RESUMEN

Estrone (E1) constitutes the primary component in oral conjugated equine estrogens (CEEs) and serves as the principal estrogen precursor in the female circulation in the post-menopause. E1 induces endothelium-dependent vasodilation and activate PI3K/NO/cGMP signaling. To assess whether E1 mitigates vascular dysfunction associated with postmenopause and explore the underlying mechanisms, we examined the vascular effects of E1 in ovariectomized (OVX) rats, a postmenopausal experimental model. Blood pressure was measured using tail-cuff plethysmography, and aortic rings were isolated to assess responses to phenylephrine, acetylcholine (ACh), and sodium nitroprusside. Responses to ACh in rings pre-incubated with superoxide dismutase (SOD), catalase (CAT), or apocynin were also evaluated. Protein expression of SOD, CAT, NOX1, NOX2, and NOX4 was determined by Western blotting. E1 treatment resulted in decreased body weight and retroperitoneal fat, increased uterine weight, and prevented elevated blood pressure in the OVX group. Furthermore, E1 improved endothelium-dependent ACh vasodilation, activated compensatory antioxidant mechanisms - i.e. increased SOD and CAT antioxidant enzymes activity, and decreased NOX4 expression. This, in turn, helped prevent oxidative stress and endothelial dysfunction in OVX rats. Additionally, E1 treatment reversed the increased total LDL cholesterol observed in the OVX group. The findings underscore protective effects of E1 on the cardiovascular system, counteracting OVX-related oxidative stress and endothelial dysfunction in Wistar rats. E1 exhibits promising therapeutic benefits for managing cardiovascular health, particularly in postmenopausal conditions.

Asunto(s)

Endotelio Vascular , Estrona , NADPH Oxidasa 4 , Ovariectomía , Ratas Wistar , Especies Reactivas de Oxígeno , Vasodilatación , Animales , Femenino , NADPH Oxidasa 4/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Vasodilatación/efectos de los fármacos , Estrona/farmacología , Presión Sanguínea/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas

RESUMEN

Estrone (E1) is a common environmental contaminant found in rivers and streams due to the farming of animals, such as swine and cattle. Our study evaluated the effects of chronic E1 exposure at environmentally relevant concentrations on spermatogenesis and the semen quality of zebrafish (Danio rerio). We exposed the fish to E1 at concentrations of 20, 200, and 2000 ng/L diluted in 0.001% ethanol (v/v) for 49 days. There were two control groups: one was exposed to water only and the other to ethanol at the same concentration used in the E1 groups. Following exposure, we analyzed the proportion of testicular cell types and other components (%), rate of cell proliferation and death, and sex steroid concentrations. Furthermore, we analyzed the expression of insulin-like growth factor 1 (IGF1), IGF2, IGF1 receptor (IGF1R), and inducible nitric oxide synthase and assessed the semen quality. E1 exposure increased spermatogonia, spermatids, Sertoli cells, Leydig cells, and the proportion of inflammatory infiltrate but decreased the spermatozoa amount. These changes were reflected by reductions in the gonadosomatic index and levels of 11-ketotestosterone in the testes. On the other hand, E1 exposure increased testicular estradiol, IGF1R expression, and nitric oxide production. After an evaluation using a computer-assisted sperm analysis (CASA) system, we observed reduced progressive motility, curvilinear velocity, and beat cross frequency of 20 and 2000 ng/L E1 groups. Our findings support that E1 causes deleterious effects on the testicular function and semen quality of D. rerio even at environmental concentrations. Thus, E1 concentrations should be monitored in surface waters for the purposes of fish conservation.

Asunto(s)

Estrona , Pez Cebra , Masculino , Animales , Porcinos , Bovinos , Pez Cebra/fisiología , Estrona/metabolismo , Estrona/farmacología , Análisis de Semen , Semen , Espermatozoides , Espermatogénesis , Testículo

RESUMEN

Estrogens play a pivotal role in the development of estrogen-dependent breast cancer and other hormone-dependent disorders. A common strategy to overcome the pathological effects of estrogens is the use of aromatase inhibitors (AIs), which bind to the enzyme and prevent the union with the natural substrate, decreasing the amount of estrogens produced. Several AIs have been developed, including inhibitors with a steroidal backbone and a nitrogen heterocycle in their structure. Encouraged by the notable results presented by current and clinical steroidal drugs, herein we present the synthesis of a steroidal spiro morpholinone derivative as a plausible aromatase inhibitor. The morpholinone derivative was synthesized over a six-step methodology starting from estrone. The title compound and its hydroxychloroacetamide derivative precursor were evaluated for their antiproliferative profile against estrogen-dependent and independent solid tumor cell lines: A549, HBL-100, HeLa, SW1573, T-47D and WiDr. Both compounds exhibited a potent antiproliferative activity in the micromolar range against the six cancer cell lines, with the hydroxychloroacetamide derivative precursor being a more potent inhibitor (GI50 = 0.25-2.4 µM) than the morpholinone derivative (GI50 = 2.0-11 µM). Furthermore, both compounds showed, in almost all cases, better GI50 values than the steroidal anticancer drugs abiraterone and galeterone. Docking simulations of the derivatives were performed in order to explain the experimental biological activity. The results showed interactions with the iron heme (derivative 3) and important residues of the steroidal binding-site (Met374) for the inhibition of human aromatase. A correlation was found between in vitro assays and the score obtained from the molecular docking study.

Asunto(s)

Antineoplásicos , Neoplasias de la Mama , Femenino , Humanos , Antineoplásicos/química , Inhibidores de la Aromatasa/química , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular , Estrógenos/farmacología , Estrona/farmacología , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Morfolinas/síntesis química , Morfolinas/farmacología

RESUMEN

Although estradiol bone contribution has been deeply studied, little is known about the action of estrone. We investigated the direct action of estrone on osteoblasts growth and differentiation, with focus on the biochemical mechanism displayed by the estrogen. Murine calvarial osteoblast cultures in vitro exposed to 10 nM estrone were employed. Estrone enhanced gene expression of the osteogenic differentiation marker, Runx2 mRNA (150% above control). The hormone significantly increased cell proliferation (38% above control), nitric oxide production (108% above control), alkaline phosphatase activity (50% above control), in addition to stimulation of extracellular matrix mineralization. Using specific antagonists, we found that the mechanism of action of estrone involves estrogen receptor, nitric oxide synthase and MAPK signalling pathways participation. The hormone acts by its own and probably not via conversion to estradiol, since 17 B HSD inhibition did not affect the hormonal action. This work shows a novel action of estrone on bone cells promoting osteoblastogenesis.

Asunto(s)

Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Estrógenos/farmacología , Estrona/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Osteoblastos/citología , Osteogénesis/efectos de los fármacos , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Animales , Animales Recién Nacidos , Células Cultivadas , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Óxido Nítrico/metabolismo , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Ratas , Ratas Wistar , Transducción de Señal

RESUMEN

Estrone (E1) produces remarkable vascular effects, including relaxation, modulation of proliferation, apoptosis and cell adhesion. This study investigated the role of estrogen receptors and endothelial signaling pathways in the vascular relaxation promoted by E1. Aortic rings from male Wistar rats (250-300 g) were contracted with phenylephrine and stimulated with graded concentrations of E1. The concentration-dependent relaxation induced by E1 was abolished after removal of the endothelium or incubation with the estrogen receptor antagonist ICI 182,780. G protein-coupled estrogen receptor antagonism did not alter the E1 effect. Pretreatment of endothelium-intact arteries with inhibitors of nitric oxide synthase, guanylyl cyclase, calmodulin (CaM) and PI3K reduced the E1-induced vasorelaxation. Incubation with inhibitors of the MEK/ERK1/2 or p38MAPK pathways did not alter the E1 vasorelaxation. Similarly, inhibition of cyclooxygenase or blockade of potassium channels did not change the E1 effect. Western blot analysis evidenced that E1 induces phosphorylation of eNOS, PI3K and Akt in rat aorta. Our data demonstrate that E1 induces aortic vascular relaxation through classic estrogen receptors activation on the endothelium. We also identify CaM and PI3K/Akt pathways as critical mediators of the NO-cGMP signaling activation by E1. These findings contribute to the notion that this estrogen regulates arterial function and represents another link, besides 17ß-estradiol (E2), between postmenopause and vascular dysfunction.

Asunto(s)

Aorta/efectos de los fármacos , GMP Cíclico/metabolismo , Estrona/farmacología , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Estrógenos/efectos de los fármacos , Sistemas de Mensajero Secundario/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Aorta/enzimología , Calmodulina/metabolismo , Relación Dosis-Respuesta a Droga , Activación Enzimática , Técnicas In Vitro , Masculino , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosforilación , Ratas Wistar , Receptores de Estrógenos/metabolismo

RESUMEN

In this work we checked the hypothesis whether estrone, progesterone, and testosterone are able to modulate the interactions between platelets, monocytes, and endothelial cells either under basal or inflammatory conditions. Using adhesion assays we demonstrated that pretreatment of endothelial cells with estrone, progesterone, or testosterone prevented monocytes and platelets adhesion induced by the proinflammatory agent bacterial lipopolysaccharide. The hormones reduced the expression of mRNA of ICAM-1, VCAM-1, and P-selectin, endothelial surface proteins that mediate monocytes and platelets adhesion respectively. Integrins are the main leukocyte proteins that allow firm adhesion. Using flow cytometry we showed that estrone treatment of monocytes reduced CD11b and CD11c expression, either under basal or injury (lipopolysaccharide) conditions. The three steroids inhibited platelet aggregation in a nitric oxide dependent manner. Platelet function was not affected by the steroid treatment. The molecular mechanisms of action exerted by the steroids included the participation of the intracellular signaling pathways PKC, MAPK, and PI3K, which selectively and differentially mediate the stimulation of nitric oxide release. We evidence that estrone, progesterone, and testosterone modulate monocyte and platelet adhesion to endothelial cells, events that play a major role in the initiation and progression of vascular lesions. The steroid action was evidenced under basal or inflammatory conditions. The mechanisms of action exerted by the steroids included stimulation of nitric oxide production and the participation of PKC, MAPK, and PI3K systems.

Asunto(s)

Células Endoteliales/fisiología , Esteroides/fisiología , Enfermedades Vasculares/metabolismo , Animales , Adhesión Celular/efectos de los fármacos , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Estrona/farmacología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Molécula 1 de Adhesión Intercelular/genética , Leucocitos/efectos de los fármacos , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Óxido Nítrico/metabolismo , Selectina-P/genética , Progesterona/farmacología , Ratas , Ratas Wistar , Transducción de Señal , Esteroides/farmacología , Testosterona/farmacología , Molécula 1 de Adhesión Celular Vascular/genética , Enfermedades Vasculares/patología

RESUMEN

In this work we provide evidence that estrone "per se" modulates cellular endothelial growth and survival, events that play key roles in the development of vascular disease. Moreover, under oxidative stress conditions the hormone prevented apoptosis triggered by hydrogen peroxide. Although estrone did not affect E-selectin and VCAM-1 mRNAs synthesis, the hormone prevented the expression of these adhesion molecules induced by the proinflammatory agent LPS. The steroid partially attenuated leukocyte adhesion not only under basal conditions but also in the presence of LPS. Using ICI182780 compound as estrogen receptor antagonist, and PD98059 as MAPK inhibitor we obtained evidence that the mitogenic action of estrone involved the participation of ER and MAPK transduction pathway activation. The presence of estradiol impaired the effect of estrone on cell proliferation and vasoactive production. These results suggest that estrone exhibits a remarkable biological action on endothelial cells, modulating vasoactive production, proliferation, apoptosis, and cell adhesion events.

Asunto(s)

Células Endoteliales/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Estrona/farmacología , 17-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Animales , Aorta/citología , Apoptosis/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Fragmentación del ADN/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , Selectina E/metabolismo , Células Endoteliales/fisiología , Endotelio Vascular/fisiología , Equilina/farmacología , Estradiol/farmacología , Femenino , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/fisiología , Óxido Nítrico/metabolismo , Ratas , Ratas Wistar , Timidina/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo

RESUMEN

A two step model mechanism of steroid action has been recently postulated. In this study, we test the hypothesis that, the biochemical action of estrone (E(1)) on vascular tissue could be performed via genomic and non-genomic actions. Rat aortic rings or vascular smooth muscle cell cultures (VSMC) were used to test the effect of the hormone on nitric oxide (NO) production, protein kinases activities and cell proliferation. Our data showed that estrone increased NO synthesis between 30 s and 20 min treatment, and this stimulatory effect was dependent on MAPK cascade activation, since it was prevented in the presence of a MAPK inhibitor (PD98059). Using a phosphorylation assay, we also showed that E(1) significantly increased MAPK activity. The effect of the hormone on PKC activity was measured in concentrations and time course studies. Direct treatment of rat aortic homogenates with E(1) significantly enhanced PKC activity (1-10 fold increase, p<0.01) at all concentrations (1; 10; 50 nM) and time tested (1-10 min). We demonstrated that 24 h of E(1) treatment markedly increased VSMC proliferation (53% above control), and this effect was suppressed by a PKC inhibitor. The rapid and the long term effects of the hormone were completely suppressed in the presence of an estradiol receptor antagonist (ICI 182780). In summary, we provided evidence that, the steroid exerts both non-genomic and genomic actions, the former associated with MAPK kinase dependent on NO production, and the latter related with induction of VSMC proliferation involving PKC pathway activation.

Asunto(s)

Aorta Torácica/efectos de los fármacos , Estrógenos/farmacología , Estrona/farmacología , Músculo Liso Vascular/efectos de los fármacos , Óxido Nítrico/biosíntesis , Transducción de Señal/efectos de los fármacos , Animales , Aorta Torácica/enzimología , Aorta Torácica/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Técnicas In Vitro , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Músculo Liso Vascular/citología , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Ratas , Ratas Wistar , Timidina/metabolismo , Factores de Tiempo

RESUMEN

Previously we demonstrated that estrone non-genomically regulates rat aortic NOS and COX activity and that this effect depends on ovarian activity. The purpose of the present study was to characterize this effect and investigate the participation of phospholipase C and phophatidylinositol-3-kinase system in the intracellular transduction pathway involved in the response. Using aortic strips isolated from female fertile rats we showed that estrone stimulate nitric oxide synthase and cyclooxygenase in a short time interval (5-20 min), and that NO production was dependent in part on PGI2 production since 1 microM indomethacin significantly reduced this free radical production. Injection of 17-beta-estradiol to ovariectomized rats restored tissue capacity to rapidly increase NO production in response to "in vitro" treatment with 1 nM estrone. We also demonstrated that in aortic strips isolated from intact animals estrone elicited a rapid phospholipase C activation, inducing a biphasic increase in diacylglycerol generation (peaking at 45 s and 5 min). The presence of protein kinase C inhibitor chelerythrine did not prevent the increase of NO released in response to hormone treatment. We proved that PI3K-Akt system does not mediate NOS and COX activation. However, PLC activation was dependent on PI3K since presence of LY 294002 in the incubation medium abolished estrone-induced DAG increment. We concluded that, estrone rapid action on vascular tissue involves a cross talk between NOS and COX system, and the activation of PLC/DAG/PKC transduction pathways.

Asunto(s)

Aorta/efectos de los fármacos , Estrona/farmacología , Transducción de Señal/efectos de los fármacos , Alcaloides/farmacología , Animales , Aorta/enzimología , Aorta/metabolismo , Benzofenantridinas/farmacología , Activación Enzimática , Epoprostenol/biosíntesis , Femenino , Técnicas In Vitro , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo I/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Ratas Wistar , Fosfolipasas de Tipo C/metabolismo

RESUMEN

The hypothesis tested in the present work is that estrone non-genomically regulates aortic nitric oxide synthase (NOS) and cyclooxygenase (COX) activities in female rats, and that such regulation depends on ovarian function. We found that physiological concentrations of estrone (E(1)) (0.1-10nM) significantly increased nitric oxide (NO) production (133 and 163% above control). The stimulatory action of E(1) on NOS activity was independent of calcium influx since the increase in NO elicited by the hormone was not affected by EGTA or verapamil. When COX activity was measured, we observed that estrone enhanced thromboxane (TXB(2)) production and prostacyclin (PGI(2)) release, but not prostaglandin (PGF(2), PGD(2), and PGE(2)) synthesis. Finally we demonstrated that the hormonal effect on NOS activity was not detected in rat aortic strips (RAS) isolated from animals deprived of ovarian activity (FR(-)) or ovariectomized rats (OVX). These results suggest that estrone exerts a direct, non-genomic action on rat aortic metabolism, which involves NOS and COX activation and depends on ovarian activity.

Asunto(s)

Aorta/efectos de los fármacos , Estrona/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Óxido Nítrico Sintasa/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Animales , Aorta/enzimología , Relación Dosis-Respuesta a Droga , Eicosanoides/análisis , Eicosanoides/biosíntesis , Femenino , Óxido Nítrico Sintasa/genética , Ovariectomía , Prostaglandina-Endoperóxido Sintasas/genética , Ratas , Ratas Wistar

RESUMEN

Spontaneously hypertriacylglycerolemic obese and diabetic inbred IIM Beta rats were treated with oleoylestrone for 10 days. Pair-feeding was performed to determine some oleoyl-estrone effects dependent on the caloric restriction it promotes. Twenty-five 200 day-old Beta males receiving a daily gavage of 0.2 ml sunflower oil were divided into the following groups: 1) daily dose of 10 nmol/g oleoyl-estrone; 2) pair-fed; 3) control. The variables measured were: whole body protein, water and lipid; retroperitoneal and epididymal fat depot weights; plasma urea, glucose, insulin, triacylglycerols and cholesterol. Biomass and food intake were assessed daily. Oleoyl-estrone and pair-fed groups expressed similar variations in body composition and significant body weight losses due to reduction in food intake. Oleoyl-estrone and pair-fed treatments significantly reduced retroperitoneal fat depot weights, but not epididymal ones. In oleoyl-estrone and pair-fed groups hyperglycemia decreased and insulinemia lowered significantly. Plasma normal total cholesterolemia and hypertriacylglycerolemia values typical of Beta rats decreased strongly compared to controls, though attaining significantly different values between oleoyl-estrone and pair-fed groups. Plasma total cholesterol appeared as more sensitive to caloric restriction than triacylglycerols through a specific oleoyl-estrone-mediated effect.

Asunto(s)

Fármacos Antiobesidad/farmacología , Restricción Calórica , Diabetes Mellitus Tipo 2/metabolismo , Estrona/análogos & derivados , Estrona/farmacología , Obesidad/metabolismo , Ácidos Oléicos/farmacología , Animales , Fármacos Antiobesidad/uso terapéutico , Peso Corporal/efectos de los fármacos , Colesterol/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ingestión de Alimentos , Estrona/uso terapéutico , Masculino , Obesidad/tratamiento farmacológico , Ácidos Oléicos/uso terapéutico , Ratas , Ratas Endogámicas , Triglicéridos/metabolismo , Pérdida de Peso/efectos de los fármacos

RESUMEN

Rats endocriadas de la línea IIMBeta con obesidad, hipertriacilglicerolemia y diabetes espontáneas fueron tratadas con oleoil-estrona durante 10 días. Un grupo con restricción alimentaria fue incluido en el estudio a fin de aislar algunos efectos de la oleoil-estrona dependientes de la restricción calórica que ésta promueve. Veinticinco ratas Beta macho de 200 dias de edad a los que se suministró 0.2 ml de aceite de girasol por día se dividieron en los seguientes grupos: (1) dosis diaria de 10 nmol/g de oleoil-estrona ; (2) restringido; (3) control. Las variables medidas fueron: proteínas corporales totales, agua y lípidios; pesos de los panículos adiposos retroperitoneal y epididimario; urea, glucosa, insulina, colesterol y triacilgliceroles plasmáticos. Los valores de biomasa y de ingesta de alimentos se registraron diariamente. Los grupos tratados con oleoil-estrona y restringido mostraron variaciones similares en composicíon corporal y disminuciones significativas en peso corporal debidas a reducciones en la ingesta de alimentos. Los tratamientos con oleoil-estrona y restringido disminuyeron significamente los pesos de los panículos adiposos retroperitoneales, pero no de los epididimarios. En los grupos tratados con oleoil-estrona y restringido la hiperglicemia disminuyó y la insulinemia lo hizo en forma significativa. Los valores de colesterol total plasmático normal y la hipertriacilglicerolemia característicos de las ratas Beta disminuyeron fuertemente comparados con los controles, aunque alcanzaron valores significa-tivamente diferentes entre los grupos tratados con oleoil-estrona y restringido. El colesterol total plasmático aparece como más sensible a la restricción calórica que los traicilgliceroles a través de un efecto específico mediado por la oleoil-estrona. (AU)

Asunto(s)

Animales , Masculino , Ratas , Fármacos Antiobesidad/farmacología , Restricción Calórica , Obesidad/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Ácidos Oléicos/farmacología , Estrona/farmacología , Fármacos Antiobesidad/uso terapéutico , Obesidad/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ratas Endogámicas , Peso Corporal/efectos de los fármacos , Colesterol/metabolismo , Triglicéridos/metabolismo , Ingestión de Alimentos , Pérdida de Peso/efectos de los fármacos , Ácidos Oléicos/uso terapéutico , Estrona/uso terapéutico

RESUMEN

Rats endocriadas de la línea IIMBeta con obesidad, hipertriacilglicerolemia y diabetes espontáneas fueron tratadas con oleoil-estrona durante 10 días. Un grupo con restricción alimentaria fue incluido en el estudio a fin de aislar algunos efectos de la oleoil-estrona dependientes de la restricción calórica que ésta promueve. Veinticinco ratas Beta macho de 200 dias de edad a los que se suministró 0.2 ml de aceite de girasol por día se dividieron en los seguientes grupos: (1) dosis diaria de 10 nmol/g de oleoil-estrona ; (2) restringido; (3) control. Las variables medidas fueron: proteínas corporales totales, agua y lípidios; pesos de los panículos adiposos retroperitoneal y epididimario; urea, glucosa, insulina, colesterol y triacilgliceroles plasmáticos. Los valores de biomasa y de ingesta de alimentos se registraron diariamente. Los grupos tratados con oleoil-estrona y restringido mostraron variaciones similares en composicíon corporal y disminuciones significativas en peso corporal debidas a reducciones en la ingesta de alimentos. Los tratamientos con oleoil-estrona y restringido disminuyeron significamente los pesos de los panículos adiposos retroperitoneales, pero no de los epididimarios. En los grupos tratados con oleoil-estrona y restringido la hiperglicemia disminuyó y la insulinemia lo hizo en forma significativa. Los valores de colesterol total plasmático normal y la hipertriacilglicerolemia característicos de las ratas Beta disminuyeron fuertemente comparados con los controles, aunque alcanzaron valores significa-tivamente diferentes entre los grupos tratados con oleoil-estrona y restringido. El colesterol total plasmático aparece como más sensible a la restricción calórica que los traicilgliceroles a través de un efecto específico mediado por la oleoil-estrona.

Asunto(s)

Animales , Masculino , Ratas , Fármacos Antiobesidad/farmacología , Restricción Calórica , Diabetes Mellitus Tipo 2 , Estrona/farmacología , Obesidad/metabolismo , Ácidos Oléicos/farmacología , Fármacos Antiobesidad/uso terapéutico , Peso Corporal/efectos de los fármacos , Colesterol/metabolismo , Diabetes Mellitus Tipo 2 , Ingestión de Alimentos , Estrona/uso terapéutico , Obesidad/tratamiento farmacológico , Ácidos Oléicos/uso terapéutico , Ratas Endogámicas , Triglicéridos/metabolismo , Pérdida de Peso/efectos de los fármacos

RESUMEN

This paper reports an investigation upon the effect of dehydroepiandrosterone (DHEA) on some mitochondrial membrane functions, such as electron transport, transmembrane electric gradient and calcium permeability. It was found that the hormone induced the efflux of accumulated matrix Ca(2+), inhibited Site I of the respiratory chain, as well as bringing about the collapse of the transmembrane potential, and mitochondrial swelling. Taking into account that cyclosporin A (CSA) inhibited Ca(2+) release and the collapse of the transmembrane potential, it is concluded that the hormone may induce the opening of a non-specific transmembrane pore. The mechanism of pore opening is ascribed to peroxidation of the membrane lipid bilayer. It should be mentioned that estrone, even at the concentration of 200 microM, failed to reproduce the behavior of dehydroepiandrosterone on mitochondrial functions.

Asunto(s)

Deshidroepiandrosterona/farmacología , Membranas Intracelulares/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Animales , Calcio/metabolismo , Bovinos , Ciclosporina/farmacología , Relación Dosis-Respuesta a Droga , Estrona/farmacología , Membranas Intracelulares/metabolismo , Transporte Iónico/efectos de los fármacos , Corteza Renal/metabolismo , Potenciales de la Membrana/efectos de los fármacos , Mitocondrias/metabolismo , Dilatación Mitocondrial/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Permeabilidad/efectos de los fármacos , Ratas , Albúmina Sérica Bovina/farmacología , Ácido Succínico/farmacología , Sustancias Reactivas al Ácido Tiobarbitúrico/análisis , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo

RESUMEN

Recent basic and clinical advances have consolidated the concept of tissue-selective estrogens, i.e. molecules that express different degrees of partial agonist, full agonist or antagonist activity in different tissues or cells. Delta8,9-Dehydroestrone sulfate (delta8,9-DHES) is a conjugated estrogen and a component of conjugated equine estrogens (CEE). It is metabolized in the human in at least a 1:1 ratio to its 17beta form, 17beta-delta8,9-DHES. To evaluate its activity in different clinical and biochemical parameters, a clinical research study was conducted with delta8,9-DHES and estrone sulfate as a comparator in postmenopausal women. Delta8,9-DHES was given orally at a daily dose of 0.125 mg for 12 weeks in a group of 10 women. Two additional groups of women received either estrone sulfate alone (1.25 mg/day) or the combination of delta8,9-DHES and estrone sulfate at the previously specified doses. A significant and consistent suppression of hot flushes (number, severity, and total score) was observed with delta8,9-DHES, reaching more than 95% suppression in all parameters of vasomotor symptoms. This level of activity was equal to that obtained with the much higher dose of estrone sulfate, and it was sustained for the duration of the treatment period (12 weeks). Measurements of a bone resorption marker, i.e. urinary excretion of N-telopeptide, demonstrated that delta8,9-DHES at 8 weeks produced a degree of suppression (40%) similar to that observed with the higher dose of estrone sulfate. Gonadotropin secretion (FSH and LH) was significantly suppressed in women receiving delta8,9-DHES, similar to that observed with estrone sulfate alone or with the combination of the two. Other parameters, such as total cholesterol, low density lipoprotein cholesterol and high density lipoprotein cholesterol were not modified significantly, whereas serum globulins (sex hormone-binding globulin and corticosteroid-binding globulin) showed only marginal increases after delta8,9-DHES administration. Taken together with preclinical data, it is found that delta8,9-DHES is an active estrogen with a distinct pharmacological profile that results in significant clinical activity in vasomotor, neuroendocrine (gonadotropin and PRL) and bone preservation parameters, whereas displaying little or no efficacy, at the dose tested, on other peripheral parameters normally affected by estrogens. Collectively, this information supports the concept that delta8,9-DHES is an integral component of CEE, with distinct tissue selectivity contributing to the CEE's overall clinical activity, and places this estrogen as a distinct member of a novel class of centrally active molecules with unique peripheral tissue selectivity.

Asunto(s)

Estrógenos/sangre , Estrona/análogos & derivados , Posmenopausia/sangre , Adulto , Resorción Ósea/sangre , Estrona/farmacología , Femenino , Sofocos/sangre , Humanos , Persona de Mediana Edad , Proyectos Piloto

RESUMEN

The aim of this work was to demonstrate the possible direct effect of several hormones upon glucose-induced insulin secretion in amphibians. Hence, pancreas pieces of Bufo arenarum were incubated for 60 min at 25 degrees with 2 and 8 mM glucose plus the addition of hormones known to affect insulin secretion in mammals, measuring the release of insulin by radioimmunoassay. Glucagon (1 microM), ACTH (2.5 microM), human and bovine growth hormone (4.6 and 2.1 microM), prolactin (0.27 microM), corticosterone (0.4 microM), androstanolone (10(-2) microM), estradiol and estrone (10 microM), triiodothyronine and thyroxine (1 microM) enhanced significantly the glucose-induced insulin secretion. Androstanolone, human and bovine growth hormone, triiodothyronine and thyroxine only exerted such effect in the presence of 8 mM glucose. Conversely, somatostatin (1 microM), adrenalin (1 microM), clonidine (2 microM), dexamethasone (0.4 microM), and 2-hydroxyestradiol (5 microM) decreased significantly the glucose-induced insulin release. However, the effect of somatostatin was only apparent in the presence of high glucose. The direct effect of all these hormones--tested for the first time in the amphibian pancreas--was similar to that described in the mammalian pancreas, thus suggesting that such hormones might participate, at least in vitro, in the fine-tuning of insulin secretion in amphibians.

Asunto(s)

Hormonas/farmacología , Insulina/metabolismo , Hormona Adrenocorticotrópica/farmacología , Animales , Bufo arenarum , Bovinos , Clonidina/farmacología , Corticosterona/análogos & derivados , Corticosterona/farmacología , Dihidrotestosterona/farmacología , Epinefrina/farmacología , Estradiol/farmacología , Estrona/farmacología , Glucagón/farmacología , Glucosa/farmacología , Humanos , Secreción de Insulina , Masculino , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Prolactina/farmacología , Somatostatina/farmacología , Tiroxina/farmacología , Triyodotironina/farmacología

RESUMEN

Catecholestrogens (CE), 2-hydroxyestradiol, 2-hydroxyestrone and primary estrogens, estradiol and estrone were tested in their ability to compete for the high affinity uptake of [3H]-GABA into crude synaptosomal fractions. Aliquots of the crude synaptosomal fraction obtained from normal rats were incubated for 10 min at 37 degrees C with [3H]-GABA in the presence, or absence, of estrogens and catecholestrogens. Neither estradiol nor estrone modified the specific [3H]-GABA uptake into crude synaptosomal fractions. On the contrary, CE significantly affected the specific [3H]-GABA uptake in a dose-dependent manner: low concentrations of CE enhanced the uptake; this effect disappeared with high concentrations of the compounds. The stimulatory effect of CE on [3H]-GABA uptake was blocked when samples were coincubated with nipecotic acid, thus suggesting that this effect is specific rather than the result of non-specific interactions of CE with the hypothalamic membrane.

Asunto(s)

Estradiol/análogos & derivados , Estrógenos de Catecol/farmacología , Hidroxiestronas/farmacología , Hipotálamo/efectos de los fármacos , Prolina/análogos & derivados , Sinaptosomas/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismo , Animales , Estradiol/farmacología , Estrona/farmacología , Femenino , Hipotálamo/metabolismo , Hipotálamo/ultraestructura , Técnicas In Vitro , Ácidos Nipecóticos/farmacología , Ratas , Ratas Sprague-Dawley , Sinaptosomas/metabolismo , Tritio

RESUMEN

The effects of 17-beta estradiol and of some catechol and non-catechol-estrogens on the synthesis and output of prostaglandins (PGs) E and F by uteri from ovariectomized rats, were explored. Uteri from castrated animals released twice as much PGE than PGF. When uterine tissue was obtained from spayed rats injected prior to sacrifice with a low dose of 17-beta estradiol (0.5 + 1.0 microgram, on two consecutive days), the output of PGE diminished significantly. With a higher dose of the hormone (0.5 + 50.0 micrograms) the depressive influence on the synthesis and release of PGE was even more marked, whereas the output of PGF rose significantly. Low or high doses of estrone or of estriol failed to affect the release of either one of the PGs determined. On the other hand, 2-0H-estradiol at a low dose had no action but at a higher one inhibited the release of PGE without influencing PGF. Neither low nor high doses of 2-0H estriol or of 2-0H estrone affected the synthesis and release of uterine PGs. It was also observed that all the compounds tested evoked a significant uterotrophic action. It appears plausible that some catechol metabolites of 17-beta estradiol, but not other catechol-estrogens, could be involved in the mechanism of action of 17-beta estradiol modulating the production of PGs by the rat uterus.

Asunto(s)

Estrógenos de Catecol/farmacología , Estrógenos/farmacología , Prostaglandinas/metabolismo , Útero/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Estradiol/farmacología , Estriol/farmacología , Estrona/farmacología , Femenino , Ovariectomía , Prostaglandinas E/metabolismo , Prostaglandinas F/metabolismo , Ratas , Útero/metabolismo

RESUMEN

The effects of 50 microM of progesterone (P4), estradiol (E2), estrone (E1), estriol (E3), dehydroepiandrosterone (DHIA), androstenedione (delta 4) and testosterone (T) on the bioconversion of [3H]pregnenolone (6 nM) to [3H]P4 were investigated by incubating 200 mg of tissue fragments as well as equivalent aliquots of microsomes from human term placenta during 30 min. All the steroids assayed, except E3, significantly inhibited the [3H]P4 formation in a microsome incubation system with respect to the control assay (P less than 0.001). Conversely in a tissue incubation system. P4, E1 as well as E3 had no effect on [3H]pregnenolone bioconversion while E2 slightly decreased the [3H]P4 formation (P less than 0.05) compared with the control. A significant inhibition was observed in this system with the other steroids (P less than 0.001). To investigate these apparent different results of inhibition-noninhibition of the same steroids irrespective of the system of incubation used, the effects of P4, E2 and T on 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta-HSD) activity were studied in tissue fragments and microsomes in kinetic terms. The results found indicate that these steroids inhibited in a competitive fashion the 3 beta-HSD activity in both systems. The different Ki values found in tissue fragments and microsomes respectively for P4 (1.8 microM vs 0.5 microM), E2 (2.3 microM vs 0.6 microM) and T (0.25 microM vs 0.3 microM) explain the bioconversion results obtained in presence of 50 microM of the same steroids. These results include inhibition of [3H]P4 formation by T in tissue fragments as well as in microsomes whereas P4 and E2 inhibited the [3H]P4 formation only in microsomes. Furthermore, the comparison of these Ki values with the available data of intraplacental and circulating concentrations of the same steroids in human term pregnancy suggest that only P4 would be expected to cause marked 3 beta-HSD inhibition in physiological conditions.

Asunto(s)

3-Hidroxiesteroide Deshidrogenasas/metabolismo , Hormonas Esteroides Gonadales/farmacología , Microsomas/enzimología , Placenta/enzimología , Progesterona/farmacología , 3-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Androstenodiona/farmacología , Unión Competitiva , Deshidroepiandrosterona/farmacología , Estradiol/farmacología , Estriol/farmacología , Estrona/farmacología , Femenino , Humanos , Cinética , Placenta/ultraestructura , Embarazo , Pregnenolona/metabolismo , Progesterona/biosíntesis , Testosterona/farmacología

Asunto(s)

Climaterio/efectos de los fármacos , Estradiol/farmacología , Estrona/farmacología , Presión Sanguínea/efectos de los fármacos , Ensayos Clínicos como Asunto , Evaluación de Medicamentos , Quimioterapia Combinada , Femenino , Humanos , Menstruación/efectos de los fármacos , Persona de Mediana Edad