RESUMEN
Endometriosis is one of the most frequent gynecologic disorders. The pathognomonic symptom of endometriosis is pelvic pain. The recommended pain medications are oral hormonal contraceptives, progestin therapy, danazol, gonadotropin-releasing hormone analogs, nonsteroidal anti-inflammatory drugs, and aromatase inhibitors. In this study, we aimed to compare the efficiency of costing dienogest (DNG) and low-cost oral contraceptives regarding visual analog scores (VAS) score of pelvic pain and also cancer antigen-125 (CA-125), anti-Mullerian hormone (AMH) levels, and size of endometrioma in the patients with endometriosis which is a chronic disease that requires a lifelong management plan. In our study, 18 to 45-year-old patients presented to our institution's gynecology and obstetrician department for various complaints over 2 years, and endometriosis diagnoses were included. Patients were divided into 3 groups (20 patients in each medication group) according to the given medication: cyclic DNG (Visanne) or 0.03 mg ethinylestradiol combined with 2 mg DNG (Dienille) or estradiol valerate combined with 2 mg DNG (Qlarista). We recorded all patients' CA-125/AMH values and VAS scores of pelvic pain. All patients gave informed consent. There was no statistically significant difference between pre-medication and post-medication levels of CA-125, AMH, VAS score, and cyst size in all groups. However, statistically, significant decreases were seen in the cyst size and VAS score, indicating response to therapy in all groups. In conclusion, we think it is more reasonable to use cost-effective oral contraceptive medications, which also cause common side effects, instead of costing DNG since all drugs have the same efficiency and success.
Asunto(s)
Endometriosis , Estradiol , Etinilestradiol , Nandrolona , Dimensión del Dolor , Dolor Pélvico , Humanos , Femenino , Endometriosis/tratamiento farmacológico , Endometriosis/complicaciones , Nandrolona/análogos & derivados , Nandrolona/uso terapéutico , Nandrolona/administración & dosificación , Adulto , Estudios Prospectivos , Dolor Pélvico/tratamiento farmacológico , Dolor Pélvico/etiología , Etinilestradiol/uso terapéutico , Etinilestradiol/administración & dosificación , Estradiol/análogos & derivados , Estradiol/uso terapéutico , Persona de Mediana Edad , Combinación de Medicamentos , Antígeno Ca-125/sangre , Adulto Joven , Hormona Antimülleriana/sangre , AdolescenteRESUMEN
The patient, an 83-year-old woman, was diagnosed with ER- and PgR-positive left breast cancer(T2N0M0, Stage â ¡A) at the age of 68. At the time, she underwent preoperative chemotherapy followed by Bp+Ax and postoperative radiotherapy to the conserved breast. She also received endocrine therapy as adjuvant therapy. At the age of 73, she underwent radiotherapy for multiple bone metastases and left axillary lymphadenectomy due to left axillary lymph node recurrence. After surgery, she received 4 regimens of endocrine therapy over a period of 5 years and 1 month for bone metastases. At the age of 79, S-1 was administered for pulmonary metastasis which continued for the next 2 years and 8 months. At the age of 81, palbociclib+letrozole were administered for 1 year and 8 months owing to the progression of bone metastases. At the age of 83, she developed liver metastases and was administered ethinyl estradiol, starting at 1.5 mg/day and continued at a reduced dose of 0.5 mg/day for 9 months. The reduction in tumor markers after treatment initiation was rapid, and there were no serious adverse events. Ethinyl estradiol was useful for maintaining QOL in this elderly patient with recurrent breast cancer.
Asunto(s)
Neoplasias de la Mama , Etinilestradiol , Recurrencia , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Etinilestradiol/administración & dosificación , Etinilestradiol/uso terapéutico , Anciano de 80 o más Años , Receptores de Estrógenos/análisis , Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos Hormonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Receptores de Progesterona/metabolismoRESUMEN
This bioequivalence research aims to evaluate the relative bioavailability and pharmacokinetic characteristics of ethinyl estradiol and drospirenone in the test preparation in comparison to the reference preparation during fasting conditions. A liquid chromatography method with tandem mass spectrometry was used to determine the concentrations of drospirenone and ethinyl estradiol in plasma. The pharmacokinetic parameters that were analyzed were the maximum plasma concentration (Cmax), time to achieve Cmax (tmax), elimination half life, and area under the concentration time curve of plasma (AUC0-t, AUC0-∞ for ethinyl estradiol, and AUC0-72h for drospirenone). Both the AUC and Cmax parameters were determined to be between 80.00% and 125.00% (90% confidence intervals), which is the acceptable range. Based on the study findings, it was concluded that the test formulation, which includes 3 mg of drospirenone and 0.03 mg of ethinyl estradiol, demonstrated bioequivalence when compared to the reference formulation.
Asunto(s)
Androstenos , Área Bajo la Curva , Etinilestradiol , Ayuno , Comprimidos , Equivalencia Terapéutica , Humanos , Etinilestradiol/farmacocinética , Etinilestradiol/administración & dosificación , Etinilestradiol/sangre , Femenino , Androstenos/farmacocinética , Androstenos/administración & dosificación , Adulto , Adulto Joven , Estudios Cruzados , Disponibilidad Biológica , Voluntarios Sanos , Combinación de Medicamentos , Espectrometría de Masas en Tándem/métodos , SemividaRESUMEN
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.
Asunto(s)
Etinilestradiol , Larva , Ostreidae , Transcriptoma , Contaminantes Químicos del Agua , Animales , Etinilestradiol/toxicidad , Larva/efectos de los fármacos , Larva/crecimiento & desarrollo , Transcriptoma/efectos de los fármacos , Ostreidae/efectos de los fármacos , Ostreidae/crecimiento & desarrollo , Ostreidae/genética , Femenino , Contaminantes Químicos del Agua/toxicidad , Masculino , Exposición Materna , Exposición Paterna/efectos adversosRESUMEN
In this study, the spectrophotometric method integrated with continuous wavelet transform (CWT) and coupled discrete wavelet transform (DWT) with fuzzy inference system (FIS) was developed for the simultaneous determination of ethinyl estradiol (EE) and drospirenone (DP) in combined oral contraceptives (COCs). The CWT approach was performed in the linearity range of 0.6-6 µg/mL for EE and 0.9 to 18 µg/mL for DP. Biorthogonal with an order of 1.3 (bior1.3) at a wavelength of 216 nm and Daubechies with an order of 2 (db2) at a wavelength of 278 nm were selected as the best wavelet families for obtaining the best zero crossing point for EE and DP, respectively. The limit of detection (LOD) of 0.7677 and 0.3222 µg/mL and the limit of quantification (LOQ) of 2.326 and 0.9765 µg/mL were obtained for EE and DP, respectively. The mean recovery of 103.24% and 99.77%, as well as root mean square error (RMSE) of 0.1896 and 0.1969, were found for EE and DP, respectively. In the DWT, the absorption of the mixtures was decomposed using different wavelets named db4, db2, Symlet2 (sym2), and bior1.3. Each of the wavelet outputs was dimension reduced by the principal component analysis (PCA) method and considered as FIS input. The wavelet of db4 with the coefficient of determination (R2) of 0.9979, RMSE of 0.0968, and mean recovery of 100.63% was chosen as the best one for the EE, while bior1.3 with R2 of 0.9955, RMSE of 0.4055, and mean recovery of 101.93% was selected for DP. These methods were successfully used to analyze the EE and DP simultaneously in tablet pharmaceutical formulation without any separation step. The suggested methods were compared with a reference method (HPLC) using analysis of variance (ANOVA) at a 95% confidence level, and no significant difference was observed in terms of accuracy. The suggested chemometric methods are reliable, rapid, and inexpensive, and can be used as an environmentally friendly alternative to HPLC for the simultaneous estimation of the mentioned drugs in commercial pharmaceutical products.
Asunto(s)
Androstenos , Anticonceptivos Orales Combinados , Etinilestradiol , Lógica Difusa , Límite de Detección , Análisis de Componente Principal , Análisis de Ondículas , Etinilestradiol/análisis , Androstenos/análisis , Anticonceptivos Orales Combinados/análisis , HumanosRESUMEN
We compared the efficacy of 4 mg drospirenone (DRSP) progestin-only pills (POPs) versus combined oral contraceptive pills (COCs) containing 0.02 mg of ethinyl estradiol (EE) and 0.075 mg of gestodene (GS) in ovulation inhibition and inducing unfavorable cervical mucus changes using a delayed-starting approach. This randomized controlled trial involved 36 participants aged 18-45 years. The major outcomes included ovulation inhibition assessed using the Hoogland and Skouby score, and cervical mucus permeability, assessed using the modified World Health Organization score. The results demonstrated ovulation inhibition rates of 77.8% for the EE/GS group and 88.9% for the DRSP group. The risk ratio and absolute risk reduction were 0.50 (95% confidence interval [CI]: 0.10, 2.40) and - 0.11 (95% CI: - 0.35, 0.13), respectively, satisfying the 20% non-inferiority margin threshold. The median time to achieve unfavorable cervical mucus changes was comparable between the DRSP (3 days, interquartile range [IQR]: 6 days) and EE/GS (3.5 days, IQR: 4 days) groups. However, the DRSP group had a higher incidence of unscheduled vaginal bleeding (55.56% vs. 11.11%; p = 0.005). DRSP-only pills, initiated on days 7-9 of the menstrual cycle, were non-inferior to EE/GS pills in ovulation inhibition. However, they exhibited delayed unfavorable cervical mucus changes compared to the standard two-day backup recommendation.Clinical trial registration: Thai Clinical Trials Registry (TCTR20220819001) https://www.thaiclinicaltrials.org/show/TCTR20220819001 .
Asunto(s)
Androstenos , Anticonceptivos Orales Combinados , Etinilestradiol , Inhibición de la Ovulación , Humanos , Femenino , Adulto , Etinilestradiol/administración & dosificación , Androstenos/administración & dosificación , Androstenos/efectos adversos , Adulto Joven , Adolescente , Anticonceptivos Orales Combinados/administración & dosificación , Inhibición de la Ovulación/efectos de los fármacos , Método Simple Ciego , Persona de Mediana Edad , Norpregnenos/administración & dosificación , Norpregnenos/efectos adversos , Ovulación/efectos de los fármacos , Moco del Cuello Uterino/efectos de los fármacosRESUMEN
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.
Asunto(s)
Coloides , Etinilestradiol , Sustancias Húmicas , Contaminantes Químicos del Agua , Coloides/química , Etinilestradiol/química , Porosidad , Adsorción , Contaminantes Químicos del Agua/química , Minerales/químicaRESUMEN
PURPOSE: To evaluate the initial impact of a combined oral contraceptive (COC) containing norgestimate (NGM) on female sexuality and on circulating androgen levels in users. MATERIALS AND METHODS: Six months modification in the McCoy Female Sexuality Questionnaire (MFSQ) and testosterone (T) and dehydroepiandrosterone sulphate (DHEAS) serum levels in women starting a monophasic pill containing ethinyl-estradiol (EE) 35 µg and NGM 0.250 mg. RESULTS: The study was completed by 36 subjects. There was a significant increase in MFSQ during treatment (p < 0.0001) (and its domains with the exclusion of vaginal lubrication domain) with concomitant decreases in T (-4.45%, p < 0.0001) and DHEAS (-19.41%, p < 0.0001) serum levels. CONCLUSIONS: Contraception with EE/NGM was associated with a short term non-deteriorating effect on sexuality despite the evident decrease in androgen levels. Female sexuality during COC use is a complex topic and is not only linked with changes in serum androgen levels.
EE/NGM treatment has a short term non-deteriorating effect on sexuality despite the evident decrease in androgen serum levels.
Asunto(s)
Anticonceptivos Orales Combinados , Etinilestradiol , Testosterona , Humanos , Femenino , Proyectos Piloto , Etinilestradiol/farmacología , Etinilestradiol/administración & dosificación , Adulto , Testosterona/sangre , Anticonceptivos Orales Combinados/farmacología , Sulfato de Deshidroepiandrosterona/sangre , Andrógenos/sangre , Sexualidad/efectos de los fármacos , Nandrolona/análogos & derivados , Nandrolona/farmacología , Encuestas y Cuestionarios , Adulto Joven , Norgestrel/análogos & derivadosRESUMEN
The ubiquitous and adverse effects of estrogens have aroused global concerns. Natural and synthetic estrogens in 255 water samples from the southern Bohai Sea were analyzed over three years. Total estrogen concentrations were 11.0-268 ng/L in river water and 1.98-99.7 ng/L in seawater, with bisphenol A (BPA) and 17α-ethynylestradiol (EE2) being the predominant estrogens, respectively. Estrogen showed the highest concentrations in summer 2018, followed by spring 2021 and spring 2019, which was consistent with the higher estrogen flux from rivers during summer. Higher estrogen concentrations in 2021 than in 2019 were driven by the higher level of BPA, an additive used in personal protective equipment. Estrogen exhibited higher concentrations in the southern coast of the Yellow River Delta and the northeastern coast of Laizhou bay due to the riverine input and aquaculture. Estrogens could disturb the normal endocrine activities of organisms and edict high ecological risks (90th simulated RQT > 1.0) to aquatic organisms, especially to fish. EE2 was the main contributor of estrogenic potency and ecological risk, which requires special concern. This is the first comprehensive study of estrogen spatiotemporal variations and risks in the Bohai Sea, providing insights into the environmental behavior of estrogens in coastal regions.
Asunto(s)
Monitoreo del Ambiente , Estrógenos , Agua de Mar , Contaminantes Químicos del Agua , Contaminantes Químicos del Agua/análisis , Medición de Riesgo , Estrógenos/análisis , Agua de Mar/química , Agua de Mar/análisis , China , Animales , Disruptores Endocrinos/análisis , Disruptores Endocrinos/toxicidad , Ríos/química , Fenoles/análisis , Fenoles/toxicidad , Compuestos de Bencidrilo/análisis , Etinilestradiol/análisis , Océanos y Mares , Estaciones del AñoRESUMEN
Oral contraceptive pills, of all types, are used by approximately 151 million women worldwide; however, a clear understanding of the concentrations of endogenous and exogenous hormones across a 28-day combination monophasic oral contraceptive pill pack is not well described. In our study of 14 female participants taking various combination monophasic oral contraceptive pills, we found significant fluctuations in endogenous and exogenous hormone levels throughout the pill cycle. Our analysis revealed significantly greater levels of ethinyl estradiol on the 20th and 21st days of active pill ingestion, compared with days 1-2 (active) and days 27-28 (inactive pill ingestion). Conversely, estradiol concentrations decreased during active pill consumption, while progestin and progesterone levels remained stable. During the 7 days of inactive pill ingestion, estradiol levels rose sharply and were significantly higher at days 27-28 compared with the mid and late active phase time points, while ethinyl estradiol declined and progestin did not change. These findings challenge the previous assumption that endogenous and exogenous hormones are stable throughout the 28-day pill cycle.NEW & NOTEWORTHY The results from this study have wide-ranging implications for research and treatment in women's health including considerations in research design and interpretation for studies including women taking oral contraceptives, the potential for more precise and personalized methods of dosing to reduce unwanted side effects and adverse events, and the potential treatment of a variety of disorders ranging from musculoskeletal to neurological with exogenous hormones.
Asunto(s)
Anticonceptivos Orales Combinados , Estradiol , Etinilestradiol , Ciclo Menstrual , Progesterona , Espectrometría de Masas en Tándem , Humanos , Femenino , Adulto , Anticonceptivos Orales Combinados/administración & dosificación , Espectrometría de Masas en Tándem/métodos , Etinilestradiol/administración & dosificación , Etinilestradiol/sangre , Progesterona/sangre , Ciclo Menstrual/efectos de los fármacos , Ciclo Menstrual/sangre , Adulto Joven , Estradiol/sangre , Cromatografía Liquida/métodos , Progestinas/sangre , Progestinas/administración & dosificación , Anticonceptivos Hormonales Orales/administración & dosificaciónRESUMEN
This parallel-arm, phase I study investigated the potential cytochrome P450 (CYP)3A induction effect of NBI-1065845 (TAK-653), an investigational α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator in phase II development for major depressive disorder. The midazolam treatment arm received the sensitive CYP3A substrate midazolam on Day 1, followed by NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with midazolam, then NBI-1065845 alone on Day 15. The oral contraceptive treatment arm received ethinyl estradiol-levonorgestrel on Day 1, then NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with ethinyl estradiol-levonorgestrel, then NBI-1065845 alone on Days 15-17. Blood samples were collected for pharmacokinetic analyses. The midazolam treatment arm comprised 14 men and 4 women, of whom 16 completed the study. Sixteen of the 17 healthy women completed the oral contraceptive treatment arm. After multiple daily doses of NBI-1065845, the geometric mean ratios (GMRs) (90% confidence interval) for maximum observed concentration were: midazolam, 0.94 (0.79-1.13); ethinyl estradiol, 1.00 (0.87-1.15); and levonorgestrel, 0.99 (0.87-1.13). For area under the plasma concentration-time curve (AUC) from time 0 to infinity, the GMRs were as follows: midazolam, 0.88 (0.78-0.98); and ethinyl estradiol, 1.01 (0.88-1.15). For levonorgestrel, the GMR for AUC from time 0 to the last quantifiable concentration was 0.87 (0.78-0.96). These findings indicate that NBI-1065845 is not a CYP3A inducer and support its administration with CYP3A substrates. NBI-1065845 was generally well tolerated, with no new safety signals observed after coadministration of midazolam, ethinyl estradiol, or levonorgestrel.
Asunto(s)
Anticonceptivos Orales Combinados , Etinilestradiol , Levonorgestrel , Midazolam , Humanos , Midazolam/farmacocinética , Midazolam/administración & dosificación , Etinilestradiol/farmacocinética , Etinilestradiol/administración & dosificación , Etinilestradiol/efectos adversos , Femenino , Adulto , Masculino , Adulto Joven , Anticonceptivos Orales Combinados/administración & dosificación , Anticonceptivos Orales Combinados/farmacocinética , Levonorgestrel/farmacocinética , Levonorgestrel/administración & dosificación , Levonorgestrel/efectos adversos , Interacciones Farmacológicas , Combinación de Medicamentos , Voluntarios Sanos , Adolescente , Citocromo P-450 CYP3A/metabolismo , Persona de Mediana Edad , Área Bajo la Curva , Inductores del Citocromo P-450 CYP3A/administración & dosificación , Inductores del Citocromo P-450 CYP3A/farmacologíaRESUMEN
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 (â¼200 × predicted environmental concentration - PEC) resulted in hypoactivity in fish larvae and exposure to 0.3 ng/L EE2 (â¼2 × 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 (â¼200 × 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.
Asunto(s)
Androstenos , Conducta Animal , Etinilestradiol , Larva , Proteómica , Contaminantes Químicos del Agua , Pez Cebra , Animales , Etinilestradiol/toxicidad , Contaminantes Químicos del Agua/toxicidad , Androstenos/toxicidad , Conducta Animal/efectos de los fármacos , Larva/efectos de los fármacos , Embrión no Mamífero/efectos de los fármacosRESUMEN
Numerous pharmaceutical and industrial chemicals are classified as endocrine-disrupting chemicals (EDCs) that interfere with hormonal homeostasis, leading to developmental disorders and other pathologies. The synthetic estrogen 17α-ethynylestradiol (EE2) is used in oral contraceptives and other hormone therapies. EE2 and other estrogens are inadvertently introduced into aquatic environments through municipal wastewater and agricultural effluents. Exposure of male fish to estrogens increases expression of the egg yolk precursor protein vitellogenin (Vtg), which is used as a molecular marker of exposure to estrogenic EDCs. The mechanisms behind Vtg induction are not fully known, and we hypothesized that it is regulated via DNA methylation. Adult zebrafish were exposed to either dimethyl sulfoxide or 20 ng/L EE2 for 14 days. Messenger RNA (mRNA) expression and DNA methylation were assessed in male zebrafish livers at 0, 0.25, 0.5, 1, 4, 7, and 14 days of exposure; and those of females were assessed at 13 days (n ≥ 4/group/time point). To test the persistence of any changes, we included a recovery group that received EE2 for 7 days and did not receive any for the following 7 days, in the total 14-day study. Methylation of DNA at the vtg1 promoter was assessed with targeted gene bisulfite sequencing in livers of adult male and female zebrafish. A significant increase in vtg1 mRNA was observed in the EE2-exposed male fish as early as 6 h. Interestingly, DNA methylation changes were observed at 4 days. Decreases in the overall methylation of the vtg1 promoter in exposed males resulted in levels comparable to those in female controls, suggesting feminization. Importantly, DNA methylation levels in males remained significantly impacted after 7 days post-EE2 removal, unlike mRNA levels. These data identify an epigenetic mark of feminization that may serve as an indicator of not only estrogenic exposure but also previous exposure to EE2. Environ Toxicol Chem 2024;43:1547-1556. © 2024 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
Asunto(s)
Islas de CpG , Metilación de ADN , Etinilestradiol , Regiones Promotoras Genéticas , Vitelogeninas , Contaminantes Químicos del Agua , Pez Cebra , Animales , Pez Cebra/genética , Masculino , Etinilestradiol/toxicidad , Metilación de ADN/efectos de los fármacos , Vitelogeninas/genética , Vitelogeninas/metabolismo , Femenino , Contaminantes Químicos del Agua/toxicidad , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Disruptores Endocrinos/toxicidadRESUMEN
The endothelin A receptor antagonist zibotentan, combined with the sodium-glucose co-transporter-2 inhibitor dapagliflozin, is being investigated for the treatment of chronic kidney disease with high proteinuria. To allow women of childbearing potential access to this treatment, highly effective contraception is required and drug interactions compromising contraception reliability must be avoided. This study investigated the risk of pharmacokinetic (PK) interaction between zibotentan and the contraceptives ethinyl estradiol and levonorgestrel. A single-sequence, within-participant comparison study was conducted in 24 healthy women of non-childbearing potential, comparing the PK of ethinyl estradiol/levonorgestrel alone and with zibotentan. Single oral doses of 0.06 mg ethinyl estradiol/0.3 mg levonorgestrel were administered on Days 1 and 15; zibotentan 10 mg was dosed orally, once-daily through Days 6-19. PK profiles were determined and ethinyl estradiol/levonorgestrel PK was compared between Day 1 and 15 based on geometric least-squares mean ratios of PK parameters, including maximum observed concentration (Cmax) and area under the plasma concentration-time curve from zero to infinity (AUCinf). Co-administration with zibotentan did not affect ethinyl estradiol PK (geometric mean ratio [90% confidence interval] Cmax 1.05 [0.99-1.11], AUCinf 1.00 [0.96-1.05]), while a weak interaction (increased exposure) was observed for levonorgestrel (Cmax 1.12 [1.02-1.23], AUCinf 1.30 [1.21-1.39]), which was regarded as without clinical relevance. Plasma exposure of ethinyl estradiol/levonorgestrel was not reduced by multiple-dose zibotentan. In conclusion, contraception containing ethinyl estradiol/levonorgestrel is regarded possible under zibotentan-containing treatments. This expands choices for women of childbearing potential, supporting diversity in the ZENITH High Proteinuria trial.
Asunto(s)
Anticonceptivos Orales Combinados , Interacciones Farmacológicas , Etinilestradiol , Levonorgestrel , Humanos , Femenino , Etinilestradiol/farmacocinética , Etinilestradiol/administración & dosificación , Etinilestradiol/efectos adversos , Levonorgestrel/farmacocinética , Levonorgestrel/administración & dosificación , Levonorgestrel/efectos adversos , Adulto , Adulto Joven , Anticonceptivos Orales Combinados/farmacocinética , Anticonceptivos Orales Combinados/administración & dosificación , Combinación de Medicamentos , Antagonistas de los Receptores de la Endotelina A/farmacocinética , Antagonistas de los Receptores de la Endotelina A/administración & dosificación , Área Bajo la CurvaRESUMEN
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.
Asunto(s)
Acetato de Ciproterona , Etinilestradiol , Humanos , Femenino , Acetato de Ciproterona/uso terapéutico , Etinilestradiol/uso terapéutico , Adulto , Resultado del Tratamiento , Metrorragia/tratamiento farmacológico , Metrorragia/etiología , Combinación de Medicamentos , Persona de Mediana Edad , Quimioterapia Combinada , Leonurus/químicaRESUMEN
Combined oral contraceptives, comprising of both an oestrogen and a progestin component, are released in aquatic environments and potentially pose a risk to aquatic wildlife by their capacity to disrupt physiological mechanisms. In this study, the endocrine disruptive potential of two mixtures, 17α-ethinylestradiol (EE2), a synthetic oestrogen, or estetrol (E4), a natural oestrogen, with the progestin drospirenone (DRSP) have been characterised in three generations of zebrafish, according to an adapted Medaka Extended One Generation Reproduction Test. Zebrafish (Danio rerio) were exposed to a range of concentrations of EE2/DRSP and E4/DRSP (â¼1×, â¼3×, â¼10× and â¼30× predicted environmental concentration, PEC). Survival, growth, hatching success, fecundity, fertilisation success, vitellogenin (VTG), gonad histopathology, sex differentiation, and transcriptional analysis of genes related to gonadal sex steroid hormones synthesis were assessed. In the F0 generation, exposure to EE2/DRSP at â¼10 and â¼30× PEC decreased fecundity and increased male VTG concentrations. The highest concentration of EE2/DRSP also affected VTG concentrations in female zebrafish and the expression of genes implicated in steroid hormones synthesis. In the F1 generation, sex determination was impaired in fish exposed to EE2/DRSP at concentrations as low as â¼3× PEC. Decreased fecundity and fertility, and abnormal gonadal histopathology were also observed. No effects were observed in the F2 generation. In contrast, E4/DRSP induced only minor histopathological changes and an increase in the proportion of males, at the highest concentration tested (â¼30× PEC) in the F1 generation and had no effect on hatching success of F2 generation. Overall, this study suggests that the combination E4/DRSP has a more favourable environmental profile than EE2/DRSP.
Asunto(s)
Androstenos , Disruptores Endocrinos , Etinilestradiol , Pez Cebra , Animales , Pez Cebra/fisiología , Etinilestradiol/toxicidad , Androstenos/toxicidad , Disruptores Endocrinos/toxicidad , Femenino , Masculino , Contaminantes Químicos del Agua/toxicidad , Vitelogeninas/metabolismo , Reproducción/efectos de los fármacosRESUMEN
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.
Asunto(s)
Anticonceptivos Orales Combinados , Estrógenos , Humanos , Femenino , Anticonceptivos Orales Combinados/farmacología , Estrógenos/farmacología , Estradiol/farmacología , Estetrol/farmacología , Tromboembolia Venosa/prevención & control , Etinilestradiol/farmacología , Etinilestradiol/efectos adversosRESUMEN
Glecaprevir/pibrentasvir (GLE/PIB) is an approved guideline-recommended chronic hepatitis C virus infection treatment. GLE/PIB coadministration with ethinyl oestradiol (EE) is not recommended in current labels owing to a Phase 1 study observing Grade ≥2 alanine aminotransferase (ALT) elevation in 2 out of 12 healthy women cotreated for 11 days with GLE/PIB and oral contraceptive (OC) containing 35 µg/250 µg EE/norgestimate. No Grade ≥2 elevation was observed with low-dose (20 µg) EE (n = 14). This Phase 1 study examined safety/tolerability of GLE/PIB coadministered with an OC containing low-dose EE using a larger sample size and longer treatment duration. Healthy premenopausal women were treated with EE/levonorgestrel alone (20/100 µg, Cycles 1-2), followed by coadministration with GLE/PIB (300/120 mg; Cycles 3-4). A safety criterion of special interest was a confirmed Grade ≥2 ALT elevation (>3× upper normal limit). Adverse events (AEs) and study drugs concentrations were examined. Of 85 enrolled women, 72 initiated combined GLE/PIB + EE/levonorgestrel treatment, 66 completed the study and 19 discontinued prematurely (non-safety reason, n = 16; AE [deemed unelated to GLE/PIB], n = 3). No participant met the safety criterion of special interest of confirmed Grade ≥2 ALT elevation. No serious/Grade ≥3 AEs were reported. Study drug concentrations were within the expected ranges. GLE/PIB in combination with an OC containing low-dose EE was generally well tolerated with no confirmed Grade ≥2 ALT elevation and no evidence of drug-induced liver injury. No pattern to the reported AEs and no new safety issues were identified. This was a Phase 1 study of healthy volunteers, not a registered clinical trial.
Asunto(s)
Antivirales , Bencimidazoles , Etinilestradiol , Voluntarios Sanos , Premenopausia , Pirrolidinas , Quinoxalinas , Sulfonamidas , Humanos , Femenino , Adulto , Bencimidazoles/efectos adversos , Bencimidazoles/administración & dosificación , Quinoxalinas/efectos adversos , Quinoxalinas/administración & dosificación , Etinilestradiol/efectos adversos , Etinilestradiol/administración & dosificación , Sulfonamidas/efectos adversos , Sulfonamidas/administración & dosificación , Antivirales/efectos adversos , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Adulto Joven , Pirrolidinas/efectos adversos , Pirrolidinas/administración & dosificación , Persona de Mediana Edad , Anticonceptivos Orales/efectos adversos , Anticonceptivos Orales/administración & dosificación , Alanina Transaminasa/sangre , Ácidos Aminoisobutíricos , Leucina/análogos & derivados , Leucina/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Combinación de MedicamentosRESUMEN
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.
Asunto(s)
Andrógenos , Anticonceptivos Orales Combinados , Anticonceptivos Hormonales Orales , Libido , Globulina de Unión a Hormona Sexual , Adolescente , Adulto , Femenino , Humanos , Persona de Mediana Edad , Adulto Joven , Andrógenos/sangre , Estetrol , Estradiol/sangre , Etinilestradiol/farmacología , Libido/efectos de los fármacos , Globulina de Unión a Hormona Sexual/metabolismo , Conducta Sexual/efectos de los fármacos , Conducta Sexual/psicología , Encuestas y Cuestionarios , Testosterona/sangreRESUMEN
BACKGROUND: Lipid metabolism changes occur in early Alzheimer's disease (AD) patients. Yet little is known about metabolic gene changes in early AD cortex. METHODS: The lipid metabolic genes selected from two datasets (GSE39420 and GSE118553) were analyzed with enrichment analysis. Protein-protein interaction network construction and correlation analyses were used to screen core genes. Literature analysis and molecular docking were applied to explore potential therapeutic drugs. RESULTS: 60 lipid metabolic genes differentially expressed in early AD patients' cortex were screened. Bioinformatics analyses revealed that up-regulated genes were mainly focused on mitochondrial fatty acid oxidation and mediating the activation of long-chain fatty acids, phosphoproteins, and cholesterol metabolism. Down-regulated genes were mainly focused on lipid transport, carboxylic acid metabolic process, and neuron apoptotic process. Literature reviews and molecular docking results indicated that ACSL1, ACSBG2, ACAA2, FABP3, ALDH5A1, and FFAR4 were core targets for lipid metabolism disorder and had a high binding affinity with compounds including adenosine phosphate, oxidized Photinus luciferin, BMS-488043, and candidate therapeutic drugs especially bisphenol A, benzo(a)pyrene, ethinyl estradiol. CONCLUSIONS: AD cortical lipid metabolism disorder was associated with the dysregulation of the PPAR signaling pathway, glycerophospholipid metabolism, adipocytokine signaling pathway, fatty acid biosynthesis, fatty acid degradation, ferroptosis, biosynthesis of unsaturated fatty acids, and fatty acid elongation. Candidate drugs including bisphenol A, benzo(a)pyrene, ethinyl estradiol, and active compounds including adenosine phosphate, oxidized Photinus luciferin, and BMS-488043 have potential therapeutic effects on cortical lipid metabolism disorder of early AD.