Vertebrate endocrine disruptors induce sex-reversal in blue mussels.

Mollusks are the second most diverse animal phylum, yet little is known about their endocrinology or how they respond to endocrine disrupting compound (EDC) pollution. Characteristic effects of endocrine disruption are reproductive impairment, skewed sex ratios, development of opposite sex characteristics, and population decline. However, whether classical vertebrate EDCs, such as steroid hormone-like chemicals and inhibitors of steroidogenesis, exert effects on mollusks is controversial. In the blue mussel, Mytilus edulis, EDC exposure is correlated with feminized sex ratios in wild and laboratory mussels, but sex reversal has not been confirmed. Here, we describe a non-destructive qPCR assay to identify the sex of M. edulis allowing identification of males and females prior to experimentation. We exposed male mussels to 17α-ethinylestradiol and female mussels to ketoconazole, EDCs that mimic vertebrate steroid hormones or inhibit their biosynthesis. Both chemicals changed the sex of individual mussels, interfered with gonadal development, and disrupted gene expression of the sex differentiation pathway. Impacts from ketoconazole treatment, including changes in steroid levels, confirmed a role for steroidogenesis and steroid-like hormones in mollusk endocrinology. The present study expands the possibilities for laboratory and field monitoring of mollusk species and provides key insights into endocrine disruption and sexual differentiation in bivalves.

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), 17ß-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.

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

OBJECTIVES: Pharmacovigilance 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. METHODS: We 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). RESULTS: The 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. CONCLUSION: The 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.

A randomised double-blind trial to determine the bleeding profile of the prolonged-release contraceptive dienogest 2 mg/ethinylestradiol 0.02 mg versus an immediate-release formulation of drospirenone 3 mg/ethinylestradiol 0.02 mg.

BACKGROUND: Dienogest (DNG) 2 mg/ethinylestradiol (EE) 0.02 mg is the first low-dose combined oral contraceptive (COC) with a prolonged-release formulation that allows stable plasma concentrations and has high contraceptive efficacy (Pearl index: 0.2). The aim of this trial was to determine the bleeding profile of this contraceptive compared to an immediate release formulation. METHODS: This prospective double-blind randomised controlled trial evaluated the bleeding patterns of DNG 2 mg/EE 0.02 mg compared with immediate-release drospirenone (DRSP) 3 mg/EE 0.02 mg in a 24/4-day regimen over nine cycles (randomisation ratio, 5:2). Participants recorded scheduled and unscheduled bleeding/spotting data using an electronic diary. A non-inferiority analysis for the proportion of participants with unscheduled bleeding/spotting was prespecified for Cycles 2-6. Safety, including adverse events, were monitored throughout the trial. RESULTS: Seven-hundred six and 288 participants received DNG/EE and DRSP/EE, respectively. Scheduled bleeding patterns per each 28-day cycle were similar in both groups. During Cycles 2-6, the proportion of participants with unscheduled bleeding/spotting was significantly lower in the DNG/EE group (50.5% [280/574] than in the DRSP/EE group (72.8% [171/235]]; treatment difference 22.3% [95% CI 15.9, 28.6%]; p < 0.0001). A low proportion of participants discontinued the trial due to bleeding disorders (1.7% and 0.7%, respectively). The safety profiles were similar for both treatments. CONCLUSIONS: The prolonged-release DNG 2 mg/EE 0.02 mg offers a significant decrease in unscheduled bleeding/spotting compared with an immediate-release COC, DRSP/EE, combined with high contraceptive efficacy and a very low adverse event profile.

The prolonged-release DNG 2 mg/EE 0.02 mg offers a significant decrease in unscheduled bleeding compared with an immediate-release COC while maintaining contraceptive efficacy and with no new safety signals.

Multiomics analysis reveal the impact of 17α-Ethinylestradiol on mortality in juvenile zebrafish.

17α-Ethinylestradiol (EE2) is known for its endocrine-disrupting effects on embryonic and adult fish. However, its impact on juvenile zebrafish has not been well established. In this study, juvenile zebrafish were exposed to EE2 at concentrations of 5 ng/L (low dose, L), 10 ng/L (medium dose, M), and 50 ng/L (high dose, H) from 21 days post-fertilization (dpf) to 49 dpf. We assessed their growth, development, behavior, transcriptome, and metabolome. The findings showed that the survival rate in the EE2-H group was 66.8 %, with all surviving fish displaying stunted growth and swollen, transparent abdomens by 49 dpf. Moreover, severe organ deformities were observed in the gills, kidneys, intestines, and heart of fish in both the EE2-H and EE2-M groups. Co-expression analysis of mRNA and lncRNA revealed that EE2 downregulated the transcription of key genes involved in the cell cycle, DNA replication, and Fanconi anemia signaling pathways. Additionally, metabolomic analysis indicated that EE2 influenced metabolism and development-related signaling pathways. These pathways were also significantly identified based on the genes regulated by lncRNA. Consequently, EE2 induced organ deformities and mortality in juvenile zebrafish by disrupting signaling pathways associated with development and metabolism. The results of this study offer new mechanistic insights into the adverse effects of EE2 on juvenile zebrafish based on multiomics analysis. The juvenile zebrafish are highly sensitive to EE2 exposure, which is not limited to adult and embryonic stages. It is a potential model for studying developmental toxicity.

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.

Rapid and random-start endometrial preparation before outpatient hysteroscopic polypectomy in patients of perimenopausal age.

OBJECTIVE: This study aimed to assess the efficacy of randomly started oral dienogest/ethinylestradiol (DNG/EE) for swift endometrial preparation prior to outpatient hysteroscopic polypectomy in perimenopausal women. METHOD: A multicenter, prospective, randomized controlled trial was conducted in university hospitals. Eighty perimenopausal women scheduled for outpatient hysteroscopic polypectomy between January 2023 and March 2024 were randomly assigned to either intervention (n = 40) or control (n = 40) groups. Exclusion criteria included concomitant endometrial pathologies, recent therapy and adnexal diseases. The intervention group received oral DNG/EE 2 mg/0.03 mg/day started on any day of the menstrual cycle for 14 days. The control group underwent polypectomy between menstrual cycle days 8 and 11 without pharmacological treatment. RESULTS: Pre-procedure (p < 0.001) and post-procedure (p < 0.001) endometrial thickness were significantly reduced in the intervention group, along with a higher incidence of hypotrophic/atrophic endometrial patterns (p < 0.001). Surgical parameters also differed significantly between groups. CONCLUSION: DNG/EE treatment offers rapid, cost-effective endometrial preparation, enhancing surgical outcomes and patient satisfaction during outpatient polypectomy. TRIAL REGISTRATION: ClinicalTrials.gov NCT06316206.

Estrogenic Responsiveness of Brown Trout Primary Hepatocyte Spheroids to Environmental Levels of 17α-Ethinylestradiol.

Three-dimensional (3D) fish hepatocyte cultures are promising alternative models for replicating in vivo data. Few studies have attempted to characterise the structure and function of fish 3D liver models and illustrate their applicability. This study aimed to further characterise a previously established spheroid model obtained from juvenile brown trout (Salmo trutta) primary hepatocytes under estrogenic stimulation. The spheroids were exposed for six days to environmentally relevant concentrations of 17α-ethinylestradiol-EE2 (1-100 ng/L). The mRNA levels of peroxisome (catalase-Cat and urate oxidase-Uox), lipid metabolism (acyl-CoA long chain synthetase 1-Acsl1, apolipoprotein AI-ApoAI, and fatty acid binding protein 1-Fabp1), and estrogen-related (estrogen receptor α-ERα, estrogen receptor ß-ERß, vitellogenin A-VtgA, zona pellucida glycoprotein 2.5-ZP2.5, and zona pellucida glycoprotein 3a.2-ZP3a.2) target genes were evaluated by quantitative real-time polymerase chain reaction. Immunohistochemistry was used to assess Vtg and ZP protein expressions. At the highest EE2 concentration, VtgA and ZP2.5 genes were significantly upregulated. The remaining target genes were not significantly altered by EE2. Vtg and ZP immunostaining was consistently increased in spheroids exposed to 50 and 100 ng/L of EE2, whereas lower EE2 levels resulted in a weaker signal. EE2 did not induce significant changes in the spheroids' viability and morphological parameters. This study identified EE2 effects at environmentally relevant doses in trout liver spheroids, indicating its usefulness as a proxy for in vivo impacts of xenoestrogens.

Pulmonary Embolism With Pulmonary Infarction in a Patient Using the Annovera® Segesterone Acetate and Ethinylestradiol Combined Vaginal Contraceptive Ring.

Combined hormonal contraceptives (CHC) are a very popular form of contraception among young women. Recently, vaginal contraceptive rings (VCR) have been formulated, offering greater convenience and ease of use. Venous thromboembolism (VTE) has been associated with CHC use and is a significant cause of mortality and morbidity in women. Here, we present the case of a 48-year-old woman who presented with right upper quadrant abdominal pain for four days associated with one day of shortness of breath. She had a history of anemia and abnormal uterine bleeding due to uterine fibroids. She was found to have a large embolus in the right pulmonary artery, associated with a right lower lobe pulmonary infarction. No evidence of lower-extremity deep venous thrombosis was found. She was using a segesterone acetate and ethinylestradiol combination VCR, which was removed. She was started on intravenous heparin anticoagulation with improvement in symptoms. This was later transitioned to an oral apixaban regimen prior to discharge. The exact mechanism of CHC-induced thrombotic risk remains unclear. They affect numerous proteins involved in the coagulation, anticoagulation, and thrombolytic pathways, thereby expressing their net thrombogenic potential. Estrogens have often been implicated as the more thrombogenic hormone, with progestogens being added to mitigate some of the risks. CHC use can cause a sixfold increased risk for VTE. Reducing the dose of estrogen and proper patient selection with attention to their risk profile remain essential for the safe use of these agents. This represents the first case report relating segesterone acetate and ethinylestradiol combination VCR to pulmonary embolism and infarction.

The efficacy of levonorgestrelintrauterine system, drospirenone & ethinylestradiol tablets (II) and dydrogesterone in preventing the recurrence of endometrial polyps.

OBJECTIVE: To analyze the efficacy of levonorgestrelintrauterine system, Drospirenone & ethinylestradiol tablets (II), and dydrogesterone in preventing the recurrence of endometrial polyps after hysteroscopic endometrial polypectomy. METHODS: One hundred seventy patients who underwent hysteroscopic endometrial polypectomy in the Gynecology Department of Tianmen First People's Hospital in Hubei Province from January 2022 to June 2023 were randomly divided into the levonorgestrelintrauterine system group, Drospirenone & ethinylestradiol tablets (II) group, dydrogesterone group, and a control group. The recurrence rates, endometrial thickness, and menstrual volume changes at 6 and 12 months post-operation were compared among these four groups. RESULTS: The recurrence rates in the levonorgestrelintrauterine system group, Drospirenone & ethinylestradiol tablets (II) group, and dydrogesterone group were lower than the control group, with statistical significance (P < 0.01), with the levonorgestrelintrauterine system group having the lowest recurrence rate. The endometrial thickness at 6 and 12 months post-operation in the levonorgestrelintrauterine system group, Drospirenone & ethinylestradiol tablets (II) group, and dydrogesterone group was thinner than that of the control group and thinner than pre-operation, with statistical significance (P < 0.01). The menstrual volume at 3 months post-operation in the levonorgestrelintrauterine system group, Drospirenone & ethinylestradiol tablets (II) group, and dydrogesterone group was significantly less than the control group, and less than the pre-operation volume. CONCLUSION: Dydrogesterone, drospirenone & ethinylestradiol tablets (II), and levonorgestrelintrauterine system all play a role in preventing the recurrence of endometrial polyps, but levonorgestrelintrauterine system is significantly better than dydrogesterone and Drospirenone & ethinylestradiol tablets (II) in terms of postoperative recurrence rate, endometrial thickness, menstrual changes, and compliance, and is worth promoting in clinical application.

Intergenerational toxicity of 17α-ethinylestradiol (EE2): Effects of parental exposure on early larval development and transcriptomic profiles in the Sydney rock oyster, Saccostrea glomerata.

This study exposed adult Sydney rock oysters, of either sex or both, to the synthetic estrogen 17α-ethinylestradiol (EE2) at 50 ng/L for 21 days, followed by an examination of developmental endpoints and transcriptomic responses in unexposed larvae. Reduced survival was observed at 1 day post-fertilisation (dpf) in larvae from bi-parental exposure (FTMT). Motile larvae at 2 dpf were fewer from maternal (FTMC), paternal (FCMT), and FTMT exposures. Additionally, shell length at 7 dpf decreased in larvae from FTMC and FTMT parents. RNA sequencing (RNA-seq) revealed 1064 differentially expressed genes (DEGs) in 1-dpf larvae from FTMT parents, while fewer DEGs were detected in larvae from FTMC and FCMT parents, with 258 and 7, respectively. GO and KEGG analyses showed significant enrichment of DEGs in diverse terms and pathways, with limited overlap among treatment groups. IPA results indicated potential inhibition of pathways regulating energy production, larval development, transcription, and detoxification of reactive oxygen species in FTMT larvae. qRT-PCR validation confirmed significant downregulation of selected DEGs involved in these pathways and relevant biological processes, as identified in the RNA-seq dataset. Overall, our results suggest that the intergenerational toxicity of EE2 is primarily maternally transmitted, with bi-parental exposure amplifying these effects.

Natural mineral colloids facilitated transport of EE2 in saturated porous media: Effects of humic acid and conjugate form.

Steroid estrogens have posed significant ecological risks to aquatic organisms due to their potent endocrine-disrupting effects. The role of natural mineral colloids in facilitating the transport of hydrophobic organic pollutants in the environment has been confirmed, but the control mechanisms of colloids on 17α-Ethinylestradiol (EE2) migration in the subsurface environment are often still not well understood. This study combined the batch sorption equilibrium experiments and dynamic transport simulations to reveal the interface interactions and co-transport characteristics between illite colloids and EE2 at both macroscopic and microscopic levels. The existing form changes of EE2 and the influence of coexisting humic acid (HA) during transport in porous media were also specifically investigated. The batch experiments demonstrated that the primary mechanisms governing EE2 sorption onto illite colloids involved surface sorption and hydrogen bonding. The coexistence of HA could load onto the surface of illite colloids, thereby enhancing the colloidal sorption capacity for EE2. Transport experiments demonstrated that the migratory ability of EE2 in silty clay was limited, but illite colloids could significantly promote its penetration, with the peak penetration content (Ct/C0) increasing from 0.64 to 0.77. In the absence of HA, EE2 primarily transported in a dissolved form, accounting for 62.86% of the total concentrations. When HA concentrations were increased to 10 mg/L and 20 mg/L, the proportion of colloidal conjugate EE2 in the effluents reached 52.13% and 54.49%, respectively. The enhanced transport of EE2 by HA was primarily attributed to the improved migration ability of illite colloids and the increased proportion of illite-EE2 conjugate, resulting in a maximum Ct/C0 value of 0.94. The validity of these results was further confirmed by employing calculations based on the Derjaguin-Landau-Verwey-Overbeek and Colloidal Filtration Theory. This study provides new insights of understanding the transport of EE2 in subsurface environment.

Evaluating the toxicity of estetrol, 17α-ethinylestradiol, and their combination with drospirenone on zebrafish larvae: A behavioural and proteomic study.

OBJECTIVE: To characterise and compare the toxicity of estetrol (E4) and 17α-ethinylestradiol (EE2), and their respective mixture with the progestin drospirenone (DRSP) in zebrafish (Danio rerio) embryos. METHODS: Zebrafish embryos were exposed to E4, EE2, DRSP, E4+DRSP, and EE2+DRSP in a fish embryo acute toxicity (FET) test. A second test examined behavioural responses and, using label-free proteomics, identified changes in protein expression in response to hormonal treatments, across a range of concentrations, including those that are considered to be environmentally relevant. RESULTS: In the FET test, no effects were found from E4 at concentrations ≤100 mg/L, while EE2 induced mortality and morphological abnormalities at concentrations of 1-2 mg/L. In the behavioural test, exposure to 30 ng/L EE2 (∼200 × predicted environmental concentration - PEC) resulted in hypoactivity in fish larvae and exposure to 0.3 ng/L EE2 (∼2 × PEC) led to quantitative changes in protein abundance, revealing potential impacts on RNA processing and protein synthesis machinery. Exposure to E4 did not alter behaviour, but several groups of proteins were modulated, mainly at 710 ng/L (∼200 × PEC), including proteins involved in oxidative phosphorylation. When combined with DRSP, EE2 induced reduced effects on behaviour and proteomic responses, suggesting an antagonistic effect of DRSP. E4+DRSP induced no significant effects on behaviour or proteomic profiles at tested concentrations. CONCLUSIONS: These findings suggest that E4-based combined oral contraceptives present a more favourable environmental profile than EE2-based contraceptives, particularly during the early developmental stages of fish.

Curative effect of motherwort combined with ethinylestradiol-cyproterone acetate on dysfunctional uterine bleeding.

OBJECTIVE: This study aimed to investigate the curative effect of motherwort combined with ethinylestradiol-cyproterone acetate (EE/CPA) on dysfunctional uterine bleeding (DUB). METHODS: Atotal of 68 patients with DUB were divided into a single medication group (treated with EE/CPA) and a combination medication group(treated with motherwort and EE/CPA). The clinical efficacy, uterine hemodynamic parameters, sex hormone levels, coagulation index levels, blood routine test levels, and adverse reactions of patients were evaluated. RESULTS: After three months of treatment, total treatment response rate of the combination medication group was significantly higher than that of the single medication group. Decreased uterine volume, endometrial thickness and resistance index (RI), increased pulsatility index(PI), average flow rate, and uterine artery blood flow, as well asreduced follicle-stimulating hormone (FSH), luteinizing hormone (LH),estradiol (E2), progesterone (P), activated partial thromboplastin time (aPTT), prothrombin time (PT), fibrinogen (FIB), thrombin time(TT), platelet count (PLT), red blood cell (RBC), and hemoglobin (Hb)levels were witnessed in patients of the two groups. In thecombination medication group, there exhibited reduced uterine volume, endometrial thickness and RI, elevated PI, average flow rate, and uterine artery blood flow, reduced P, E2, FSH, LH, aPTT, PT, FIB, TT,PLT, RBC, and Hb levels in comparison to the single medication group. CONCLUSION: The combination of motherwort and EE/CPA is clinically effective in the treatment of DUB.

Oestrogens in oral contraception: considerations for tailoring prescription to women's needs.

BACKGROUND: The oestrogenic component of combined oral contraceptives (COCs) has changed over years with the aim of reducing oestrogen-related side effects and risks, whilst maintaining oestrogen beneficial effects, particularly on cycle control. PURPOSE: To describe the pharmacological profiles of different oestrogens commonly used in COCs to provide insights on contraceptive prescription tailored to women's needs. RESULTS: All COCs ensure a high contraceptive efficacy. COCs containing the natural oestrogens oestradiol (E2), oestradiol valerate (E2V) and estetrol (E4) have limited impact on liver metabolism, lipid and carbohydrate metabolism, haemostasis and sex hormone binding globulin levels, compared with ethinylestradiol (EE). COCs with E2 and E2V appear also to entail a lower elevation of the risk of venous thromboembolism vs. EE-containing pills. No epidemiological data are available for E4-COC. E2- and E2V-containing COCs seem to exert a less stabilising oestrogenic effect on the endometrium compared with EE-COCs. The E4-COC results in a predictable bleeding pattern with a high rate of scheduled bleeding and minimal unscheduled bleeding per cycle. Based on in vitro and in vivo animal data, E4 seems to be associated with a lower effect on cell breast proliferation. CONCLUSION: Today various COCs contain different oestrogens. Prescribers must be familiar with the different properties of each oestrogen for a tailored contraceptive recommendation, considering their safety and contraceptive efficacy, as well as women's needs and preferences.

For contraceptive pills physicians can choose among different oestrogens, besides many progestins. Natural oestrogens have less metabolic impact vs EE, while EE and E4 seem to provide a better cycle control. Knowing the different oestrogen characteristics is crucial for adjusting pill prescription to women's needs and desires.

Correlation of sexual desire with sexual hormone binding globulin and free androgen index in women using combined contraceptives.

PURPOSE: To correlate the sexual desire levels with sexual hormone binding globulin and free androgen index in women taking different types of hormonal contraceptives (HCs) containing ethinylestradiol (EE), oestradiol valerate (E2V), 17ß-oestradiol (E2), or estetrol (E4), combined or in phasic formulation with different progestogens having antiandrogenic properties. METHODS: Three hundred and sixty-seven women (age range 18-46) participated in the study. SHBG and total testosterone (TT) were measured, and the Free Androgen Index (FAI) was calculated. The Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale (FSDS) questionnaires were used to assess sexual function and distress, respectively. RESULTS: The highest SHBG values and the lowest FAIs were obtained of women on HCs containing EE than those of women on HCs containing E2V/17ß E2 or E4 (p < 0.001). Desire scores and FSFI total scores were lower in women on HCs with EE than in those using HCs containing E2V, 17ß E2, or E4 (p ≤ 0.001). The women who were on HCs containing EE reported FSDS levels higher than those containing all the other types of oestrogen. Finally, sexual desire and FSFI total scores had a negative correlation with the SHBG values and a positive correlation with FAI percentage (p ≤ 0.0001). CONCLUSIONS: A minority of women using HCs with EE might experience a decreased sexual desire. This was not observed in women on HCs containing E2V, 17 E2, or E4. To avoid HC discontinuation, due to sexual desire reduction, HCs having minor antiandrogenic effects could be taken into consideration.

A Proof-of-Concept for a Hypolipidemic Brown Trout Model.

The impacts of hypolipidemic pharmaceuticals on fish lipid metabolism remain unexplored. However, data points to similar effects and mechanisms of action between fish and humans. Therefore, fish may be a strong model for screening hypolipidemic drug candidates and water pollution by lipid-modulating agents. This study aimed to test a new hypolipidemic model assay with juvenile brown trout using atorvastatin (ATV)-a hypolipidemic chemical. We selected 17α-ethinylestradiol (EE2), known to cause hyperlipidemia in fish, to ensure model functionality. Fish received intramuscular injections of 4 µL/g for two weeks under the following experimental conditions: control-C (0.7% NaCl), solvent control-SC (0.7% NaCl, 0.9% ethanol, 0.1% dimethyl sulfoxide), ATV (0.3 µg/g), EE2 (2 µg/g), and a mixture of both compounds-MIX (0.3 µg/g ATV and 2 µg/g EE2). Endpoints included blood lipid biochemistry, hepatic lipid droplet quantification, and liver mRNA expression of lipid-related target genes (related to lipogenesis, lipid transport, and ß-oxidation pathways). ATV lowered blood total cholesterol, high-density lipoproteins (HDL), and low-density lipoproteins (LDL) levels, whilst triglycerides and very-low-density lipoproteins (VLDL) were highest under EE2. Hepatic lipid droplet deposition significantly increased in the ATV, EE2, and MIX groups. ATV and MIX caused a significant downregulation of the peroxisome proliferator-activated receptor γ (pparγ) and acetyl Co-A oxidase 3 (acox3). EE2 upregulated acyl-CoA long-chain synthetase 1 (acsl1) and downregulated both fatty acid binding protein 1 (fabp1) and acetyl Co-A oxidase 1-3I (acox1-3I). ATV caused hypolipidemic effects in juvenile brown trout and could even counteract EE2-stimulated hyperlipidemia, reinforcing the potential of fish hypo- and hyperlipidemic models.

Adenomyotic Lesions Are Induced in the Mouse Uterus after Exposure to NSAID and EE2 Mixtures at Environmental Doses.

The aim of this study was to assess the long-term effect of exposure to environmentally relevant doses of non-steroidal anti-inflammatory drugs (NSAIDs; ibuprofen, and diclofenac) and 17ß-ethinylestradiol (EE2) on the mouse uterus. NSAID-EE2 mixtures were administered in the drinking water from gestational day 8 until 8 weeks post-birth (i.e., during embryo development, lactation, puberty, and sexual maturity). The incidence of adenomyosis lesions (presence of endometrial glands in the inner myometrium) increased up to 60% in the uterus of 8-week-old exposed females (F1) and to 85% in F2 females (exposed father). Histological analysis revealed aberrant proliferation and apoptosis, vacuolization of epithelial cells, and increased incidence of abnormal glands in the luminal and glandular epithelium in F1 and F2 uteri. Moreover, myofibroblast proportion (alpha-smooth muscle actin (α-SMA) expression analysis) and collagen expression (Picrosirius red stain; a fibrosis hallmark) were increased in F1 and F2 endometrium. Connexin-43 was aberrantly distributed in the endometrial stroma and glands of F1 and F2 uteri. Conversely, uterine 17ß-estradiol and progesterone levels were not affected in F1 and F2 females. These findings demonstrated that in mice, chronic exposure to NSAID and EE2 mixtures at environmental doses intergenerationally affects uterine physiology, particularly the endometrium. It may serve as a model to study the pathophysiology of human adenomyosis.

Core-Shell Nanocables Decorated with Carbon Spherical Shells and Silver Nanoparticles for Sensing Ethinylestradiol Hormone in Water Sources and Pills.

The selective, rapid detection of low levels of hormones in drinking water and foodstuffs requires materials suitable for inexpensive sensing platforms. We report on core-shell Ag@C nanocables (NCs) decorated with carbon spherical shells (CSSs) and silver nanoparticles (AgNPs) by using a hydrothermal green approach. Sensors were fabricated with homogeneous, porous films on screen-printed electrodes, which comprised a 115 nm silver core covered by a 122 nm thick carbon layer and CSSs with 168 nm in diameter. NCs and CSSs were also decorated with 10-25 nm AgNPs. The NC/CSS/AgNP sensor was used to detect ethinylestradiol using square wave voltammetry in 0.1 M phosphate buffer (pH 7.0) over the 1.0-10.0 µM linear range with a detection limit of 0.76 µM. The sensor was then applied to detect ethinylestradiol in tap water samples and a contraceptive pill with recovery percentages between 93 and 101%. The high performance in terms of sensitivity and selectivity for hormones is attributed to the synergy between the carbon nanomaterials and AgNPs, which not only increased the sensor surface area and provided sites for electron exchange but also imparted an increased surface area.

Ursodeoxycholic acid and 18ß-glycyrrhetinic acid alleviate ethinylestradiol-induced cholestasis via downregulating RORγt and CXCR3 signaling pathway in iNKT cells.

Estrogen-induced intrahepatic cholestasis (IHC) is a mild but potentially serious risk and urges for new therapeutic targets and effective treatment. Our previous study demonstrated that RORγt and CXCR3 signaling pathway of invariant natural killer T (iNKT) 17 cells play pathogenic roles in 17α-ethinylestradiol (EE)-induced IHC. Ursodeoxycholic acid (UDCA) and 18ß-glycyrrhetinic acid (GA) present a protective effect on IHC partially due to their immunomodulatory properties. Hence in present study, we aim to investigate the effectiveness of UDCA and 18ß-GA in vitro and verify the accessibility of the above targets. Biochemical index measurement indicated that UDCA and 18ß-GA presented efficacy to alleviate EE-induced cholestatic cytotoxicity. Both UDCA and 18ß-GA exhibited suppression on the CXCL9/10-CXCR3 axis, and significantly restrained the expression of RORγt in vitro. In conclusion, our observations provide new therapeutic targets of UDCA and 18ß-GA, and 18ß-GA as an alternative treatment for EE-induced cholestasis.