenol, and Estradiol Protection from Rotenone-Induced Mitochondrial Oxidative Stress in Dermal Fibroblasts.

Skin aging is associated with the increased production of mitochondrial reactive oxygen species (mtROS) due to mitochondrial dysfunction, and various phytonutrients and estrogens have been shown to improve skin health. Thus, the aim of the current study was to examine damage to dermal fibroblasts by chemically induced mitochondrial dysfunction and to study the mechanism of the protective effects of carotenoids, polyphenols, and estradiol. Rotenone, a Complex I inhibitor, caused mitochondrial dysfunction in human dermal fibroblasts, substantially reducing respiration and ATP levels, followed by increased mitochondrial and cytosolic ROS, which resulted in apoptotic cell death, an increased number of senescent cells, increased matrix metalloproteinase-1 (MMP1) secretion, and decreased collagen secretion. Pre-treatment with carotenoid-rich tomato extracts, rosemary extract, and estradiol reversed these effects. These protective effects can be partially explained by a cooperative activation of antioxidant response element (ARE/Nrf2) transcriptional activity by the protective compounds and rotenone, which led to the upregulation of antioxidant proteins such as NQO1. To determine if ARE/Nrf2 activity is crucial for cell protection, we inhibited it using the Nrf2 inhibitors ML385 and ochratoxin A. This inhibition markedly reduced the protective effects of the test compounds by diminishing their effect to reduce cytosolic ROS. Our study results indicate that phytonutrients and estradiol protect skin cells from damage caused by mtROS, and thus may delay skin cell senescence and improve skin health.

Differential effects of exercise and hormone treatment on spinal cord injury-induced changes in micturition and morphology of external urethral sphincter motoneurons.

Background: Spinal cord injury (SCI) results in lesions that destroy tissue and spinal tracts, leading to deficits in locomotor and autonomic function. We have previously shown that after SCI, surviving motoneurons innervating hindlimb muscles exhibit extensive dendritic atrophy, which can be attenuated by treadmill training or treatment with gonadal hormones post-injury. We have also shown that following SCI, both exercise and treatment with gonadal hormones improve urinary function. Animals exercised with forced running wheel training show improved urinary function as measured by bladder cystometry and sphincter electromyography, and treatment with gonadal hormones improves voiding patterns as measured by metabolic cage testing. Objective: The objective of the current study was to examine the potential protective effects of exercise or hormone treatment on the structure and function of motoneurons innervating the external urethral sphincter (EUS) after contusive SCI. Methods: Gonadally intact young adult male rats received either a sham or a thoracic contusion injury. Immediately after injury, one cohort of animals was implanted with subcutaneous Silastic capsules filled with estradiol (E) and dihydrotestosterone (D) or left blank; continuous hormone treatment occurred for 4 weeks post-injury. A separate cohort of SCI-animals received either 12 weeks of forced wheel running exercise or no exercise treatment starting two weeks after injury. At the end of treatment, urinary void volume was measured using metabolic cages and EUS motoneurons were labeled with cholera toxin-conjugated horseradish peroxidase, allowing for assessment of dendritic morphology in three dimensions. Results: Locomotor performance was improved in exercised animals after SCI. Void volumes increased after SCI in all animals; void volume was unaffected by treatment with exercise, but was dramatically improved by treatment with E + D. Similar to what we have previously reported for hindlimb motoneurons after SCI, dendritic length of EUS motoneurons was significantly decreased after SCI compared to sham animals. Exercise did not reverse injury-induced atrophy, however E + D treatment significantly protected dendritic length. Conclusions: These results suggest that some aspects of urinary dysfunction after SCI can be improved through treatment with gonadal hormones, potentially through their effects on EUS motoneurons. Moreover, a more comprehensive treatment regime that addresses multiple SCI-induced sequelae, i.e., locomotor and voiding deficits, would include both hormones and exercise.

Effects of Curcumin and Estrogen Receptor Alpha in Luminal Breast Cancer Cells.

This work examined the potential benefit of curcumin in breast cancer patients as a supplementary drug in ER-positive cancers. The results indicated that in the MCF-7 human breast cancer cell line, E2 and curcumin decreased cell proliferation and the colony-forming capacity and down-regulated protein expression as well as important molecules associated with cell proliferation, such as PCNA and estrogen receptor alpha; genes associated with the epithelial-mesenchymal transition, such as ß-catenin, Vimentin, and E-cadherin; and molecules associated with apoptosis. Clinical studies in bioinformatics have indicated a positive correlation between ESR1 and either CCND1 or BCL2 gene expression in all breast cancer patients. Thus, curcumin could become a potential natural adjuvant treatment for patients with estrogen receptor alpha-positive breast cancer and those with resistance or a poor response to endocrine therapy since the reactivation of estrogen receptor alpha is inevitable.