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Rev. bras. ginecol. obstet ; 41(12): 703-709, Dec. 2019. tab, graf
Article in English | LILACS | ID: biblio-1057889


Abstract Objective To investigate the action of testosterone (T), isolated or associated with estradiol benzoate (EB), on the proliferation markers and apoptosis of breasts of ovariectomized rats. Methods A total of 48 castrated female Wistar rats were divided into 6 groups, and each of them were submitted to one of the following treatments for 5 weeks: 1) control; 2) EB 50 mcg/day + T 50 mcg/day; 3) T 50mcg/day; 4) EB 50 mcg +T 300 mcg/day; 5) T 300 mcg/day; and 6) EB 50 mcg/day. After the treatment, the mammary tissue was submitted to a histological analysis and immunoexpression evaluation of proliferation markers (proliferating cell nuclear antigen, PCNA) and apoptosis (caspase-3). Results There was a statistically significant difference among the groups regarding microcalcifications and secretory activity, with higher prevalence in the groups treated with EB. There was no difference among the groups regarding atrophy, but a higher prevalence of atrophy was found in the groups that received T versus those that received EB +T. There was a difference among the groups regarding the PCNA (p = 0.028), with higher expression in the group submitted to EB +T 300 mcg/day. Regarding caspase-3, there was no difference among the groups; however, in the group submitted to EB +T 300 mcg/day, the expression was higher than in the isolated T group. Conclusion Isolated T did not have a proliferative effect on the mammary tissue, contrary to EB. Testosterone in combination with EB may or may not decrease the proliferation, depending on the dose of T.

Resumo Objetivo Investigar a ação da testosterona (T) isolada ou associada ao benzoato de estradiol (EB) na proliferação e apoptose de mamas de ratas ovariectomizadas. Métodos Um total de 48 ratas Wistar castradas foram divididas em 6 grupos, e cada um foi submetido a um dos seguintes tratamentos durante 5 semanas: 1) controle; 2) BE 50 mcg/dia + T 50mcg/dia; 3) T 50 mcg/dia; 4) BE 50 mcg + T 300mcg/dia; e) T 300 mcg/dia; e f) BE 50 mcg/dia. Após o tratamento, o tecido mamário foi submetido a análise histológica e avaliação de imunoexpressão de marcadores de proliferação (antígeno nuclear de células proliferantes, PCNA) e apoptose (caspase-3). Resultados Houve diferença estatisticamente significante entre os grupos com relação às microcalcificações e à atividade secretora, com maior prevalência nos grupos tratados com BE. Não houve diferença entre os grupos quanto à atrofia, mas houve maior prevalência de atrofia nos grupos que receberam T versus os que receberam BE+ T. Houve diferença entre os grupos quanto ao ANCP (p= 0,028), com maior expressão no grupo BE+ T 300 mcg/dia. Com relação à caspase-3, não houve diferença entre os grupos, mas, no grupo BE+ T 300 mcg/dia, a expressão foi maior do que no grupo de T isolada. Conclusão A T isolada não apresentou efeito proliferativo do tecido mamário, contrariamente ao EB. A T em associação ao EB pode diminuir ou não a proliferação, a depender da dose de T.

Animals , Female , Testosterone/pharmacology , Breast/cytology , Apoptosis/drug effects , Cell Proliferation/drug effects , Breast/pathology , Calcinosis/pathology , Ovariectomy , Biomarkers/analysis , Rats, Wistar , Proliferating Cell Nuclear Antigen/analysis , Estradiol/analogs & derivatives , Estradiol/pharmacology , Caspase 3/analysis
Rev. bras. ginecol. obstet ; 41(7): 449-453, July 2019. tab
Article in English | LILACS | ID: biblio-1020606


Abstract Objective To analyze the effects of estrogen alone or in combination with progestogens and tibolone (TIB) on the expression of the extracellular matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), of perlecan, and of heparanase (HPSE) of the vascular walls of the carotid arteries. Methods A total of 30 250-day-old ovariectomized Wistar rats were orally treated for 5 weeks with: a) 1 mg/kg of estradiol benzoate (EB); b) EB + 0.2 mg/kg of medroxyprogesterone acetate (MPA); c) EB + 0.2mg/kg of norethisterone acetate (NETA); d) EB + 2 mg/kg of dydrogesterone (DI); e) 1 mg/kg of TIB; f) placebo (CTR). Following treatment, the expression of mRNA for MMP-2, MMP-9, and HPSE was analyzed by realtime polymerase chain-reaction (PCR), and the expression of MMP-2, of MMP-9, of tissue inhibitor of metalloproteinase 2 (TIMP-2), and of perlecan was quantified by immunohistochemistry in the carotid arteries. Results The groups showed significant differences on mRNA HPSE expression (p = 0.048), which was higher in the EB, EB + MPA, and TIB groups. There was no statistically significant difference in mRNA MMP-2 or MMP-9 expression. The immunohistochemical expression of MMP-2, of TIMP-2, of MMP-9, of HPSE, and of perlecan showed no differences between groups. Conclusion Estradiol alone or associated with MPA and TIB treatment can increase mRNA HSPE expression of the walls of the carotid arteries in ovariectomized rats.

Resumo Objetivo Analisar os efeitos do estrogênio isolado ou em combinação com progestogênios e tibolona (TIB) na expressão das metaloproteinases 2 e 9 da matriz extracelular (MMP-2 e MMP-9), da perlecan e da heparanase (HPSE) das paredes vasculares das artérias carótidas. Métodos Trinta ratas Wistar ovariectomizadas com 250 dias de idade foram tratadas oralmente por 5 semanas com: a) 1 mg/kg de benzoato de estradiol (EB); b) EB + 0,2 mg/kg de acetato de medroxiprogesterona (MPA); c) EB + 0,2mg/kg de acetato de noretisterona (NETA); d) EB + 2 mg/kg de didrogesterona (DI); e) 1 mg/kg de TIB; f) placebo (CTR). Após o tratamento, a expressão de mRNA para MMP-2, MMP- 9, e HPSE foi analisada por reação em cadeia da polimerase (RCP) em tempo real, e a expressão de MMP-2, MMP-9, inibidor tecidual de metaloproteinase 2 (TIMP-2), e de perlecan foi quantificado por imunohistoquímica em artérias carótidas. Resultados Os grupos apresentaram diferenças significativas na expressão do mRNA HPSE (p = 0,048), sendo maiores nos grupos EB, EB + MPA e TIB. Não houve diferença estatisticamente significativa nas expressões de mRNA MMP-2 ou MMP-9. A expressão imunohistoquímica de MMP-2, TIMP-2, MMP-9, HPSE e perlecan não mostrou diferenças entre os grupos. Conclusão O estradiol isolado ou associado ao tratamento com MPA e TIB pode aumentar a expressão de mRNA HSPE nas paredes das artérias carótidas em ratas ovariectomizadas.

Animals , Female , Rats , Progestins/pharmacology , Carotid Arteries/enzymology , Heparin Lyase/drug effects , Estradiol/analogs & derivatives , Contraceptive Agents, Hormonal/pharmacology , Norpregnenes/pharmacology , Progestins/administration & dosage , Ovariectomy , Carotid Arteries/drug effects , Estrogen Replacement Therapy , Gene Expression Regulation, Enzymologic/drug effects , Administration, Oral , Rats, Wistar , Heparin Lyase/genetics , Heparin Lyase/metabolism , Heparan Sulfate Proteoglycans/genetics , Heparan Sulfate Proteoglycans/metabolism , Matrix Metalloproteinase 2/drug effects , Matrix Metalloproteinase 2/genetics , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/drug effects , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Models, Animal , Estradiol/administration & dosage , Estradiol/pharmacology , Contraceptive Agents, Hormonal/administration & dosage , Norpregnenes/administration & dosage
Acta cir. bras ; 31(10): 661-667, Oct. 2016. tab, graf
Article in English | LILACS | ID: biblio-827656


ABSTRACT PURPOSE: To develop a model for studying cerebrovascular disease prevention in elderly women. METHODS: Sixty 18-month-old Sprague Dawley (SD) rats were randomly divided into an estrogen administration group (EA, n=30) and a non-administration group (NA, n=30); thirty 4-month-old SD rats were allocated to a control group. The EA group received estradiol benzoate starting on the 5th day of a 34-day breeding period, and the serum levels of estradiol (E2), estrogen receptor (ER), and malondialdehyde (MDA) were measured. The MCA of each group was then sampled for viscoelastic experiments. RESULTS: The serum levels of E2 and MDA in the EA group showed significant differences compared to those in the control group (p<0.05), while the difference in ER between the EA and control groups was not significant (p>0.05). The decrease in MCA stress at 7,200 s and the increase in strain at 7,200 s in the EA group showed no significant differences compared to the control group (p>0.05). CONCLUSION: Estradiol administration inhibited the formation of lipid peroxidation products and restored middle cerebral arterial viscoelasticity in aged female rats.

Animals , Female , Middle Cerebral Artery/drug effects , Estradiol/analogs & derivatives , Estrogens/pharmacology , Reference Values , Time Factors , Viscosity/drug effects , Lipid Peroxidation/drug effects , Random Allocation , Receptors, Estradiol/blood , Rats, Sprague-Dawley , Middle Cerebral Artery/physiology , Elasticity/drug effects , Estradiol/administration & dosage , Estradiol/blood , Estradiol/pharmacology , Estrogens/administration & dosage , Malondialdehyde/blood
Journal of Reproduction and Infertility. 2016; 17 (2): 97-103
in English | IMEMR | ID: emr-178812


Background: The purpose of this study was to determine the optimal endometrial preparation protocol by comparing the clinical outcome of two methods of endometrial preparation in frozen-thawed embryo transfer [FET] cycles, including that is, oral estradiol and 17 beta-estradiol transdermal patch

Methods: In this randomized controlled trial, women underwent either conventional IVF or intracytoplasmic sperm injection [ICSI] who had at least two top-quality embryos appropriate for cryopreservation and frozen embryos from previous cycles. In the study group [n=45], 17-B estradiol transdermal patches 100 microg were applied from the second day of the cycle and continued every other day. Then, each patch was removed after four days. In the control group [n=45], oral estradiol valerate 6 mg was started at the same time and continued daily

Results: There was a significant difference in estradiol level on the day of progesterone administration and the day of embryo transfer between the two groups [p=0.001 in both], but no significant difference was observed between them in biochemical and clinical pregnancy rates [32.6% vs. 33.3%, p=1.000 and 30.2% vs. 33.3%, p=0.810, respectively]

Conclusion: It is suggested that estradiol transdermal patches be used instead of oral estradiol in FET cycles. Due to the reduced costs, drug dose, and emotional stress as well as the simplicity of the protocol for patients

Humans , Women , Adult , Estradiol/analogs & derivatives , Endometrium , Transdermal Patch , Embryo Transfer , Prospective Studies , Pregnancy Outcome
Biol. Res ; 49: 1-13, 2016. ilus, graf, tab
Article in English | LILACS | ID: biblio-950869


BACKGROUND: Computer-based technology is becoming increasingly essential in biological research where drug discovery programs start with the identification of suitable drug targets. 2-Methoxyestradiol (2ME2) is a 17ß-estradiol metabolite that induces apoptosis in various cancer cell lines including cervical cancer, breast cancer and multiple myeloma. Owing to 2ME2's poor in vivo bioavailability, our laboratory in silico-designed and subsequently synthesized a novel 2ME2 analogue, 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10),15-tetraen-17-ol (ESE-15-ol), using receptor- and ligand molecular modeling. In this study, the biological effects of ESE-15-ol (180 nM) and its parent molecule, 2ME2 (1 µM), were assessed on morphology and apoptosis induction in cervical cancer cells. RESULTS: Transmission electron microscopy, scanning electron microscopy and polarization-optical transmitted light differential interference contrast (PlasDIC) images demonstrated morphological hallmarks of apoptosis including apoptotic bodies, shrunken cells, vacuoles, reduced cell density and cell debris. Flow cytometry analysis showed apoptosis induction by means of annexin V-FITC staining. Cell cycle analysis showed that ESE-15-ol exposure resulted in a statistically significant increase in the G2M phase (72%) compared to 2ME2 (19%). Apoptosis induction was more pronounced when cells were exposed to ESE-15-ol compared to 2ME2. Spectrophotometric analysis of caspase 8 activity demonstrated that 2ME2 and ESE-15-ol both induced caspase 8 activation by 2- and 1.7-fold respectively indicating the induction of the apoptosis. However, ESE-15-ol exerted all of the above-mentioned effects at a much lower pharmacological concentration (180 nM) compared to 2ME2 (1 µM physiological concentration). CONCLUSION: Computer-based technology is essential in drug discovery and together with in vitro studies for the evaluation of these in silico-designed compounds, drug development can be improved to be cost effective and time consuming. This study evaluated the anticancer potential of ESE-15-ol, an in silico-designed compound in vitro. Research demonstrated that ESE-15-ol exerts antiproliferative activity accompanied with apoptosis induction at a nanomolar concentration compared to the micromolar range required by 2ME2. This study is the first study to demonstrate the influence of ESE-15-ol on morphology, cell cycle progression and apoptosis induction in HeLa cells. In silico-design by means of receptor- and ligand molecular modeling is thus effective in improving compound bioavailability while preserving apoptotic activity in vitro.

Humans , Female , Sulfonamides/pharmacology , Carbonic Anhydrase Inhibitors/pharmacology , Uterine Cervical Neoplasms/drug therapy , Computer-Aided Design , Estradiol/analogs & derivatives , Antineoplastic Agents/pharmacology , Time Factors , HeLa Cells , Microscopy, Electron, Scanning , Cell Cycle/drug effects , Cell Cycle/physiology , Cells, Cultured , Uterine Cervical Neoplasms/pathology , Reproducibility of Results , Apoptosis/drug effects , Culture Media , Microscopy, Electron, Transmission , Estradiol/pharmacology , Caspase 8/metabolism , Flow Cytometry/methods , 2-Methoxyestradiol , Microscopy, Polarization
Article in English | WPRIM | ID: wpr-225580


This study evaluated the efficacy of a stepwise regimen of estradiol valerate for height control in girls with Marfan syndrome. Eight girls with Marfan syndrome who had completed estrogen treatment for height control were included. Estradiol valerate was started at a dose of 2 mg/day, and then was increased. The projected final height was estimated using the initial height percentile (on a disease-specific growth curve for Korean Marfan syndrome [gcPFHt]), and the initial bone age (baPFHt). After the estrogen treatment, the projected final height was compared to the actual final height (FHt). The median baseline chronological and bone age were 10.0 and 10.5 years, respectively. After a median of 36.5 months of treatment, the median FHt (172.6 cm) was shorter than the median gcPFHt (181.0 cm) and baPFHt (175.9 cm). In the six patients who started treatment before the age of 11 years, the median FHt (171.8 cm) was shorter than the median gcPFHt (181.5 cm) and baPFHt (177.4 cm) after treatment. The median differences between the FHt and gcPFHt and baPFHt were 9.2 and 8.3 cm, respectively. In two patients started treatment after the age of 11, the differences between FHt and gcPFHt, and baPFHt after treatment were -4 and 1.4 cm, and -1.2 and 0 cm for each case, respectively. A stepwise increasing regimen of estradiol valerate may be an effective treatment for height control in girls with Marfan syndrome, especially when started under 11 years old.

Body Height , Child , Contraceptive Agents/therapeutic use , Estradiol/analogs & derivatives , Female , Growth Disorders/pathology , Humans , Marfan Syndrome/diagnosis , Treatment Outcome
Braz. j. med. biol. res ; 48(11): 1004-1009, Nov. 2015. tab, graf
Article in English | LILACS | ID: lil-762903


Sex hormones from environmental and physiological sources might play a major role in the pathogenesis of hepatoblastoma in children. This study investigated the effects of estradiol and bisphenol A on the proliferation and telomerase activity of human hepatoblastoma HepG2 cells. The cells were divided into 6 treatment groups: control, bisphenol A, estradiol, anti-estrogen ICI 182,780 (hereinafter ICI), bisphenol A+ICI, and estradiol+ICI. Cell proliferation was measured based on average absorbance using the Cell Counting-8 assay. The cell cycle distribution and apoptotic index were determined by flow cytometry. Telomerase activity was detected by polymerase chain reaction and a telomeric repeat amplification protocol assay. A higher cell density was observed in bisphenol A (P<0.01) and estradiol (P<0.05) groups compared with the control group. Cell numbers in S and G2/M phases after treatment for 48 h were higher (P<0.05), while the apoptotic index was lower (P<0.05) and telomerase activities at 48 and 72 h (P<0.05) were higher in these groups than in the control group. The cell density was also higher in bisphenol A+ICI (P<0.01) and estradiol+ICI (P<0.05) groups compared with the ICI group. Furthermore, cell numbers were increased in S and G2/M phases (P<0.05), while the apoptotic index was lower (P<0.05) and telomerase activities at 48 and 72 h were higher (P<0.05) in these groups than in the ICI group. Therefore, bisphenol A and estradiol promote HepG2 cell proliferation in vitro by inhibition of apoptosis and stimulation of telomerase activity via an estrogen receptor-dependent pathway.

Humans , Benzhydryl Compounds/pharmacology , Cell Proliferation/drug effects , Estradiol/pharmacology , Estrogen Receptor Antagonists/pharmacology , Estrogens, Non-Steroidal/pharmacology , /drug effects , Phenols/pharmacology , Telomerase/drug effects , Apoptosis/drug effects , Cell Survival/drug effects , Estradiol/analogs & derivatives , Flow Cytometry , /enzymology , Interphase/drug effects , Telomerase/metabolism
Braz. j. med. biol. res ; 48(2): 146-153, 02/2015. tab, graf
Article in English | LILACS | ID: lil-735854


Although 17β-estradiol (E2) deficiency has been linked to the development of osteoarthritis (OA) in middle-aged women, there are few studies relating other estrogens and estrogen metabolites (EMs) to this condition. We developed a high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) method to measure the levels of six EMs (i.e., estrone, E2, estriol, 2-hydroxyestrone, 2-hydroxyestradiol, and 16a-hydroxyestrone) in healthy pre- and postmenopausal women and women with OA. This method had a precision ranging from 1.1 to 3.1% and a detection limit ranging from 10 to 15 pg. Compared to healthy women, serum-free E2 was lower in the luteal and postmenopausal phases in women with OA, and total serum E2 was lower in postmenopausal women with OA. Moreover, compared to healthy women, total serum 2-hydroxyestradiol was higher in postmenopausal women with OA and total serum 2-hydroxyestrone was lower in both the luteal and follicular phases in women with OA. In conclusion, our HPLC-ESI-MS/MS method allowed the measurement of multiple biochemical targets in a single assay, and, given its increased cost-effectiveness, simplicity, and speed relative to previous methods, this method is suitable for clinical studies.

Adult , Aged , Female , Humans , Middle Aged , Chromatography, High Pressure Liquid/methods , Estrogens/blood , Osteoarthritis/blood , Postmenopause/blood , Premenopause/blood , Spectrometry, Mass, Electrospray Ionization/methods , Estradiol/analogs & derivatives , Estradiol/blood , Estriol/blood , Estrogens/metabolism , Estrone/blood , Follicular Phase/blood , Hydroxyestrones/blood , Limit of Detection , Luteal Phase/blood , Osteoarthritis/metabolism , Postmenopause/metabolism , Premenopause/metabolism , Statistics, Nonparametric
Braz. j. otorhinolaryngol. (Impr.) ; 80(1): 18-23, Jan-Feb/2014. tab, graf
Article in Portuguese | LILACS | ID: lil-704082


Introdução: A literatura indica uma correlação entre estrogênio elevado no soro e sintomas nasais ou alterações inflamatórias na mucosa nasal. Os receptores de estrogênio tendem a ser controlados por retroalimentação negativa, para evitar um estímulo nocivo sobre as diversas funções corporais em períodos de hiperestrogenismo. Propomos uma hipótese em que os mecanismos que regulam a expressão de receptores de estradiol na mucosa nasal estão ausentes em alguns pacientes, e a sua concentração permanece estável mesmo em períodos de elevada concentração sérica hormonal, o que pode conduzir a sintomas locais na mucosa nasal. Desenho do estudo: Estudo prospectivo experimental. Objetivo: Determinar se altos níveis de estrogênio induzem à redução no número de receptores de estrogênio na mucosa nasal. Material e método: Trinta cobaias foram submetidas à biópsia da concha nasal, recebendo 0,5 ml de cipionato de estradiol por via intraperitoneal por trinta dias consecutivos. Em seguida foram obtidas amostras da concha nasal contralateral. As análises imuno-histoquímicas dos receptores de estrógeno foram realizadas antes e depois da hormonioterapia. Resultados: O grupo pós-tratamento mostrou uma redução da expressão dos receptores (p = 5,2726-5). Conclusão: Redução na expressão do receptor de estrogênio nasal foi encontrada após trinta dias de administração de estradiol. .

Introduction: Some clinical trials revealed a correlation between increased serum estrogen and nasal symptoms or inflammatory changes in nasal mucosa. Estrogen receptors tend to be controlled by a negative feedback, to avoid a deleterious stimulus over several body functions while in hyperestrogenic periods. This study proposes a hypothesis where mechanisms regulating expression of estradiol receptors in nasal mucosa are absent in some patients, and their concentration remains steady even in periods of high serum hormonal concentration, potentially leading to local estrogenic symptoms in nasal mucosa. Study design: This was an experimental prospective study. Aim: To determine whether estrogen levels induce the reduction of the number of estrogen receptors in the nasal mucosa. Methods: In the present study, 30 adult male guinea pigs were subjected to a biopsy of the middle nasal turbinate and received 0.5 mL of estradiol cypionate intraperitoneally for 30 consecutive days. Afterwards, samples from contralateral middle turbinate were obtained. Immunohistochemical analysis of estrogen receptors were performed pre- and post-treatment. Results: The post-treatment group showed reduction of receptor expression when compared to the pre-treatment group. (p = 5.2726-5). Conclusion: A reduction in the expression of the nasal estrogen receptor was observed after 30 days of estradiol administration. .

Animals , Guinea Pigs , Male , Estradiol/analogs & derivatives , Nasal Mucosa/metabolism , Receptors, Estrogen/metabolism , Estradiol/administration & dosage , Immunohistochemistry , Prospective Studies , Time Factors
Biol. Res ; 47: 1-7, 2014. ilus, graf
Article in English | LILACS | ID: biblio-950735


BACKGROUND: Novel, in silico-designed anticancer compounds were synthesized in our laboratory namely, 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10),15-tetraen-17-ol (ESE-15-ol) and 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (ESE-16). These compounds were designed to have improved bioavailability when compared to their source compound, 2-methoxyestradiol. This theoretically would be due to their increased binding affinity to carbonic anhydrase II, present in erythrocytes. Since the novel compounds under investigation are proposed to be transported within erythrocytes bound to carbonic anhydrase II, the morphological effect which they may exert on whole blood and erythrocytes is of great significance. A secondary outcome included revision of previously reported procedures for the handling of the whole blood sample. The purpose of this study was twofold. Firstly, the ultrastructural morphology of a healthy female's erythrocytes was examined via scanning electron microscopy (SEM) after exposure to the newly in silico-designed compounds. Morphology of erythrocytes following exposure to ESE-15-ol and ESE-16 for 3 minutes and 24 hours at 22°C were described with the use of SEM. The haemolytic activity of the compounds after 24 hours exposure were also determined with the ex vivo haemolysis assay. Secondly, storage conditions of the whole blood sample were investigated by determining morphological changes after a 24 hour storage period at 22°C and 37°C. RESULTS: No significant morphological changes were observed in the erythrocyte morphology after exposure to the novel anticancer compounds. Storage of the whole blood samples at 37°C for 24 hours resulted in visible morphological stress in the erythrocytes. Erythrocytes incubated at 22°C for 24 hours showed no structural deformity or distress. CONCLUSIONS: From this research the optimal temperature for ex vivo exposure of whole blood samples to ESE-15-ol and ESE-16 for 24 hours was determined to be 22°C. Data from this study revealed the potential of these compounds to be applied to ex vivo study techniques, since no damage occurred to erythrocytes ultrastructure under these conditions. As no structural changes were observed in erythrocytes exposed to ESE-15-ol and ESE-16, further ex vivo experiments will be conducted into the potential effects of these compounds on whole blood. Optimal incubation conditions up to 24 hours for whole blood were established as a secondary outcome.

Humans , Female , Middle Aged , Sulfonamides/pharmacology , Computer Simulation , Carbonic Anhydrase Inhibitors/pharmacology , Erythrocytes/drug effects , Estradiol/analogs & derivatives , Estrenes/pharmacology , Antineoplastic Agents/pharmacology , Sulfonamides/toxicity , Sulfonamides/pharmacokinetics , Temperature , Carbonic Anhydrase Inhibitors/pharmacokinetics , Biological Availability , Microscopy, Electron, Scanning , Carrier Proteins/pharmacology , Carrier Proteins/pharmacokinetics , Carbonic Anhydrase II/drug effects , Qualitative Research , Erythrocytes/ultrastructure , Estradiol/toxicity , Estradiol/pharmacology , Estradiol/pharmacokinetics , Estrenes/pharmacokinetics , Drug Discovery , Hemolysis/drug effects , Antineoplastic Agents/pharmacokinetics
International Journal of Women's Health and Reproduction Sciences. 2014; 2 (3): 186-194
in English | IMEMR | ID: emr-148623


Polycystic ovary syndrome [PCOS] is the most frequent cause of female infertility, affecting about 4% to 8% of women in the age of procreation. For evaluation the protective effects of omega-3 polyunsaturated fatty acid on ovarian structure in experimental PCO induced by estradiol-valerat, this research was done. Wistar female rats [n=40] were allocated into four groups, one control [n=10] and three test groups [n=30], that one group received omega-3 [60 mg/rat/orally/daily], second and third groups were induced PCO by single injection of estradiol-valerate [16mg/ kg/ i.m], third group also received omega-3 [240 mg/kg] for 60 consequence days. Animals were kept in standard conditions. On day 60, the ovarian tissue of Rats in whole groups were removed and prepared for pathological analysis. Vacuolated area and rough endoplasmic reticulum expanded, de-granulated, disorganized were seen in PCO groups; however, these side effects decreased in the groups that received omega-3 significantly. [p<0.05] in comparison to experiment groups and ovarian weights in PCO experimental decreased significantly [p<0.05]. Results revealed that administration of omega-3 could significantly treat PCO. This suggested that polyunsaturated fatty acid could diminish negative side effects of PCO on ovary tissue

Female , Animals, Laboratory , Organelles/drug effects , Ovary/drug effects , Polycystic Ovary Syndrome , Microscopy, Electron, Transmission , Rats, Wistar , Estradiol/analogs & derivatives
Korean Journal of Urology ; : 677-686, 2014.
Article in English | WPRIM | ID: wpr-192660


PURPOSE: To investigate the effects of estrogen on the expression of the alpha1 receptor and nitric oxide synthase (NOS) in rat urethra and bladder after oophorectomy. MATERIALS AND METHODS: Forty-five mature female Sprague-Dawley rats (aged 10-11 weeks, 235-250 g) were randomly assigned to one of three groups: control group, oophorectomy group (Opx), or oophorectomy and estradiol replacement group (Opx+ Est). The degree of expression of alpha1 receptor (alpha1A and D) and NOS (neuronal NOS [nNOS] and endothelial NOS [eNOS]) in bladder and urethral tissues was investigated by using immunohistochemical staining and Western blotting. RESULTS: In the bladder, the expression rates of alpha1 receptor (alpha1A and alpha1D) increased in the Opx group but decreased in the Opx+Est group. These changes were not statistically significant. The alpha1A and alpha1D receptor of the urethra decreased in the Opx group but increased in the Opx+Est group. These changes were not statistically significant. In the bladder and urethra, the expression rates of nNOS and eNOS significantly increased in the Opx group but decreased in the Opx+Est group (p<0.05). CONCLUSIONS: These data suggest that estrogen depletion increases NOS and alpha1 receptor expression in the rat bladder. However, these changes could be restored by estrogen replacement therapy.

Animals , Collagen/metabolism , Estradiol/analogs & derivatives , Estrogen Replacement Therapy/methods , Female , Muscle, Smooth/pathology , Nitric Oxide Synthase/metabolism , Ovariectomy , Rats, Sprague-Dawley , Receptors, Adrenergic, alpha-1/metabolism , Urethra/drug effects , Urinary Bladder/drug effects
Acta cir. bras ; 28(8): 582-588, Aug. 2013. ilus, graf
Article in English | LILACS | ID: lil-680612


PURPOSE:To investigate the effects of classical acupuncture (Ac) and electroacupuncture (EAc) on estradiol-induced inflammation and oxidative stress in health rodents. METHODS: Twenty-four eight-week old female rats were treated with estradiol valerate (EV) 4.0 mg i.m. single dose and randomly assigned to four groups (n=6): G1(control), G2 (Ac), G3 (EAc 2 Hz) and G4 (EAc 100 Hz). After 60 days all rats were anesthetized with chloral hydrate 10% (0.1 ml/30 g weight of the animal) and submitted to Ac/EAc for twenty minutes. The procedures were repeated on days three, five, seven and nine of the study. The equivalent of the human right ST-36 (Zusanli) and SP-6 (Sanyinjiao) acupoints were chosen for needling and electrical stimulation. On the 10th day of the experiment, all rats were anesthetized for collection of blood and tissues (ovaries) samples for biochemical analysis and histological examination. RESULTS:Glutathione (GSH) and malonaldehyde (MDA) concentrations increased significantly in all groups (plasma and ovary) while myeloperoxidase (MPO) activity decreased significantly in all groups compared with control group (G1). CONCLUSIONS:Both classical acupuncture and electroacupuncture decrease systemic and local oxidative stress and ovary inflammation in healthy rats exposed to estrogenic stimulation. EAc enhances lipid peroxidation at systemic and local levels in female rats exposed to estrogenic stimulation.

Animals , Female , Rats , Acupuncture Points , Electroacupuncture/methods , Oxidative Stress , Oophoritis/therapy , Ovary/drug effects , Estradiol/analogs & derivatives , Estradiol/pharmacology , Estrogens/pharmacology , Glutathione/analysis , Lipid Peroxidation , Malondialdehyde/analysis , Oophoritis/chemically induced , Ovary/pathology , Peroxidase/analysis , Random Allocation , Rats, Wistar , Reproducibility of Results , Time Factors
Arq. neuropsiquiatr ; 71(5): 313-319, maio 2013. graf
Article in English | LILACS | ID: lil-674229


In addition to antioxidative effects, estrogens also exert pro-oxidative actions. The effect of chronic administration of a high dose of estradiol valerate on Morris water maze tasks and brain tissues oxidative damage was investigated. The Sham-Est and OVX-Est groups were treated with estradiol valerate (4 mg/kg) for 12 weeks. Escape latency and traveled path in the Sham-Est and OVX-Est groups were significantly higher than in the Sham and OVX groups (p≪0.01 and p≪0.001). In the probe trial, the animals of the Sham-Est and OVX-Est groups spent lower time in Q1 compared to Sham and OVX groups (p≪0.05 and p≪0.001). In Sham-Est and OVX-Est groups, the brain tissue total thiol concentration was significantly lower, and malondialdehyde (MDA) concentrations were higher than in the Sham and OVX groups (p≪0.05 and p≪0.001). It is concluded that administration of high exogenous levels of estradiol impairs performance and enhances oxidative stress.

Além dos efeitos antioxidantes, os estrógenos também têm ação pró-oxidativa. Foi investigado o efeito da administração crônica de alta dose de valereato de estradiol no desempenho do labirinto aquático de Morris e o dano oxidativo ao tecido cerebral. Os grupos Sham-Est e OVX-Est foram tratados com valereato de estradiol (4 mg/kg) por 12 semanas. O tempo de latência para escapada e o caminho percorrido foram significativamente maiores nos grupos Sham-Est e OVX-Est em relação aos grupos Sham e OVX (p≪0,01 e p≪0,001). No estudo probe, os animais dos grupos Sham-Est e OVX-Est levaram menos tempo no Q1 em comparação aos grupos Sham e OVX (p≪0,05 e p≪0,001). Nos grupos Sham-Est e OVX-Est, a concentração total de tiol foi significativamente menor, enquanto a concentração de malondialdehydo (MDA) for maior do que aquela dos grupos Sham e OVX (p≪0,05 e p≪0,001). Concluiu-se que a administração de altas doses de estradiol exógeno compromete o desempenho e aumenta o estresse oxidativo naqueles animais.

Animals , Female , Rats , Brain/drug effects , Estradiol/analogs & derivatives , Maze Learning/drug effects , Memory/drug effects , Ovariectomy , Oxidative Stress/drug effects , Dose-Response Relationship, Drug , Estradiol/administration & dosage , Estradiol/adverse effects , Estrogens/administration & dosage , Estrogens/adverse effects , Malondialdehyde/analysis , Rats, Wistar , Time Factors , Treatment Outcome
Journal of Gorgan University of Medical Sciences. 2013; 15 (3): 13-17
in Persian | IMEMR | ID: emr-140866


Estradiol plays an important role in folliculogenesis and its developmental stages of embryo. This study was done to determine the quantitative assessment of mouse embryo development yielded from in vitro fertilization of ovulated mature oocytes after ovarian stimulation using human menopausal gonadotropin [HMG] and Estradiol valerate [E2]. In this experimental study, 40 female NMRI mice were allocated into two groups. Control and treatment groups received HMG alone [10 IU/mouse] and a combination of HMG and E2 [1microg/mouse] in single dose manner, respectively. Following the induction of ovulation by HCG, the oocytes collected and morphologically evaluated. MII oocytes for in vitro fertilization [IVF] were transferred into medium containing capacitated and incubated sperm derived from male NMRI mice. The yielded embryos subsequently transferred into developmental medium for reaching to the blastocyst stage. The difference between the mean percentage of yielded oocytes and healthy MII oocytes in the control and treatment groups was not significant. The percentages of the fertilized oocytes reached to two-cells was 34.22 +/- 21.87 and 36.83 +/- 20.68 in control and treatment groups, respectively. The percentages of the blastocys stages of embryos was 49.41 +/- 26.5 and 62.02 +/- 30.11 in control and treatment groups, respectively. The addition of estradiol to HMG as an ovarian stimulator can not increase the rates of yielded MII oocytes and embryonic development

Female , Animals, Laboratory , Fertilization in Vitro , Oocytes , Ovulation Induction , Menotropins , Estradiol/analogs & derivatives , Mice
Article in English | WPRIM | ID: wpr-223718


Bortezomib is a proteasome inhibitor used for the treatment of relapsed/refractory multiple myeloma (MM). However, intrinsic and acquired resistance to bortezomib has already been observed in MM patients. In a previous report, we demonstrated that changes in the expression of mitochondrial genes lead to changes in mitochondrial activity and bortezomib susceptibility or resistance, and their combined effects contribute to the differential sensitivity or resistance of MM cells to bortezomib. Here we report that the combination treatment of bortezomib and 2-methoxyestradiol (2ME), a natural estrogen metabolite, induces mitochondria-mediated apoptotic cell death of bortezomib-resistant MM KMS20 cells via mitochondrial reactive oxygen species (ROS) overproduction. Bortezomib plus 2ME treatment induces a higher level of cell death compared with treatment with bortezomib alone and increases mitochondrial ROS and Ca2+ levels in KMS20 cells. Pretreatment with the antioxidant N-acetyl-L-cysteine scavenges mitochondrial ROS and decreases cell death after treatment with bortezomib plus 2ME in KMS20 cells. Moreover, we observed that treatment with bortezomib plus 2ME maintains the activation of c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase kinase kinase 4/7 (MKK4/7). Collectively, combination treatment with bortezomib and 2ME induces cell death via JNK-MKK4/7 activation by overproduction of mitochondrial ROS. Therefore, combination therapy with specific mitochondrial-targeting drugs may prove useful to the development of novel strategies for the treatment of bortezomib-resistant MM patients.

Acetylcysteine/pharmacology , Apoptosis/drug effects , Boronic Acids/pharmacology , Calcium/metabolism , Cell Line, Tumor , Drug Resistance, Neoplasm , Drug Synergism , Estradiol/analogs & derivatives , Humans , Mitochondria/drug effects , Mitogen-Activated Protein Kinase Kinases/metabolism , Pyrazines/pharmacology , Reactive Oxygen Species/metabolism
Arq. neuropsiquiatr ; 70(11): 874-879, Nov. 2012. graf
Article in English | LILACS | ID: lil-655926


The effects of a high estradiol dose on memory and on nitric oxide metabolites in hippocampal tissues were investigated. Sham-Est and OVX-Est Groups were treated with 4 mg/kg of estradiol valerate for 12 weeks. Time latency and path length were significantly higher in the Sham-Est and OVX-Est Groups than in the Sham and OVX Groups, respectively (p<0.001). The animals in the Sham-Est and OVX-Est Groups spent lower time in the target quadrant (Q1) than those of the Sham and OVX Groups during the probe trial test (p<0.05 and <0.001, respectively). Significantly lower nitric oxide metabolite levels in the hippocampi of the Sham-Est and OVX-Est Groups were observed than in the Sham and OVX ones (p<0.001). These results suggest that decreased nitric oxide levels in the hippocampus may play a role in the learning and memory deficits observed after treatment with a high dose of estradiol, although the precise underlying mechanisms remain to be elucidated.

Os efeitos de uma alta dose de estradiol na memória e nos metabólitos do óxido nítrico de tecidos hipocampais foram estudados. Os Grupos Sham-Est e OVX-Est foram tratados com 4 mg/kg de valerato de estradiol por 12 semanas. O tempo de latência e o comprimento do caminho foram significativamente maiores nos Grupos Sham-Est e OVX-Est em relação aos Grupos Sham e OVX, respectivamente (p<0,001). Os animais dos Grupos Sham-Est e OVX-Est passaram menos tempo na meta do quadrante (Q1) do que aqueles dos Grupos Sham e OVX durante o teste inicial (p<0,05 e <0,001, respectivamente). Níveis significativamente menores de metabólitos do óxido nítrico foram observados nos hipocampos dos Grupos Sham-Est e OVX-Est em relação aos Grupos Sham e OVX (p<0,001). Esses resultados sugerem que os níveis diminuídos de óxido nítrico no hipocampo podem ter um papel nos déficits de aprendizado e de memória, que são observados após tratamento com alta dose de estradiol, embora os mecanismos específicos envolvidos nestes achados ainda precisam ser elucidados.

Animals , Female , Humans , Rats , Contraceptive Agents/administration & dosage , Estradiol/analogs & derivatives , Hippocampus/metabolism , Learning Disabilities/etiology , Memory Disorders/etiology , Nitric Oxide/metabolism , Analysis of Variance , Dose-Response Relationship, Drug , Estradiol/administration & dosage , Hippocampus/drug effects , Learning Disabilities/metabolism , Maze Learning/drug effects , Memory Disorders/metabolism , Memory/drug effects , Nitric Oxide/biosynthesis , Ovariectomy , Random Allocation , Rats, Wistar
IJRM-Iranian Journal of Reproductive Medicine. 2012; 10 (2): 113-120
in English | IMEMR | ID: emr-124486


"Polycystic ovary syndrome [PCOS] is a complex endocrine and metabolic disorder associated with ovulatory dysfunction". "Autonomic and central nervous systems play important roles in the regulation of ovarian physiology". The noradrenergic nucleus locus coeruleus [LC] plays a central role in the regulation of the sympathetic nervous system and synaptically connected to the preganglionic cell bodies of the ovarian sympathetic pathway and its activation is essential to trigger spontaneous or induced LH surges. This study evaluates sympathetic outflow in central and peripheral pathways in PCO rats. Our objectives in this study were [1] to estimate LC activity in rats with estradiol valerate [EV]-induced PCO; [2] to antagonized alpha2a adrenoceptor in systemic conditions with yohimbine. Forty two rats were divided into two groups: 1] LC and yohimbine and 2] control. Every group subdivided in two groups: eighteen rats were treated with estradiol valerate for induction of follicular cysts and the remainders were sesame oil groups. Estradiol concentration was significantly augmented by the LC lesion in PCO rats [p<0.001], while LC lesion could not alter serum concentrations of LH and FSH, like yohimbine. The morphological observations of ovaries of LC lesion rats showed follicles with hyperthecosis, but yohimbine reduced the number of cysts, increased corpus lutea and developed follicles. Rats with EV-induced PCO increased sympathetic activity. LC lesion and yohimbine decreased the number of cysts and yohimbine increased corpus lutea and developed follicles in PCO rats

Female , Animals, Laboratory , Polycystic Ovary Syndrome , Sympathetic Nervous System , Ovary/physiology , Rats, Wistar , Estradiol/analogs & derivatives , Yohimbine , Gonadotropins
Article in English | WPRIM | ID: wpr-110120


Estrogen has anti-colorectal cancer effects which are thought to be mediated by mismatch repair gene (MMR) activity. Estrogen receptor (ER) expression is associated with microRNA (miRNA) expression in ER-positive tumors. However, studies of direct link between estrogen (especially estradiol E2), miRNA expression, and MMR in colorectal cancer (CRC) have not been done. In this study, we first evaluated the effects of estradiol (E2) and its antagonist ICI182,780 on the expression of miRNAs (miR-31, miR-155 and miR-135b) using COLO205, SW480 and MCF-7 cell lines, followed by examining the association of tissue miRNA expression and serum E2 levels using samples collected from 18 colorectal cancer patients. E2 inhibited the expressions of miRNAs in COLO205 cells, which could be reversed by E2 antagonist ICI 182.780. The expression of miR-135b was inversely correlated with serum E2 level and ER-beta mRNA expression in CRC patients' cancer tissues. There were significant correlations between serum E2 level and expression of ER-beta, miR-135b, and MMR in colon cancer tissue. This study suggests that the effects of estrogen on MMR function may be related to regulating miRNA expression via ER-beta, which may be the basis for the anti-cancer effect in colorectal cells.

Adaptor Proteins, Signal Transducing/genetics , Adult , Aged , Cell Line, Tumor , Colorectal Neoplasms/genetics , DNA Mismatch Repair/genetics , Estradiol/analogs & derivatives , Estrogen Antagonists/pharmacology , Estrogen Receptor beta/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Male , MicroRNAs/genetics , Middle Aged , MutS Homolog 2 Protein/genetics , Nuclear Proteins/genetics , RNA, Messenger/biosynthesis
Rev. Assoc. Med. Bras. (1992) ; 57(2): 177-181, mar.-abr. 2011. ilus, tab
Article in Portuguese | LILACS | ID: lil-584069


OBJETIVO: Avaliar as alterações histomorfométricas nas mamas de ratas tratadas com estrogênio e/ou progestagênio por curto período de tempo. MÉTODOS: Foram divididas em quatro grupos 40 ratas ooforectomizadas: GC-recebeu veículo; GE-recebeu benzoato de estradiol (37,6 µg/animal); GP-recebeu acetato de medroxiprogesterona (11,28 mg/animal) e, GEP-recebeu benzoato de estradiol (37,6 µg/animal) e acetato de medroxiprogesterona (11,28 mg/animal). No grupo GE, o estradiol foi administrado durante sete dias, por via subcutânea. Já no grupo EP o estradiol foi administrado nos primeiros sete dias e o progestagênio por mais 23 dias, por via subcutânea. Vinte e quatro horas após a última administração dos hormônios, os animais foram anestesiados e o primeiro par de mamas inguinais removido, imerso em formaldeído a 10 por cento e processado para inclusão em parafina, sendo os cortes corados pela Hematoxilina-Eosina. Foram avaliadas a morfologia e a área ocupada pelo parênquima mamário, sendo os dados submetidos à análise de variância complementado pelo teste de Kruskal-Wallis (p < 0,05). RESULTADOS: As mamas no grupo-controle apresentaram-se atrofiadas, sendo que, nos animais dos grupos GE e GEP, nota-se a presença de alvéolos típicos contendo secreção no seu interior, já nos animais tratados somente com progestagênio (GP) notam-se alvéolos formados por células volumosas que ocupam praticamente todo o lúmen alveolar. A morfometria mostrou haver maior área de parênquima mamário nos animais tratados com hormônios (GE = GP > GEP > GC; p < 0,05) CONCLUSÃO: O estradiol e o progestagênio apresentaram efeito proliferativo no parênquima mamário. No entanto, a administração prévia de estradiol modifica a ação do progestagênio no tecido mamário da rata.

OBJECTIVE: To evaluate the breast histomorphometric changes in rats treated with estrogen and/or progestogen for a short period of time. METHODS: Forty oophorectomized rats were divided into four groups: GC, vehicle; GE, treated with estradiol benzoate (37.6 mg/animal); GP, treated with medroxyprogesterone acetate (11.2 mg/animal) and GEP, treated with estradiol benzoate (37.6 mg/animal) plus medroxyprogesterone acetate (11.28 mg/animal). In GE group, estradiol was administered subcutaneously for seven days; in GEP group, estradiol was administered once in a day for the first seven days and the progestogen over the next 23 days both subcutaneously. Twenty-four hours after the last hormone administration, the animals were killed upon deep anesthesia and the first inguinal breasts were removed, fixed in 10 percent formaldehyde and processed to be included in paraffin, with the sections being stained by hematoxylin-eosin. Morphology and the area occupied by mammary parenchyma were assessed, with the data undergoing analysis of variance followed by the Kruskal-Wallis test (p < 0.05). RESULTS: The control group breasts were found atrophic and, in GE and GEP group animals, typical alveoli with secretion inside are present; in progestogen-treated animals (GP), alveoli formed by large cells occupying almost the entire alveolar lumen are noted. Morphometric analysis showed a larger mammary parenchyma area in hormone-treated animals (GE = GP > GEP > GC; p < 0.05). CONCLUSION: Estradiol and progestogen had a proliferative effect on mammary parenchyma. However, prior estradiol administration changes the progestogen action on rat mammary tissue.

Animals , Female , Rats , Estradiol/pharmacology , Estrogen Replacement Therapy , Mammary Glands, Animal/drug effects , Medroxyprogesterone Acetate/pharmacology , Progestins/pharmacology , Estradiol/analogs & derivatives , Mammary Glands, Animal/pathology , Ovariectomy , Random Allocation , Rats, Wistar