Is the expression of the components of the carotid matrix of rats influenced by estrogen, progestin and tibolone? / A expressão dos componentes da matriz carotídea de ratos é influenciada pelo estrogênio, progestagênio e tibolona?

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.

Efeitos da tibolona sobre o parênquima mamário: estudo experimental / Effects of tibolone on the breast parenchyma: experimental study

OBJETIVO: Avaliar o efeito da terapia hormonal com tibolona, em três períodos de tempo diferentes, sobre o tecido mamário de ratas castradas. MÉTODO: Foram utilizadas 60 ratas Wistar adultas e virgens, submetidas à ooforectomia. Após 21 dias de pós-operatório (PO), confirmado o hipoestrogenismo, os animais foram divididos aleatoriamente em 6 grupos: tibolona 1 (n=10) recebeu tibolona 1 mg/dia por 23 dias, tibolona 2 (n=10), por 59 dias, tibolona 3 (n=10), por 118 dias; os subgrupos controle 1 (n=8), controle 2 (n=7) e controle 3 (n=10) receberam a água destilada por 23, 59 e 118 dias, respectivamente. Após o tratamento, foram ressecados seis pares de mamas, destinados à análise histológica pela coloração de hematoxilina e eosina (HE); o procedimento seguiu de eutanásia. Os parâmetros histológicos avaliados foram: hiperplasia epitelial e atividade secretora (AS). As variáveis foram submetidas à análise estatística, adotando-se como significante p<0,05. RESULTADOS: Foram observadas alterações histológicas em 20/55 ratas, sendo: hiperplasia epitelial leve (HEB1) em 7/55, hiperplasia epitelial moderada (HEB2) em 5/55, hiperplasia alvéolo-nodular (HAN) em 7/55, atipia sem proliferação epitelial em 1/55, não sendo encontrada hiperplasia severa (HEB3). Encontrou-se AS em 31/55 das ratas. A AS foi significativamente maior no grupo tibolona (T), em todos os tempos avaliados (p=0,001). As alterações histológicas analisadas não foram significantes comparando (p>0,05) os grupos controle (C) e T. A variável tempo de exposição à droga não apresentou significância, quando comparados os três períodos avaliados. CONCLUSÃO: Não foi verificada relação entre as alterações histológicas e a terapêutica com tibolona em curto, médio e longo prazo. .

OBJECTIVE: To assess the effect of tibolone on mammary tissue of castrated rats over 3 different periods of time. METHODS: Sixty virgin female Wistar rats were submitted to oophorectomy. Twenty-one days after surgery, with hypoestrogenism confirmed, the experimental rats were randomly assigned to six groups: Tibolone 1 (n=10) received tibolone 1 mg/day for 23 days, tibolone 2 (n=10) for 59 days and tibolone 3 (n=10) for 118 days. The groups control 1 (n=8), control 2 (n=7) and control 2 (n=10) received distilled water for 23, 59 and 118 days, respectively. After treatment, all six pairs of mammary glands were removed and stained with hematoxylin and eosin (HE) for histological analysis after euthanasia. The histological parameters evaluated were: epithelial cell proliferation and secretory activity. The variables were analyzed statistically, with the level of significance set at 0.05. RESULTS: Histological changes were observed in 20/55 rats, mild epithelial hyperplasia in 7/55, moderate epithelial hyperplasia in 5/55, alveolar-nodular hyperplasia in 7/55, atypia without epithelial proliferation in 1/55, and no cases of severe epithelial hyperplasia were found. Secretory activity was observed in 31/55 rats. The secretory activity was significantly higher in the tibolone groups compared to control at all the time points assessed (p=0,001). The histological changes were did not show significance when the control and tibolone groups were compared. The time of exposure to tibolone did not show significance when the three different periods of evaluation were compared. CONCLUSION: No relation between histological modification and tibolone treatment was verified after short-, medium- and long-term treatment. .

Efeito de doses elevadas de tibolona sobre o peso corporal e perfil lipídico de ratas ooforectomizadas / Effect of high doses of tibolone in body weight and lipid profile of ovariectomized rats

OBJETIVO: avaliar o efeito do uso prolongado de alta dose de tibolona na variação do peso corporal e no perfil lipídico de ratas ooforectomizadas. MÉTODOS: foram utilizadas 15 ratas Wistar, pesando 250 g, que foram divididas aleatoriamente em dois grupos. O Grupo Experimental (n=9) recebeu diariamente 1 mg/dia de tibolona via oral. O Grupo Controle (n=6) recebeu diariamente solução de carboximetilcelulose a 0,5 por cento, por gavagem, em volume de 0,5 mL/rata. Foi realizada ooforectomia bilateral 30 dias antes do início do experimento. No dia 0 do experimento, os animais começaram a receber os respectivos tratamentos por 20 semanas. O peso corporal foi controlado semanalmente e o consumo de ração foi medido a cada três a quatro dias ao longo do experimento, estabelecendo o consumo médio/dia por animal. Os resultados foram comparados pelo teste t de Student, com nível de significância de p<0,05. RESULTADOS: o Grupo Tibolona teve consumo de ração diário significativamente (p<0,001) menor (12,7±1,2 g), quando comparado ao Grupo Controle (14,5±1,4 g). Essa diferença também foi significativa em relação ao peso dos animais, uma vez que o Grupo Tibolona teve peso corporal inferior (p<0,001) ao longo do experimento, alcançando peso médio final de 215,6±9,3 versus 243,6±6,4 g no Grupo Controle. Com relação ao perfil lipídico, o Grupo Tibolona apresentou valores inferiores de colesterol total em comparação ao Grupo Controle (30,3 versus 78,6 mg/dL) mostrando diferença significativa (p<0,001). A dosagem de HDL-c também mostrou diferença significativa (p<0,001), com o Grupo Tibolona apresentando níveis inferiores ao Controle (9,0 versus 52,0 mg/dL). Quanto aos demais parâmetros bioquímicos analisados (LDL-c, VLDL-c e triglicerídeos), não houve diferença entre os grupos. CONCLUSÕES: A tibolona causa redução de HDL-c e colesterol total e tem efeito deletério sobre o peso corporal de ratas ooforectomizadas, que pode estar relacionado ao menor consumo ...

PURPOSE: to evaluate the effect of the prolonged use of a high dose of tibolone on the body weight variation and lipid profile of oophorectomized female rats. METHODS: 15 Wistar rats weighing 250 g were randomly divided into two groups. The Experimental Group (n=9) received 1 mg/day of oral tibolone. The Control Group (n=6) received daily 0.5 mL of 0.5 percent carboxymethylcellulose by gavage. Bilateral oophorectomy was performed 30 days before the beginning of the experiment. On day 0 of the experiment, the animals began to receive the respective treatment for 20 weeks. Body weight was controlled every seven days and food consumption was measured every three to four days along the experiment, in order to establish the daily mean consumption per animal. The results were compared by the Student's t-test, with the significance level set at p<0.05. RESULTS: the daily food consumption of the Tibolone Group was significantly lower (12.7±1.2 g, p<0.001) compared to the Control Group (14.5±1.4 g). This difference was also significant when the body weight was compared between the Tibolone and Control Groups (p<0.001), with the Tibolone Group having lower weight along the experiment. At the end of the experiment, the mean body weight was 215.6±9.3 g in the Tibolone Group and 243.6±6.4 g in the Control Group. Regarding the lipid profile, the Tibolone Group had significantly (p<0.001) lower total cholesterol compared to the Control Group (30.3 versus 78.6 mg/dL). The level of HDL-c was also significantly different (p<0.001), with the Tibolone Group showing lower levels than the Control Group (9.0 versus 52.0 mg/dL). No significant difference between the groups was registered in the other biochemical parameters examined (LDL-c, VLDL-c and triglycerides). CONCLUSIONS: tibolone causes a significant reduction of HDL-c and total cholesterol and has a deleterious effect on the body weight of oophorectomized rats, which may be related to the lower food ...

A double blind randomized control trial, comparing effect of drospirenone and gestodene to sexual desire and libido.

BACKGROUND: Oral contraceptive is the most commonly used method of fertility control. Yasmin is a combination of a novel progestogen with anti-androgenic and anti-mineralcorticoid activities (3 mg Drospirenone (DRSP) and 30 microg ethinylestradiol (EE)). It has been shown in many clinical trials that Yasmin is an efficacious oral contraceptive, lacking undesired effects as with other oral contraceptives such as weight gain. However the effects of Yasmin on sexual desire and libido have not been intensively investigated so far OBJECTIVE: Investigate the effects of Yasmin on sexual desire, libido and changes in the free androgen index (FAI) compare to Meliane (75 microg gestodene + 20 microg ethinylestradiol). MATERIAL AND METHOD: The authors' report the results of a double blind randomized controlled study using a translated version of the Female Sexual Function Index questionnaire (FSFI) for the assessment of the sexual function. The free androgen index was calculated from measurements of testosterone and sexual hormone binding globulin. RESULT: The result shows statistically significant improvements regarding sexual desire, arousal and overall satisfaction in the Yasmin group. Additionally, an increased frequency of orgasms in the Meliane group was reported. Statistically significant differences between the two treatments regarding changes in the FSFI score and changes in the free androgen index have not been observed. CONCLUSION: The novel oral contraceptive containing drospirenone (Yasmin) and the non-anti-androgenic progestin containing oral contraceptive (Meliane) do not show unfavorable effects on sexual response and libido.

Efecto diferencial sobre el IGF-1 sérico de tibolona (5 mg/día) vs combinado continuo de estrógeno/progestina en mujeres postmenopáusicas / Differential effects on serum IGF-1 of tibolone (5 mg/day) vs combined continuous estrogen/progestagen in post menopausal women

BACKGROUND: Tibolone has estrogenic, androgenic and progestational effects and is used in post menopausal women. It apparently has weaker effects on endometrial proliferation and mammary stimulation than conventional hormone replacement therapy. AIM: To compare the metabolic effects of tibolone (5 mg/day) and continuous combined conjugated estrogens/medroxyprogesterone acetate in postmenopausal women. PATIENTS AND METHODS: Postmenopausal women, aged 45 to 60 years old, receiving estradiol valerate and medroxyprogesterone were included in the study. After a two months wash out period, in a double blind fashion, they were randomly assigned to oral tibolone 5 mg/day or equine conjugated estrogens 0.625 mg + medroxiprogesterone acetate 2.5 mg/day (ECE/MPA). At baseline, 30 and 45 days of treatment, fasting serum osteocalcin, somatomedin C (IGF-1, insulin-like growth factor 1), growth hormone (GH), and follicle stimulating hormone and first morning urine calcium and creatinine were measured. RESULTS: Thirty women were studied. There was more than 50 per cent fall in urine calcium with either tibolone or ECE/MPA, while fasting GH or osteocalcin did not show significant changes. Serum IGF-1 increased significantly with tibolone at basal, 30 (+109 per cent) and 45 days of treatment and did not change in the ECE/MPA group. CONCLUSIONS: Tibolone (5 mg/day) and ECE/MPA induced a similar reduction in urinary calcium. Tibolone increased serum IGF-1 levels. This may be due to undetected increment of overall GH secretion or to a specific action or IGF-1 generation from the liver and appears to be a novel differential effect of tibolone.