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AbstractObjectiveMethodResultsConclusionTrial registrationThis 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.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.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.DNG/EE treatment offers rapid, cost-effective endometrial preparation, enhancing surgical outcomes and patient satisfaction during outpatient polypectomy.ClinicalTrials.gov NCT06316206. [ABSTRACT FROM AUTHOR]

The female prostate, also known as Skene's gland, is present in both humans and rodents. Prenatal exposure to ethinylestradiol (EE2), a synthetic estrogen found in oral contraceptives, induces pormotes neoplasic prostate lesions in gerbils (Meriones unguiculatus). Conversely, pequi oil (Pe), extracted from the Brazilian Cerrado fruit, has antioxidant, anti-inflammatory, and anticancer properties, mitigates risks associated with chronic diseases related to lifestyle and aging. This study evaluates the impact of prenatal exposure to Pe (300 mg/kg) on senile gerbil offspring's male and female prostates under normal conditions and EE2 exposure (15 μg/kg/day). Histological and morphometric analyses revealed that Pe reduced male body weight and prostate epithelial height, along with a thinner muscle layer. In females, EE2 exposure reduced prostatic weight, while Pe exposure lowered epithelial height and the relative stromal compartment volume, increasing the muscle layer. Pequi oil holds potential in mitigating alterations induced by exposure to the endocrine disruptor EE2. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Ethinylestradiol and drospirenone combined oral contraceptive formulations have been marketed for >20 years. Drospirenone has antimineralocorticoid and anti-androgenic effects that may offer several health benefits. Recently, 2 new drospirenone-containing oral contraceptives entered the market, 1 as a progestin-only pill containing 4 mg drospirenone and the other as a combined oral contraceptive containing 15 mg estetrol and 3 mg drospirenone. Estetrol has a unique differential effect on nuclear and membrane estrogen α-receptors when compared with other estrogens, leading to low impact on the liver, breast, and hemostasis parameters and a beneficial effect on the endometrium, vagina, cardiovascular system, bone, and brain. Phase 3 clinical studies demonstrated that the Pearl Index (pregnancies per 100-woman-years) for drospirenone alone is 4.0 in the United States and 0.93 in the European Union and for the estetrol-drospirenone combination it is 2.65 and 0.44, respectively. Drospirenone alone demonstrates high rates of unscheduled bleeding and low rates of scheduled bleeding, whereas the estetrol-drospirenone combination demonstrates a predictable and regular bleeding profile for most users with a high stable rate of scheduled bleeding and a low rate of unscheduled bleeding, reported primarily as spotting only. The adverse event profiles and discontinuation rates owing to adverse events are comparable, and no clinically significant effects were observed on metabolic parameters with either product. Hemostatic assays for drospirenone do not fully evaluate all parameters although the testing that is available suggests negligible effects, whereas validated hemostatic assays demonstrate that the estetrol-drospirenone combination has limited impact on hemostasis. The introduction of 4 mg drospirenone and 15 mg estetrol with 3 mg drospirenone are valuable additions to the contraceptive market. Adding estetrol to 3 mg drospirenone provides advantages of contraceptive efficacy and a regular, predictable bleeding profile with minimal impact on hemostasis parameters.

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. To describe the pharmacological profiles of different oestrogens commonly used in COCs to provide insights on contraceptive prescription tailored to women's needs. 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. 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. [ABSTRACT FROM AUTHOR]

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), 17β-oestradiol (E2), or estetrol (E4), combined or in phasic formulation with different progestogens having antiandrogenic properties. 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. The highest SHBG values and the lowest FAIs were obtained of women on HCs containing EE than those of women on HCs containing E2V/17β 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, 17β 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). 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. [ABSTRACT FROM AUTHOR]

BackgroundVenous 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).MethodsA 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.ResultsThe 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 conclusionDespite 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.

Understanding species differences in sensitivity to toxicants is a critical issue in ecotoxicology. We recently established that double‐crested cormorant (DCCO) embryos are more sensitive than Japanese quail (JQ) to the developmental effects of ethinylestradiol (EE2). We explored how this difference in sensitivity between species is reflected at a transcriptomic level. The EE2 was dissolved in dimethyl sulfoxide and injected into the air cell of eggs prior to incubation at nominal concentrations of 0, 3.33, and 33.3 µg/g egg weight. At midincubation (JQ 9 days; DCCO 16 days), livers were collected from five embryos/treatment group for RNA sequencing. Data were processed and analyzed using EcoOmicsAnalyst and ExpressAnalyst. The EE2 exposure dysregulated 238 and 1,987 genes in JQ and DCCO, respectively, with 78 genes in common between the two species. These included classic biomarkers of estrogen exposure such as vitellogenin and apovitellenin. We also report DCCO‐specific dysregulation of Phase I/II enzyme‐coding genes and species‐specific transcriptional ontogeny of vitellogenin‐2. Twelve Kyoto Encyclopedia of Genes and Genomes pathways and two EcoToxModules were dysregulated in common in both species including the peroxisome proliferator‐activated receptor (PPAR) signaling pathway and fatty acid metabolism. Similar to previously reported differences at the organismal level, DCCO were more responsive to EE2 exposure than JQ at the gene expression level. Our description of differences in transcriptional responses to EE2 in early life stage birds may contribute to a better understanding of the molecular basis for species differences. Environ Toxicol Chem 2024;43:772–783. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

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 17β-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 17β-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. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to analyze the effects of combined oral contraceptive active ingredients, Drospirenone, Ethinyl Estradiol, and Ethinyl Estradiol+Drospirenone, on liver histopathological changes and endoplasmic reticulum stress levels. Material and Methods: In the study, 37 Balb/c female mice were used. Mice were randomly divided into the Control, Sham, Drospirenone, Ethinyl Estradiol, and Ethinyl Estradiol+Drospirenone groups. The experimental groups were administered with gavage to 8-week-old female mice for 35 days. Kidney tissue sections were applied with Hematoxylin&Eosin, Orcein, Mallory's Azan, and Periodic Acid-Schiff to detect histopathological changes, and Chop and Grp78 were used to detect Endoplasm Reticulum Stress. Results: Significant loss of microvilli and a decrease in glycogen accumulation were observed in the apical part of some of the proximal tubules of animals in the Drospirenone and Ethinyl Estradiol+Drospirenone groups. The amount of collagen fiber stained with Mallory's Azan increased in the parietal layer of Bowman's capsule of the kidney tissues of the Drospirenone and Ethinyl Estradiol+Drospirenone applied groups, but no difference was observed in elastic fibers in all groups. The expression level of Grp78 and Chop proteins in the kidney tubules of female mice given Drospirenone, Ethinyl Estradiol, and Ethinyl Estradiol+Drospirenone was significantly higher compared to the control group. Conclusion: In this study, it was shown that the expression of Grp78 and Chop markers detected in the mouse kidney increased as a result of Drospirenone, Ethinyl Estradiol and Ethinyl Estradiol + Drospirenone administration, thus causing kidney cell apoptosis by inducing ER-dependent death pathway activity. [ABSTRACT FROM AUTHOR]

Abstract Background Cholestasis is an important predisposing factor for hepatocyte damage, liver fibrosis, primary biliary cirrhosis, and even liver failure. Silybum marianum L. (SM) plant is used in teas or eaten in some countries due to its antioxidant and hepatoprotective properties. Because of its low and poor oral bioavailability, so we improve the therapeutic activity of Silybum marianum L. extract (SM) by studying the potential effects of nanoformulation of Silybum marianium L. extract (nano-SM) on 17α-ethinylestradiol (EE)-induced intrahepatic cholestasis. Methods Thirty female Sprague-Dawley rats were divided into 5 groups (6 rats/group). Group I: Rats were received the treatment vehicle and served as normal group. Group II:Rats were injected daily with EE (10 mg/kg) for five successive days. Group III-V: Rats were injected daily with EE (10 mg/kg) and treated with either Ursodeoxycholic acid (UDCA) (40 mg/kg), SM (100 mg/kg) and nano-SM (100 mg/kg) orally once/day throughout the trialfor five successive days, respectively. Results Nano-SM greatly dampened the increase in serum levels of total and direct bilirubin, alanine aminotransaminase, aspartate aminotransaminase, and alkaline phosphatase caused by EE. Furthermore, nano-SM increased the hepatic contents of reduced glutathione (GSH) and catalase (CAT) and also upregulated the relative hepatic gene expressions of Rho-kinase (ROCK-1), myosin light chain kinase (MLCK), and myosin phosphatase target subunit (MYPT1) compared to the EE-induced group. Administration of nano-SM reduced hepatic lipid peroxidation and downregulated the relative hepatic expressions of the nuclear factor-kappa B (NF-ҡB) and interleukin-1β (IL-1β). In addition, nano-SM improved the histopathological changes induced by EE. Conclusion Nano-SM possessed a superior effect over SM, which can be considered an effective protective modality against EE-induced cholestatic liver injury through its antioxidant, anti-inflammatory activities, and enhancing bile acid (BA) efflux.

Background: Cholestasis is an important predisposing factor for hepatocyte damage, liver fibrosis, primary biliary cirrhosis, and even liver failure. Silybum marianum L. (SM) plant is used in teas or eaten in some countries due to its antioxidant and hepatoprotective properties. Because of its low and poor oral bioavailability, so we improve the therapeutic activity of Silybum marianum L. extract (SM) by studying the potential effects of nanoformulation of Silybum marianium L. extract (nano-SM) on 17α-ethinylestradiol (EE)-induced intrahepatic cholestasis. Methods: Thirty female Sprague-Dawley rats were divided into 5 groups (6 rats/group). Group I: Rats were received the treatment vehicle and served as normal group. Group II:Rats were injected daily with EE (10 mg/kg) for five successive days. Group III-V: Rats were injected daily with EE (10 mg/kg) and treated with either Ursodeoxycholic acid (UDCA) (40 mg/kg), SM (100 mg/kg) and nano-SM (100 mg/kg) orally once/day throughout the trialfor five successive days, respectively. Results: Nano-SM greatly dampened the increase in serum levels of total and direct bilirubin, alanine aminotransaminase, aspartate aminotransaminase, and alkaline phosphatase caused by EE. Furthermore, nano-SM increased the hepatic contents of reduced glutathione (GSH) and catalase (CAT) and also upregulated the relative hepatic gene expressions of Rho-kinase (ROCK-1), myosin light chain kinase (MLCK), and myosin phosphatase target subunit (MYPT1) compared to the EE-induced group. Administration of nano-SM reduced hepatic lipid peroxidation and downregulated the relative hepatic expressions of the nuclear factor-kappa B (NF-ҡB) and interleukin-1β (IL-1β). In addition, nano-SM improved the histopathological changes induced by EE. Conclusion: Nano-SM possessed a superior effect over SM, which can be considered an effective protective modality against EE-induced cholestatic liver injury through its antioxidant, anti-inflammatory activities, and enhancing bile acid (BA) efflux. [ABSTRACT FROM AUTHOR]

Objective: We aimed to evaluate the effects of combined oral contraceptive active ingredients ethinylestradiol, drospirenone, and ethinylestradiol+drospirenone for histopathological changes, and endoplasmic reticulum stress levels in the liver. Methods: In the study, 37 to 8-week-old Balb/c female mice were used. Mice were randomly divided into the control, sham, ethinylestradiol, drospirenone, and ethinylestradiol+drospirenone groups. Experimental groups were administered ethinylestradiol, drospirenone, and ethinylestradiol+drospirenone with gavage for 35 days. In liver tissue sections, histopathological changes were detected with hematoxylin&eosin, orcein, Mallory's Azan, and periodic acid-Schiff, and the presence of endoplasmic reticulum stress was detected by Chop and Grp78 immunostaining. Results: The ethinylestradiol+drospirenone group showed significant histopathological changes compared to the control group. Some degenerative changes were noted such as swelling and size differences in hepatocytes in the ethinylestradiol+drospirenone group. When compared to the control group, an increased collagen and elastic fibers density around the vena centralis was observed in the ethinylestradiol+drospirenone group. The expression level of Grp78 protein in female mice given ethinylestradiol+drospirenone was statistically significantly increased compared to the control group. The expression level of Chop protein was significantly increased in the ethinylestradiol, drospirenone, and ethinylestradiol+drospirenone groups. Conclusion: We concluded that the use of combined oral contraceptives increases endoplasmic reticulum stress in mouse liver tissue, and as a result, it may cause liver histopathological disorders by promoting cell death. [ABSTRACT FROM AUTHOR]

Quantification of ethinylestradiol (EE) in biological matrices is challenging as it is a very potent drug with a very low Cmax (75 pg.ml−1). Despite the high sensitivity of fluorometric methods, the detection of EE was confined because its structure exhibited very limited fluorescence. Therefore, it must be derivatized first using a fluorogenic agent to produce a more potent fluorescence derivative to achieve the desired ultrasensitive bioanalysis. Here, for the first time, we proposed a promising click fluorescent probe, 4‐azido‐7‐nitrobenzoxadiazole (NBD‐AZ) to react with the alkyne group of EE, with the help of copper sulphate and l‐ascorbic acid to give a highly fluorescent and stable 1,2,3‐triazole derivative. Density functional theory calculation revealed how the triazole formation affects the quantum yield and fluorescence of click reaction product when compared with NBD‐AZ. The resulting triazole exhibited a strong signal at a wavelength of 540 nm after excitation at 470 nm. Reaction parameters impacting the intensity of fluorescence were cautiously studied and optimized. The suggested approach has shown outstanding performance, high linearity (25–300 pg.ml−1) and a low detection limit of 7.5 pg.ml−1. The enhanced sensitivity and selectivity were exploited for analyzing EE in plasma using liquid–liquid extraction for samples cleaning up without interference from any biological components and with a mean % recovery of 100.13 ± 0.39. Accuracy, sensitivity, selectivity, simplicity, and cost–effectiveness make this approach a convincing, promising, and appealing alternative to the reported analytical methods for EE bioanalysis in different matrices. [ABSTRACT FROM AUTHOR]

Ethinylestradiol and drospirenone combined oral contraceptive formulations have been marketed for >20 years. Drospirenone has antimineralocorticoid and anti-androgenic effects that may offer several health benefits. Recently, 2 new drospirenone-containing oral contraceptives entered the market, 1 as a progestin-only pill containing 4 mg drospirenone and the other as a combined oral contraceptive containing 15 mg estetrol and 3 mg drospirenone. Estetrol has a unique differential effect on nuclear and membrane estrogen α-receptors when compared with other estrogens, leading to low impact on the liver, breast, and hemostasis parameters and a beneficial effect on the endometrium, vagina, cardiovascular system, bone, and brain. Phase 3 clinical studies demonstrated that the Pearl Index (pregnancies per 100-woman-years) for drospirenone alone is 4.0 in the United States and 0.93 in the European Union and for the estetrol-drospirenone combination it is 2.65 and 0.44, respectively. Drospirenone alone demonstrates high rates of unscheduled bleeding and low rates of scheduled bleeding, whereas the estetrol-drospirenone combination demonstrates a predictable and regular bleeding profile for most users with a high stable rate of scheduled bleeding and a low rate of unscheduled bleeding, reported primarily as spotting only. The adverse event profiles and discontinuation rates owing to adverse events are comparable, and no clinically significant effects were observed on metabolic parameters with either product. Hemostatic assays for drospirenone do not fully evaluate all parameters although the testing that is available suggests negligible effects, whereas validated hemostatic assays demonstrate that the estetrol-drospirenone combination has limited impact on hemostasis. The introduction of 4 mg drospirenone and 15 mg estetrol with 3 mg drospirenone are valuable additions to the contraceptive market. Adding estetrol to 3 mg drospirenone provides advantages of contraceptive efficacy and a regular, predictable bleeding profile with minimal impact on hemostasis parameters.

Ethinylestradiol (EE) is a potent estrogen widely used to treat diseases such as breast cancer, prostate cancer, and menopausal syndrome. The poor aqueous solubility of EE leads to erratic oral absorption, resulting in suboptimal plasma levels. Developing a formulation to enhance the solubility of EE in the gastrointestinal tract would be beneficial to increase the bioavailability of EE. Thereafter, we prepare diethylenetriamine‐β‐cyclodextrin/ethinylestradiol (DETA‐β‐CD/EE) complex, aiming to increase the solubility of EE in water, and design and prepare core‐shell composite hydrogel capsules with aldocellulose and hydroxyethyl cellulose as the core and sodium alginate as the shell. The stability, swelling, drug release behavior and biocompatibility of the core‐shell hydrogel capsules are carefully investigated. And the results show that the prepared hydrogel capsules have the controlled and sustained release ability of soluble DETA‐β‐CD/EE, can achieve pH‐responding to intestinal fluid, and are non‐toxic to normal human cells. [ABSTRACT FROM AUTHOR]

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 17β-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 17β-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.

Both Food and Drugs Administration and European Medicine Agency (EMA) approve the use of a triphasic combined oral contraceptive (COC) containing ethinyl-oestradiol (EE) and norgestimate (NGM) for acne vulgaris treatment in women requiring an effective contraception. COCs can target sebum production and may also play a role in decreasing follicular hyperkeratinisation. Specific advantages of the use of an anti-androgenic progestin such as NGM in this condition are presented in this review, including the lowest venous thrombosis risk in the COCs scenario, as established by the EMA, associated with a very satisfactory cycle control. The results of aggregate analysis of published data (n = 163 vs. n = 161 treated subjects) demonstrate a significant effect in comparison with the placebo of a greater than 50% reduction, in terms of inflammatory lesions (from 19.0 to 8.2), comedones (from 35.2 to 17.7) and total lesions (from 54.3 to 25.9) count. The choice of a triphasic combination of EE/NGM seems a referenced, highly effective, easy-to-use and safe therapeutic approach for acne vulgaris, alone or in combination with different targeted drugs. Triphasic ethinyl-oestradiol and norgestimate is on label for mild to moderate acne vulgaris treatment worldwide, in women requiring an effective contraception. This combination demonstrated a significant effect in comparison with the placebo of a greater than 50% reduction, in terms of inflammatory lesions, comedones and total lesions count. [ABSTRACT FROM AUTHOR]

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IL-17 is closely associated with inflammation in intrahepatic cholestasis (IHC). Targeting IL-17 ameliorates IHC in mice. Invariant natural killer T (iNKT) cells are predominantly enriched in the liver and they mediate drug-induced liver injury through their secreted cytokines. However, whether iNKT17 cells are involved in ethinylestradiol (EE)-induced IHC remains unclear. In the present study, the administration of EE (10 mg/kg in vivo and 6.25 μM in vitro) promoted the activation and expansion of iNKT17 cells, which contributed to a novel hepatic iNKT17/Treg imbalance. iNKT cell-deficient Jα18−/− mice and the RORγt inhibitor digoxin (20 μg) alleviated EE-induced cholestatic hepatotoxicity and downregulated the IL-17 signalling pathway. In contrast, the co-administration of EE with recombinant IL-17 (1 μg) to Jα18−/− mice induced cholestatic hepatotoxicity and increased the infiltration of hepatic neutrophils and monocytes. Importantly, the administration of IL-17−/− iNKT cells (3.5 × 105) to Jα18−/− mice resulted in the attenuation of hepatotoxicity and the recruitment of fewer hepatic neutrophils and monocytes than the adoptive transfer of wild-type iNKT cells. These results indicated that iNKT17 cells could exert pathogenic effects. The recruitment and activation of iNKT17 cells could be attributed to the high level of CXCR3 expression on their surface. CXCL10 deficiency ameliorated EE-induced cholestatic liver damage, reduced hepatic CXCR3+ iNKT cells and inhibited RORγt expression. These findings suggest that iNKT17 cells play a key role in EE-induced cholestatic liver injury via CXCR3-mediated recruitment and activation. Our study provides new insights and therapeutic targets for cholestatic diseases. [ABSTRACT FROM AUTHOR]

Aquatic organisms inhabiting polluted waterways face numerous adverse effects, including physiological disruption by endocrine disrupting compounds (EDCs). Little is known about how the temperatures associated with global climate change may influence the response of organisms exposed to EDCs, and the effects that these combined stressors may have on molecular endpoints such as gene expression. We exposed Menidia beryllina (inland silversides) to environmentally relevant concentrations (1 ng/L) of two estrogenic EDCs (bifenthrin and 17α-ethinylestradiol; EE2) at 22 °C and 28 °C. We conducted this experiment over multiple generations to better understand the potential effects to chronically exposed populations in the wild. We exposed adult parental fish (F0) for 14 days prior to spawning of the next generation. F1 larvae were then exposed from fertilization until 21 days post hatch (dph) before being transferred to clean water tanks. F1 larvae were reared to adulthood, then spawned in clean water to test for further effects of parental exposure on offspring (F2 generation). Gene expression was quantified by performing qPCR on F0 and F1 gonads, as well as F1 and F2 larvae. We did not detect any significant differences in the expression of genes measured in the parental or F1 adult gonads. We found that the 28 °C EE2 treatment significantly decreased the expression of nearly all genes measured in the F1 larvae. This pattern was transferred to the F2 generation for expression of the follicle-stimulating hormone receptor (FSHR) gene. Expression of 17β-hydroxysteroid dehydrogenase (17β-HSD) and G protein-coupled receptor 30 (GPR30) revealed changes not measured in the previous generation. Effects of the bifenthrin treatments were not observed until the F2 generation, which were exposed to the chemicals indirectly as germ cells. Our results indicate that effects of EDCs and their interactions with abiotic factors, may not be adequately represented by singular generation testing. These findings will contribute to the determination of the risk of EDC contamination to organisms inhabiting contaminated waterways under changing temperature regimes.

BackgroundThe use of oral contraceptives (OCs) is associated with an increased risk of cardiovascular events such as arterial and venous thrombosis (VTE). Cardiovascular diseases (CVDs) are the leading cause of death worldwide, with low- and middle-income nations accounting for over three-quarter of CVD deaths. The aim of this systematic review is to provide a comprehensive synthesis of the available evidence on the link between OC use and CVD risk in premenopausal women and to further assess the role of geographic disparities in the reported prevalence of CVD risk in women on OCs.MethodsA comprehensive search of databases such as MEDLINE, Academic Search Complete, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Health Source: Nursing/Academic Edition was conducted, right from the inception to the present, by using the EBSCOhost search engine. The Cochrane Central Register of Clinical trials (CENTRAL) was also searched to augment relevant sources of information. OpenGrey, which is a repository of information providing open access to bibliographical references, was searched and the reference list of the selected studies was also scanned. The potential risk of bias of the included studies was assessed using the modified Downs and Black checklist. Data analysis was performed using the Review Manager (RevMan) version 5.3.ResultsWe included 25 studies that comprised 3,245 participants, of which 1,605 (49.5%) are OC users, while 1,640 (50.5%) are non-OC users. A total of 15 studies were included for meta-analysis, and the overall pooled estimates suggested a significant increase in the traditional cardiovascular risk variables [standardized mean difference (SMD) = 0.73, (0.46, 0.99) (Z = 5.41, p

17a-ethinylestradiol (EE2) is a female synthetic hormone with high estrogenic activity that can disrupt the environment, which can lead to dire health problems. The current standard method is very time-consuming and expensive, so the objective of this study is to develop chemical sensors that are faster and much cheaper to detect EE2 in water samples. In this work, an electrochemical sensor using a combination of multiwall carbon nanotubes (MWCNT), gold nanoparticles (AuNPs), and silica microspheres (Si) as a modified electrode is reported to demonstrate 17a-ethinylestradiol (EE2) detection using electrochemical analysis. MWCNT-AuNPs, MWCNT-Si, and Si-AuNPs are prepared for the development of this chemical sensor by depositing each material on the carbon electrode by using the drop casting method. The resistance and conductivity of MWCNT-AuNPs, MWCNT-Si, and Si-AuNPs modified electrodes demonstrated stable electrochemical current responses towards the detection of EE2. It demonstrates that when MWCNTs and AuNPs are combined with Si, the sensitivity and R2 value improves at EE2 concentrations ranging from 10 to 50 µM, respectively. [ABSTRACT FROM AUTHOR]

Flow injection analysis with chronoamperometry detection using a cathodically pretreated boron-doped diamond electrode (CPT-BDDE) was employed to develop and optimize a novel method for the determination of the hormones 17-α-ethinylestradiol (EE2) and cyproterone acetate (CPA). The electrochemical properties of EE2 and CPA were evaluated by cyclic voltammetry and oxidation peaks were observed at 0.97 V and 1.60 V in 0.04 mol L−1 Britton-Robinson buffer (pH 2.0). Analytical curves were linear in the concentration range from 0.070 to 10.0 µmol L−1 for EE2 and 1.0 to 80.0 µmol L−1 for CPA with detection limits of 0.023 and 0.23 µmol L−1, respectively. The developed methods presented good precision and accuracy for EE2 and CPA quantification in commercial pharmaceutical samples. The obtained results were satisfactory and consistent compared with a reference high-performance liquid chromatography method at a confidence level of 95%. Furthermore, recovery studies carried out in synthetic urine and lake water show that these methods do not suffer any significant matrix interferences and are potentially applicable for the determination of these hormones in real samples. Thus, the developed procedure for EE2 and CPA determination are simple and fast, with an analytical frequency of ∼83 determinations per hour, and attractive for routine analysis. [ABSTRACT FROM AUTHOR]

Study Question: Does an estradiol-based combined oral contraceptive (COC) have a milder effect on the serum proteome than an ethinylestradiol (EE)-based COC or dienogest (DNG) only?Summary Answer: The changes in serum proteome were multifold after the use of a synthetic EE-based COC compared to natural estrogen COC or progestin-only preparation.What Is Known Already: EE-based COCs widely affect metabolism, inflammation, hepatic protein synthesis and blood coagulation. Studies comparing serum proteomes after the use of COCs containing EE and natural estrogens are lacking.Study Design, Size, Duration: This was a spin-off from a randomized, controlled, two-center clinical trial. Women (n = 59) were randomized to use either EE + DNG, estradiol valerate (EV) + DNG or DNG only continuously for 9 weeks.Participants/materials, Setting, Methods: Participants were healthy, young, white volunteer women. Serum samples were collected before and after 9 weeks of hormonal exposure. Samples from 44 women were available for analysis (EE + DNG n = 14, EV + DNG n = 16 and DNG only n = 14). Serum proteins were analyzed by quantitative, discovery-type label-free proteomics.Main Results and the Role Of Chance: Altogether, 446 proteins/protein families with two or more unique peptides were detected and quantified. The number of proteins/families that altered over the 9-week period within the study groups was 121 for EE + DNG and 5 for EV + DNG, while no changes were detected for DNG only. When alterations were compared between the groups, significant differences were detected for 63 proteins/protein families, of which 58 were between the EE + DNG and EV + DNG groups. The most affected functions during the use of EE + DNG were the complement system, acute phase response signaling, metabolism and the coagulation system. The results were validated by fetuin-B and cortisol-binding globulin ELISA and sex hormone-binding globulin immunoassay.Large Scale Data: Data are available via ProteomeXchange with identifiers PXD033617 (low abundance fraction) and PXD033618 (high abundance fraction).Limitations, Reasons For Caution: The power analysis of the trial was not based on the proteomic analysis of this spin-off study. In the future, targeted proteomic analysis with samples from another trial should be carried out in order to confirm the results.Wider Implications Of the Findings: The EE-based COC exerted a broader effect on the serum proteome than the EV-based COC or the DNG-only preparation. These results demonstrate that the effects of EE in COCs go far beyond the established endpoint markers of estrogen action, while the EV combination is closer to the progestin-only preparation. The study indicates that EV could provide a preferable option to EE in COCs in the future and signals a need for further studies comparing the clinical health outcomes of COCs containing EE and natural estrogens.Study Funding/competing Interest(s): Funding for this researcher-initiated study was obtained from the Helsinki University Hospital research funds, the Hospital District of Helsinki and Uusimaa, the Sigrid Juselius Foundation, the Academy of Finland, the Finnish Medical Association, the University of Oulu Graduate School, the Emil Aaltonen Foundation, the Swedish Cultural Foundation in Finland, the Novo Nordisk Foundation, Orion Research Foundation and the Northern Ostrobothnia Regional Fund. The funders had no role in study design, data collection and analysis, publishing decisions or manuscript preparation. T.P. has received honoraria for lectures, consultations and research grants from Exeltis, Gedeon Richter, MSD, Merck, Pfizer, Roche, Stragen and Mithra Pharmaceuticals. O.H. occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have nothing to disclose. O.H. occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have nothing to disclose.Trial Registration Number: ClinicalTrials.gov NCT02352090.Trial Registration Date: 27 January 2015.Date Of First Patient’s Enrolment: 1 April 2015. [ABSTRACT FROM AUTHOR]

Objective: To compare the impact on thrombin generation of the new combined oral contraceptive containing 15 mg estetrol and 3 mg drospirenone with ethinylestradiol (30 or 20 mcg) associated either with 150 mcg levonorgestrel or with 3 mg drospirenone. Methods: Data were collected from the "E4/DRSP Endocrine Function, Metabolic Control and Hemostasis Study" (NCT02957630). Overall, the per-protocol set population included 24 subjects in the ethinylestradiol/levonorgestrel arm, 28 subjects in the ethinylestradiol/drospirenone arm, and 34 subjects in the estetrol/drospirenone arm. Thrombograms and thrombin generation parameters (lag time, peak, time to peak, endogenous thrombin potential, and mean velocity rate index) were extracted for each subject at baseline and after 6 cycles of treatment. Results: After 6 cycles of treatment, ethinylestradiol-containing products arms show a mean thrombogram outside the upper limit of the reference range, that is the 97.5th percentile of all baseline thrombograms. On the other hand, the mean thrombogram of estetrol/drospirenone is within this reference interval. After 6 cycles of treatment, all thrombin generation parameters are statistically less affected by estetrol/drospirenone than ethinylestradiol-containing products. Conclusions: In conclusion, an association of 15 mg estetrol with 3 mg drospirenone does not have an impact on thrombin generation compared with ethinylestradiol-containing products that, either associated with levonorgestrel or drospirenone, are able to increase the production of procoagulant factors and decrease the production of anticoagulant ones, shifting the patient to a prothrombotic state. Ethinylestradiol-containing products thus generate prothrombotic environments contrary to estetrol which demonstrates a neutral profile on hemostasis. [ABSTRACT FROM AUTHOR]

Reproductive abnormalities, that could lead to possible effects at the population level, have been observed in wild fish throughout the United States, with high prevalence in largemouth bass (LMB; Micropterus salmoides) and smallmouth bass (Micropterus dolomieu). Estrone (E1) and atrazine (ATR) are common environmental contaminants often associated with agricultural land use. 17alpha-ethinylestradiol (EE2) is a contaminant associated with wastewater treatment effluent, and a representative, well-studied estrogen commonly used for fish toxicity testing. Our objective was to assess whether early gonad recrudescence in adult fish was a period of sensitivity for alterations in reproductive condition and function. Adult male LMB were exposed from post-spawning to early gonad recrudescence to either a mixture of E1 (47.9 ng/L) + ATR (5.4 µg/L), or EE2 (2.4 ng/L) in outdoor experimental ponds. Gonad samples were collected from fish just prior to the start of exposure (July), at the end of the exposure period (December), the following spring just prior to spawning (April), and post spawning (May). Gonadosomatic index (GSI) was significantly reduced in E1 + ATR-exposed and EE2-exposed males compared to control at every post-exposure time point. Reduced sperm count and sperm motility were observed in the mixture treatment (E1 + ATR) compared to the control. Sperm motility was also reduced in the EE2 treatment. These data together indicate that estrogenic endocrine-disrupting compounds can lessen the reproductive condition of adult male LMB, and that effects of exposure during early gonad recrudescence can persist at least through the subsequent spawning cycle. [ABSTRACT FROM AUTHOR]

Objectives: Ethinylestradiol (EE)-based combined oral contraceptives (COC) affect adrenal function by altering steroid and corticosteroid-binding globulin (CBG) synthesis that may contribute to adverse effects related to these drugs. The effects of COCs containing natural estrogens remain unclear. We compared the effects of COCs containing estradiol valerate (EV) and EE on cortisol and other adrenal steroid hormones.Study Design: A spin-off study of a randomized, open-label trial. Fifty-nine healthy women were allocated to groups that engaged in the continuous use of EV+dienogest (DNG), EE+DNG, or DNG only for 9 weeks. We measured changes in adrenal steroids, CBG, and the free cortisol index (FCI).Results: Treatment with EE+DNG increased total cortisol (mean increment 668 nmol/L, p < 0.001) and cortisone (10 nmol/L, p= 0.001) levels, whereas the change from the baseline was insignificant for the EV+DNG and DNG-only groups. Dehydroepiandrosterone sulfate decreased by 24% in the EE+DNG group but remained unchanged in the EV+DNG and DNG-only groups. Aldosterone and 17-hydroxyprogesterone levels did not differ between the groups. All preparations increased CBG, but the increase in the EE+DNG group (median increment 42 µg/mL, p < 0.001) was 9- and 49-fold higher than that in the EV+DNG and DNG-only groups, respectively. The FCI remained unchanged in all study groups, indicating that cortisol and CBG mainly increased in parallel, although some individuals demonstrated larger alterations in the cortisol-CBG balance.Conclusion: In COCs, EV had a milder effect on circulating CBG and adrenal steroid levels than EE; however, further research is necessary to determine the long-term effects.Trial Registration: ClinicalTrials.gov NCT02352090 IMPLICATIONS: EV-based COC had reduced effects on circulating CBG and adrenal steroids compared to EE, probably due to a lower hepatic impact. Whether the sensitization of the adrenals to ACTH varies according to COC contents and whether it relates to experienced side effects needs to be investigated. These results encourage further research and development of contraceptives containing natural estrogens. [ABSTRACT FROM AUTHOR]

Cenerimod, a sphingosine-1-phosphate 1 receptor modulator, is in development for the treatment of systemic lupus erythematosus, a disease mainly affecting women of childbearing potential. The effect of cenerimod on the pharmacokinetics (PK) of a combined oral contraceptive (COC, 100 µg levonorgestrel and 20 µg ethinylestradiol (EE)) was investigated. A randomized, double-blind, parallel-group study was performed in 24 healthy male and female subjects. A single oral dose of COC was administered alone and after 35 days of once daily (o.d.) administration of cenerimod 0.5 (n = 10) or 4 (n = 14) mg. Exposure to EE alone or in combination with cenerimod was comparable as reflected by the geometric mean ratios and the respective 90% confidence intervals, while a slight increase in exposure (approximately 10–25%) to levonorgestrel was observed at clinically relevant concentrations of cenerimod. Overall, COC alone or in combination with cenerimod was safe and well tolerated. Two subjects reported one adverse event each (one headache after COC alone, and gastroenteritis in combination with cenerimod 4 mg). In conclusion, cenerimod does not affect the PK of levonorgestrel or EE to a clinically relevant extent. Therefore, COC can be selected as method of contraception during and after cenerimod therapy without the risk of interaction. [ABSTRACT FROM AUTHOR]

Chemical risk assessment for avian species typically depends on information from toxicity tests performed in adult birds. Early‐life stage (ELS) toxicity tests have been proposed as an alternative, but incorporation of these data into existing frameworks will require knowledge about the similarities/differences between ELS and adult responses. The present study uses transcriptomics to assess hepatic gene expression in ELS and adult Japanese quail following exposure to ethinylestradiol (EE2). Prior to incubation, ELS quail were dosed with measured EE2 concentrations of 0.54, 6.3, and 54.2 µg/g egg weight via air cell injection. Adult quail were fed a single dose of EE2 at nominal concentrations of 0, 0.5, and 5 mg/kg body weight by gavage. Liver tissue was collected from five to six individuals per dose group at mid‐incubation for ELS quail and 4 days after dosing for adults. A total of 283 and 111 differentially expressed genes (DEGs) were detected in ELS and adult quail, respectively, 16 of which were shared across life stages. Shared DEGs included estrogenic biomarkers such as vitellogenin genes and apovitellenin‐1. For the dose groups that resulted in the highest number of DEGs (ELS, 6.3 µg/g; adult, 5 mg/kg), 21 and 35 Kyoto Encyclopedia of Genes and Genomes pathways were enriched, respectively. Ten of these pathways were shared between life stages, including pathways involved with signaling molecules and interaction and the endocrine system. Taken together, our results suggest conserved mechanisms of action following estrogenic exposure across two life stages, with evidence from differential expression of key biomarker genes and enriched pathways. The present study contributes to the development and evaluation of ELS tests and toxicogenomic approaches and highlights their combined potential for screening estrogenic chemicals. Environ Toxicol Chem 2022;41:2769–2781. © 2022 SETAC [ABSTRACT FROM AUTHOR]

Worldwide, the scientific researches performed during the last years are focused on the determination of the negative effects caused by natural and antropogeneous chemical compounds on aquatic species; these species are more exposed to most pollutants than the land species, for the simple reason that the aquatic environment is the last destination for most residues. Our research team proposed to test the toxic effect caused by ethinylestradiol on embryo development in common carp (Cyprinus carpio). Common carp embryos were purchased from the fish farm S.C. Acva Prod S.R.L. Cefa, Bihor County these were obtained by artificial reproduction. After taking and selection, the fecundated spawns were introduced in 10 Nunk culture plates of 45 ml, where we introduced 40 ml water, too. We created 3 batches, with two replications, namely: batch 1 – control, batch 2 – in water, we added ethinylestradiol (EE2) in concentration of 1.5 ng L-1 and batch 3 – we added in water a concentration of 7 ng L-1 EE2. During the incubation, the Nunk plates were kept in breeding aquariums, at a temperature of 24°C. Successive to the supervision of embryos in batch 3, 48 hours post-fecundation, we could observe evolution stagnations, 70% of them being in the stage of 40 somites of the segmentation period. At the same age, 100% of the control batch- embryos entered the stage of advanced faringula, and in batch 2 all embryos were in the stage of incipient faringula. 60-72 hours post-fecundation, all embryos in the batch 3 died, 90% in the 40 somite stage of the segmentation period and 10% in the stage of incipient faringula. 85 hours post-fecundation, all embryos belonging to the control batch were in the larva stage, while in batch 2, 90% were in the larva stage and 10% died in the stage of advanced faringula.

A method for the determination of 15 sex hormones in shrimp meat by EMR solid phase extraction combined with ultra performance liquid chromatography-tandem mass spectrometry was established. The samples was extracted with 0.1 mol/L ethylenediaminetetraacetic acid disodium solution and acetonitrile solution, purified by Captiva EMR SPE cartridge, separated by CAPCELLPAK C18 BB-H (3 µm, 2.1 mm×150 mm) column, and scanned by positive and negative ions of electrospray ion source. Ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) with multiple reaction monitoring mode was used for detection, and blank matrix matching external standard method was used for quantification. The positive ion mobile phase was methanol and 0.1% formic acid, and androgen and progesterone were detected. The negative ion mobile phase was acetonitrile and 0.01% ammonia aqueous solution to detect estrogen. The results showed that the 15 kinds of sex hormone residues in shrimp meat samples purified by EMR solid phase extraction had a good linear relationship in the concentration range of 1~50 μg/kg, and the correlation coefficients (r) were all greater than 0.99. The detection limits of the method were 0.0015~0.436 μg/kg, and the quantitative limits were 0.0051~1.453 μg/kg. The average recoveries were 85.31%~119.84%, and the relative standard deviations were 2.11%~9.86% (n=6). The method was rapid, simple, reproducible and sensitive, which was suitable for the detection of 15 kinds of sex hormone residues in shrimp meat.

Ethinylestradiol (EE), is widely used to treat conditions such as breast cancer, prostate cancer and climacteric syndrome. However, due to the low water solubility of EE, the bioavailability of EE is low. Herein, to improve the bioavailability of EE, a hydrosoluble cyclodextrin drug carrier system, diethylenetriamine‐β‐cyclodextrin/ethinylestradiol (DETA‐β‐CD/EE) was prepared. High performance liquid chromatography (HPLC), fourier transform infrared (FTIR), 2D rotating frame overhauser effect spectroscopy (ROESY) spectrum and scanning electron microscope (SEM) were used to characterize the DETA‐β‐CD/EE. HPLC test showed that DETA‐β‐CD was the optimal host molecule, which can improve the solubility of EE to 496 mg L−1. Phase solubility indicated the formation of a soluble inclusion complex with 1 : 1 stoichiometry. In terms of practical application, the solubility and stability of DETA‐β‐CD/EE in blood was proved by dissolution rate studies. Overall, by the encapsulation in polysaccharide DETA‐β‐CD, the water solubility of EE is increased by 100 times. The establishment of hydrosoluble cyclodextrin drug carrier system provides support for the sustained release system or large dose drug delivery. [ABSTRACT FROM AUTHOR]

Ethinylestradiol (EE2) is classified as an estrogenic pharmaceutical compound. It is an agonist of the estrogen receptors and is approved for treating estrogen deficiency and osteoporosis prophylaxis in the short term when a choice of medicines is limited. EE2 is administered for the treatment of female hypogonadism and menstrual disorders. This strong estrogen is known to cause nausea, fluid retention, and thrombosis as side effects. It is, therefore, necessary to monitor EE2 levels in biological, environmental, and pharmaceutical samples. Various ultra-sensitive analytical methods were introduced during the last decades but modified electrochemical methods have great attention due to their undeniable properties. Here, all electrochemical analytical methods used for the determination of EE2 are considered and discussed. [ABSTRACT FROM AUTHOR]

Bleeding irregularities are one of the major reasons for discontinuation of oral contraceptives (OCs), and therefore clinicians need to set expectations during consultations. In this review we provide an overview of bleeding data of recently marketed cyclic combined OCs (COCs) and one progestin-only pill (POP). We evaluated data from phase 3 trials (≥12 months) used to gain regulatory approval. Overall, each type of OC has its own specific bleeding pattern. These patterns however were assessed by using different bleeding definitions, which hampers comparisons between products. In COCs, the estrogen balances the effects of the progestin on the endometrium, resulting in a regular bleeding pattern. However, this balance seems lost if a too low dose of ethinylestradiol (EE) (e.g., 10 µg in EE/norethindrone acetate 1 mg) is used in an attempt to lower the risk of venous thromboembolism. Replacement of EE by 17β-estradiol (E2) or E2 valerate could lead to suboptimal bleeding profile due to destabilization of the endometrium. Replacement of EE with estetrol (E4) 15 mg in the combination with drospirenone (DRSP) 3 mg is associated with a predictable and regular scheduled bleeding profile, while the POP containing DRSP 4 mg in a 24/4 regimen is associated with a higher rate of unscheduled and absence of scheduled bleeding than combined products. [ABSTRACT FROM AUTHOR]

The aim of the study was to analyse the cardiorespiratory response to exercise during an oral contraceptive (OC) cycle in endurance-trained women. Sixteen low-dose monophasic OC pill (OCP) users performed an interval-running protocol. The protocol consisted of eight 3 min bouts at 85% of participants' maximal aerobic speed (vV̇o2peak) with a 90s recovery at 30% vV̇o2peak in two OC phases: a withdrawal phase (WP) and an active pill phase (APP). The non-parametric Wilcoxon test was applied to analyse differences (p < 0.05) in performance variables between OC cycle phases. Throughout the high-intensity intervals, higher ventilation (WP 80.90 ± 11.49 L/min, APP 83.10 ± 13.33 L/min; p < 0.001) and relative perceived exertion (WP 14.51 ± 2.58, APP 15.11 ± 3.11; p = 0.001) during the APP were found, whereas carbon dioxide production (WP 2040.92 ± 262.93 mL/min, APP 2010.25 ± 305.68 mL/min; p = 0.003) was higher in the WP. During the active recovery intervals, ventilation (WP 65.78 ± 9.90 L/min, APP 67.88 ± 12.66 L/min; p < 0.001) was higher in the APP, while heart rate (WP 159.93 ± 10.26 bpm, APP 159.74 ± 12.83 bpm; p = 0.029) was higher in the WP. An increase in ventilation occurs during the APP, which is accompanied by higher perceived exertion. Therefore, coaches and athletes should be aware of these variations, especially perceived exertion, in regard to women's training programmes, in order to improve their performance, wellness and adherence to physical activity. [ABSTRACT FROM AUTHOR]

Introduction: The increased risk of venous thromboembolism associated with the use of hormonal contraception is well recognized, but evidence regarding hormonal contraception containing natural estradiol is limited. This study aimed to assess the associations between the patterns of use of different systemic hormonal contraceptives and the risk of venous thromboembolism during 2017–2019. Material and Methods: All fertile‐aged women (15–49 years) living in Finland in 2017 and using hormonal contraception in 2017 and their 1:1 age‐ and residence‐matched controls not using hormonal contraception in 2017 (altogether 587 559 women) were selected from the Prescription Centre. All incident venous thromboembolism cases during 2018–2019 and their 4:1 age‐matched controls were further analyzed in a prospective nested case–control design to assess the associations between the use (starting, stopping, continuous vs no use) of different hormonal contraception types and venous thromboembolism. Results: Altogether, 1334 venous thromboembolism cases occurred during the follow‐up period (incidence rate 1.14 per 1000 person‐years, 95% confidence interval [CI] 1.08–1.20), with an incidence rate ratio of hormonal contraception vs no hormonal contraception use of 1.42 (95% CI 1.27–1.58). Compared with non‐use, starting the use of gestodene and ethinylestradiol (adjusted odds ratio [aOR] 2.85; 95% CI 1.62–5.03), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 0.98–2.44), desogestrel and ethinylestradiol (aOR 1.97; 95% CI 0.99–3.92), and transdermal patch releasing norelgestromin and ethinylestradiol (aOR 5.10; 95% CI 1.12–23.16), as well as continuing the use of gestodene and ethinylestradiol (aOR 2.60; 95% CI 1.61–4.21), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 1.02–2.37), cyproterone‐acetate and estrogen/ethinylestradiol (aOR 1.66; 95% CI 1.06–2.61), and vaginal ring releasing etonogestrel and ethinylestradiol (aOR 3.27; 95% CI 1.95–5.48) were associated with venous thromboembolism risk. Regarding the type of estrogen, the highest risk was associated with current use (vs non use in the previous 180 days) of ethinylestradiol‐containing preparations (aOR 2.20; 95% CI 1.82–2.65), followed by estradiol‐containing preparations (aOR 1.39; 95% CI 1.04–1.87) with no risk for progestin‐only hormonal contraception. Current use of estradiol‐containing preparations was not associated with venous thromboembolism risk after exclusion of cyproterone‐acetate and estrogen/ethinylestradiol (aOR 1.05; 95% CI 0.66–1.66). Conclusions: An increased risk of venous thromboembolism is associated with ethinylestradiol‐containing combined preparations. The use of estradiol‐containing combined preparations confers only a slightly increased risk, possibly driven by cyproterone‐containing combined oral contraceptives, whereas the use of progestin‐only contraception is not associated with venous thromboembolism. [ABSTRACT FROM AUTHOR]

The present study reports the results obtained after the analysis of the thermal stability and decomposition kinetics of widely used synthetic derivative of estradiol, ethinylestradiol (EE), as a pure active pharmaceutical ingredient. As investigational tools, Fourier transformed infrared spectroscopy (FTIR), thermal analysis, and decomposition kinetics modeling of EE were employed. The kinetic study was realized using three kinetic methods, namely Kissinger, Friedman, and Flynn-Wall-Ozawa. The results of the kinetic study are in good agreement, suggesting that the main decomposition process of EE that takes place in the 175–375 °C temperature range is a single-step process, invariable during the modification of heating rate of the sample. [ABSTRACT FROM AUTHOR]

Nowadays there is a growing concern with the environment and sustainability, which means that better methods, including pollutants analysis, with less consumption of materials, organic solvents, and energy, need to be developed. Considering the almost inexistent information about the topic, the main goal of this work was to compare the environmental impacts of two analytical methods, a traditional one based on liquid chromatography with fluorescence detection and a newly developed carbon paper sensor. The selected analyte was 17α-ethinylestradiol, which is a contaminant of emergent concern in aquatic ecosystems due to its endocrine disruptor behavior. The life cycle assessment data showed that the sensor detection presents an almost negligible environmental impact when compared with the extraction step (the same for both methods) and the liquid chromatographic determination (roughly 80 times higher than with the sensor). The sensor values for all categories of damage are below 3% of the total method impacts, i.e., 1.6, 1.9, 2.4, and 2.9% for resources, climate change, human health, and ecosystem quality. The extraction represents 98.1% of the sensor environmental impacts (and 99.6% of its life cycle costing) and 38.8% of the chromatographic method. This study evidences the need of developing and applying greener analytical (detection and extraction) strategies. [ABSTRACT FROM AUTHOR]

The disease caused by SARS-CoV-2 is still considered a global pandemic. Transdermal patches (TP) with immunoregulators such as estrogen and progesterone compounds could be a feasible option to treat COVID-19 because of their accessibility and relative safety. The objective of the current study was to evaluate the additional treatment with norelgestromin and ethinylestradiol in TP on the clinical and biochemical evolution of COVID-19 patients. The present is a clinical-trial pilot study that included subjects diagnosed with COVID-19, randomized into two groups; the experimental Evra® TP (norelgestromin 6 mg and ethinylestradiol 0.60 mg) was administered such that it was applied on arrival and replaced at day 8 and day 15. The control continued with the conventional COVID-19 treatment protocol. A blood sample was taken each week in order to evaluate relevant biochemical parameters, clinical signs, and evolution. In total, 44 subjects participated in this study, 30 in the experimental group and 14 in the control group. Both groups were homogeneous in terms of age and comorbidities. The experimental group had a significantly lower hospital stay (p = 0.01), high flow supplemental oxygen (p = 0.001), mechanical ventilation (p = 0.003), and intubation (p = 0.01), and the oxygen saturation significantly increased (p = 0.01) in comparison with control group when patients were exposed to room air. A decrease in ferritin (p < 0.05) was observed, with no significant increase in ESR (p > 0.05), D dimer (p > 0.05) and platelets (p > 0.05) in an auto-controlled analysis in the experimental group. Norelgestromin and ethinylestradiol TP could be a safe and effective treatment for moderate and severe COVID-19 patients. [ABSTRACT FROM AUTHOR]

Testicular oocytes in wild adult bass (Micropterus spp.) are considered a potential indication of exposure to estrogenic compounds in municipal, agricultural, or industrial wastewater. However, our ability to interpret links between testicular oocyte occurrence in wild fish species and environmental pollutants is limited by our understanding of normal and abnormal gonadal development. We previously reported low‐to‐moderate testicular oocyte prevalence (7%–38%) among adult male bass collected from Minnesota waters with no known sources of estrogenic compounds. In the present study, two experiments were conducted in which smallmouth bass (Micropterus dolomieu) fry were exposed to control water or 17‐α‐ethinylestradiol (EE2) during gonadal differentiation, then reared in clean water for an additional period. Histological samples were evaluated at several time points during the exposure and grow‐out periods, and the sequence and timing of gonadal development in the presence of estrogen were compared with that of control fish. Testicular oocytes were not observed in any control or EE2‐exposed fish. Among groups exposed to 1.2 or 5.1 ng/L EE2 in Experiment 1 or 3.0 ng/L EE2 in Experiment 2, ovaries were observed in 100% of fish up to 90 days after exposure ceased, and approximately half of those ovaries had abnormal characteristics, suggesting that they likely developed in sex‐reversed males. Groups exposed to 0.1, 0.4, or 1.0 ng/L in Experiment 2 developed histologically normal ovaries and testes in proportions not significantly different from 1:1. These findings suggest that, while presumably able to cause sex reversal, juvenile exposure to EE2 may not be a unique cause of testicular oocytes in wild bass, although the long‐term outcomes of exposure are unknown. Environ Toxicol Chem 2022;41:1416–1428. © 2022 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

The presence of micropollutants in the environment has been detected in a number of springs in Brazil and in several other countries. Despite the low concentrations of these compounds in aquatic environments, they are capable of causing biological effects on aquatic organisms. Thus, new methods for removing these contaminants need to be pursued. This work reports the synthesis and characterization of a xerogel based on an inorganic core of rigid silica obtained by the sol-gel method, and four adsorbents were synthesized from the organofunctionalization of a silica network, with the ligands cyclohexylamine (CyA), aniline (PhA), benzylamine (BnA) and 2-picolylamine (AMPy), which showed high potential for application as an adsorbent for the emerging contaminant ethinylestradiol. The materials were characterized using IR, 13C and 29Si NMR, CHN, TGA, SEM, and BET techniques, which show that adsorbents were formed and that they are particulate, non-porous, and thermally stable up to approximately 548 K. Adsorbent properties were studied, observing the optimum pH value of 5.5 and the equilibrium time in 60 minutes. The experimental data for the adsorption isotherms were closely modeled on the Langmuir and Freundlich models, as a spontaneous process that fits both models and showing adsorption capacity values between 1.05 and 1.46 mmol g−1. The regeneration conditions with acetonitrile were tested; reuse was studied for six cycles and showed very satisfactory results. Highlights: A simple and easily obtainable method for silica matrices is described. Xerogel organofunctionalization follows a simple route for development of adsorbents. The final matrices show high adsorption capacity of the contaminant ethinylestradiol. Adsorbents showed high regeneration and reusability over 6 cycles. [ABSTRACT FROM AUTHOR]

More than 600 thousands abortions are performed annually in Russia. Women presenting for abortion care are often motivated by the pregnancy to use effective contraception; they are also at high risk for repeat unintended pregnancy. Contraceptive counseling and the supply of contraceptive methods are part of post-abortion care and positively influence the subsequent use of contraceptive methods. Oral contraceptives (OCs) following induced abortion offer a reliable method to avoid repeated abortion. Immediate administration of combined OCs after abortion may reduce vaginal bleeding time and amount, shorten the menstruation recovery period, and reduce the risk of complications and unintended pregnancies. Сombination of ethinylestradiol 30 g + drospirenone 3 mg demonstrates the advantages of a low estrogen dose with the antimineralocorticoid activity of drospirenone that is responsible for the drugs significant antiandrogenic and antimineralocorticoid effects, reflected clinically in lower rates of adverse events including less fluid retention. Сombination of ethinylestradiol 30 g + drospirenone 3 mg and Metafolin has similar contraceptive efficacy, side effect, safety and benefits profile to other drospirenone-containing contraceptives. The article presents the results of the latest studies about using of combined OCs (ethinylestradiol 30 g + drosperinone 3 mg and Metafolin) after abortion.

Abstract Purpose We aimed to evaluate the efficacy and safety of 28‐day Cyclic and 84‐day Extended regimens of NPC‐16 (ethinylestradiol 0.02 mg plus levonorgestrel 0.09 mg) in patients with dysmenorrhea. Methods This was a placebo‐controlled, double‐blind, randomized trial conducted in Japan. A total of 251 primary and secondary dysmenorrhea patients were randomly assigned to the NPC‐16‐Cyclic group, NPC‐16‐Extended group, or the Placebo group. The primary end point was a comparison of the efficacy and safety of the Cyclic and Extended NPC‐16 regimen for the treatment of dysmenorrhea relative to the Placebo. Main findings Significantly greater reductions in total dysmenorrhea score and visual analog scale score were observed in the Cyclic and Extended groups compared with the Placebo group. Compared with the Cyclic regimen as a secondary end point, the Extended regimen exhibited greater efficacy in the treatment of dysmenorrhea over the course of the study period, particularly in patients with severe dysmenorrhea. The incidence of adverse drug reactions (ADRs) was significantly higher in the Cyclic and Extended groups than in the Placebo group. Conclusion The Cyclic and Extended regimens of NPC‐16 significantly reduced dysmenorrhea severity compared to placebo. The Extended regimen was superior to cyclic regimen in reducing the dysmenorrhea.

Migraine is a major neurological disorder affecting one in nine adults worldwide with a significant impact on health care and socioeconomic systems. Migraine is more prevalent in women than in men, with 17% of all women meeting the diagnostic criteria for migraine. In women, the frequency of migraine attacks shows variations over the menstrual cycle and pregnancy, and the use of combined hormonal contraception (CHC) or hormone replacement therapy (HRT) can unveil or modify migraine disease. In the general population, 18–25% of female migraineurs display a menstrual association of their headache. Here we present an overview on the evidence supporting the role of reproductive hormones, in particular estrogens, in the pathophysiology of migraine. We also analyze the efficacy and safety of prescribing exogenous estrogens as a potential treatment for menstrual-related migraine. Finally, we point to controversial issues and future research areas in the field of reproductive hormones and migraine. [ABSTRACT FROM AUTHOR]

Keywords: ethinylestradiol; lysyl hydroxylase 2; target identification; yeast three-hybrid screen EN ethinylestradiol lysyl hydroxylase 2 target identification yeast three-hybrid screen 421 431 11 03/11/22 20220301 NES 220301 Introduction Many fundamental processes in biology rely on small ligand-protein interactions which form the basis for pharmacological intervention of human diseases. After washing, bound proteins were eluted with SDS and heat, and analyzed by SDS-PAGE and Western Blotting using a PLOD2 antibody for staining, or a GAL4 antibody for the detection of the GAL4 AD fusion protein from the Y3H vector. Having confirmed that our Y3H setup can indeed detect small molecule-protein interactions, we next wanted to employ this system for the identification of protein binding partners of small molecules out of a pool of proteins. [Extracted from the article]