RESUMEN
The present investigation addresses the pharmacokinetics of human chorionic gonadotropin (hCG), intramuscularly (i.m.) administered to goats. Nine pluriparous does of the Boer goat breed, 2-6 years of age and weighing 45-60 kg, were administered 500 IU hCG (2 ml Chorulon) deep into the thigh musculature 18 h after superovulatory FSH treatment. Blood samples were drawn from the jugular vein at 2 âh intervals for the first 24h, at 6 h intervals until 42 h, and at 12 h intervals until 114 h after administration. After centrifugation, plasma hCG concentrations were determined by electrochemiluminescence immunoassay. Pharmacokinetical parameters were as follows: lag time, 0.4 (s.e.m. 0.1) h; absorption rate constant, 0.34 (s.e.m. 0.002) h; absorption half-life, 2.7 (s.e.m. 0.5) h; elimination rate constant, 0.02 (s.e.m. 0.002) h; biological half-life, 39.4 (s.e.m. 5.1) h; and apparent volume of distribution, 16.9 (s.e.m. 4.3) l. The plasma hCG profile was characterized by an absorption phase of 11.6 (s.e.m. 1.8) h and an elimination phase of 70.0 (s.e.m. 9.8) h, with considerable individual variation in bioavailability and pharmacokinetical parameters. Biological half-life was negatively correlated (P<0.05) with peak concentration (r=-0.76), absorption rate constant (r=-0.78), and elimination rate constant (r=-0.87). The results indicate that after rapid absorption, hCG remains in the circulation for an extended period. This has to be taken into account when assessing the stimulatory response to hCG treatment on an ovarian level.
Asunto(s)
Gonadotropina Coriónica/administración & dosificación , Gonadotropina Coriónica/farmacocinética , Cabras/metabolismo , Animales , Gonadotropina Coriónica/sangre , Femenino , Semivida , Humanos , Inyecciones Intramusculares/veterinaria , Inducción de la Ovulación/métodos , Inducción de la Ovulación/veterinaria , SuperovulaciónRESUMEN
Ecdysteroids are steroids found in invertebrates and plants. In mammals they have protein anabolic effects. We have recently published antiosteoporotic effects of Tinospora cordifolia (TC) extract and the search for the possible active ingredients yielded the presence of beta-Ecdysone (Ecd). Therefore, we investigated the effects of pure Ecd in ovariectomized rats on morphological changes in joint, epiphyseal cartilage and trabecular tissue. Following ovariectomy rats were fed for 1 month with Ecd containing food at a dose of 52.8 mg/day/animal. Positive and negative control animals received 17-beta Estradiol (E(2), 132 microg/day/animal) and soy free (sf) food respectively. At sacrifice, specimens consisting of upper tibiae-lower femurs and knee joint were harvested and processed for histomorphometry. The parameters measured included thickness of the joint cartilage, thickness of the whole epiphyseal growth plate and its three zones. Furthermore, the percentage of trabecular bone in the metaphysis region of tibiae was quantified. Ecd and E(2) induced a significant increase in the thickness of joint cartilage. The whole epiphyseal growth plate and its proliferative and hypertrophic zones were also increased by Ecd whereas E(2) reduced their size. The percentage of trabecular area in the metaphysis of tibia was significantly increased in Ecd and E(2) treated animals. Results provide a plausible explanation for the antiosteoporotic effects of TC. Hence, TC as well as other Ecd producing plants or pure Ecd may be of value in the prevention and treatment of osteoporosis and osteoarthritis which is of increasing importance due to aging and obesity among individuals.
Asunto(s)
Conservadores de la Densidad Ósea/farmacología , Huesos/efectos de los fármacos , Ecdisterona/farmacología , Placa de Crecimiento/efectos de los fármacos , Articulación de la Rodilla/efectos de los fármacos , Extractos Vegetales/farmacología , Tinospora/química , Animales , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/uso terapéutico , Dieta , Quimioterapia Combinada , Ecdisterona/uso terapéutico , Estradiol/farmacología , Estradiol/uso terapéutico , Femenino , Fémur/efectos de los fármacos , Osteoartritis de la Rodilla/tratamiento farmacológico , Osteoporosis/tratamiento farmacológico , Osteoporosis/prevención & control , Ovariectomía , Fitoterapia , Extractos Vegetales/uso terapéutico , Ratas , Ratas Wistar , Alimentos de Soja , Tibia/efectos de los fármacosRESUMEN
BACKGROUND: Fracture healing in osteoporosis is delayed. Quality and speed of fracture healing in osteoporotic fractures are crucial with regard to the outcome of patients. The question arises whether established antiosteoporotic drugs can further improve fracture healing. MATERIALS AND METHODS: Osteoporosis manifests predominantly in the metaphyseal bone. Nevertheless, an established metaphyseal fracture model is lacking. A standardized metaphyseal fracture-healing model with stable plate fixation was developed for rat tibiae. The healing process was analyzed by biomechanical, gene expression, and histomorphometric methods in ovariectomized (OVX) and sham-operated rats (SHAM), compared to standardized estrogen (E)- and raloxifene (R)-supplemented diets. RESULTS: Estrogen and raloxifene improved the biomechanical properties of bone healing compared to OVX (Yield load: SHAM = 63.1 +/- 20.8N, E = 60.8 +/- 17.9N, R = 44.7+/-17.5N, OVX = 32:5 +/- 22.0N). Estrogen vs OVX was significant based on a denser trabecular network. Raloxifene greatly induced total callus formation ((R = 5.3 +/- 0.9 mm2, E = 4.7 +/- 0.5 mm2, SHAM = 4.51 +/- 0.61 mm2, OVX =4.1 +/- 0.6 mm2), whereas estrogen mainly enhanced new endosteal bone formation. There was no correlation between the gene expression (osteocalcin, collagen1alpha1, IGF-1, tartrate-resistant phosphatase) in the callus and the morphology and quality of callus formation. CONCLUSION: Raloxifene and estrogen improve fracture healing in osteoporotic bone significantly with regard to callus formation, resistance, and elasticity. The biomechanically stable metaphyseal osteotomy model with T-plate fixation presented here has proven to be appropriate to investigate fracture healing in osteoporosis.
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Conservadores de la Densidad Ósea/uso terapéutico , Modelos Animales de Enfermedad , Estradiol/análogos & derivados , Osteoporosis/complicaciones , Clorhidrato de Raloxifeno/uso terapéutico , Fracturas de la Tibia/terapia , Análisis de Varianza , Animales , Fenómenos Biomecánicos , Conservadores de la Densidad Ósea/farmacología , Quimioterapia Combinada , Estradiol/farmacología , Estradiol/uso terapéutico , Femenino , Colorantes Fluorescentes , Fijación Interna de Fracturas , Curación de Fractura/efectos de los fármacos , Microrradiografía , Osteotomía , Ovariectomía , Clorhidrato de Raloxifeno/farmacología , Ratas , Ratas Sprague-Dawley , Fracturas de la Tibia/diagnóstico por imagen , Fracturas de la Tibia/etiologíaRESUMEN
During reproductive aging female rats enter an anovulatory state of persistent estrus (PE). In an animal model of reinstatement of estrus cyclicity in middle-aged PE rats we injected the animals with progesterone (0.5 mg progesterone/kg body weight) at 12:00 for 4 days whereas control animals received corn oil injections. After the last injection animals were analyzed at 13:00 and 17:00. Young regular cycling rats served as positive controls and were assessed at 13:00 and 17:00 on proestrus. Progesterone treatment of middle-aged PE rats led to occurrence of luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin surges in a subset of animals that were denoted as responders. Responding middle-aged rats displayed a reduction of ER-beta mRNA in the preoptic area which was similar to the effect in young rats. Within the mediobasal hypothalamus, only young rats showed a decline of ER-alpha mRNA expression. A decrease of ER-alpha mRNA levels in the pituitary was observed in progesterone-responsive rats and in young animals. ER-beta mRNA expression was reduced in young regular cycling rats. ER-beta mRNA levels in the ovary were reduced following progesterone treatment in PE rats and in young rats. Taken together our data show that cyclic administration of progesterone reinstates ovulatory cycles in intact aging females which have already lost their ability to display spontaneous cyclicity. This treatment leads to the occurrence of preovulatory LH, FSH and prolactin surges which are accompanied by differential modulation of ERs in the hypothalamus, the pituitary and the ovary.
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Envejecimiento/fisiología , Ciclo Estral/fisiología , Terapia de Reemplazo de Hormonas , Sistema Hipotálamo-Hipofisario/metabolismo , Ovario/metabolismo , Progesterona/metabolismo , Receptores de Estrógenos/metabolismo , Envejecimiento/efectos de los fármacos , Animales , Ciclo Estral/efectos de los fármacos , Femenino , Ovario/efectos de los fármacos , Progesterona/administración & dosificación , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
Phytoestrogens might be an alternative medication in prophylaxis and treatment of osteoporosis. In this study, the osteoprotective effects of genistein (GEN) and equol (EQO) were evaluated. After ovariectomy, 44 rats received soy-free food (Control, C) and developed substantial osteoporosis over the course of two months. After that period, the rats were divided into different groups and fed estradiol (E), GEN or EQO for 35 days. To analyze the osteoprotective effects of the tested substances, bone biomechanical properties and histomorphometric changes of the lumbar vertebrae were evaluated. In analyzing the vertebral body compression strength, we found that the EQO (103.8%) and GEN (96.8%) groups reached similar levels relative to the E group, while the C group reached 77.7% of the biomechanical properties of the E group. EQO was significantly superior to C. The histomorphometric evaluation demonstrated an increased number of nodes in EQO- and E-treated rats compared to GEN- and C-treated rats. E led to an improvement of cortical as well as trabecular bone, an advantage that was only partly seen in the other groups. Treatment with phytoestrogens induced improved bone quality. EQO and GEN might be alternatives for hormone replacement therapy, although further studies are needed to elucidate possible side effects.
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Enfermedades Óseas Metabólicas/tratamiento farmacológico , Huesos/efectos de los fármacos , Genisteína/farmacología , Isoflavonas/farmacología , Fitoestrógenos/farmacología , Animales , Fenómenos Biomecánicos , Huesos/fisiología , Fuerza Compresiva , Equol , Estradiol/farmacología , Femenino , Osteocalcina/sangre , Ovariectomía , RatasRESUMEN
Epidemiological studies demonstrate that affective disorders are at least twice as common in women as in men, but surprisingly, very few preclinical studies have been conducted on female experimental animals. Therefore, the necessity of developing valid animal models for studying the pathophysiology of stress-related disorders in women is obvious. Chronic social stress has the potential to induce depression in humans and therefore we characterize here a chronic social instability stress paradigm in female rats. This consists of a 4-week period with alternating stressful social situations, including phases of isolation and crowding, in an unpredictable manner. At the physiological level, increased adrenal weight and plasma corticosterone levels indicated hyperactivity of the hypothalamus-pituitary-adrenal axis. Elevated plasma luteinizing hormone and disruption of the estrus cycle together with increased serum prolactin levels revealed disrupted regulation of the hypothalamus-pituitary-gonadal axis. Body temperature regulation was affected during the last week of stress such that stressed rats reduced their body temperature less during the rest phase than the controls, thus exhibiting a flattened temperature curve. Behaviorally, chronically stressed rats showed reduced sucrose preference and food intake. However, we did not observe any effect of stress on performance in the forced swim test and hippocampal neurotrophin levels were similarly unaffected. Our results indicate that, by using this social instability paradigm, female rats can be kept under chronic stress for weeks without habituation, and that ultimately the animals develop a depressive-like phenotype. This model may provide a valuable tool for further analyses of the neurobiology of stress-related disorders in women and has the potential to serve as a paradigm for screening novel antidepressant drugs with special efficacy in women.
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Trastorno Depresivo , Conducta Social , Estrés Psicológico/fisiopatología , Glándulas Suprarrenales/patología , Animales , Regulación de la Temperatura Corporal/fisiología , Corticosterona/sangre , Modelos Animales de Enfermedad , Ingestión de Alimentos/fisiología , Ciclo Estral/fisiología , Femenino , Preferencias Alimentarias/fisiología , Hipocampo/fisiopatología , Hormona Luteinizante/sangre , Tamaño de los Órganos , Fenotipo , Polisacáridos/metabolismo , Prolactina/sangre , Distribución Aleatoria , Ratas , Ratas Wistar , Aislamiento Social , Estrés Psicológico/patología , Estrés Psicológico/psicologíaRESUMEN
INTRODUCTION: Currently, osteoporosis research is rarely undertaken in males but an increase in male life expectancy in the company of hypogonadism suggests the necessity for potential therapeutic options. MATERIALS AND METHODS: In this study, the changes in bone structure under standardized testosterone- (T), raloxifene- (R) and estrogen (E)-supplemented diets were analyzed in osteoporotic castrated male rats. RESULTS: Unexpected biomechanical results could be only explained by the histomorphometry, but not by BMD measurements obtained from the qCT. All tested substances showed a significant improvement in the trabecular network (trabecular bone area for C: 2.55 mm(2), T: 4.25 mm(2), R: 4.22 mm(2) and E: 4.28 mm(2)), and suggests that the bone structure was preserved. For the metaphyseal cortical bone, a significant loss was detected in T (CBP: 18.7%) compared to R (CBP: 30.0%), E (CBP: 26.8%) and even to the osteoporotic control (CBP: 28.6%). This explains the observed early mechanical final failure after T supplementation. However, due to the preserved trabecular bone in T, the occurrence of the first microfractures (yL: 49 +/- 21.4 N) was significantly later than in the osteoporotic control (yL: 39.5 +/- 15.5 N). Raloxifene performed well in hindering the bone loss associated with osteoporosis. However, its effect (yL: 83.3 +/- 16.5 N) did not approach the protective effect of E (yL: 99.2 +/- 21.1 N). CONCLUSION: Testosterone only preserved the deterioration of the trabecular bone but not of the cortical bone. Raloxifene prevented the bone loss associated with osteoporosis at all bony structures. This effect did not approach the protective effect of estrogen on trabecular bone, but it is more suitable for male individuals because it has no feminizing effects on the subject.
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Huesos/fisiopatología , Estrógenos/uso terapéutico , Terapia de Reemplazo de Hormonas , Orquiectomía/efectos adversos , Osteoporosis/tratamiento farmacológico , Clorhidrato de Raloxifeno/uso terapéutico , Testosterona/uso terapéutico , Administración Oral , Animales , Fenómenos Biomecánicos , Densidad Ósea/efectos de los fármacos , Densidad Ósea/fisiología , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/fisiopatología , Huesos/efectos de los fármacos , Huesos/patología , Modelos Animales de Enfermedad , Estrógenos/administración & dosificación , Estrógenos/farmacología , Masculino , Osteoporosis/etiología , Osteoporosis/fisiopatología , Clorhidrato de Raloxifeno/administración & dosificación , Clorhidrato de Raloxifeno/farmacología , Ratas , Ratas Sprague-Dawley , Testosterona/administración & dosificación , Testosterona/farmacologíaRESUMEN
Osteoporosis research undertaken in males is rare and there are only a few therapeutic options. Phytoestrogens might be a safe alternative for prophylaxis. Sixty 3-month-old male rats were orchidectomized and divided into five groups. The groups either received soy-free food (C), estradiol (E), testosterone (T) or Vitex agnus castus in different concentrations (AC high/AC low) for 12 weeks. The tibia metaphysis was tested biomechanically and histomorphometrically. The AC high group reached 87% of the biomechanical values of the estradiol group and was significantly superior to the control group. Testosterone supplementation resulted in poor biomechanical properties. The cortical bone parameters of the AC group were similar to the control group, while supplementation with estradiol and testosterone demonstrated a reduction of cortical bone. The AC high group reached 88.4% of trabecular bone area, 80.7% of trabecular number and 66.9% of the number of trabecular nodes compared with estradiol supplementation. Vitex agnus castus demonstrated osteoprotective effects in males. It preserves the cortical as well as the trabecular bone and might be a safe alternative for HRT. Testosterone supplementation has positive effects on trabecular bone, which are concurrently counteracted by the loss of cortical bone.
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Conservadores de la Densidad Ósea/farmacología , Osteoporosis/prevención & control , Fitoterapia , Vitex/química , Animales , Fenómenos Biomecánicos , Densidad Ósea/efectos de los fármacos , Estradiol/farmacología , Masculino , Orquiectomía , Fitoestrógenos/farmacología , Ratas , Ratas Sprague-Dawley , Resistencia a la Tracción , Testosterona/farmacología , Tibia/efectos de los fármacosRESUMEN
AIM OF THE STUDY: Recently, Tinospora cordifolia (TC) was shown to affect prostate growth in rats. It is not known whether this is a direct effect of TC or whether it is induced by altered hormone release. To investigate the actions of TC on the prostate, human LNCaP cells were exposed to an ethanolic extract of TC. MATERIALS AND METHODS: LNCaP cells were incubated with the test substances for 48 h. Proliferation was measured by MTT test and prostate-specific antigen (PSA) secretion was determined with ELISA. RESULTS: TC showed a dose-dependent stimulation of proliferation of LNCaP cells. Co-incubation with the anti-androgen flutamide (FLU) reversed the TC-induced stimulation of PSA secretion. CONCLUSIONS: The reference compound dihydrotestosterone (DHT) caused a significant increase of growth of LNCaP cells. Similarly, TC stimulated proliferation of these prostate cells. The anti-androgen FLU reversed the increase of PSA release caused by either DHT or TC. Thus, we suggest that TC may contain androgenic compounds, which appear to act via androgen receptor (AR).
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Andrógenos/farmacología , Etanol/química , Extractos Vegetales/farmacología , Tinospora/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , MasculinoRESUMEN
UNLABELLED: The available courses of therapy to osteoporosis in menopausal women are limited by several side effects generated. A need therefore arises to explore herbal alternatives that are effective and safe. OBJECTIVE: Present animal studies were conducted to investigate the potential of Tinospora cordifolia (TC) ethanolic stem extract as an antiosteoporotic agent. METHODS: Three-month-old female Sprague-Dawley rats were either ovariectomized (ovx) or sham operated and treated with vehicle (benzyl benzoate:castor oil; 1:4), E(2) (1 microg/day) or TC (10, 50, 100 mg/kg b.wt) subcutaneously for 4 weeks. At the end of experiment bone mineral density of tibiae was measured by quantitative computer tomography. Serum was analyzed for the activity of alkaline phosphatase and levels of osteocalcin, cross-laps and lipids. Uterus and mammary gland were processed for histological studies. RESULTS: Ovx rats treated with TC (10 mg/kg b.wt) showed an osteoprotective effect as the bone loss in tibiae was slower than ovx controls. Serum osteocalcin and cross-laps levels were significantly reduced. All the above effects of TC were much milder than those produced by E(2). Alkaline phosphatase activity was higher in TC treatment groups. Total cholesterol and LDL levels remained unaltered but HDL levels were significantly lowered with TC (50 mg/kg b.wt) treatment. Uterus and mammary gland showed no signs of proliferation after treatment with TC extract. CONCLUSION: TC extract showed estrogen like effects in bone but not in reproductive organs like uterus and mammary gland. Thus, this study demonstrates that extract of T. cordifolia has the potential for being used as antiosteoporotic agent.
Asunto(s)
Conservadores de la Densidad Ósea/farmacología , Densidad Ósea/efectos de los fármacos , Osteoporosis Posmenopáusica/prevención & control , Fitoterapia , Extractos Vegetales/farmacología , Tinospora , Animales , Modelos Animales de Enfermedad , Estradiol/farmacología , Estrógenos/farmacología , Femenino , Humanos , Osteocalcina/efectos de los fármacos , Tallos de la Planta , Ratas , Ratas Sprague-Dawley , Útero/efectos de los fármacosRESUMEN
AIM: The aim of the present study was to evaluate the uterotropic effects of the administration of dietary equol, a metabolite of soy-derived daidzein or formononetin present in red clover, in an ovariectomized rat model of menopause. METHOD: Two doses of racemic equol were used (50 mg/kg of chow and 400 mg/kg of chow) and the results were compared with two doses of estradiol-3 benzoate (E2B) (4.3 mg/kg of chow and 17.3 mg/kg of chow). After 3 months, animals were sacrificed and the uteri were removed, weighed and paraffin-embedded for morphometrical and immunohistochemical evaluation. The expression of selected uterine estrogen-responsive genes was also measured using real-time reverse transcription-polymerase chain reaction. RESULTS: Compared to controls, uterine weights in animals treated with high-dose equol were significantly higher, presented histologic features of mild estrogenic stimulation and had greater epithelial height and thickness of the uterine stroma and myometrium. Staining for the presence of the proliferating cell nuclear antigen (PCNA) also showed a greater prevalence of the PCNA-positive cells in the uterine stroma in animals treated with high-dose equol. Conversely, the percentage of PCNA-positive cells in the uterine epithelium was lower compared to the controls. Dietary high-dose equol treatment also increased significantly levels of uterine insulin-like growth factor 1, progesterone receptor and complement protein 3 mRNA. Although statistically significant, all these effects were, however, lower in magnitude compared to the effects of low- and high-dose E2B treatment. Low-dose equol did not have any effects on the above-studied parameters. CONCLUSION: Long-term high-dose dietary equol administration to ovariectomized rats exerts uterotropic effects at the cellular and molecular level which question the safety of uncontrolled and unlimited consumption of soy or red clover supplements by postmenopausal women with intact uteri.
Asunto(s)
Estrógenos no Esteroides/farmacología , Isoflavonas/farmacología , Ovariectomía , Hipófisis/efectos de los fármacos , Animales , Dieta , Relación Dosis-Respuesta a Droga , Equol , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Femenino , Hormona Luteinizante/sangre , Tamaño de los Órganos/efectos de los fármacos , Hipófisis/metabolismo , Prolactina/sangre , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Útero/efectos de los fármacosRESUMEN
In females, it is well established that changes in the expression of neurotransmitters and peptides regulating the activity of the gonadotrophin-releasing hormone (GnRH) pulse generator are altered during ageing. By contrast, little is known about whether those age-related changes also occur in males. Therefore, we designed an animal study with orchidectomised young and middle-aged male rats to investigate changes in luteinising hormone (LH) secretion profiles and changes in the mRNA expression of genes regulating the activity of the GnRH pulse generator. Our results demonstrate that middle-aged rats exhibit lower serum LH levels and relatively fewer LH pulses with attenuated amplitude compared to young animals. Furthermore, upon ageing, GnRH mRNA expression is up-regulated in the preoptic area and the septum where GnRH neurones reside. Analysis of mRNA levels of glutamate decarboxylase (GAD) enzymes revealed that GAD(65) and GAD(67) mRNA expression increased in the mediobasal hypothalamus (MBH) and that GAD(67) mRNA levels decreased in the suprachiasmatic nucleus. In addition, we observed an age-related increase of oestrogen receptor (ER)alpha mRNA in the MBH, and both ERalpha and ERbeta mRNA expression was up-regulated in the pituitary of middle-aged rats compared to young animals. Taken together, our data support the existence of a male 'andropause' that is, like the menopause in females, accompanied by changes in neurotransmitter and hormone receptor expression that are involved in regulating the function of the GnRH pulse generator.
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Envejecimiento/fisiología , Regulación de la Expresión Génica/fisiología , Hormona Liberadora de Gonadotropina/metabolismo , Hipotálamo/metabolismo , Hormona Luteinizante/sangre , Animales , Perfilación de la Expresión Génica , Glutamato Descarboxilasa/genética , Glutamato Descarboxilasa/metabolismo , Hormona Liberadora de Gonadotropina/genética , Masculino , Periodicidad , Hipófisis/fisiología , ARN Mensajero/análisis , Ratas , Ratas Wistar , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Estadísticas no Paramétricas , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
Prostate cancer is more frequently diagnosed in men from Western countries than from Asian societies. Therefore, nutritional factors such as phyto-oestrogens from soya are considered to cause this prostate cancer prevention effect. As there is no curative therapy for hormone-refractory prostate cancer, new strategies are in demand which might include phyto-oestrogens or inhibitors of histone deacetylases. Both approaches have in common the potential to reduce the aberrant androgen receptor and IGF receptor signalling. Furthermore, invasiveness and acquired survival strategies of tumours can be diminished. Reduced tumour cell proliferation and PSA secretion coincide with altered gene expression in the aforementioned processes. In addition, selective knock-down of genes by RNA interference afforded functional analyses regarding impact and succession of expression events involved in the beneficial effects caused by phyto-oestrogens and histone deacetylase inhibitors.
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Terapias Complementarias , Inhibidores de Histona Desacetilasas , Fitoestrógenos/uso terapéutico , Fitoterapia , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/terapia , Biomarcadores de Tumor/genética , División Celular/efectos de los fármacos , División Celular/genética , Expresión Génica/efectos de los fármacos , Humanos , Masculino , ARN Interferente Pequeño/genética , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
The aim of our study was to evaluate the effects of dietary equol, metabolite of a phytoestrogen daidzein, on the secretion of prolactin (PRL) and lutenizing hormone (LH), as well as the expression of estrogen receptors (ERalpha, ERbeta and truncated estrogen receptor-1 (TERP-1) in the pituitary gland of ovariectomized (ovx) female Sprague-Dawley rats. Two doses of equol (50 mg/kg of chow and 400 mg/kg of chow) were used and the results were compared with the effects of estradiol 3-benzoate (E2B), also given at two doses (4.3 mg/kg of chow and 17.3 mg/kg of chow). Treatment period was 3 months. Dietary equol administration at the high dose increased significantly serum PRL levels. This effect was also observed in the E2B group but this difference did not reach statistical significance. Surprisingly, high dose dietary equol treatment also significantly increased serum LH levels, which was in contrast to E2B treatment where serum LH levels were significantly decreased at both doses. Serum LH levels in the equol low group were unaffected. Equol treatment had no effects on pituitary ERalpha or ERbeta gene expression. In contrast, high dose E2B treatment increased significantly pituitary ERalpha mRNA levels but decreased those of ERbeta. Both doses of E2B also increased significantly pituitary TERP-1 mRNA levels. This effect was also observed in the equol high group but at a much smaller magnitude. In conclusion, high dose dietary equol administration to ovx rats exerts estrogenic like effects on the lactotropes and anti-estrogenic on the gonadotropes.
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Estrógenos no Esteroides/farmacología , Isoflavonas/farmacología , Ovariectomía , Hipófisis/efectos de los fármacos , Animales , Dieta , Equol , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Femenino , Hormona Luteinizante/sangre , Tamaño de los Órganos/efectos de los fármacos , Hipófisis/metabolismo , Prolactina/sangre , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Útero/efectos de los fármacosRESUMEN
Challenge with low-dose apomorphine causes a rise in growth hormone (GH) in patients with Parkinson's disease (PD). We studied 18 patients with early PD, who showed an increase of GH in the low-dose apomorphine test, by means of [(123)I] FP-CIT-SPECT. The mean specific dopamine transporter binding of the 18 patients was 1.50 +/- 0.56 in the striatum, 1.20 +/- 0.59 in the putamen, and 1.76 +/- 0.59 in the caudate nucleus. The increase of GH (1.05 +/- 1.01 ng/ml at baseline to 9.46 +/- 6.36 ng/ml 45 min after apomorphine injection; p < 0.001) was significant. There was a significant negative correlation of the increase of GH with the mean specific dopamine transporter binding in all three regions (r between -0.490 and -0.587; p between 0.04 and 0.01). Challenge with low-dose apomorphine may therefore be used as an indirect tool to measure the extent of nigrostriatal neurodegeneration in early PD.
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Apomorfina , Cuerpo Estriado/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Hormona del Crecimiento/sangre , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismo , Sustancia Negra/metabolismo , Adulto , Anciano , Apomorfina/farmacología , Unión Competitiva/efectos de los fármacos , Unión Competitiva/fisiología , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/fisiopatología , Dopamina/metabolismo , Agonistas de Dopamina/farmacología , Femenino , Hormona del Crecimiento/análisis , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/fisiopatología , Valor Predictivo de las Pruebas , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/fisiopatología , Tomografía Computarizada de Emisión de Fotón Único , Tropanos/farmacocinéticaRESUMEN
Estrogen deficiency may be partly responsible for the metabolic syndrome and the condition may be reversible with hormone replacement therapy. However, after the heart and estrogen/progestin replacement study and the women's health initiative study the prospect of HRT on CVD has changed dramatically. As the pituitary and the liver are targets for estrogen action we assessed the effect of ovariectomy (OVX) and long-term (3 months) estradiol (E2) treatment by means of subcutaneously (s.c.) implanted silastic capsules on pituitary and liver function in young and middle-aged female rats. Our results demonstrate that triglyceride serum levels increased, whereas insulin-like growth factor-1 (IGF-1), high density lipoprotein cholesterol (HDL), and glucose levels decreased during the transition from young to middle-age. E2 treatment increased dose-independently growth hormone (GH) secretion. IGF-1 levels were increased upon OVX in middle-aged rats and the high dose of E2 decreased IGF-1 concentrations in both age groups. Cholesterol concentrations increased after OVX and were attenuated by E2 administration in middle-aged rats. Both, low density lipoprotein cholesterol (LDL) and HDL levels raised after castration and both parameters decreased in response to E2 in young and middle-aged rats. Glucose serum concentrations decreased after E2 treatment in all animals. Taken together, our results clearly demonstrate that the pituitary and the liver metabolism of middle-aged rats remain susceptible to the influence of OVX and E2 treatment.
Asunto(s)
Envejecimiento/metabolismo , Estradiol/farmacología , Hormona del Crecimiento/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Lípidos/sangre , Ovariectomía , Animales , Glucemia/metabolismo , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Femenino , Hígado/efectos de los fármacos , Hígado/metabolismo , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Ratas , Ratas Sprague-Dawley , Triglicéridos/sangreRESUMEN
Phytoestrogens are a group of plant-derived biologically active substances with a chemical structure that resembles that of 17beta-estradiol (E2). As the presence of estrogen receptors (ER) has been identified in several immune cells, phytoestrogens may also have a great impact on the immune system. The aim of our study was to determine the in vitro effects of genistein and resveratrol on the production of interferon-gamma (IFNgamma) and interleukin-10 (IL-10) by stimulated murine splenocytes and compare them with the effects of natural E2. Phorbol 12-miristate 13-acetate (PMA) together with ionomycin was used to stimulate the cells. E2 and genistein did not show any significant effects on the stimulated production of IFNgamma. Resveratrol had a mild inhibitory effect on IFNgamma production at the concentration of 10(-7)M; however, this difference did not reach statistical significance (p>0.05). IL-10 levels in the splenocytes culture supernatants were found to be increased in the presence of E2, genistein and resveratrol; however, these effects were also not statistically significant. To determine whether the exposure to our studied phytoestrogens induced a shift in the T-helper 1/T-helper 2 (Th1/Th2) balance, we calculated the ratio between the production of IFNgamma, the prototypic Th1 cytokine, and the production of IL-10, the prototypic Th2 cytokine, at different concentrations of our tested substances. Genistein at the concentrations of 10(-6) and 10(-7)M and resveratrol at the concentrations of 10(-6)M decreased significantly the IFNgamma/IL-10 ratio. This decrease was comparable to that of E2 at the concentrations of 10(-7)M. From our in vitro experiments we conclude that genistein and resveratrol, similarly to E2, by decreasing the IFNgamma/IL10 ratio may shift the Th1/Th2 balance towards the Th2 response.
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Genisteína/farmacología , Fitoestrógenos/farmacología , Fitoterapia , Plantas Medicinales , Bazo/efectos de los fármacos , Estilbenos/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Genisteína/administración & dosificación , Genisteína/uso terapéutico , Técnicas In Vitro , Interferón gamma/biosíntesis , Interleucina-10/biosíntesis , Masculino , Ratones , Ratones Endogámicos C57BL , Fitoestrógenos/administración & dosificación , Fitoestrógenos/uso terapéutico , Resveratrol , Bazo/citología , Bazo/metabolismo , Estilbenos/administración & dosificación , Estilbenos/uso terapéuticoRESUMEN
The lack of estrogen during menopause is associated with various symptoms including osteoporosis, cardiovascular diseases, and menopausal symptoms. For many years, conventional hormone replacement therapy has been successfully used to treat these conditions. However, in light of recent studies that draw attention to potential hazards of conventional HRT, various attempts were undertaken to search for alternatives of classical HRT. Phytoestrogens are supposed to ameliorate various discomforts associated with menopause. Resveratrol (RES) is present in red wine, grapes and peanuts and has been implicated in cardioprotection and prevention of adverse side effects observed after regular HRT. As the pituitary-thyroid axis is a target of estrogen action, we first assessed the effects of E2 administration on thyroid hormone stimulating hormone releasing hormone (TRH)-induced thyroid stimulating hormone (TSH) secretion from pituitary cell cultures in vitro. Our data reveal that E2 treatment augments the TRH-induced TSH secretion. We furthermore designed a long-term study of three months to assess the effects of subcutaneous and oral administration of 17beta-estradiol (E2), as well as the actions of RES on the pituitary-thyroid axis in ovariectomized (OVX) female rats. Our results demonstrate that serum levels of 1.0 and 8.1 microM RES lead to a significant increase in total serum triiodthyronine (T3) levels. OVX induces TSHbeta mRNA in the adenohypohysis and E2 treatment attenuates this effect. Treatment of rats with subcutaneous implants of E2 does not affect the pituitary-thyroid axis, whereas orally applied E2 benzoate (E2B) increases plasma TSH and total thyroxine (T4) in OVX rats. In all animals, we could not detect changes in thyroid morphology as assessed by hematoxylin-eosin (HE) and Perjod-Acid Schiff's (PAS) staining.
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Estradiol/farmacología , Hipófisis/fisiología , Estilbenos/farmacología , Glándula Tiroides/fisiología , Vasodilatadores/farmacología , Administración Oral , Alimentación Animal , Animales , Arachis , Cardiotónicos/farmacología , Técnicas de Cultivo de Célula , Estradiol/administración & dosificación , Femenino , Inyecciones Subcutáneas , Sistemas Neurosecretores/efectos de los fármacos , Sistemas Neurosecretores/fisiología , Ovariectomía , Hipófisis/citología , Hipófisis/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Resveratrol , Glándula Tiroides/citología , Glándula Tiroides/efectos de los fármacos , Tirotropina de Subunidad beta/genética , VinoRESUMEN
Phytoestrogens are increasingly consumed in artificially high doses as herbal preparations and nutritional supplements. The flavanone 8-prenylnaringenin (8PN) is a potent phytoestrogen, but its benefits and risks after long-term application are poorly identified. Therefore, we tested two doses of 8PN and 17beta-estradiol-3-benzoate (E2B) (effective doses: 6.8 and 68.4 mg/kg body weight (BW) of 8PN, and 0.17 and 0.7 mg/kg BW of 17beta-estradiol (E2)) and compared their effects on uterine weight, pituitary hormones (LH, FSH and prolactin) and the expression of estrogen-regulated genes and of estrogen receptor (ER)alpha and ERbeta in the hypothalamus, pituitary and uterus. Both doses of E2 and the high dose of 8PN suppressed serum LH and FSH, and stimulated serum prolactin levels, uterine weight, and progesterone receptor, insulin-like growth factor I and complement protein C3 mRNA transcripts. In the preoptic and the mediobasal areas of the hypothalamus, all treatments had negligible effects on ERalpha and ERbeta and gonadotropin-releasing hormone (GnRH) receptor gene expression, while ERbeta and GnRH receptor transcripts in the anterior pituitary were reduced under both E2 doses and the high 8PN dose. The mRNA concentrations of the LHalpha and -beta subunits in the pituitary were suppressed by E2 and 8PN. In summary, 8PN had very similar though milder effects than E2 on all tested parameters. Inhibition of climacteric complaints by E2 takes place in the hypothalamus, where it inhibits the overactive GnRH pulse generator. Hence, 8PN may be used to inhibit climacteric symptoms effectively. Human pharmacologic studies will show whether the stimulatory effect on the uterus that was found in the present animal model would require the concomitant administration of progestins to prevent endometrial overstimulation.
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Flavanonas/farmacología , Hipotálamo/efectos de los fármacos , Adenohipófisis/efectos de los fármacos , Útero/efectos de los fármacos , Animales , Disponibilidad Biológica , Complemento C3/genética , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Estradiol/farmacología , Receptor alfa de Estrógeno/análisis , Receptor beta de Estrógeno/análisis , Femenino , Hormona Liberadora de Gonadotropina/sangre , Hormona Liberadora de Gonadotropina/genética , Gonadotropinas Hipofisarias/sangre , Gonadotropinas Hipofisarias/genética , Hipotálamo/química , Factor I del Crecimiento Similar a la Insulina/genética , Tamaño de los Órganos/efectos de los fármacos , Ovariectomía , Adenohipófisis/química , Prolactina/sangre , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Receptores LHRH/análisis , Receptores LHRH/genética , Receptores de Progesterona/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estimulación Química , Factores de Tiempo , Útero/químicaRESUMEN
INTRODUCTION: Phytoestrogenes are plant-derived compounds that have been shown to exert an antiproliferative potential on prostate cancer cells, although the exact mechanisms are still unclear. In prostate cancer cells proliferation is regulated by modulation of the IGF-1 receptor (IGF-R-1) by the androgen receptor (AR) and its co-activator prostate derived Ets factor (PDEF). Phytooestrogenes interact with these mechanisms as demonstrated exemplarily in the presented study with the isoflavone tectorigenin derived from Belamcanda chinensis. MATERIAL AND METHODS: Cultured androgen-sensitive LNCaP prostate cancer cells were treated with tectorigenin of 100 microM for 24 hours. The mRNA-expression of AR, PSA, PDEF, hTERT, TIMP-3 and IGF-R-1 were quantified by real-time RT-PCR. Furthermore, the expression or activity of PSA, telomerase and IGF-R-1 was measured on the protein level. In addition, we investigated in nude mice the influence of a diet of extracts of Belamcanda chinensis on the growth of subcutaneously injected LNCaP cells versus a control group of animals fed with a soy-free diet. RESULTS: In cultured LNCaP cells treatment with tectorigenin resulted in a significant down-regulation of the gene expression of AR, PDEF, PSA, IGF-R-1 and hTERT. On the protein level PSA secretion and the activity of telomerase and IGF-R-1 expression was also decreased. The gene expression of TIMP-3 was distinctly up-regulated by tectorigenin. Nude mice fed with Belamcanda chinensis extract showed a significantly decreased incidence and tumor growth compared to controls. CONCLUSIONS: Tectorigenin shows an inhibition of the IGF-1-R modulated cell proliferation of PCa-Cells, due to modulation of the activity the co-activator PDEF independently from the AR. Furthermore, tectorigenin has pro-apoptotic effects and decreases tissue invasion by up-regulation of TIMP-3. Therefore, phytooestrogenes are an interesting option in the therapy of prostate especially advanced prostate cancer.