Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 29
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
J Am Heart Assoc ; 7(13)2018 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-29959137

RESUMO

BACKGROUND: Although estrogen receptor α (ERα) acts primarily as a transcription factor, it can also elicit membrane-initiated steroid signaling. Pharmacological tools and transgenic mouse models previously highlighted the key role of ERα membrane-initiated steroid signaling in 2 actions of estrogens in the endothelium: increase in NO production and acceleration of reendothelialization. METHODS AND RESULTS: Using mice with ERα mutated at cysteine 451 (ERaC451A), recognized as the key palmitoylation site required for ERα plasma membrane location, and mice with disruption of nuclear actions because of inactivation of activation function 2 (ERaAF20 = ERaAF2°), we sought to fully characterize the respective roles of nuclear versus membrane-initiated steroid signaling in the arterial protection conferred by ERα. ERaC451A mice were fully responsive to estrogens to prevent atheroma and angiotensin II-induced hypertension as well as to allow flow-mediated arteriolar remodeling. By contrast, ERαAF20 mice were unresponsive to estrogens for these beneficial vascular effects. Accordingly, selective activation of nuclear ERα with estetrol was able to prevent hypertension and to restore flow-mediated arteriolar remodeling. CONCLUSIONS: Altogether, these results reveal an unexpected prominent role of nuclear ERα in the vasculoprotective action of estrogens with major implications in medicine, particularly for selective nuclear ERα agonist, such as estetrol, which is currently under development as a new oral contraceptive and for hormone replacement therapy in menopausal women.


Assuntos
Doenças da Aorta/prevenção & controle , Artérias/metabolismo , Aterosclerose/prevenção & controle , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Receptor alfa de Estrogênio/metabolismo , Hipertensão/prevenção & controle , Animais , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Artérias/efeitos dos fármacos , Artérias/patologia , Artérias/fisiopatologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Pressão Sanguínea , Membrana Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Modelos Animais de Doenças , Estetrol/farmacologia , Estradiol/farmacologia , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/genética , Estrogênios/farmacologia , Feminino , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica , Receptores de LDL/genética , Receptores de LDL/metabolismo , Transdução de Sinais , Remodelação Vascular
3.
J Clin Endocrinol Metab ; 103(9): 3239-3249, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29931320

RESUMO

Context: Luteinizing hormone-releasing hormone (LHRH) agonists have replaced estrogens for endocrine treatment of advanced prostate cancer (PC) because of cardiovascular side effects. The fetal estrogen estetrol (E4) may be safer for PC treatment and is expected to decrease testosterone (T) and prevent estrogen deficiency. Objective: To investigate the safety and T-suppressive effect of E4 in healthy men. Design: Double-blind, randomized, placebo-controlled, dose-escalating study. Setting: The study was conducted at a phase I clinical unit (QPS, Netherlands). Participants: Healthy male volunteers aged 40 to 70 years. Intervention(s): Three treatment cohorts of 15 volunteers with placebo (n = 5) and E4 (n = 10). Estetrol doses tested were 20, 40, and 60 mg/d. Subjects were treated for 4 weeks. Main Outcome Measures: Subjective side effects, pharmacodynamic effects on hemostatic variables, lipids, glucose, bone parameters, and endocrine parameters related to T metabolism. Results: Total and free T decreased dose-dependently and significantly. Nipple tenderness occurred in 40% and decrease of libido occurred in 30% of E4-treated men. The unwanted estrogenic effects on hemostasis were small, dose dependent, and in some cases significant. Lipid and bone parameters showed a favorable trend. Conclusion: The effect of E4 on testosterone levels is insufficient for standalone PC treatment. Taking all clinical and pharmacodynamic variables into consideration, a daily dose of 40 mg E4 seems safe for further evaluation of endocrine PC treatment in combination with LHRH analogs.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Estetrol/administração & dosagem , Adulto , Idoso , Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/efeitos adversos , Antagonistas de Androgênios/farmacologia , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/farmacologia , Biomarcadores/sangue , Glicemia/metabolismo , Remodelação Óssea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Estetrol/efeitos adversos , Estetrol/farmacologia , Terapia de Reposição de Estrogênios/métodos , Voluntários Saudáveis , Hemostasia/efeitos dos fármacos , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Testosterona/sangue
4.
Mol Cell Endocrinol ; 477: 132-139, 2018 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-29928930

RESUMO

Estetrol (E4) is a natural estrogen synthesized exclusively during pregnancy by the human fetal liver, and the physiological role of this hormone is unknown. Interestingly, E4 was recently evaluated in preclinical and phase II-III clinical studies in combination with a progestin, with the advantage to not increase the circulating level of coagulation factors, at variance to oral estradiol or ethinylestradiol. Here, we evaluated the effect of E4 on hemostasis and thrombosis in mouse. Following chronic E4 treatment, mice exhibited a prolonged tail-bleeding time and were protected from arterial and also venous thrombosis in vivo. In addition, E4 treatment decreased ex vivo thrombus growth on collagen under arterial flow conditions. We recently showed that E4 activates uterine epithelial proliferation through nuclear estrogen receptor (ER) α. To analyze the impact of nuclear ERα actions on hemostasis and thrombosis, we generated hematopoietic chimera with bone marrow cells deficient for nuclear ERα. E4-induced protection against thromboembolism was significantly reduced in the absence of hematopoietic nuclear ERα activation, while the increased tail-bleeding time was not impacted by this deletion. In addition to its "liver friendly" profile described in women, our data shows that E4 has anti-thrombotic properties in various mouse models. Altogether, the natural fetal estrogen E4 could represent an attractive alternative to classic estrogens in oral contraception and treatment of menopause.


Assuntos
Artérias/patologia , Núcleo Celular/metabolismo , Estetrol/uso terapêutico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Trombose Venosa/tratamento farmacológico , Animais , Artérias/efeitos dos fármacos , Coagulação Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Colágeno/farmacologia , Modelos Animais de Doenças , Estetrol/farmacologia , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Hemorreologia/efeitos dos fármacos , Hemorragia/sangue , Hemorragia/complicações , Cavalos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Contagem de Plaquetas , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Útero/efeitos dos fármacos , Trombose Venosa/sangue , Trombose Venosa/prevenção & controle
5.
Maturitas ; 99: 1-9, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28364860

RESUMO

BACKGROUND: Estetrol (E4) is a natural estrogen produced solely during human pregnancy. E4 is suitable for clinical use since it acts as a selective estrogen receptor modulator. In clinical trials E4 has been seen to have little or no effect on coagulation. Hence, it is interesting to investigate whether E4 alters endothelial-dependent fibrinolysis. OBJECTIVES: We studied the effects of E4 on the fibrinolytic system and whether this could influence the ability of endothelial cells to migrate. In addition, we compared the effects of E4 with those of 17ß-estradiol (E2). STUDY DESIGN: Human umbilical vein endothelial cells (HUVEC) were obtained from healthy women. Expression of plasminogen-activator inhibitor-1 (PAI-1), urokinase-type plasminogen activator (u-PA) and tissue plasminogen activator (t-PA) proteins was evaluated by Western blot analysis. Endothelial cell migration was studied by razor-scrape horizontal and multiwell insert systems assays. RESULTS: E4 increased the expression of t-PA, u-PA and PAI-1 in HUVEC, but less so than did equimolar amounts of E2. The effects of E4 on t-PA, u-PA and PAI-1 were mediated by the induction of the early-immediate genes c-Jun and c-Fos. E4 in combination with E2 antagonized the effects induced by pregnancy-like E2 concentrations but did not impair the effects of postmenopausal-like E2 levels. We also found that the increased synthesis of PAI-1, u-PA and t-PA induced by E2 and E4 is important for horizontal and three-dimensional migration of HUVEC. CONCLUSIONS: These results support the hypothesis that E4 acts as an endogenous selective estrogen receptor modulator (SERM), controlling the fibrinolytic system and endothelial cell migration.


Assuntos
Movimento Celular/efeitos dos fármacos , Estetrol/farmacologia , Fibrinólise/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , Ativador de Plasminogênio Tipo Uroquinase/efeitos dos fármacos , Western Blotting , Células Cultivadas , Células Endoteliais , Endotélio Vascular/efeitos dos fármacos , Estradiol/farmacologia , Estrogênios/farmacologia , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ativador de Plasminogênio Tecidual/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/metabolismo
6.
Menopause ; 24(6): 677-685, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28169916

RESUMO

OBJECTIVE: Estetrol (E4) is an estrogen produced exclusively by the human fetal liver during pregnancy. In this study the pharmacodynamic effects of escalating doses of E4 in postmenopausal women were investigated. METHODS: This was a partly randomized, open-label, multiple-rising-dose study in 49 postmenopausal women. Participants were randomized to receive either 2 mg E4 or 2 mg estradiol-valerate (E2 V) for 28 days. Subsequent dose-escalation groups were (non-randomized): 10, 20 and 40 mg E4. Blood samples were collected regularly for measuring endocrine and hemostasis variables, lipids and lipoproteins, fasting glucose and bone turnover markers. RESULTS: Estetrol treatment resulted in a decrease of follicle-stimulating hormone and luteinizing hormone and an increase of sex-hormone binding globulin. Changes in hemostasis variables were small. A lowering effect on low-density lipoprotein cholesterol was accompanied with an increase in high-density lipoprotein cholesterol and no or minimal changes in triglycerides. The considerable decrease in osteocalcin levels in the three highest E4 dose groups and the small decrease in C-telopeptide levels were comparable to the E2 V control group and suggest a preventive effect on bone loss. All changes observed were dose-dependent. CONCLUSIONS: In this study, estetrol treatment showed dose-dependent estrogenic effects on endocrine parameters, bone turnover markers, and lipids and lipoproteins. The effect on triglycerides was small as were the effects on hemostatic variables. These results support the further investigation of estetrol as a candidate for hormone therapy. Quantitatively, the effects of 10 mg estetrol were similar to the study comparator 2 mg estradiol valerate.


Assuntos
Estetrol/administração & dosagem , Estetrol/farmacologia , Pós-Menopausa/efeitos dos fármacos , Idoso , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Colágeno Tipo I/sangue , Relação Dose-Resposta a Droga , Estradiol/administração & dosagem , Estradiol/análogos & derivados , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/sangue , Pessoa de Meia-Idade , Osteocalcina/sangue , Osteoporose Pós-Menopausa/prevenção & controle , Peptídeos/sangue , Globulina de Ligação a Hormônio Sexual/análise
7.
J Endocrinol ; 232(1): 85-95, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27799463

RESUMO

Estetrol (E4) has strong antioxidative, neurogenic and angiogenic effects in neural system resulting in the attenuation of neonatal hypoxic-ischemic encephalopathy. We aimed to define the role of estrogen receptors in E4-dependent actions in neuronal cell cultures and prove the promyelinating effect of E4. In vitro the antioxidative and cell survival/proliferating effects of E4 on H2O2-induced oxidative stress in primary hippocampal cell cultures were studied using different combinations of specific inhibitors for ERα (MPP dihydrochloride), ERß (PHTTP), GPR30 (G15) and palmytoilation (2-BR). LDH activity and cell survival assays were performed. In vivo the promyelinating role of different concentrations of E4 (1 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 50 mg/kg/day) was investigated using the hypoxic-ischemic brain damage model in the 7-day-old immature rats before/after the induction of hypoxic-ischemic insult. Myelin basic protein (MBP) immunostaining was performed on brain coronal sections. Our results show that LDH activity is significantly upregulated in cell cultures where the E4's effect was completely blocked by concomitant treatment either with ERα and ERß inhibitors (MPP and PHTPP, respectively), or ERα and ERß inhibitors combined with 2-BR. Cell survival is significantly downregulated in cell cultures where the effect of E4 was blocked by ERß inhibitor (PHTTP) alone. The blockage of GRP30 receptor did affect neither LDH activity nor cell survival. MBP immunostaining is significantly upregulated in E4-pretreated groups at a concentration of 5 mg/kg/day and 50 mg/kg/day E4, whereas the MBP-positive area OD ratio is significantly increased in all the E4-treated groups. E4's antioxidative actions mostly depend on ERα and ERß, whereas neurogenesis and possibly promyelinating activities might be realized through ERß.


Assuntos
Estetrol/farmacologia , Hipocampo/efeitos dos fármacos , Hipóxia-Isquemia Encefálica/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Hipocampo/metabolismo , Peróxido de Hidrogênio/farmacologia , Proteína Básica da Mielina/metabolismo , Neurônios/metabolismo , Projetos Piloto , Ratos , Ratos Sprague-Dawley
8.
Maturitas ; 91: 93-100, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27451327

RESUMO

OBJECTIVE: Estetrol (E4) is a natural fetal estrogen. The safety of increasing doses of E4 and its preliminary effects on the vagina, endometrium and menopausal vasomotor symptoms were investigated. STUDY DESIGN: This was a partly randomized, open-label, multiple-rising-dose study in 49 postmenopausal women. Subjects with an intact uterus were randomized to receive either 2mg E4 or 2mg estradiol-valerate (E2V) for 28days. Subsequent dose-escalation groups (non-randomized) were: 10mg E4 (intact uterus and ≥35 hot flushes/week); and 20mg and 40mg E4 (hysterectomized subjects). MAIN OUTCOME MEASURE: Adverse events (AEs) and vaginal cytology were evaluated in all treatment groups; hot flushes/sweating and endometrial proliferation were analyzed with 2 and 10mg E4 and 2mg E2V. RESULTS: Estetrol appeared to be safe, without serious drug-related AEs. In all the groups there was a clear shift from parabasal to superficial vaginal cells, indicating an estrogenic effect and a potential for the treatment of vulvovaginal atrophy. The endometrial thickness remained stable in the 2mg E4 group and increased with E2V and 10mg E4. A decrease in the mean number of hot flushes and sweating was seen with 2 and 10mg E4 and 2mg E2V. CONCLUSIONS: Estetrol in a dose range of 2-40mg per day improved vaginal cytology and vasomotor symptoms in postmenopausal women. Endometrial proliferation occurred with the 10mg dose. Estetrol seems a safe and suitable candidate to develop further for hormone therapy.


Assuntos
Endométrio/efeitos dos fármacos , Estetrol/uso terapêutico , Fogachos/tratamento farmacológico , Pós-Menopausa , Doenças Vaginais/tratamento farmacológico , Idoso , Relação Dose-Resposta a Droga , Estetrol/administração & dosagem , Estetrol/efeitos adversos , Estetrol/farmacologia , Terapia de Reposição de Estrogênios , Feminino , Fogachos/patologia , Humanos , Pessoa de Meia-Idade , Resultado do Tratamento , Doenças Vaginais/patologia
9.
Oncotarget ; 7(23): 33722-43, 2016 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-27231853

RESUMO

Estetrol (E4), estradiol (E2) and progesterone (P4) have important antioxidative and neuroprotective effects in neuronal system. We aimed to study the consequence of combined steroid therapy in neonatal hypoxic-ischemic encephalopathy (HIE). In vitro the effect of E4 combined with other steroids on oxidative stress and the cell viability in primary hippocampal cultures was evaluated by lactate dehydrogenase and cell survival assays. In vivo neuroprotective and therapeutic efficacy of E4 combined with other steroids was studied in HIE model of immature rats. The rat pups rectal temperature, body and brain weights were evaluated.The hippocampus and the cortex were investigated by histo/immunohistochemistry: intact cell number counting, expressions of markers for early gray matter lose, neuro- and angiogenesis were studied. Glial fibrillary acidic protein was evaluated by ELISA in blood samples. In vitro E4 and combinations of high doses of E4 with P4 and/or E2 significantly diminished the LDH activity and upregulated the cell survival.In vivopretreatment or treatment by different combinations of E4 with other steroids had unalike effects on body and brain weight, neuro- and angiogenesis, and GFAP expression in blood. The combined use of E4 with other steroids has no benefit over the single use of E4.


Assuntos
Estetrol/farmacologia , Hipóxia-Isquemia Encefálica , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Animais Recém-Nascidos , Estradiol/farmacologia , Hipocampo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Progesterona/farmacologia , Ratos , Ratos Sprague-Dawley
10.
Artigo em Inglês | MEDLINE | ID: mdl-26212489

RESUMO

OBJECTIVES: Estetrol (E4) is a natural estrogen produced by the human fetal liver. In combination with drospirenone (DRSP) or levonorgestrel (LNG), E4 blocks ovulation and has less effect on haemostatic biomarkers in comparison with ethinylestradiol (EE) combined with DRSP. This study evaluates the impact of several doses of E4/DRSP and E4/LNG on safety parameters such as liver function, lipid metabolism, bone markers and growth endocrine parameters. METHODS: This was a dose-finding, single-centre, controlled study performed in healthy women aged 18 to 35 years with a documented pretreatment ovulatory cycle. Participants received 5 mg or 10 mg E4/3 mg DRSP; 5 mg, 10 mg or 20 mg E4/150 µg LNG; or 20 µg EE/3 mg DRSP as a comparator for three consecutive cycles in a 24/4-day regimen. Changes from baseline to end of treatment in liver parameters, lipid metabolism, bone markers and growth endocrinology were evaluated. RESULTS: A total of 109 women were included in the study. Carrier proteins were minimally affected in the E4/DRSP and E4/LNG groups, in comparison with the EE/DRSP group, where a significant increase in sex hormone-binding globulin was observed. Similarly, minor effects on lipoproteins were observed in the E4 groups, and the effects on triglycerides elicited by the E4 groups were significantly lower than those in the EE/DRSP group. No imbalances in bone markers were observed in any groups. No alterations in insulin-like growth factor were observed in the E4 groups. CONCLUSIONS: E4-containing combinations have a limited effect on liver function, lipid metabolism, and bone and growth endocrine parameters.


Assuntos
Androstenos/farmacologia , Anticoncepcionais Orais Combinados/farmacologia , Estetrol/farmacologia , Etinilestradiol/farmacologia , Levanogestrel/farmacologia , Fígado/efeitos dos fármacos , Adolescente , Adulto , Fosfatase Alcalina/sangue , Aspartato Aminotransferases/sangue , HDL-Colesterol/sangue , HDL-Colesterol/efeitos dos fármacos , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Colágeno Tipo I/sangue , Colágeno Tipo I/efeitos dos fármacos , Anticoncepcionais Orais Combinados/farmacocinética , Anticoncepcionais Orais Sintéticos/farmacologia , Estetrol/farmacocinética , Estrogênios/farmacologia , Feminino , Hormônio do Crescimento/sangue , Hormônio do Crescimento/efeitos dos fármacos , Humanos , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like II/efeitos dos fármacos , Fator de Crescimento Insulin-Like II/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/fisiologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Osteocalcina/sangue , Osteocalcina/efeitos dos fármacos , Peptídeos/sangue , Peptídeos/efeitos dos fármacos , Globulina de Ligação a Hormônio Sexual/efeitos dos fármacos , Globulina de Ligação a Hormônio Sexual/metabolismo , Triglicerídeos/sangue , Adulto Jovem , gama-Glutamiltransferase/sangue
11.
Oncotarget ; 6(19): 17621-36, 2015 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-26056044

RESUMO

Increased risk of breast cancer is a critical side effect associated with the use of a menopausal hormone therapy (MHT). Estetrol (E4) is a natural estrogen produced by the human fetal liver and is a promising compound for clinical use in MHT. However, its impact on breast cancer is controversial and poorly defined. In this preclinical study, we show that E4 acts as a weak estrogen by stimulating the growth of hormone-dependent breast cancer only at concentrations exceeding menopausal therapeutic needs. E4 presents also an antitumor activity by decreasing the strong proliferative effect of estradiol (E2). While estrogen receptor alpha (ERα) is the predominant receptor mediating its effects, the dual weak-estrogenic/anti-estrogenic feature of E4 results from differential signaling pathways activation. Both nuclear and rapid extra-nuclear signaling pathway are necessary for a complete estrogenic effect of E4. However, the antitumor action of E4 is not due to a capacity to antagonize E2-induced nuclear activity. Altogether, our results highlight that E4 has a limited impact on breast cancer and may offer a safe therapeutic window for the treatment of menopausal symptoms.


Assuntos
Neoplasias da Mama/induzido quimicamente , Proliferação de Células/efeitos dos fármacos , Estetrol/farmacologia , Terapia de Reposição de Estrogênios/efeitos adversos , Terapia de Reposição de Estrogênios/métodos , Animais , Western Blotting , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Imunofluorescência , Xenoenxertos , Humanos , Camundongos , Reação em Cadeia da Polimerase em Tempo Real
12.
Steroids ; 95: 104-10, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25595451

RESUMO

INTRODUCTION: Estetrol (E4), a naturally occurring estrogen produced exclusively by human fetal liver, is currently being evaluated for potential use in contraception and menopausal care in humans. The present study was designed to profile E4 effects on the central nervous system, to assess the in vivo effects of E4 administration on Beta-Endorphin (ß-END) release in specific brain structures and to evaluate whether E4 has synergic or antagonistic effects on estradiol-mediated ß-END synthesis. EXPERIMENTAL: Intact female adult rats received different doses of E4 and ovariectomized (OVX) rats received different doses of E4 or E2V or combinations of both drugs. The concentrations of ß-END were assessed in the frontal and parietal cortex, hippocampus, hypothalamus, neurointermediate lobe, anterior pituitary and plasma. RESULTS: E4 at the dose of 1mg/kg/day did not alter ß-END content in most brain areas, as well as, plasma levels of intact animals E4 administered at a dose of 5mg/kg/day decreased ß-END content in the hippocampus, hypothalamus, and in the neurointermediate lobe, as well as, plasma levels, compared to intact animals receiving vehicle. E4 increased ß-END values in the frontal cortex, but not in the plasma, following the administration of 1mg/kg/day in OVX rats, whereas treatment with 5mg/kg/day in OVX rats induced a significant increase in ß-END levels in most brain areas and in the plasma. However, in the presence of estradiol, E4 showed an estrogen-antagonistic effect in selected brain structures at the dose of 5mg/kg/day and in plasma levels of ß-END at the dose of 1mg/kg/day and 5mg/kg/day. CONCLUSION: In OVX rats, E4 increases CNS and peripheral levels of ß-END, behaving as a weak estrogen-agonist. The antagonistic effect observed after combined estradiol and E4 administration further profiles E4 as a natural SERM.


Assuntos
Estetrol/farmacologia , beta-Endorfina/metabolismo , Animais , Relação Dose-Resposta a Droga , Antagonismo de Drogas , Sinergismo Farmacológico , Estradiol/análogos & derivados , Estradiol/farmacologia , Feminino , Ovariectomia , Ratos , Ratos Wistar
13.
Eur J Contracept Reprod Health Care ; 20(1): 29-35, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25213195

RESUMO

OBJECTIVES: Oestetrol (15-alpha-hydroxyoestriol, E4) is an endogenous oestradiol metabolite mainly produced at high concentrations in the fetal liver. In earlier studies E4 was investigated for its use as marker for pregnancies at risk, especially with vascular problems. Some current investigations suggest that the use of E4 in hormone therapy or contraception may have advantages in terms of breast cancer risk when compared to other oestrogens. METHODS: Proliferation of two oestrogen receptor-positive breast cancer cell lines (ZR 75-1 and HCC 1500) was investigated after incubation with oestrone (E1), oestradiol (E2), oestriol (E3), and oestetrol (E4). Receptor expression of oestrogen receptor-alpha (ERα) and -beta (ERß) was determined by Western-Blot. RESULTS: All four oestrogens elicited a significant proliferative stimulation at concentrations of 10(-10) und 10(-9) M as compared to controls. Oestrone displayed a significantly weaker effect than E2. Oestetrol was significantly less effective than E2 at the lower concentration. Expression of ERα and ERß was significantly upregulated by all oestrogens tested, without differences between the latter. CONCLUSIONS: Our results indicate a slightly lower proliferative effect of E4, but only at low concentrations. However, no difference was found regarding receptor expression. Breast cancer risk associated with use of oestetrol should be tested in clinical trials.


Assuntos
Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Estetrol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Estradiol/farmacologia , Estriol/genética , Estriol/farmacologia , Estrona/farmacologia , Feminino , Humanos , Proteínas de Membrana/metabolismo , Receptores de Progesterona/metabolismo
14.
J Endocrinol ; 224(1): 85-95, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25359896

RESUMO

Estetrol (E4) is a natural estrogen produced exclusively by the human fetal liver during pregnancy. Its physiological activity remains unknown. In contrast to ethinyl estradiol and estradiol (E2), E4 has a minimal impact on liver cell activity and could provide a better safety profile in contraception or hormone therapy. The aim of this study was to delineate if E4 exhibits an activity profile distinct from that of E2 on mammary gland. Compared with E2, E4 acted as a low-affinity estrogen in both human in vitro and murine in vivo models. E4 was 100 times less potent than E2 to stimulate the proliferation of human breast epithelial (HBE) cells and murine mammary gland in vitro and in vivo respectively. This effect was prevented by fulvestrant and tamoxifen, supporting the notion that ERα (ESR1) is the main mediator of the estrogenic effect of E4 on the breast. Interestingly, when E4 was administered along with E2, it significantly antagonized the strong stimulatory effect of E2 on HBE cell proliferation and on the growth of mammary ducts. This study characterizes for the first time the impact of E4 on mammary gland. Our results highlight that E4 is less potent than E2 and exhibits antagonistic properties toward the proliferative effect of E2 on breast epithelial cells. These data support E4 as a potential new estrogen for clinical use with a reduced impact on breast proliferation.


Assuntos
Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Estetrol/farmacologia , Antagonistas de Estrogênios/farmacologia , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Humanas/efeitos dos fármacos , Adolescente , Adulto , Animais , Células Cultivadas , Células Epiteliais/fisiologia , Feminino , Humanos , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/fisiologia , Glândulas Mamárias Humanas/citologia , Glândulas Mamárias Humanas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Adulto Jovem
15.
EMBO Mol Med ; 6(10): 1328-46, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25214462

RESUMO

Estetrol (E4) is a natural estrogen with a long half-life produced only by the human fetal liver during pregnancy. The crystal structures of the estrogen receptor α (ERα) ligand-binding domain bound to 17ß-estradiol (E2) and E4 are very similar, as well as their capacity to activate the two activation functions AF-1 and AF-2 and to recruit the coactivator SRC3. In vivo administration of high doses of E4 stimulated uterine gene expression, epithelial proliferation, and prevented atheroma, three recognized nuclear ERα actions. However, E4 failed to promote endothelial NO synthase activation and acceleration of endothelial healing, two processes clearly dependent on membrane-initiated steroid signaling (MISS). Furthermore, E4 antagonized E2 MISS-dependent effects in endothelium but also in MCF-7 breast cancer cell line. This profile of ERα activation by E4, uncoupling nuclear and membrane activation, characterizes E4 as a selective ER modulator which could have medical applications that should now be considered further.


Assuntos
Membrana Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Estetrol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Útero/efeitos dos fármacos , Animais , Western Blotting , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Endotélio Vascular/metabolismo , Estetrol/química , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Células HeLa , Células Hep G2 , Humanos , Imuno-Histoquímica , Células MCF-7 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Moleculares , Estrutura Molecular , Ovariectomia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Útero/metabolismo
16.
J Steroid Biochem Mol Biol ; 143: 285-90, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24787659

RESUMO

INTRODUCTION: Estetrol (E4), a naturally occurring estrogen only produced by the human fetal liver, is being evaluated in human studies for potential use in contraception and menopausal care. The present study was designed to profile E4 in the central nervous system, to assess the in vivo effects of E4 administration on allopregnanolone (AP) synthesis in specific brain structures and to evaluate whether E4 has synergic or antagonistic effects on estradiol-mediated AP synthesis. MATERIAL AND METHODS: Intact female adult rats received different doses of E4, and ovariectomized OVX rats received different doses of E4 or E2V or combinations of both drugs. The concentrations of AP were assessed in the frontal and parietal cortex, hippocampus, hypothalamus, anterior pituitary, and serum. RESULTS: E4 did not alter AP in intact animals in any region. E4 at a dosage of 5mg/kg/day increased AP levels in different brain areas and in the serum of OVX animals. However, in the presence of estradiol, E4 showed an estrogen-antagonistic effect on the brain and serum levels of AP. CONCLUSION: E4 increases the CNS and peripheral levels of AP, behaving as a weak estrogen-agonist in OVX rats. The antagonistic effect observed with E2V co-administration further profile E4 as a natural SERM.


Assuntos
Biomarcadores/análise , Encéfalo/metabolismo , Estetrol/administração & dosagem , Ovariectomia , Pregnanolona/análise , Animais , Encéfalo/efeitos dos fármacos , Estetrol/farmacologia , Feminino , Radioimunoensaio , Ratos , Ratos Wistar
17.
Rejuvenation Res ; 17(2): 157-8, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23992378

RESUMO

Evidence is given that replicative senescence--possibly as organismal aging--constitutes epigenetic phenomena, counteracted by homeostatic factors such as, e.g., the molecular chaperones, which are housekeeping molecules essential for the folding, repair, and transport of proteins, RNA, and DNA. Weakening of the chaperone defense with age probably contributes to the frailty in senescence. The present review presents evidence that the human fetal estrogen hormone estetrol, by promotion of chaperone functions, homeostasis, and cancer resistance, may prove useful as a supplement during human senescence.


Assuntos
Resistência à Doença/genética , Epigênese Genética/efeitos dos fármacos , Estetrol/farmacologia , Longevidade/genética , Chaperonas Moleculares/metabolismo , Neoplasias/genética , Humanos , Longevidade/efeitos dos fármacos
18.
J Endocrinol ; 215(1): 97-106, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22798015

RESUMO

This study compared ex vivo relaxing responses to the naturally occurring human hormone estetrol (E(4)) vs 17ß-estradiol (E(2)) in eight different vascular beds. Arteries were mounted in a myograph, contracted with either phenylephrine or serotonin, and cumulative concentration-response curves (CRCs) to E(4) and E(2) (0·1-100  µmol/l) were constructed. In all arteries tested, E(4) had lower potency than E(2), although the differential effect was less in larger than smaller arteries. In uterine arteries, the nonselective estrogen receptor (ER) blocker ICI 182 780 (1  µmol/l) caused a significant rightward shift in the CRC to both E(4) and E(2), indicating that the relaxation responses were ER dependent. Pharmacological blockade of nitric oxide (NO) synthases by N(ω)-nitro-L-arginine methyl ester (L-NAME) blunted E(2)-mediated but not E(4)-mediated relaxing responses, while inhibition of prostaglandins and endothelium-dependent hyperpolarization did not alter relaxation to either E(4) or E(2) in uterine arteries. Combined blockade of NO release and action with L-NAME and the soluble guanylate cyclase (sGC) inhibitor ODQ resulted in greater inhibition of the relaxation response to E(4) compared with E(2) in uterine arteries. Endothelium denudation inhibited responses to both E(4) and E(2), while E(4) and E(2) concentration-dependently blocked smooth muscle cell Ca(2)(+) entry in K(+)-depolarized and Ca(2)(+)-depleted uterine arteries. In conclusion, E(4) relaxes precontracted rat arteries in an artery-specific fashion. In uterine arteries, E(4)-induced relaxations are partially mediated via an endothelium-dependent mechanism involving ERs, sGC, and inhibition of smooth muscle cell Ca(2)(+) entry, but not NO synthases or endothelium-dependent hyperpolarization.


Assuntos
Artérias/efeitos dos fármacos , Estetrol/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Artérias/fisiologia , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/metabolismo , Artérias Carótidas/fisiologia , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Feminino , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores Estrogênicos/metabolismo , Receptores Estrogênicos/fisiologia , Artéria Renal/efeitos dos fármacos , Artéria Renal/metabolismo , Artéria Renal/fisiologia , Artéria Uterina/efeitos dos fármacos , Artéria Uterina/metabolismo , Artéria Uterina/fisiologia , Vasodilatadores/farmacologia
19.
Minerva Ginecol ; 63(3): 299-304, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21654614

RESUMO

The synthetic estrogen ethinylestradiol (EE)given by mouth is stable and yields satisfactory results in terms of ovulation inhibition and effects on the endometrium. It increases however the risk especially for venous thrombotic events and to a lesser degree also arterial thrombosis. Therefore research focused on diminuition of the EE dosage and the development of a different estrogen component in oral contraceptives, specifically an estrogen occurring during physiological processes in the female body. Two estrogens emerge: 17ß Estradiol is the most potent natural estrogen and it is the major estrogen secreted by the ovaries. Estetrol is a human sex steroid (15 alpha hydroxyestriol) which is only produced during pregnancy by the fetal liver. The pharmacolokinetic and pharmacodynamic properties of these estrogens are compared to those of EE (absorption, metabolization, bioavailability etc.) and the clinical profile is described as far it is known from a limited number of studies.


Assuntos
Anticoncepcionais Orais/farmacologia , Estetrol/farmacologia , Estrogênios/farmacologia , Etinilestradiol/farmacologia , Feminino , Humanos
20.
Climacteric ; 11 Suppl 1: 22-8, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18464018

RESUMO

OBJECTIVE: To evaluate the effect of estetrol (E(4)) on vaginal cornification and uterine wet weight in the ovariectomized rat. METHODS: Adult female rats served as experimental animals. Six groups of ovariectomized rats (eight per group) were treated orally once daily for 7 days as follows: vehicle (negative) control; E(4): 0.1, 0.3, 1.0 and 3.0 mg/kg/day, and ethinylestradiol 0.05 mg/kg/day as active (positive) control. Vaginal lavages were obtained daily and uterine wet weight was determined on day 7. RESULTS: Vaginal cornification was observed by day 5 in all rats at all E(4) doses and in the animals receiving ethinylestradiol, but not in the control rats. The onset of cornification with E(4) was dose-dependent. After 7 days' treatment, the two highest E(4) doses (1.0 and 3.0 mg) induced statistically significant higher uterine wet weight compared to vehicle. CONCLUSION: Estetrol has estrogenic effects on the vagina and on the uterus of ovariectomized rats. The potency of E(4) is approximately 20-fold lower compared to ethinylestradiol.


Assuntos
Estetrol/farmacologia , Ovariectomia , Útero/efeitos dos fármacos , Útero/patologia , Vagina/efeitos dos fármacos , Vagina/patologia , Administração Oral , Animais , Relação Dose-Resposta a Droga , Feminino , Humanos , Tamanho do Órgão/efeitos dos fármacos , Distribuição Aleatória , Ratos , Irrigação Terapêutica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA