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
INTRODUCTION: Sepsis-induced acute kidney injury (AKI) remains a major challenge in intensive care, contributing significantly to morbidity and mortality. Tibolone, known for its neuroprotective and hormonal properties, has not been explored for its potential in AKI management. This study investigates the protective effects of Tibolone and its underlying mechanisms involving Sirtuin-1 (SIRT1) and Yes-Associated Protein (YAP) in a rat sepsis model. MATERIALS AND METHODS: Thirty-six female Wistar albino rats underwent cecal ligation and puncture (CLP) to induce sepsis. They were randomly assigned to control, CLP+Saline, and CLP+Tibolone groups. Tibolone was administered intraperitoneally. Biomarkers, including Sirtuin (SIRT1), Yes-associated protein (YAP), Tumor necrosis factor (TNF-α), High mobility group box 1 (HMGB1), malondialdehyde (MDA), creatinine, and urea, were assessed. Histopathological examination evaluated renal damage. RESULTS: Tibolone administration significantly reduced plasma TNF-α, HMGB1, MDA, creatinine, and urea levels compared to the CLP+Saline group. Moreover, Tibolone elevated SIRT1 and YAP levels in kidney tissues. Histopathological examination demonstrated a significant decrease in tubular epithelial necrosis, luminal debris, dilatation, hemorrhage, and interstitial inflammation in Tibolone-treated rats. CONCLUSION: This study unveils the protective role of Tibolone against sepsis-induced AKI in rats. The improvements in inflammatory and oxidative biomarkers and histological evidence suggest Tibolone's potential as a therapeutic intervention in sepsis-associated kidney injury. The upregulation of SIRT1 and YAP indicates their involvement in Tibolone's renoprotective mechanisms. Further investigations are warranted to explore Tibolone's translational potential in human sepsis-induced AKI.
- MeSH
- Acute Kidney Injury * etiology prevention & control drug therapy MeSH
- Biomarkers MeSH
- Rats MeSH
- Kidney drug effects metabolism MeSH
- Disease Models, Animal MeSH
- Norpregnenes * therapeutic use pharmacology MeSH
- Rats, Wistar * MeSH
- HMGB1 Protein metabolism MeSH
- Sepsis * complications drug therapy MeSH
- Sirtuin 1 * metabolism MeSH
- Tumor Necrosis Factor-alpha metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Nitroděložní systém s levonorgestrelem má vynikající antikoncepční účinnost za současného snížení menstruační krevní ztráty. V perimenopauze jej lze s výhodou využít k léčbě hyperplazie endometria. Jako gestagenní složka hormonální substituční terapie vykazuje výbornou kontrolu proliferace endometria. V kombinaci s transdermální aplikací estrogenu má výhodu nulového zvýšení rizika tromboembolické nemoci.
Levonorgestrel releasing intrauterine system have excellent contraceptive efficacy with simultaneous lowering of menstruation’s blood loss. It could be used for therapy of endometrial hyperplasia in perimenopause. In position of gestagen part of the hormone replacement therapy it has high control of endometrial proliferation. It is conjoined with the zero increasing of risk of thromboembolic disease in combination with transdermal oestrogen’s application.
- MeSH
- Administration, Cutaneous MeSH
- Endometrium drug effects MeSH
- Hormone Replacement Therapy * methods MeSH
- Endometrial Hyperplasia prevention & control MeSH
- Levonorgestrel administration & dosage pharmacology therapeutic use MeSH
- Humans MeSH
- Menopause * drug effects MeSH
- Intrauterine Devices, Medicated MeSH
- Thromboembolism chemically induced MeSH
- Check Tag
- Humans MeSH
- Female 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
- MeSH
- Dydrogesterone administration & dosage therapeutic use MeSH
- Estrogens administration & dosage therapeutic use MeSH
- Hormone Replacement Therapy MeSH
- Climacteric * psychology drug effects MeSH
- Levonorgestrel administration & dosage therapeutic use MeSH
- Humans MeSH
- Medroxyprogesterone Acetate administration & dosage therapeutic use MeSH
- Hot Flashes drug therapy MeSH
- Perimenopause MeSH
- Progesterone administration & dosage therapeutic use MeSH
- Receptors, Estrogen MeSH
- Selective Serotonin Reuptake Inhibitors administration & dosage therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
- Keywords
- relugolix, Reygo, studie LIBERTY 1, studie LIBERTY 2,
- MeSH
- Hormone Antagonists administration & dosage therapeutic use MeSH
- Adult MeSH
- Estradiol administration & dosage therapeutic use MeSH
- Drug Therapy, Combination MeSH
- Leiomyomatosis * diagnosis complications MeSH
- Humans MeSH
- Norethindrone Acetate administration & dosage therapeutic use MeSH
- Randomized Controlled Trials as Topic MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
- Geographicals
- Czech Republic 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.
