Natural Estrogens Research Articles

In Silico, In Vitro, and In Vivo Studies Indicate the Endocrine-Disrupting Effects of Cyproconazole Stereoisomers.

The widespread use of chiral triazole fungicide cyproconazole (CPZ) in agricultural fields has led to frequent detection of CPZ in the environment. The restriction of CPZ in the EU raised wide concerns regarding its potential endocrine-disrupting effects (EDEs). The present study was conducted to evaluate EDEs of CPZ stereoisomers in vitro, in silico, and in vivo. The reporter gene assay indicated that all CPZ stereoisomers were agonists to the human estrogenic receptor α. (2S,3S)-(+)- and (2R,3S)-(-)-CPZ exhibited stronger binding capacities to ERα compared with (2R,3R)-(-)- and (2S,3R)-(+)-CPZ. Our computational studies showed consistent results with reporter gene assay, elucidating the stereoselective binding mode of CPZ to estrogen receptor. In zebrafish embryos, the 96h-lethality of CPZ stereoisomers ordered (2R,3R)-(-)- > (2R,3S)-(-)- > (2S,3S)-(+)- > Rac- > (2S,3R)-(+)-CPZ. Stereoselective developmental toxicity of CPZ was observed while (2R,3S)-(-)-CPZ is the most toxic isomer. The estrogenic hormones were significantly decreased in (2S,3R)-(+)- and (2R,3S)-(-)-CPZ groups and enhanced in (2S,3S)-(+)- and (2R,3R)-(-)-CPZ, along with the gene expression in hypothalamic-pituitary-gonad axis altered. CPZ shows no thyroid hormone activity. These data clarified that CPZ is a new-found endocrine disruptor threatening human health and each stereoisomer of CPZ showed stereoselective EDEs by regulating the nuclear receptor-mediated gene expression.

Association of contemporary hormonal contraception and the risk of arterial thrombosis

Abstract Background While contemporary hormonal contraception is effective in preventing unwanted pregnancies, its potential link to an increased risk of stroke and myocardial infarction raises safety concerns. Purpose This study aimed to investigate the association between the use of contemporary hormonal contraception and the occurrence of ischemic stroke and myocardial infarction. Methods A nationwide prospective cohort study was conducted, comprising of all Danish women aged 15-49 years without a history of arterial and venous thrombosis, thrombophilia, and cancer from 1996 to 2021. Data on hormonal contraception use, stroke and myocardial infarction diagnoses, and potential confounders were collected from nationwide registers. A Poisson regression analysis was performed adjusting for age, education level, calendar year, hypertension, statin use, diabetes, and atrial fibrillation. Results The study followed 2,205,794 women over 23,700,659 person-years. Weighted median age was 33 (interquartile range (IQR): 24-41) for non-users and 25 (20-34) for users. A total of 5,346 ischemic strokes (22.6 per 100,000 person-years) and 2,351 myocardial infarctions (9.9 per 100,000 person-years) occurred during the study period. When compared to no use, oral contraceptives containing ethinyl estradiol at a dose of 30 to 40 μg was associated with the following adjusted incidence rate ratios (and 95% confidence intervals) for ischemic stroke and myocardial infarction, according to progestin type: levonorgestrel, 1.9 (1.7 to 2.2) and 2.0 (1.7 to 2.4); norgestimate, 1.9 (1.5 to 2.3) and 1.9 (1.4 to 2.6); desogestrel, 2.4 (2.0 to 2.9) and 2.2 (1.6 to 3.0); gestodene, 1.9 (1.7 to 2.2) and 1.9 (1.5 to 2.2); drospirenone, 2.0 (1.6 to 2.5) and 1.8 (1.1 to 2.8); cyproterone acetate, 1.7 (1.2 to 2.3) and 2.1 (1.3 to 3.4), respectively. At a dose of 20 μg of ethinyl estradiol, the incidence rate ratios for ischemic stroke and myocardial infarction varied based on the type of progestin as follows: desogestrel, 1.9 (1.6 to 2.2) and 1.4 (1.0 to 1.9); gestodene, 1.7 (1.4 to 2.0) and 1.7 (1.2 to 2.4); drospirenone, 1.4 (0.7 to 2.6) and 1.1 (0.3 to 4.4); For transdermal patch, the incidence rate ratio was 3.4 (1.4 to 8.2) and 0.0 (0.0 to 0.0); for vaginal ring, 2.2 (1.4 to 3.3) and 3.2 (1.7 to 6.3); for intrauterine device, 1.1 (0.9 to 1.2) and 1.1 (0.9 to 1.3); for implant, 2.0 (1.2 to 3.5) and 1.3 (0.4 to 3.9); for injection, 1.9 (0.9 to 3.8) and 0.6 (0.1 to 4.0). Conclusion Use of contemporary hormonal contraception appeared to be associated with ischemic stroke and myocardial infarction when compared to non-users. The incidence rate ratios varied across type of hormonal contraception, estrogen dose, progestin type and route of administration. The findings underscore the importance of informed decision-making when considering contraceptive options, with implications for public health and individual health choices.FlowchartAdjusted incidence rate ratios

Aromatase, testosterone, TMPRSS2: determinants of COVID-19 severity

BackgroundMale sex has been identified as a risk factor for worse COVID-19 outcomes. This sex difference has been mostly attributed to the complex role of sex hormones. Cell surface entry of SARS-CoV-2 is mediated by the transmembrane protease serine 2 (TMPRSS2) which is under transcriptional regulation by androgens. P450 aromatase enzyme converts androgens to estrogens. This study measured concentrations of aromatase enzyme, testosterone, estradiol, and TMPRSS-2 in plasma of hospitalized COVID-19 patients to elucidate the dynamics of sex-linked disparity in COVID-19 and correlate them with disease severity and mortality.MethodsIn this prospective cohort study, a total of 265 patients (41% women), age 18 years and older, who had a positive COVID-19 PCR test and were hospitalized for COVID-19 at Memorial Hermann Hospital in Houston, (between May 2020 and May 2021) were enrolled in the study if met inclusion criteria. Plasma concentrations of Testosterone, aromatase, TMPRSS-2, and estradiol were measured by ELISA. COVID-19 patients were dichotomized based on disease severity into moderate-severe (n = 146) or critical (n = 119). Mann Whitney U and logistic regression were used to correlate the analytes with disease severity and mortality.ResultsTMPRSS2 (2.5 ± 0.31 vs. 1.73 ± 0.21 ng/mL, p < 0.01) and testosterone (1.2 ± 0.1 vs. 0.44 ± 0.12 ng/mL, p < 0.01) were significantly higher in men as compared to women with COVID-19 after adjusting for age in a multivariate model. There was no sex difference seen in the level of estradiol and aromatase in COVID-19 patients. TMPRSS2 and aromatase were higher, while testosterone was lower in patients with increased COVID-19 severity. They were independently associated with COVID-19 severity, after adjusting for several baseline risk factors in a multivariate logistic regression model. In terms of mortality, TMPRRS2 and aromatase levels were significantly higher in non-survivors.ConclusionsOur study demonstrates that testosterone, aromatase, and TMPRSS2 are markers of COVID-19 severity. Estradiol levels do not change with disease severity in COVID-19. In terms of mortality prediction, higher aromatase and TMPRSS-2 levels can be used to predict mortality from COVID-19 in hospitalized patients.Plain English SummaryCOVID-19 has caused over a million deaths in the U.S., with men often getting sicker than women. Testosterone, a male hormone, helps control a protein called TMPRSS-2, which allows the COVID-19 virus to spread more easily in the body. A protein called aromatase converts the male hormone testosterone into the female hormone estrogen. It is thought that female hormone estrogen helps protect women from getting seriously ill from COVID-19. To understand the role of these hormones in COVID-19 and sex differences, we measured levels of testosterone, estrogen, aromatase (which turns testosterone into estrogen), and TMPRSS-2 in hospitalized COVID-19 patients. We also checked how this level might reflect the severity of the disease. We found that critically ill COVID-19 patients (the ones in ICU) had higher levels of TMPRSS-2 and aromatase, and lower testosterone levels. When we used these hormone levels to predict death in hospitalized COVID-19 patients, higher levels of TMPRSS-2 and aromatase were linked to a lower chance of survival.

Ramadan fasting and exercise combination therapy: A novel approach for osteoporosis prevention in ovariectomized rats

BackgroundOsteoporosis is a chronic bone metabolic disease that affects millions of people worldwide, particularly the elderly and postmenopausal women. It is characterized by weakened bones, increasing the risk of fractures and leading to significant morbidity and mortality. The goal of the current study is to examine the reported osteo-preservative effects of exercise and/or fasting in the Ramadan fasting model (RFM) in ovariectomized (OVX) rats.MethodsThe experimental intervention started 1 month following the ovariectomy procedure and consisted of five 15-min exercise sessions per week at 18–25 m/min and/or an approximately 13-h fast from sunrise to sunset (6:00 AM–19:00 PM). Serum bone metabolism biomarker levels were measured, and mineral concentrations in femoral ashed bones and digested serum were determined. Additionally, serum bone alkaline phosphatase (b-ALP), parathyroid hormone, osteocalcin, calcitonin, and vitamin D3 concentrations were measured using the competitive enzyme immunoassay technique.ResultsCalcium, magnesium, and phosphorus showed a notable decrease in mineral concentration among OVX rat femurs compared with the combination group (OVX + RFM + E) and control groups. In addition, homeostasis of serum concentrations of calcium, magnesium, and phosphorus was observed to increase in the OVX + RFM + E group rather than in the OVX group without intervention when compared with a control group. Furthermore, fasting and exercise, either alone or concurrently with ovariectomy, induced a non-significant elevation in osteocalcin, parathyroid hormone, and vitamin D3, whereas b-ALP and calcitonin increased significantly compared with those in control rats.ConclusionThe combination of the Ramadan fasting model and moderate intensity exercises among OVX rats manifested advantageous effects in bone biomarkers compared with OVX rats without intervention. This could be recommended as a lifestyle modification that is protective against osteoporosis, especially in the context of depleted estrogen hormone after menopause.

Abemaciclib (Verzenio)

Canada’s Drug Agency recommends that public drug plans reimburse Verzenio in combination with endocrine therapy for the adjuvant treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early-stage breast cancer at high risk of recurrence based on clinicopathological features if certain conditions are met. Verzenio, in combination with endocrine therapy, should only be covered in patients whose breast cancer has receptors for the estrogen and progesterone hormones, tests negative for the HER2 protein, has been removed by surgery, and is at high risk of coming back based on clinicopathological features, including 4 or more positive axillary lymph nodes (ALNs), or 1 to 3 positive ALNs plus histologic grade 3 disease, or 1 to 3 positive ALNs plus a tumour size of 5 cm or more, or 1 to 3 positive ALNs plus a Ki-67 score of 20% or more (if tumour size is &lt; 5cm and disease is not grade 3). Verzenio, in combination with endocrine therapy, should only be reimbursed if prescribed by clinicians with expertise delivering systemic treatment and if the cost is reduced.

Triad of female athletes

The female sports triad is a spectrum of dysfunctions related to energy availability, menstrual function, and bone mineral density. Energy availability is considered the trigger for the triad. Scientists have proven that women who do sports consume approximately 30% less energy and carbohydrates in relation to their body weight. Sufficient energy availability ensures the presence of a menstrual cycle, directly affects the stimulation of the production of female sex hormones (estrogen in particular). Thus, it prevents resorption of bone tissue. When energy availability is too low, a physiological mechanism reduces the amount of energy used for cell maintenance, thermoregulation, growth, and reproductive function. This compensation tends to restore energy balance and promotes survival, but impairs health. Low body weight in women of reproductive age, particularly in adolescence and the first reproductive age, is a biological marker of somatic and reproductive dysfunction. Osteoporosis in young female athletes is manifested by fractures unusual for young women or by frequent and multiple bone fractures during an athletic career. In this review article, an analytical review of literary and informational sources regarding the history of research on the problem of the triad of female athletes is carried out. The specifics of the negative impact of the athlete triad on the female body, the components of the athlete triad (amenorrhea, eating disorders, and osteoporosis) are examined in detail. The article focuses on its main cause - energy imbalance. The impact of the triad of female athletes on the psyche and behavior is considered. The question of its consequences for health both in the short-term and in the long-term perspective is considered. The prevention of RED-S syndrome was also investigated. The purpose of the study: Systematization of current knowledge about the triad of female athletes (relative energy deficiency syndrome (RED-S)). Research methods. Theoretical analysis of literary sources, systematization, generalization of scientific-methodical and special literature.

Lower reporting of venous thromboembolisms events with natural estrogen-based COCs compared to ethinylestradiol containing pills: A disproportionality analysis of the Eudravigilance database

ObjectivesPharmacovigilance data analysis can accelerate the identification of drug-related safety signals or reassure on the safety profile. This study evaluates the VTE risk of newer COC formulations with natural estrogens, such as estradiol (E2) and estetrol (E4), using data from the EudraVigilance database. MethodsWe conducted a disproportionality reporting rate analysis of VTE events associated with various COC formulations by extracting individual case reports from EudraVigilance database up to July 28th 2024. The study compared the proportionality reporting rate between natural estrogen-based COCs (E2 and E4) and conventional synthetic estrogen-based COCs (EE), with a comparison to EE-levonorgestrel (EE-LNG). ResultsThe analysis revealed that COCs containing natural estrogens exhibited significantly lower proportionality reporting rates for thrombotic events compared to EE-based COCs. Specifically, E4-drospirenone (E4-DRSP) showed the lowest proportionality reporting rate (0.12) similar to progestin-only pills. EE-drospirenone (EE-DRSP) had the highest proportionality reporting rate (2.25), suggesting an increased thrombotic risk. ConclusionThe study supports the safer thrombotic profile of natural estrogen-based COCs, particularly E2 and E4 formulations, over synthetic estrogen-based COCs containing EE. These findings support the hypothesis that E2- and E4-based pills are safer than EE-based pills, aligning with a shift towards safer contraceptive options in clinical practice.

Effect of Bypass Fat on Genital Status and Blood Biochemical Profiles in Pubertal Swamp Buffalo Heifers and Puerperal Swamp Buffalo Cows

Background: The interaction between nutrition and reproduction has long been known to have important implications for the reproductive performance in animal.The present study highlights the effect of by-pass fat supplementation on genital changes and blood biochemical profile in pubertal swamp buffalo heifers and puerperal swamp buffalo cows. Methods: 24 heifers of 2-2.5 years of age and 24 puerperal cows on the day of parturition, irrespective of parity were used as experimental animal. The analytical method was based on the treatment protocols of 3 groups in both heifers and cows (n=8 in each group) viz., treated with oral bypass fat alone (I), oral bypass fat, mineral mixtures and injectable phosphorus (II) and control (III) respectively. Genital status, metabolic hormone (leptin, Ghrelin and IGF-1), reproductive hormone (estrogen and progesterone) and mineral constituents (calcium, phosphorus, zinc and copper) were analyzed on day 0, day 15 and day 30 in heifers and day 15, day 30 and day 45 in cows respectively. Result: Feeding of bypass fat alone or bypass fat fortified with minerals and injectable phosphorus was not found to induce significant genital changes in heifers and cows. The serum leptin and IGF-1 levels were increased significantly (p less than 0.05) in heifers at day 30 in Group I and II. However, a significant rise (p less than 0.05) of leptin was recorded at day 45 in group I and II cows. IG1-1 level was recorded increased significantly only in cows treated with fortified bypass fat (Group II). With the progression of treatment the serum phosphorus level was increased significantly (p less than 0.05) in Group I and II cows. Serum estrogen levels were increased in both heifers and cows with progression of treatment in both Group I and II. However, serum progesterone levels were increased significantly only in heifers of Group I and II with progression of treatment.

Role of glucose in regulating menstrual cycle

Goal of the study: To find correlation between estrogen hormone and glucose intake. Introduction: The main estrogens: estradiol, estrone and their acyl-esters have been studied essentially related to their classical estrogenic functions. However their main effect in the body is probably the sustained control of core energy metabolism. With regard to energy, the estrogen molecular species act through control of glucose availability. Material and methods: There were analyzed articles from the PubMed database, from the last 5 years 2019-2024, mentioning such words as “estrogen”, “glucose”, “ menstrual cycle” [1]. Results: Estrogens play a paramount and continued regulatory role, to maintain energy (lipid / glucose) homeostasis. Estrogens have extensive and powerful control of energy homeostasis. Premenopausal women exhibit enhanced insulin sensitivity and reduced incidence of type 2 diabetes, compared with age matched men, but this advantage disappears after menopause with disrupted glucose homeostasis, in part owing to a reduction in circulating 17 β –estradiol (E2). Moreover a study shows the efficacy of a glucagon like peptide-1 and estrogen dual agonist (GLP1-E2) in pancreatic islet protection. The enzymes that are involved in the menstrual cycle are β-glucoronidase, thought to be involved in the final stages of mucopolysaccharide breakdown. Conclusion: So far there is limited information on the major role played by different forms of physiological estrogens in the control of energy metabolism at the whole body level. E2 protects the functionality of the pancreatic β cells, preventing apoptosis, adapting their function to insulin resistance and maintaining their insulin content. The lack of E2 availability also increases hepatic insulin clearance. Estrogen receptor α plays a crucial role in regulating glucose. However, the underlying mechanisms remain incompletely understood and therefore studies on the maintenance of (lipid / glucose) homeostasis are ongoing [2-10] in various neuro-endocrine and visceral multisystem biomedical areas, where the diagnostic role of markers is essential [11,12].

Role of Membrane Estrogen Receptor Alpha on the Positive Feedback of Estrogens on Kisspeptin and GnRH Neurons.

Estrogens act through nuclear and membrane-initiated signaling. Estrogen receptor alpha (ERα) is critical for reproduction, but the relative contribution of its nuclear and membrane signaling to the central regulation of reproduction is unclear. To address this question, two complementary approaches were used: estetrol (E4) a natural estrogen acting as an agonist of nuclear ERs, but as an antagonist of their membrane fraction, and the C451A-ERα mouse lacking mERα. E4 dose- dependently blocks ovulation in female rats, but the central mechanism underlying this effect is unknown. To determine whether E4 acts centrally to control ovulation, its effect was tested on the positive feedback of estradiol (E2) on neural circuits underlying luteinizing hormone (LH) secretion. In ovariectomized females chronically exposed to a low dose of E2, estradiol benzoate (EB) alone or combined with progesterone (P) induced an increase in the number of kisspeptin (Kp) and gonadotropin-releasing hormone (GnRH) neurons coexpressing Fos, a marker of neuronal activation. E4 blocked these effects of EB, but not when combined to P. These results indicate that E4 blocked the central induction of the positive feedback in the absence of P, suggesting an antagonistic effect of E4 on mERα in the brain as shown in peripheral tissues. In parallel, as opposed to wild-type females, C451A-ERα females did not show the activation of Kp and GnRH neurons in response to EB unless they are treated with P. Together these effects support a role for membrane-initiated estrogen signaling in the activation of the circuit mediating the LH surge.

12539 Estrogen Type In Contraceptives Matters: Effects On Spatial Memory And Anxiety-Like Behaviors In A Female Rat Model

Abstract Disclosure: A.P. Hegwood: None. S. Kujawa: None. A.V. Prakapenka: None. According to U.S. Centers for Disease Control &amp; Prevention, ∼12% of the U.S. population uses combined oral contraceptives (COCs). Behavioral side effects are common factors in COC discontinuation. Management of COC-related side effects primarily centers around altering the synthetic ethinyl estradiol (EE) dose, the predominant estrogen in COCs. Estradiol valerate (EV) is a recently introduced natural estrogen alternative to EE. EE-containing COCs, such as EE/dienogest (DNG), were found to decrease free steroid hormone serum levels compared to EV-containing COCs, such as EV/DNG. In women and in female rodent models, steroid hormones (e.g., 17-ß estradiol (E2), testosterone) dose-dependently modulate spatial memory and anxiety-related behaviors. We hypothesized that in a rat model of hormonal contraceptive use, EE/DNG differentially modulates spatial memory and anxiety-like behaviors compared to EV/DNG, corresponding to circulating steroid hormone levels. Thirty-six young-adult (3-4-months-old) female rats were randomly assigned to EE/DNG (0.13µg EE and 8.6µg DNG per day), EV/DNG (8.6µg EV and 8.6µg DNG per day), or vehicle treatment (propylene glycol) continuously administered by subcutaneous osmotic pump. At four weeks of treatment, rats were tested on the delayed spontaneous alternation (dSA) task to evaluate spatial memory and the elevated plus maze (EPM) to evaluate anxiety-like behavior. Following EPM, serum was collected and analyzed for E2, progesterone, androstenedione, and testosterone levels using liquid chromatography-mass spectrometry and corticosterone levels using radioimmunoassay. Spontaneous alternation behaviors were similar across all three groups on the dSA. However, EE/DNG increased use of an egocentric navigational strategy, the use of consecutive turns, on the dSA compared to vehicle and EV/DNG. Egocentric strategy is likely mediated by the striatal memory system, engagement of which is elevated with stress and anxiety. Of note, EE/DNG decreased time spent in the open arms of the EPM compared to vehicle and EV/DNG, indicating increased anxiety-like behaviors with EE/DNG. Both EE/DNG and EV/DNG decreased androstenedione, testosterone, and E2 circulating levels compared to vehicle. Steroid hormone serum levels did not differ between EE/DNG and EV/DNG; 58% of EE/DNG serum samples were undetermined/below threshold for E2 levels, limiting statistical analysis. Altogether, we found that, compared to vehicle and the natural EV, the synthetic EE component in hormonal contraceptives elevates anxiety-like behaviors in female rats, an effect that corresponds to increased use of an egocentric navigational strategy on a spatial memory task. Our findings support the notion that estrogen type matters for behavioral outcomes associated with contraceptive use, identifying estrogen type as a possible tool for management of COC-related side effects. Presentation: 6/1/2024

TEMPORARY REMOVAL: Effect of soy isoflavones on measures of estrogenicity: A systematic review and meta-analysis of randomized controlled trials

BackgroundDespite recommendations to increase plant food consumption for public and planetary health and the role that soy foods can play in plant-predominant diets, controversies around the effects of soy foods and especially soy isoflavones, are a barrier to their intake. Given their cardioprotective effects and ability to alleviate menopausal symptoms, addressing these concerns is particularly relevant to women. ObjectiveThis systematic review and meta-analysis of randomized controlled trials aimed to determine the effect of soy isoflavones on measures of estrogenicity in postmenopausal women. MethodsMEDLINE, Embase, and Cochrane Library were searched through August 2024 for randomized trials 3-months investigating soy isoflavones versus non-isoflavone controls in postmenopausal women. Outcomes included endometrial thickness (ET), vaginal maturation index (VMI), follicle-stimulating hormone (FSH), and estradiol. Independent authors extracted data and assessed risk of bias. GRADE (grading of recommendations assessment, development, and evaluation) was used to assess certainty of evidence. ResultsWe included 40 trials (52 trial comparisons, n=3285) assessing the effect of a median reported dose of 75mg/day of soy isoflavones in substitution for non-isoflavone controls over a median of 24 weeks. Soy isoflavones had no statistically significant effect on any measure of estrogenicity; ET (mean difference, -0.22mm [95% confidence interval, -0.45, 0.01mm], PMD=0.059), VMI (2.31 [-2.14, 6.75], PMD=0.310), FSH (-0.02IU/L [-2.39, 2.35IU/L], PMD=0.987), and estradiol (1.61pmol/L [-1.17, 4.38pmol/L], PMD=0.256). The certainty of evidence was high-to-moderate for all outcomes. ConclusionsCurrent evidence suggests that soy isoflavones do not exhibit estrogenic effects compared to non-isoflavone controls on 4 measures of estrogenicity in postmenopausal women. This synthesis supports that soy isoflavones likely act as selective estrogen receptor modulators, differing clinically from the hormone estrogen. Addressing public health concerns may promote soy foods as high-quality plant protein sources with low environmental impact and cost, particularly benefiting postmenopausal women, and aligning with sustainable dietary patterns and guidelines. RegistrationPROSPERO (CRD42023439239)

Exposure of antral follicles to medroxyprogesterone acetate during stimulation does not cause molecular perturbations in gonadotropin-responsiveness and steroidogenic function of granulosa cells in progestin-primed cycles.

Does medroxyprogesterone acetate (MPA) exposure in progestin-primed ovarian stimulation (PPOS) cycles cause molecular perturbations in the steroidogenic function and gonadotropin responsiveness of the granulosa cells? PPOS cycles are identical to traditional GnRH antagonist cycles not only for clinical IVF characteristics but also for gonadotropin receptor expression, response to gonadotropins, and steroidogenic function at the molecular level. PPOS is increasingly used as an alternative to GnRH antagonists due to the inhibitory effect of progesterone on LH release by reducing GnRH pulsatility at the hypothalamic level. Although a growing body of evidence from clinical studies did not indicate significant differences between PPOS and antagonist protocols for IVF cycle characteristics and obstetrical outcomes, it is still unknown whether exposure of the antral follicle cohort to progesterone or its synthetic derivatives during ovarian stimulation causes any subtle molecular aberrations in terms of steroidogenesis and gonadotropin responsiveness. To address this issue, detailed comparative molecular analyses were conducted in the luteinized mural granulosa cells (GCs) obtained from normal responding IVF patients undergoing PPOS and antagonist cycles. A clinical translational research study was conducted with IVF patients. This study included 55 normal responding IVF patients who underwent ovarian stimulation with either PPOS using MPA (5 mg twice daily) or GnRH antagonist cetrorelix acetate. Recombinant forms of FSH and hCG were used for ovarian stimulation and ovulation triggering, respectively. Luteinized mural GCs obtained during the oocyte retrieval procedure were used for the experiments. Cell culture, quantitative real-time PCR, immunoblotting, confocal time-lapse live cell imaging, and hormone assays were used. Demographic and IVF cycle characteristics of the patients undergoing ovarian stimulation with PPOS and GnRH antagonist were similar, including ovarian response, mature oocyte yield, and fertilization rates. Molecular analyses revealed that the expression of the enzymes involved in sex-steroid synthesis (StAR, SCC, 3β-HSD, 17β-HSD, aromatase) and the uptake/storage/utilization of cholesterol (LDL receptor, Hormone-sensitive lipase, hydroxy-methyl glutaryl Co-enzyme-A reductase, and Sterol O-acyltransferase1) in the GCs of the PPOS cycles were comparable to those of the antagonist cycles. The expression of the receptors for gonadotropins, estrogen, and progesterone hormones was also similar. Basal and hCG-induced increases in 3β-HSD expression and progesterone production and basal and FSH-induced increases in aromatase expression and E2 output of the GCs from PPOS patients did not exhibit any meaningful differences when compared with GCs from antagonist cycles. Furthermore, basal and hCG-induced up-regulation in the LDL receptor expression and cholesterol uptake did not differ between the groups. Confocal imaging also revealed similar patterns of expression for the steroidogenic enzymes and their co-localization with mitochondria. Lastly, the expression of the other important genes regulating cumulus expansion, ovulation, and luteal function [Relaxin, ADAMTS-1, and epidermal growth factor (EGF)-like growth factor amphiregulin] in the GCs of the PPOS and antagonist cycles were similar. N/A. Caution should be exercised when interpreting our data which was derived from normally responding patients whose ovulation was triggered with hCG. It is unclear whether the molecular parameters assessed vary according to infertility etiologies, magnitude of ovarian response, mode of trigger, and any other underlying ovarian pathologies or systemic diseases. MPA was the progestin used for PPOS and whether these findings can be generalized to other progestins is unknown. This study provides reassuring molecular evidence that exposure of antral follicle cohorts to MPA during the follicular growth phase does not have any detrimental effects on steroidogenic, ovulatory, and luteal functions when compared with GnRH antagonist cycles. This study was funded by the School of Medicine, the Graduate School of Health Sciences of Koc University and Koç University Research Center for Translational Medicine (KUTTAM), and equally funded by the Republic of Turkey Ministry of Development Research Infrastructure Support Program. All authors declare no conflict of interest. N/A.

Simultaneous removal of E1, E2, EE2 and levonorgestrel from water using TiO2 catalyst anchored on activated carbon: Processes optimization, materials characterization, and assessment of the estrogenicity reduction

Removal of estrogen hormones from water matrices is crucial owing to its adverse effects on aquatic ecosystems and human health. The present investigation applies an advanced approach to assess the effectiveness of combined processes (adsorption and visible-light-driven photo-degradation) for simultaneous removal of estrone (E1), 17β-estradiol (E2), 17α-ethinylestradiol (EE2), and levonorgestrel (LEVO) in water, applying TiO2-activated carbon composite selected through design of experiment (DoE) for process optimization. Based on a central composite rotatable design (CCRD), composites were synthesized with percentages of activated carbon (AC) ranging from 2.93% to 17.07% (wt.) and calcination temperatures between 259 and 541 °C. The composite with the best performance TiO2-AC15%-541 (15% wt. AC, calcined at 541 °C), achieved a total removal of 98.3 ± 1.15% for E1, 99.0 ± 1% for E2, 99.3 ± 1.15% for EE2, and 96.0 ± 2.65% for LEVO at the initial concentration of 100 μg L−1 under simulated solar irradiation. Further optimization using once more CCRD involved three independent variables: pH; hormone concentration/TiO2-AC15%-541 loading ratio; and the intensity of simulated solar irradiation. Under optimized conditions (pH 2.64, hormone concentration/TiO2-AC15%-541 loading ratio of 3.8 mg g−1, and irradiation intensity of 41 W m−2 UV-A), the TiO2-AC15%-541 composite removed 99.8% of E1, 99.8% of E2, 99.0% of EE2, and 92.1% of LEVO. Furthermore, the process achieved a 99.9% reduction in estrogenic activity, assessed with yeast estrogen screen (YES) assay. These results demonstrate that TiO2-AC15%-541 is an efficient and cost-effective remediation agent for treating mixed estrogen compounds in water, with significant potential for commercial applications.

Deleterious Biological Effects of Endocrine Disruptors: An Insight into Human Health Risks.

Endocrine-disrupting chemicals (EDCs) are environmental pollutants. Since EDCs are present in various consumer products, contamination of human beings is very common. EDCs have deleterious effects on various systems of the body, especially the endocrine and reproductive systems. EDCs interfere with the synthesis, metabolism, binding, or cellular responses of natural estrogens and alter various pathways. Biological samples such as blood, saliva, milk, placental tissue, and hair are frequently used for biomonitoring and the detection of EDCs. Early detection and intervention may help in preventing congenital anomalies and birth defects. The common methods for determining the presence of EDCs in body fluids include gas chromatography, high-performance liquid chromatography, and mass spectrometry. Understanding the health effects and dangers of EDC is important, given their widespread use. This mini-review aims to summarize the adverse biological effects of several important classes of EDCs and highlights future perspectives for appropriate control.

Neem Leaves Extract Reduces Sex Steroids and Gonadal Function in Female Wistar Albino Rats

The neem plant (Azadirachta indica) is one of the most important medicinal plants in Asia and Africa. This study aimed to investigate the possible anti-fertility potential of dietary neem leaves' extract in female Wistar albino rats as. This model could be further applied to stray dogs. In this experiment 24 adult female albino Wister rats were divided into two groups: control and treated with neem leave extract, they were tested for estrous regularity by vaginal smears, progesterone, and estrogen hormone were measured. Ovarian caspase-3 expression and histopathological inspection were examined. The results have revealed reducing sex steroids, increment in ovarian caspase-3 expression, and histological deteriorations in the ovary and uterus. The study concluded that neem flower extract can be used as an antifertility agent in animals.

The bioassay tests and mass spectrometry for evaluation of xenoestrogens in tuna fish

Exposure to xenoestrogens through food is a significant concern. These compounds have estrogen-like activity and lead to cell proliferation. In this study, MCF-7 cells were utilized for bioassay tests and evaluation of cell proliferation of extracts prepared from canned tuna fish. First, a pre-screening using the MTT test was done with the solid and liquid parts of the canned tuna fish. It was observed that the proliferation of cells in the solid part of canned tuna cans actually occurs in tuna meat. Therefore, this portion of canned tuna fish was selected for further studies. The binding affinity with ERα and ERβ receptors was determined through RT-qPCR, and the extract was analyzed via mass spectrometry to identify estrogenic components. The study revealed an increased cell proliferation rate upon treatment with the canned tuna fish extract. 17β-estradiol was considered as positive control. The cell proliferation rate ranged from 27 % to 36.6 % compared to 17β-estradiol. Both ERα and ERβ receptors of MCF-7 cells were stimulated almost equally in the sample extract group. Mass spectrometry analysis identified bisphenol A(BPA) and other estrogenic compounds such as phytoestrogens, phthalates, polychlorinated biphenyls, natural and synthetic estrogen hormones. Our findings emphasize the necessity of using a combination of bioassay tests and analytical methods to carefully manage and evaluate the combined estrogenic effects of components in food samples.

Estrogenic control of reward prediction errors and reinforcement learning.

Gonadal hormones act throughout the brain 1 , and neuropsychiatric disorders vary in symptom severity over the reproductive cycle, pregnancy, and perimenopause 2-4 . Yet how hormones influence cognitive processes is unclear. Exogenous 17 β -estradiol modulates dopamine signaling in the nucleus accumbens core (NAcc) 5,6 , which instantiates reward prediction errors (RPEs) for reinforcement learning 7-16 . Here we show that endogenous 17 β -estradiol enhances RPEs and sensitivity to previous rewards by reducing dopamine reuptake proteins in the NAcc. Rats performed a task with different reward states; they adjusted how quickly they initiated trials across states, balancing effort against expected rewards. NAcc dopamine reflected RPEs that predicted and causally influenced initiation times. Elevated endogenous 17 β -estradiol increased sensitivity to reward states by enhancing dopaminergic RPEs in the NAcc. Proteomics revealed reduced dopamine transporter expression. Finally, knockdown of midbrain estrogen receptors suppressed reinforcement learning. 17 β -estradiol therefore controls RPEs via dopamine reuptake, mechanistically revealing how hormones influence neural dynamics for motivation and learning.

THE EFFECT OF RED DRAGON FRUIT PEEL EXTRACT (HYLOCEREUS POLYRHIZUS) ON COLLAGEN DEPOSITION IN THE KIDNEYS OF MENOPAUSAL MODEL RATS (RATTUS NORVEGICUS)

Background: The estrogen hormone possesses nephroprotective properties during menopause that can influence kidney function. This increases collagen deposition in the kidneys. Estrogen deficiency during menopause can be replaced by phytoestrogens. The skin of red dragon fruit (Hylocereus polyrhizus) contains numerous anthocyanin contents, which have been proven to exhibit activities as phytoestrogens. Objective: To determine whether there are changes in collagen deposition in the kidneys of menopausal rat models with the administration of Hylocereus polyrhizus peel extract. Methods: This research utilized a randomized post-test control group design with three sample groups that had undergone ovariectomy. The three groups consist a control group without intervention (P0), an intervention group with red dragon fruit peel extract at a dose of 60mg/200gBW (P1), and an intervention group with red dragon fruit peel extract at a dose of 90mg/200gBW (P2). Results: The mean percentage of collagen expression in menopausal rat kidneys in groups P0, P1, and P2 were 0.876 ± 0.433, 0.189 ± 0.102, and 0.162 ± 0.108, respectively. The Kruskal-Wallis test revealed a significant difference with a p-value of 0.000. Post-Hoc Mann-Whitney U test found a significant difference between groups P0 and P1 (p = 0.000), as well as groups P0 and P2 (p = 0.000). However, there was no significant difference between P1 and P2 (p = 0.436). Conclusion: The extract of Hylocereus polyrhizus peel has an effect on the collagen deposition in the kidneys of menopausal rat models. The lowest level of collagen deposition in the kidneys was observed in the intervention group with a dose of 90mg/200gBW. Keywords : Hylocereus polyrhizus, collagen, kidney, menopause

PARP7 Inhibitors and AHR Agonists Act Synergistically Across a Wide-Range of Cancer Models.

Small molecule inhibitors of the mono (ADP) ribosyl transferase PARP7 are being evaluated as a monotherapy for tumors overexpressing PARP7 and in combination with immune checkpoint blockade. We previously showed that sensitivity to the PARP7 inhibitor (PARP7i) RBN-2397 could be enhanced by co-treatment with agonists of the Aryl Hydrocarbon Receptor (AHRa) in cell lines that show strong intrinsic sensitivity to RBN-2397. Here we demonstrate that a range of tumor cell lines that are relatively insensitive to PARP7i or AHRa as individual agents are unexpectedly profoundly sensitive to the combination. Our data show that this synergistic response is dependent on AHR/ARNT and is associated with increased levels of nuclear AHR and increased transcription of AHR target genes. In some hormone receptor-positive cell lines, we find that combination treatment is associated with proteasomal turnover of the steroid hormone receptors, androgen receptor and estrogen receptor. Both wildtype and hormone-resistant mutant forms of these receptors are degraded upon treatment with AHRa and PARP7i in breast and prostate cancer models. These results suggest that combining PARP7i with AHRa may extend the utility of these drugs to a wider range of tumors, including those that are refractory to hormone therapy.