Spermatogenesis starts with the onset of puberty within the seminiferous epithelium of the testes. It is a complex process under intricate control of the endocrine system. Physiological regulations by steroid hormones in general and by estrogens in particular are due to their chemical nature prone to be disrupted by exogenous factors acting as endocrine disruptors (EDs). 17α-Ethynylestradiol (EE2) is an environmental pollutant with a confirmed ED activity and a well-known effect on spermatogenesis and chromatin remodeling in haploid germ cells. The aim of our study was to assess possible effects of two doses (2.5ng/ml; 2.5 μg/ml) of EE2 on both histone-to-protamine exchange and epigenetic profiles during spermatogenesis performing a multi/transgenerational study in mice. Our results demonstrated an impaired histone-to-protamine exchange with a significantly higher histone retention in sperm nuclei of exposed animals, when this process was accompanied by the changes of histone post-translational modifications (PTMs) abundancies with a prominent effect on H3K9Ac and partial changes in protamine 1 promoter methylation status. Furthermore, individual changes in molecular phenotypes were partially transmitted to subsequent generations, when no direct trans-generational effect was observed. Finally, the uncovered specific localization of the histone retention in sperm nuclei and their specific PTMs profile after EE2 exposure may indicate an estrogenic effect on sperm motility and early embryonic development via epigenetic mechanisms.
- MeSH
- Endocrine Disruptors pharmacology toxicity MeSH
- Epigenesis, Genetic * drug effects MeSH
- Ethinyl Estradiol * pharmacology MeSH
- Histones * metabolism MeSH
- Mice MeSH
- Protein Processing, Post-Translational drug effects MeSH
- Protamines * metabolism genetics MeSH
- Spermatogenesis * drug effects genetics MeSH
- Spermatozoa drug effects metabolism MeSH
- Testis * drug effects metabolism MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Quinestrol therapeutic use MeSH
- Estrogens * therapeutic use MeSH
- Flavonoids * therapeutic use MeSH
- Immunotherapy methods MeSH
- Humans MeSH
- Tumor Microenvironment drug effects MeSH
- Neoplasms * immunology therapy MeSH
- Quercetin therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Newspaper Article MeSH
- News MeSH
- MeSH
- Administration, Oral MeSH
- Ethinyl Estradiol administration & dosage pharmacology MeSH
- Drug Combinations MeSH
- Hormonal Contraception methods MeSH
- Clinical Studies as Topic MeSH
- Contraceptives, Oral, Hormonal administration & dosage pharmacology MeSH
- Contraceptives, Oral, Combined * administration & dosage pharmacology MeSH
- Delayed-Action Preparations * administration & dosage pharmacology MeSH
- Humans MeSH
- Menstrual Cycle drug effects MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Review MeSH
Estrogeny jsou klíčové hormony, které hrají zásadní roli ve fyziologii reprodukčního systému u žen. Jejich terapeutické využití v hormonální léčbě, antikoncepci a léčbě hormonálně závislých onemocnění však může být spojeno s řadou nežádoucích účinků, zejména na játra. Tento článek se zaměřuje na mechanizmy působení estrogenů a jejich potenciální hepatotoxické účinky, stejně jako na rizikové faktory a možné rozdíly mezi jednotlivými představiteli.
Estrogens are key hormones that play a vital role in the physiology of the reproductive system in women. However, their therapeutic use in hormonal treatment, contraception, and the treatment of hormone-dependent diseases may be associated with a number of side effects, especially on the liver. This article focuses on the mechanisms of action of estrogens and their potential hepatotoxic effects, as well as risk factors and possible differences between representatives.
- MeSH
- Estetrol pharmacology metabolism adverse effects MeSH
- Estradiol pharmacology metabolism adverse effects MeSH
- Estrogens * pharmacology metabolism adverse effects MeSH
- Ethinyl Estradiol pharmacology metabolism adverse effects MeSH
- Liver * metabolism pathology drug effects MeSH
- Drug Interactions physiology MeSH
- Chemical and Drug Induced Liver Injury etiology metabolism MeSH
- Humans MeSH
- Check Tag
- Humans MeSH
Microtubule dynamic is exceptionally sensitive to modulation by small-molecule ligands. Our previous work presented the preparation of microtubule-targeting estradiol dimer (ED) with anticancer activity. In the present study, we explore the effect of selected linkers on the biological activity of the dimer. The linkers were designed as five-atom chains with carbon, nitrogen or oxygen in their centre. In addition, the central nitrogen was modified by a benzyl group with hydroxy or methoxy substituents and one derivative possessed an extended linker length. Thirteen new dimers were subjected to cytotoxicity assay and cell cycle profiling. Dimers containing linker with benzyl moiety substituted with one or more methoxy groups and longer branched ones were found inactive, whereas other structures had comparable efficacy as the original ED (e.g. D1 with IC50 = 1.53 μM). Cell cycle analysis and immunofluorescence proved the interference of dimers with microtubule assembly and mitosis. The proposed in silico model and calculated binding free energy by the MM-PBSA method were closely correlated with in vitro tubulin assembly assay.
- MeSH
- Apoptosis MeSH
- Ethinyl Estradiol * chemistry pharmacology MeSH
- G2 Phase Cell Cycle Checkpoints drug effects MeSH
- Microtubules MeSH
- Tubulin Modulators * chemistry pharmacology MeSH
- Cell Line, Tumor MeSH
- Antineoplastic Agents * chemistry pharmacology MeSH
- Triazoles * chemistry pharmacology MeSH
- Tubulin * metabolism MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Cíl: Navzdory značným pokrokům s nedávno vyvinutými formami kombinované perorální antikoncepce (COC – combined oral contraceptive), které vedly ke sníženému výskytu nežádoucích příhod při plném zachování antikoncepční účinnosti, zájem o další inovace přetrvává. Materiály a metody: Nový typ COC kombinuje přirozený estrogen estetrol (E4) a gestagen drospirenon (DRSP). Evropský panel odborníků hodnotil farmakologické vlastnosti, účinnost, bezpečnost a snášenlivost této kombinace. Zjištění jsou prezentována formou přehledového článku. Výsledky: Kombinace 15 mg E4/3 mg DRSP v režimu 24+4 představuje účinnou antikoncepci s dobrou regulací cyklu, charakterizovanou pravidelným krvácením a minimálním neplánovaným krvácením, a stejně tak i dobrým bezpečnostním profilem. Spojován je s vysokou spokojeností uživatelek, dobrým zdravotním stavem a minimálními změnami tělesné hmotnosti. Účinky na endokrinní a metabolické parametry jsou omezeny a kombinace má též omezený vliv na jaterní funkce a metabolizmus lipidů a sacharidů. Na hemostatické parametry má menší vliv než porovnatelná léčiva s obsahem 20 μg etinylestradiolu (EE) /3 mg DRSP a 30 μg EE/150 μg levonorgestrelu. Závěr: Kombinace 15 mg E4/3 mg DRSP poskytuje bezpečnou a účinnou antikoncepci s vysokou mírou spokojenosti uživatelek a předvídatelným krvácením. Další výzkum se bude věnovat hodnocení dlouhodobé bezpečnosti COC.
Purpose: Despite considerable advances in recently developed combined oral contraceptives (COCs), resulting in lower rates of adverse events while maintaining contraceptive efficacy, there is interest in further innovation. Materials and Methods: Estetrol (E4), a native oestrogen, and progestin drospirenone (DRSP) were combined in a new COC. A European expert panel reviewed the pharmacology, efficacy, and safety and tolerability of this combination. Their findings are presented as a narrative review. Results: E4 15mg/DRSP 3 mg in a 24/4 regimen provided effective contraception with good cycle control, characterised by a predictable regular bleeding pattern and minimal unscheduled bleeding, together with a good safety profile. The combination was associated with high user satisfaction, wellbeing, and minimal changes in body weight. The effects on endocrine and metabolic parameters were limited, and the combination was found to have a limited impact on liver function and lipid and carbohydrate metabolism. Moreover, its effect on several haemostatic parameters was lower than that of comparators containing ethinyl oestradiol (EE) 20 mg/DRSP 3 mg and EE 30 mg/levonorgestrel 150 mg. Conclusion: E4 15 mg/DRSP 3 mg provides safe and effective contraception, with high user satisfaction and predictable bleeding. Further research will evaluate the long-term safety of the COC.
- MeSH
- Chlormadinone Acetate pharmacology therapeutic use MeSH
- Ethinyl Estradiol therapeutic use MeSH
- Contraceptive Agents, Hormonal therapeutic use MeSH
- Contraceptives, Oral, Hormonal * classification therapeutic use MeSH
- Humans MeSH
- Progestins therapeutic use MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Interview MeSH
OBJECTIVES: We tested the toxicity of ethinylestradiol, a semisynthetic estrogen used in oral contraceptives, on all-male triploid zebrafish using commercial feeds and three different doses concentrations. We aimed to determine whether ethinylestradiol peroral administration resulted in vitellogenin production and whether all-male triploid zebrafish could serve as a model species for xenoestrogen testing. METHODS: The actual concentrations of 17α-ethinylestradiol were 0.0035 (low); 0.0315 (medium) and 0.365 (high) μg/g. Positive control represented commercial feeds containing 0.0465 μg/g of β-estradiol. The experiment lasted 8 weeks. RESULTS: Our results indicate that 17α-ethinylestradiol consumption does induce vitellogenin production in triploid zebrafish. CONCLUSIONS: The simple presence of vitellogenin is a definite symptom indicative of the potential for such changes due to the action of estrogenic substances. As such, this experiment has shown that the use of all-male triploid zebrafish populations, rather than the mixed-sex populations of other species previously used, could serve as a suitable alternative model population for controlled testing of the effects of xenoestrogens on fish.
- MeSH
- Water Pollutants, Chemical * MeSH
- Zebrafish * genetics MeSH
- Estrogens pharmacology MeSH
- Ethinyl Estradiol toxicity MeSH
- Triploidy MeSH
- Vitellogenins genetics MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Metformin, an oral antidiabetic drug, recently demonstrated a reducing effect on bile acids (BA) plasma concentrations in one patient with intrahepatic cholestasis of pregnancy (ICP) by unknown mechanism. Therefore, the aim of the present study was to examine the effect of metformin on BA homeostasis and related molecular pathways in the liver and intestine using a mouse model of ICP. The cholestasis was induced in female C57BL/6 mice by repeated administration of ethinylestradiol (10 mg/kg BW s.c.) and/or metformin (150 mg/kg BW orally) over 5 consecutive days with subsequent bile collection and molecular analysis of samples. We demonstrated that metformin significantly increased the rate of bile secretion in control mice. This increase was BA dependent and was produced both by increased liver BA synthesis via induced cholesterol 7α-hydroxylase (Cyp7a1) and by increased BA reabsorption in the ileum via induction of the apical sodium-dependent BA transporter (Asbt). In contrast, metformin further worsened ethinylestradiol-induced impairment of bile secretion. This reduction was also BA dependent and corresponded with significant downregulation of Bsep, and Ntcp, major excretory and uptake transporters for BA in hepatocytes, respectively. The plasma concentrations of BA were consequently significantly increased in the metformin-treated mice. Altogether, our data indicate positive stimulation of bile secretion by metformin in the intact liver, but this drug also induces serious impairment of BA biliary secretion, with a marked increase in plasma concentrations in estrogen-induced cholestasis. Our results imply that metformin should be used with caution in situations with hormone-dependent cholestasis, such as ICP.
- MeSH
- Cholestasis chemically induced metabolism pathology MeSH
- Ethinyl Estradiol adverse effects MeSH
- Hepatocytes drug effects metabolism MeSH
- Homeostasis drug effects MeSH
- Intestinal Absorption drug effects MeSH
- Metformin pharmacology MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Bile Acids and Salts metabolism MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Contraception * methods trends MeSH
- Contraceptive Devices, Male trends MeSH
- Administration, Intravaginal MeSH
- Estetrol administration & dosage pharmacology MeSH
- Ethinyl Estradiol adverse effects therapeutic use MeSH
- Abortion, Induced methods statistics & numerical data legislation & jurisprudence MeSH
- Cardiovascular Diseases prevention & control MeSH
- Contraceptive Agents administration & dosage MeSH
- Metals adverse effects MeSH
- Humans MeSH
- Nanomedicine classification methods trends MeSH
- Intrauterine Devices classification adverse effects MeSH
- Receptors, Progesterone therapeutic use MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Review MeSH
