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
• chemické látky znečišťující vodu * MeSH
• dánio pruhované * genetika   MeSH
• estrogeny farmakologie   MeSH
• ethinylestradiol toxicita   MeSH
• triploidie MeSH
• vitelogeniny genetika   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chemické látky znečišťující vodu * MeSH
• estrogeny MeSH
• ethinylestradiol MeSH
• vitelogeniny MeSH

Estrogen is known to regulate bone metabolism in both women and men, but substantial gaps remain in our knowledge of estrogen and estrogen receptor alpha (ERα) regulation of adult bone metabolism. Studies using global ERα-knockout mice were confounded by high circulating sex-steroid levels, and osteocyte/osteoblast-specific ERα deletion may be confounded by ERα effects on growth versus the adult skeleton. Thus, we developed mice expressing the tamoxifen-inducible CreERT2 in osteocytes using the 8-kilobase (kb) Dmp1 promoter (Dmp1CreERT2 ). These mice were crossed with ERαfl//fl mice to create ERαΔOcy mice, permitting inducible osteocyte-specific ERα deletion in adulthood. After intermittent tamoxifen treatment of adult 4-month-old mice for 1 month, female, but not male, ERαΔOcy mice exhibited reduced spine bone volume fraction (BV/TV (-20.1%, p = 0.004) accompanied by decreased trabecular bone formation rate (-18.9%, p = 0.0496) and serum P1NP levels (-38.9%, p = 0.014). Periosteal (+65.6%, p = 0.004) and endocortical (+64.1%, p = 0.003) expansion were higher in ERαΔOcy mice compared to control (Dmp1CreERT2 ) mice at the tibial diaphysis, reflecting the known effects of estrogen to inhibit periosteal apposition and promote endocortical formation. Increases in Sost (2.1-fold, p = 0.001) messenger RNA (mRNA) levels were observed in trabecular bone at the spine in ERαΔOcy mice, consistent with previous reports that estrogen deficiency is associated with increased circulating sclerostin as well as bone SOST mRNA levels in humans. Further, the biological consequences of increased Sost expression were reflected in significant overall downregulation in panels of osteoblast and Wnt target genes in osteocyte-enriched bones from ERαΔOcy mice. These findings thus establish that osteocytic ERα is critical for estrogen action in female, but not male, adult bone metabolism. Moreover, the reduction in bone formation accompanied by increased Sost, decreased osteoblast, and decreased Wnt target gene expression in ERαΔOcy mice provides a direct link in vivo between ERα and Wnt signaling. © 2022 American Society for Bone and Mineral Research (ASBMR).

• Klíčová slova
• ESTROGENS AND SERMs, GENETIC ANIMAL MODELS, OSTEOCYTES, OSTEOPOROSIS, SEX STEROIDS,
• MeSH
• adaptorové proteiny signální transdukční metabolismus   MeSH
• alfa receptor estrogenů * genetika   metabolismus   MeSH
• dospělí MeSH
• estrogeny metabolismus   farmakologie   MeSH
• kojenec MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• mezibuněčné signální peptidy a proteiny metabolismus   MeSH
• myši knockoutované MeSH
• myši MeSH
• osteoblasty metabolismus   MeSH
• osteocyty * metabolismus   MeSH
• tamoxifen farmakologie   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• alfa receptor estrogenů * MeSH
• estrogeny MeSH
• messenger RNA MeSH
• mezibuněčné signální peptidy a proteiny MeSH
• tamoxifen MeSH

In normal hormonal conditions, increased neuronal activity in the ventromedial hypothalamus (VMH) induces lordosis whereas activation of the preoptic area (POA) exerts an opposite effect. In the present work, we explored the effect of bilateral infusion of different doses of the apelin-13 (0.37, 0.75, 1.5, and 15 μg) in both brain areas on the expression of lordosis behavior. Lordosis quotient and lordosis reflex score were performed at 30, 120, and 240 min. Weak lordosis was observed following the 0.37 μg dose of apelin-13 at 30 min in the VMH of EB-primed rats; however, the rest of the doses induced significant lordosis relative to the control group. At 120 min, all doses induced lordosis behavior, while at 240 min, the highest dose of 15 μg did not induce significant differences. Interestingly, only the 0.75 μg infusion of apelin in the POA induced significant lordosis at 120 and 240 min. These results indicate that apelin-13 acts preferably in HVM and slightly in POA to initiate lordosis behavior in estrogen-primed rats.

• Klíčová slova
• Apelin-13, Lordosis, Preoptic area, Ventromedial hypothalamus,
• MeSH
• area praeoptica * účinky léků   patologie   MeSH
• estradiol farmakologie   MeSH
• estrogeny farmakologie   MeSH
• hypothalamus účinky léků   patologie   MeSH
• krysa rodu Rattus MeSH
• lordóza * chemicky indukované   MeSH
• mezibuněčné signální peptidy a proteiny * farmakologie   MeSH
• nucleus ventromedialis hypothalami účinky léků   patologie   MeSH
• progesteron farmakologie   MeSH
• sexuální chování zvířat účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• apelin-13 peptide MeSH Prohlížeč
• estradiol MeSH
• estrogeny MeSH
• mezibuněčné signální peptidy a proteiny * MeSH
• progesteron MeSH

Although produced largely in the periphery, gonadal steroids play a key role in regulating the development and functions of the central nervous system and have been implicated in several chronic neuropsychiatric disorders, with schizophrenia and Alzheimer's disease (AD) most prominent. Despite major differences in pathobiology and clinical manifestations, in both conditions, estrogen transpires primarily with protective effects, buffering the onset and progression of diseases at various levels. As a result, estrogen replacement therapy (ERT) emerges as one of the most widely discussed adjuvant interventions. In this review, we revisit evidence supporting the protective role of estrogen in schizophrenia and AD and consider putative cellular and molecular mechanisms. We explore the underlying functional processes relevant to the manifestation of these devastating conditions, with a focus on synaptic transmission and plasticity mechanisms. We discuss specific effects of estrogen deficit on neurotransmitter systems such as cholinergic, dopaminergic, serotoninergic, and glutamatergic. While the evidence from both, preclinical and clinical reports, in general, are supportive of the protective effects of estrogen from cognitive decline to synaptic pathology, numerous questions remain, calling for further research.

• Klíčová slova
• Adjuvant therapy, Animal models, Cognitive deficit, Menopause, Neuroprotection, Plasticity,
• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• estrogenní substituční terapie metody   MeSH
• estrogeny metabolismus   farmakologie   MeSH
• lidé MeSH
• schizofrenie farmakoterapie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• estrogeny MeSH

Selective agonism of the estrogen receptor (ER) subtypes, ERα and ERβ, has historically been difficult to achieve due to the high degree of ligand-binding domain structural similarity. Multiple efforts have focused on the use of classical organic scaffolds to model 17β-estradiol geometry in the design of ERβ selective agonists, with several proceeding to various stages of clinical development. Carborane scaffolds offer many unique advantages including the potential for novel ligand/receptor interactions but remain relatively unexplored. We synthesized a series of para-carborane estrogen receptor agonists revealing an ERβ selective structure-activity relationship. We report ERβ agonists with low nanomolar potency, greater than 200-fold selectivity for ERβ over ERα, limited off-target activity against other nuclear receptors, and only sparse CYP450 inhibition at very high micromolar concentrations. The pharmacological properties of our para-carborane ERβ selective agonists measure favorably against clinically developed ERβ agonists and support further evaluation of carborane-based selective estrogen receptor modulators.

• MeSH
• beta receptor estrogenů agonisté   MeSH
• estrogeny chemická syntéza   chemie   farmakologie   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• molekulární struktura MeSH
• sloučeniny boru chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• beta receptor estrogenů MeSH
• estrogeny MeSH
• sloučeniny boru MeSH

OBJECTIVE: To describe effects of non-ablative erbium-doped:yttrium-aluminium-garnet (Er:YAG) laser on vaginal atrophy induced by iatrogenic menopause in the ewe. DESIGN: Animal experimental, randomised, sham and estrogen-treatment controlled study with blinding for primary outcome. SETTING: KU Leuven, Belgium. SAMPLE: Twenty-four ewes. METHODS: Menopause was surgically induced, after which the ewes were randomised to three groups receiving vaginal Er:YAG laser application three times, with a 1-month interval; three sham manipulations with a 1-month interval; or estrogen replacement and sham manipulations. At given intervals, ewes were clinically examined and vaginal wall biopsies were taken. Vaginal compliance was determined by passive biomechanical testing from explants taken at autopsy. MAIN OUTCOME MEASURES: Vaginal epithelial thickness (primary), composition of the lamina propria (collagen, elastin, glycogen and vessel content), vaginal compliance, clinical signs. RESULTS: Animals exposed to Er:YAG laser application and sham manipulation, but not to estrogens, displayed a significant and comparable increase in vaginal epithelial thickness between baseline and 7 days after the third application (69% and 67%, respectively, both P < 0.0008). In laser-treated ewes, temporary vaginal discharge and limited thermal injury were observed. Estrogen-substituted ewes displayed a more prominent increase in epithelial thickness (202%; P < 0.0001) and higher vaginal compliance (P < 0.05). None of the interventions induced changes in the lamina propria. CONCLUSIONS: Vaginal Er:YAG laser has comparable effect to sham manipulation in menopausal ewes. TWEETABLE ABSTRACT: Vaginal Er:YAG laser has comparable effect to sham manipulation in menopausal ewes #LASER #GSM #RCT.

• Klíčová slova
• Atrophy, epithelium, estrogen, laser, planar biaxial testing, sheep, vagina,
• MeSH
• atrofie * diagnóza   farmakoterapie   etiologie   radioterapie   MeSH
• biopsie metody   MeSH
• estrogenní substituční terapie metody   MeSH
• estrogeny farmakologie   MeSH
• laserová terapie s nízkou intenzitou světla * škodlivé účinky   metody   MeSH
• lasery pevnolátkové terapeutické užití   MeSH
• menopauza * MeSH
• modely nemocí na zvířatech MeSH
• ovce MeSH
• vagina patologie   MeSH
• vaginální onemocnění * farmakoterapie   patologie   radioterapie   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• estrogeny MeSH

The equilibrium dissociation constant of competitive antagonists represents the affinity of the receptor-ligand interaction, and it is a key characteristic of many therapeutic drugs or toxic compounds. Two commonly used methods by which the affinity of the antagonist can be estimated are Schild analysis and the Cheng-Prusoff method. However, both methods yield different results when applied to systems with slopes not equal to one. The Gaddum equation, which is fundamental for both methods, should be extended to incorporate the slope parameter of the dose-response curves and this extension should diminish the differences between the Schild and Cheng-Prusoff methods. In this study, we derived a novel form of the Gaddum equation with a slope parameter (Hill coefficient) of agonist dose-response curve. We also derived the subsequent equations for Schild and Cheng-Prusoff analysis and we validated the proposed model by the measurement of several known estrogen receptor competitive antagonists. Standardized in vitro yeast reporter gene assay (BMAEREluc/ERα) has been used for the measurements and the range of used antagonist concentrations was 1.37-46.03 μM. By applying our mathematical model, both Schild and Cheng-Prusoff methods provide more similar values of antagonist affinity than the original mathematical approach. The correctness of the model has also been demonstrated by the measurement of a partial agonist with a known receptor affinity. The presented mathematical model significantly reduces the differences in values calculated by the Cheng-Prusoff and Schild methods and yields more accurate estimations of antagonist affinity.

• Klíčová slova
• Antagonists, Equilibrium constant, Gaddum equation, Inhibition curve analysis, Receptor theory, Schild analysis,
• MeSH
• alfa receptor estrogenů antagonisté a inhibitory   metabolismus   MeSH
• antagonisté estrogenového receptoru metabolismus   farmakologie   MeSH
• benzhydrylové sloučeniny metabolismus   toxicita   MeSH
• biologické modely * MeSH
• endokrinní disruptory metabolismus   toxicita   MeSH
• estradiol metabolismus   farmakologie   MeSH
• estrogeny metabolismus   farmakologie   MeSH
• fenoly metabolismus   toxicita   MeSH
• kompetitivní vazba MeSH
• lidé MeSH
• ligandy MeSH
• parciální agonismus léků MeSH
• reprodukovatelnost výsledků MeSH
• vazba proteinů MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• alfa receptor estrogenů MeSH
• antagonisté estrogenového receptoru MeSH
• benzhydrylové sloučeniny MeSH
• bisphenol A MeSH Prohlížeč
• endokrinní disruptory MeSH
• estradiol MeSH
• estrogeny MeSH
• fenoly MeSH
• ligandy MeSH

Microtubule dynamics is one of the major targets for new chemotherapeutic agents. This communication presents the synthesis and biological profiling of steroidal dimers based on estradiol, testosterone and pregnenolone bridged by 2,6-bis(azidomethyl)pyridine between D rings. The biological profiling revealed unique properties of the estradiol dimer including cytotoxic activities on a panel of 11 human cell lines, ability to arrest in the G2/M phase of the cell cycle accompanied with the attenuation of DNA/RNA synthesis. Thorough investigation precluded a genomic mechanism of action and revealed that the estradiol dimer acts at the cytoskeletal level by inhibiting tubulin polymerization. Further studies showed that estradiol dimer, but none of the other structurally related dimeric steroids, inhibited assembly of purified tubulin (IC50, 3.6 μM). The estradiol dimer was more potent than 2-methoxyestradiol, an endogenous metabolite of 17β-estradiol and well-studied microtubule polymerization inhibitor with antitumor effects that was evaluated in clinical trials. Further, it was equipotent to nocodazole (IC50, 1.5 μM), an antimitotic small molecule of natural origin. Both estradiol dimer and nocodazole completely and reversibly depolymerized microtubules in interphase U2OS cells at 2.5 μM concentration. At lower concentrations (50 nM), estradiol dimer decreased the microtubule dynamics and growth life-time and produced comparable effect to nocodazole on the microtubule dynamicity. In silico modeling predicted that estradiol dimer binds to the colchicine-binding site in the tubulin dimer. Finally, dimerization of the steroids abolished their ability to induce transactivation by estrogen receptor α and androgen receptors. Although other steroids were reported to interact with microtubules, the estradiol dimer represents a new structural type of steroid inhibitor of tubulin polymerization and microtubule dynamics, bearing antimitotic and cytotoxic activity in cancer cell lines.

• Klíčová slova
• 17β-Estradiol (E2) (PubChem CID: 5757), 2-Methoxyestradiol (2-ME) (PubChem CID: 66414), Antimitotic activity, Dihydrotestosterone (DHT) (PubChem CID: 10635), Luciferase reporter assay, Microtubule dynamics, Microtubules, Molecular dynamics simulation, Nocodazole (PubChem CID: 4122), Paclitaxel (PubChem CID: 36314), Steroid dimer, Steroid receptor, Tubulin assembly,
• MeSH
• buněčný cyklus MeSH
• estradiol chemie   farmakologie   MeSH
• estrogeny chemie   farmakologie   MeSH
• lidé MeSH
• mikrotubuly účinky léků   fyziologie   MeSH
• modulátory tubulinu chemie   farmakologie   MeSH
• nádorové buňky kultivované MeSH
• nádory farmakoterapie   metabolismus   patologie   MeSH
• polymerizace MeSH
• proliferace buněk MeSH
• tubulin chemie   účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• estradiol MeSH
• estrogeny MeSH
• modulátory tubulinu MeSH
• tubulin MeSH

The crucial role that oestrogens play in male reproduction has been generally accepted; however, the exact mechanism of their action is not entirely clear and there is still much more to be clarified. The oestrogen response is mediated through oestrogen receptors, as well as classical oestrogen receptors' variants, and their specific co-expression plays a critical role. The importance of oestrogen signalling in male fertility is indicated by the adverse effects of selected oestrogen-like compounds, and their interaction with oestrogen receptors was proven to cause pathologies. The aims of this review are to summarise the current knowledge on oestrogen signalling during spermatogenesis and sperm maturation and discuss the available information on oestrogen receptors and their splice variants. An overview is given of species-specific differences including in humans, along with a detailed summary of the methodology outcome, including all the genetically manipulated models available to date. This review provides coherent information on the recently discovered mechanisms of oestrogens' and oestrogen receptors' effects and action in both testicular somatic and germ cells, as well as in mature sperm, available for mammals, including humans.

• Klíčová slova
• humans, mice, oestrogen receptors, oestrogen-like compounds, oestrogens, pigs, rats, signalling, sperm, testes,
• MeSH
• aromatasa nedostatek   genetika   MeSH
• estrogeny farmakologie   MeSH
• lidé MeSH
• receptory pro estrogeny metabolismus   MeSH
• signální transdukce MeSH
• spermatogeneze účinky léků   MeSH
• testis účinky léků   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• aromatasa MeSH
• estrogeny MeSH
• receptory pro estrogeny MeSH

OBJECTIVES: The term "endocrine disruptor" (ED) is used for compounds that mimic or antagonize the effects of endogenous hormones. Synthetic estrogen 17α-ethinylestradiol (EE2) and a human carcinogen benzo[a]pyrene (BaP) are assigned as exogenous endocrine disruptors and an estrogenic hormone estradiol is a natural endogenous disruptor. Here, the potency of these three disruptors administered to rats individually and in combination to induce expression of cytochrome P450 (CYP) enzymes involved in their own metabolism (CYP1A1, 2C and 3A) in vivo was investigated. METHODS: Changes in CYP protein expression after exposure of rats to BaP, EE2 or estradiol were analyzed by Western blotting. Using the HPLC method, CYP1A1, 2C and 3A specific activities in hepatic microsomes isolated from exposed rats were analyzed. RESULTS: Whereas exposure to BaP induces expression of CYP1A1 protein and its marker activity (Sudan I oxidation) in liver, kidney and lung of rats, no significant induction of this CYP and its enzyme activity was produced by EE2 and estradiol. Treatment of BaP in combination with EE2 and/or estradiol decreased the BaP-mediated CYP1A1 induction in liver of exposed rats. BaP also induces CYP2C11 protein in rat liver and kidney, but does not increase its enzyme activity measured as testosterone 16α-hydroxylation. The enzyme activity of another enzyme of the 2C subfamily, CYP2C6, diclofenac 4'-hydroxylation, is even decreased by BaP. The CYP2C11 protein expression and/or its activity are also increased in liver of rats treated with EE2 and estradiol, but its expression is significantly decreased in lung. The CYP2C6 activity is also elevated by treatment of rats with EE2 and estradiol administered individually as well as in their combination. Whereas only a slight increase in CYP3A protein expression was found by BaP in rat liver, its enzyme activity, testosterone 6β-hydroxyalation, increased significantly in this organ. In contrast, no effect or even a decrease in CYP3A expression and its enzyme activity was produced by EE2 and estradiol in rats exposed to these compounds.

• MeSH
• benzopyren farmakologie   MeSH
• endokrinní disruptory farmakologie   MeSH
• estradiol farmakologie   MeSH
• estrogeny farmakologie   MeSH
• ethinylestradiol farmakologie   MeSH
• jaterní mikrozomy metabolismus   MeSH
• krysa rodu Rattus MeSH
• potkani Wistar MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzopyren MeSH
• endokrinní disruptory MeSH
• estradiol MeSH
• estrogeny MeSH
• ethinylestradiol MeSH
• systém (enzymů) cytochromů P-450 MeSH