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.

Sangrado y terapia hormonal en la menopausia (THM) / Bleeding during menopause hormone therapy (MHT)

La definición de sangrado ginecológico anormal durante terapia hormonal de la menopausia es aquel sangrado no programado durante el uso de la terapia. Este artículo es un pauteo que describe: 1) cuándo diagnosticar unsangrado anormal, ya que difiere según el tipo de esquema hormonal utilizado; 2) eldiagnóstico diferencial del origen del sangrado anormal; 3) los métodos de evaluación para diagnosticar el origen del sangrado. Se destacan los aspectos principales para el diagnóstico diferencial entre patología orgánica versus disrupción endometrial debida al tratamiento hormonal. Además, se describen los ajustes posibles para resolver el sangrado cuando éste se debe a disrupción del endometrio.

Abnormal bleeding related to menopausal hormone therapy is defined as unscheduled bleeding during the use of the therapy. This article outlines when to diagnose an abnormal bleeding -as this differs according to the type of hormonal scheme used-, the differential diagnosis of the origin of abnormal bleeding, and the methods of evaluation to assess the origin of the bleeding. The main aspects are highlighted on the differentiation of organic pathology versus disruption of the endometrium due to treatment. Also, treatment adjustments to resolve bleeding when it is due to disruption of the endometrium are outlined.

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. .

Efficacy and safety investigation of Kuntai capsule for the add-back therapy of gonadotropin releasing hormone agonist administration to endometriosis patients: a randomized, double-blind, blank- and tibolone-controlled study / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>As a Chinese Traditional Medicine product, Kuntai capsule could improve the peri-menopausal symptoms in postmenopausal women. But it is still not clear whether Kuntai capsule has a good effect on alleviating peri-menopausal symptoms induced by gonadotropin releasing hormone agonist (GnRH-a) treatment. The purpose of this study was to investigate the clinical effectiveness and safety of Kuntai capsule, on peri-menopausal symptoms in endometriosis (EMS) patients, with postoperative GnRH-a treatment.</p><p><b>METHODS</b>Ninety EMS ovarian cyst women with postoperative GnRH-a administration were enrolled in the study, and were randomly divided into Kuntai group, Tibolone group, or blank Control group. The therapeutic strategy in Kuntai group was 4 Kuntai capsules tid,po for 12 weeks after the first GnRH-a injection, while Tibolone 2.5 mg qd, po for 12 weeks in Tibolone group. There was no drug addition in Control group. Climacteric complaints were evaluated by Kupperman menopausal index (KMI) and hot flash/sweating score. Liver and renal functions, lipid profile, serum sex hormone levels and endometrial thickness were measured, and the frequency of adverse events in Kuntai and Tibolone groups was recorded.</p><p><b>RESULTS</b>(1) Before GnRH-a therapy, the baseline parameter results were comparable in the three groups (P > 0.05). (2) After GnRH-a therapy, KMI and hot flash/sweating scores in all the three groups increased significantly (P < 0.05). At the 4 th week after GnRH-a therapy, KMI and hot flash/sweating score results were as follows: Control group > Kuntai group > Tibolone group (P < 0.05); at the 8 th and 12 th week after GnRH-a therapy, KMI and hot flash/sweating score in Control group were significantly higher than the other two groups (P < 0.05), and no significant difference was identified between Kuntai and Tibolone group (P > 0.05). (3) No statistical change took place in the liver and renal functions and lipid profile in all the three groups after the treatment (P > 0.05). (4) The posttherapeutic serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) level and endometrial thickness decreased significantly in all the three groups (P < 0.05). After therapy, serum E2 level in Tibolone group was obviously higher than the other two groups (P < 0.05), while FSH and LH levels were obviously lower (P < 0.05). (5) The incidence of vaginal bleeding, breast distending pain in Tibolne group was obviously higher than Kuntai group (P < 0. 05).</p><p><b>CONCLUSIONS</b>Kuntai capsule is effective on the peri-menopausal symptoms induced by postoperative GnRH-a administration to EMS patients, although its clinical effect might be a few weeks later than Tibolone. Kuntai capsule might be a little safer than Tibolone tablet.</p>

Preparation and release mechanism of gestodene reservoir-type intravaginal rings / 药学学报

This study taking gestodene (GEST) as a model, investigated the factors affecting reservoir-type intravaginal ring (IVR)'s drug release. This paper reported a gestodene intravaginal ring of reservoir design, comprising a gestodene silicone elastomer core encased in a non-medicated silicone sheath, separately manufactured by reaction injection moulding at 80 degrees C and heating vulcanization at 130 degrees C is reported. The test investigated the factors affecting drug release through a single variable method, taking the drug release rates of 21 days as standards. When changing the thickness of the controlling sheath outside, the ratio of the first day of drug release and mean daily release (MDR), named the relatively burst effect, is closing to 1 with the thickness of controlling sheath increasing, while the 1.25 mm sheath corresponding to 1.04 controlled the burst release effectively; a positive correlation (r = 0.992 2) existed between the average drug release (Q/t) and drug loading (A) within a certain range. The C6-165 controlling sheath with high solubility of GEST is easier to achieve controlled release of the drug; GEST crystalline power is more effective to implement controlled release of drugs among difficent states of the drug. A 1/4 fractional segment core gives a relatively burst effect of 1.76, while the 1/1 and 1/2 are 1.93 and 1.87 separately, at the same drug loading, concluding that use of a fractional segment core would allow development of a suitable GEST reservoir IVR. In summary, GEST reservoir-type IVR could be adjusted by the thickness of controlling sheath, the loading of drug, the material properties of controlling sheath, the dispersion state of drug, the additive composition and structure of intravaginal ring, to control the drug release behavior and achieve the desired drug release rate.

Influence of estrogen deficiency and tibolone therapy on trabecular and cortical bone evaluated by computed radiography system in rats / Influência da deficiência estrogênica e do tratamento com tibolona no osso trabecular e cortical avaliada pelo sistema de radiografia computadorizada em ratas

PURPOSE: To verify the effects of tibolone administration on trabecular and cortical bone of ovariectomized female rats by computed radiography system (CRS). METHODS: The experiment was performed on two groups of rats previously ovariectomized, one received tibolone (OVX+T) while the other did not (OVX), those groups were compared to a control group (C) not ovariectomized. Tibolone administration (1mg/day) began thirty days after the ovariectomy and the treatment remained for five months. At last, the animals were euthanized and femurs and tibias collected. Computed radiographies of the bones were obtained and the digital images were used to determine the bone optical density and cortical thickness on every group. All results were statistically evaluated with significance set at P<0.05 percent. RESULTS: Tibolone administration was shown to be beneficial only in the densitometric analysis of the femoral head, performing higher optical density compared to OVX. No difference was found in cortical bone thickness. CONCLUSION: Ovariectomy caused bone loss in the analyzed regions and tibolone administered in high doses over a long period showed not to be fully beneficial, but preserved bone mass in the femoral head.

OBJETIVO: Verificar o efeito da administração de tibolona no tecido ósseo cortical e trabecular de ratas castradas através de radiografia computadorizada. MÉTODOS: O experimento foi realizado em dois grupos de ratas previamente ooforectomizadas, onde um grupo recebeu tibolona (OVX+T) e o outro não (OVX). Esses grupos foram comparados a um grupo controle (C) não ooforectomizado. A administração de tibolona (1mg/dia) começou trinta dias após a ooforectomia e o tratamento teve duração de cinco meses. No final, os animais foram mortos e fêmures e tibias coletados. As radiografias computadorizadas dos ossos foram obtidas e as imagens digitais usadas para determinar a densidade óssea e a espessura cortical em todos os grupos. Todos os resultados foram avaliados estatisticamente com significância estabelecida a 5 por cento. RESULTADOS: A administração de tibolona mostrou ser benéfica apenas para análise densitométrica da cabeça do fêmur, apresentando maiores valores de densidade comparada ao grupo OVX. Nenhuma diferença significativa foi encontrada para espessura óssea cortical. CONCLUSÃO: A ooforectomia ocasionou perda óssea nas regiões analisadas e a tibolona administrada, em dose elevada e durante um longo período, mostrou não ser totalmente benéfica, porém preservou a massa óssea na cabeça femoral.

Clinical Characteristics of Breast Cancer Detected during Hormone Therapy in Korean Women / 대한폐경학회지

OBJECTIVES: This study was performed to assess the risk factors, histologic and clinical features of breast cancer in postmenopausal women receiving hormone therapy (HT). METHODS: We evaluated 40 breast cancer patients who received HT due to postmenopausal symptoms by reviewing their medical charts at Pusan National University Hospital. Research variables, including patients' history, type and duration of received HT, moment of cancer debut after starting HT, radiological characteristics of breast cancer stage, histologic type, tumor size, grade, lymph node metastasis, estrogen and progesterone receptor status and 5-year survival were investigated. RESULTS: In the risk factors of breast cancer patients, only one patient had familial history of breast cancer. No patient had smoking history. The average body mass index (BMI) was 23.2 kg/m2. Twelve patients (30%) had estrogen only therapy, 13 patients (32.5%) had combined estrogen and progesterone therapy, 10 patients (25%) had tibolone therapy and the others consecutively received combination therapy of the above regimens. The mean duration of treatment was 31 +/- 27.9 months (range 0.4-115 months). In the distribution of the cancer debut after starting HT, in 4 cases (10%) was within 1 year, 5 cases (12.5%) within 1-2 years, 10 cases (25%) within 2-3 years, 4 cases (10%) within 3-4 years, 1 case (2.5%) within 4-5 years, and 16 cases (40%) within more than 5 years. The average diameter of tumor size was 1.7 cm. In 92.5% of cases, the tumor was of ductal type. Tumor stage 0 and 1 appeared in 66% and grade I was present in 38% of investigated cases. Hormone receptor-positive breast cancers were 85% and 70% of patients had negative lymph node metastases. The 5-year survival rate was 92%. CONCLUSION: The breast cancers which emerged during HT in postmenopausal women had hormone receptor-positive tendency. The size and stage of these breast cancers were shown as small and low, and represented low-grade differentiation. Recurrences of disease were uncommon and we found favorable 5-year survival rates and good prognosis.

The Effect of Tibolone and Estradiol-based Hormone Therapy on Bone Mineral Density and Serum Lipid Profiles / 대한골다공증학회지

OBJECTIVES: To investigate the differences between the effect of tibolone and estradiol (E2)-based hormone therapy (HT) on bone mineral density (BMD) and serum lipid profiles in postmenopausal Korean women. MATERIALS AND METHODS: A retrospective study was conducted with 65 postmenopausal women receiving tibolone or E2-based hormone therapy in university hospital. BMD at lumbar spine (LS) and proximal femur was measured before and after 1 year of therapy and serum total cholesterol, triglyceride (TG) and high-density lipoprotein (HDL) was determined by enzymatic methods. RESULTS: BMD at LS increased after 1 year of tibolone (mean change: 3.0%) or E2-based HT (mean change: 1.6%), and the changes were significant (P=0.002 and 0.04, respectively). In E2 group, serum total cholesterol has decreased significantly after 1 year of therapy (P=0.02). Moreover, the change of HDL level was statistically significant in tibolone group compared to E2 group (P=0.01). The changes of levels of total cholesterol, TG and HDL has demonstrated negative relationship of BMD changes at femur neck and trochanter in tibolone group, whereas only the HDL changes were significantly related to the change of trochanter BMD in E2 group. CONCLUSIONS: Both tibolone and E2-based hormone therapy increased BMD at lumbar spine. The changes of serum lipid levels may be associated with the BMD changes in both groups although the relationships were different according to the regimen.

Prescription Patterns of Anti-osteoporosis Medications by Gynecologists / 대한폐경학회지

OBJECTIVES: To describe prescription patterns by gynecologists for osteoporosis therapy and to compare with the prescription patterns by physicians of other medical specialties based on the data from the Health Insurance Review and Assessment Service. METHODS: A total of 28,568 prescription claims by gynecologists of 633,870 prescription claims by physicians with medications for osteoporosis alone or medications for other indications, including osteoporosis, were analyzed. The medications for osteoporosis alone were, selective estrogen receptor modulators (SERMs), calcitonin (injection or nasal spray), vitamin K2, ipriflavone, and fluoride. The medications for other indications including osteoporosis were estrogen, tibolone, testosterone, calcium, calcium-vitamin D complex, vitamin D, and oxymetholone. RESULTS: Anti-osteoporosis medications were prescribed by 4.7% of gynecologists. Calcium and vitamin D were the most commonly prescribed medications by gynecologists (60.7%), followed by hormones, including tibolone (44%). Bisphosphonates, including bisphosphonate complex, were prescribed by 27.5% of gynecologists and SERMs were prescribed by 3.6% of gynecologists. Amongst all prescribers, the percentage of gynecologists was highest for hormones (50.6%), followed by tibolone (31.0%). When both medications were combined, the percentage of gynecologists among prescribers was 81.6%. The combination rate of calcium with other anti-osteoporosis medications was highest in gynecologists among prescribers of medical specialties (34.1%). CONCLUSION: A very small percentage of gynecologists prescribed anti-osteoporosis medications, while calcium, vitamin D, and hormones, including tibolone, were commonly prescribed by gynecologists.

Prescription Patterns of Anti-osteoporosis Medications by Gynecologists / 대한폐경학회지

OBJECTIVES: To describe prescription patterns by gynecologists for osteoporosis therapy and to compare with the prescription patterns by physicians of other medical specialties based on the data from the Health Insurance Review and Assessment Service. METHODS: A total of 28,568 prescription claims by gynecologists of 633,870 prescription claims by physicians with medications for osteoporosis alone or medications for other indications, including osteoporosis, were analyzed. The medications for osteoporosis alone were, selective estrogen receptor modulators (SERMs), calcitonin (injection or nasal spray), vitamin K2, ipriflavone, and fluoride. The medications for other indications including osteoporosis were estrogen, tibolone, testosterone, calcium, calcium-vitamin D complex, vitamin D, and oxymetholone. RESULTS: Anti-osteoporosis medications were prescribed by 4.7% of gynecologists. Calcium and vitamin D were the most commonly prescribed medications by gynecologists (60.7%), followed by hormones, including tibolone (44%). Bisphosphonates, including bisphosphonate complex, were prescribed by 27.5% of gynecologists and SERMs were prescribed by 3.6% of gynecologists. Amongst all prescribers, the percentage of gynecologists was highest for hormones (50.6%), followed by tibolone (31.0%). When both medications were combined, the percentage of gynecologists among prescribers was 81.6%. The combination rate of calcium with other anti-osteoporosis medications was highest in gynecologists among prescribers of medical specialties (34.1%). CONCLUSION: A very small percentage of gynecologists prescribed anti-osteoporosis medications, while calcium, vitamin D, and hormones, including tibolone, were commonly prescribed by gynecologists.

The National Use of Hormonal Therapy in Postmenopausal Women in 2010 / 대한폐경학회지

OBJECTIVES: To analyze the domestic consumption of postmenopausal hormonal medicine in the year 2010 and compare it with those since 2002. METHODS: Data from Intercontinental Marketing Services were used to analyze the consumption of hormonal medicine in the year 2010. Total hormonal medicines consisted of estrogen (ET), estrogen+progestogen (EPT), and Tibolone. We compared the respective consumption of hormonal medicines in the year 2010 with those since 2002. The percentage and frequency of usage of ET, ET/EPT, and tibolone in the year 2010 were also estimated. RESULTS: We found that 4.5% of women over 50 years of age had taken the postmenopausal hormonal medicine in the year 2010. The usage rate of each medicine showed 60% for ET/EPT compound, and 40% for Tibolone. The usage of postmenopausal hormonal medicine in 2010 increased by 7% compared to the previous year reaching 3.81 billion Korean won. There was 9% increase in the use of ET/EPT compound, and 4% increase in Tibolone. CONCLUSION: The total consumption of postmenopausal hormonal medicine was markedly decreased between 2002 and 2007. Since 2007, however, it has been steadily increasing from 3.01 billion to more than 3.81 billion Korea won in 2010, which maybe due to the reappraisal of the WHI study results, the change of doctor's recognition, and the increased consumption of Tibolone. When initiating postmenopausal hormone replacement therapy, the risk-benefit of hormonal therapy should be thoroughly explored.

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 ...

Comparing the effects of continuous hormone replacement therapy and tibolone on the genital tract of menopausal women; a randomized controlled trial

Many postmenopausal women who are on hormone replacement therapy discontinue medications due to vaginal bleeding. Tibolone, a synthetic steroid, has minimal stimulatory effect on the endometrium. The aim of this study was to assess the effects of continuous HRT regimen and tibolone on the onset of vaginal bleeding and vaginal maturation value. A total of 150 healthy women in postmenopausal period were randomly enrolled in this controlled clinical trial. Patients were randomly allocated into three groups, and were followed for six months. The first 50 women received 2.5 mg tibolone plus a Cal+D tablet [500 mg Calcium and 200 IU vitamin D] daily, the second 50 women received 0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate [CEE/MPA] plus one Cal+D tablet daily, and the remaining 50 received only one Cal+D tablet per day and served as the control group. Symptoms were recorded using a questionnaire that assessed vaginal bleeding or spotting, vaginal dryness and intention to continue the medications. Vaginal maturation value was assessed by examining vaginal smears before and after the treatment. The results for the three groups were analyzed using statistical methods. In comparison with the control group, CEE/MPA and tibolone increased vaginal maturation value and decreased the frequency of vaginal dryness [p, 0.01]. Women in tibolone group were more likely to continue the treatment regimen than those in the CEE/MPA or the control groups [p<0.01]. Tibolone can serve as an appropriate choice for HRT as it has low rates of vaginal bleeding/ spotting episodes and high acceptance rate in postmenopausal women

The change of hormone therapy in postmenopausal women in Korea before and after women's health initiative study: 2000~2009 / 대한산부인과학회지

OBJECTIVE: This study aims to survey the change of comsumption of hormone therapy (HT) before and after publication of Women's Health Initiative Study(WHI) result in Korea from 2000 to 2009. METHODS: Data from Intercontinental Marketing Services were used to analyze and ten years of hormone consumption from 2000 to 2009 was expressed in terms of hormone sales amount (Korean won, KRW, 1 dollar=1,100 won). Total hormone consisted of Estrogen (ET), Estrogen/Progestogen (EPT), and Tibolone. To identify changes in total hormone consumption, the cumulative growth rate was based on the sales in 2002. RESULTS: After publication of WHI result in 2002, HT consumption had been continuously decreased by 39% from 51.1 billion (bn) KRW in 2002 to 31.4 bn KRW in 2006. From 2007 to 2009, HT consumption has been slightly increased to 3.56 bn KRW. The decreased consumption of HT is mainly due to decrease of ET/EPT comsumption by 49%. Tibolone consumption was decreased by 25% during next 2years after WHI publication, but thereafter gradually increased over pre-WHI publication level in 2009. The proportion of consumption of low dosage regimen was markedly increased from 3.5% in 2002 to 41.8% in 2009. CONCLUSION: The total hormone consumption was markedly decreased after WHI. Low dosage regimen consumption was increased, comprising 3.5~41.8% of total EPT consumption. Tibolone consumption was transiently decreased during 2 years after WHI publication, but thereafter increased gradually and reached over the level of pre-WHI publication in 2009. We expect that low-dosage regimen of HT and tibolone will be more widely used. An individual-based treatment approach is essential in assessing the appropriateness of initiating hormone replacement therapy.

The National Use of Antiosteoporosis Medication in 2009 / 대한폐경학회지

OBJECTIVES: Osteoporosis is the most common chronic skeletal disease in postmenopausal women. The total sales of anti-osteoporosis medications have rapidly increased in Korea in recent years because of the rapid aging of our society. This study was intended to evaluate the trend in the use of anti-osteoporosis medications in 2009. METHODS: Data from the International Marketing Service (IMS) were used to analyze the sales of medications for osteoporosis. The total sales of anti-osteoporosis medications were considered to correspond to the use of anti-osteoporosis medications. RESULTS: The total market of anti-osteoporosis medications including hormones and calcium was 213.9 billion Korea won (KRW). The proportion of anti-osteoporosis medications accounted for by hormones and calcium was 16% and 84%, respectively. The total consumption of calcium was 26.9 billion KRW and nearly all the sales were over-the-counter products. Total hormone consumption was 35.6 billion KRW, of which tibolone comprised 41%. Bisphosphonate consumption was 129.6 billion KRW; the proportion of bisphosphonates in non-hormonal medications was 85.6%, followed in order by vitamin D (6.9%), raloxifene (5.0%), and calcitonin (2.0%). CONCLUSION: The most commonly used anti-osteoporosis medications based on sales were bisphosphonates comprising 60.6% of the total sales, followed by hormones and vitamin D.

Comparison of the Effects of Hormone Replacement Therapy on Bone Mineral Density, Lipid Profiles, and Biochemical Markers of Bone Metabolism / 대한폐경학회지

OBJECTIVES: To assess the effects of hormone replacement therapy on bone mineral density (BMD), biochemical markers of bone turnover, and lipid profiles in postmenopausal women. METHODS: We retrospectively reviewed the medical records of 199 postmenopausal women who had received care at the Department of Obstetrics and Gynecology of Catholic University Seoul St. Mary's Hospital between January 1994 and December 2008. The patients were divided into the following three groups: group 1 received combined estrogen and progesterone therapy (n = 91); group 2 received estrogen only (n = 65); and group 3 received tibolone (n = 43). We compared the changes in biochemical markers of bone turnover, lipid profiles, and BMD during therapy. RESULTS: The BMD of the lumbar spine increased in groups 1 and 3 by 2.0% and 1.2%, respectively, and the BMD of the total femur increased in groups 1 and 2 by 2.3% and 0.5% from the initial values after 3 years, respectively. However, the BMD of the femoral neck and total femur decreased significantly in group 3 by 4.8% and 1.9%, respectively, 3 years after treatment initiation (P < 0.05). Serum osteocalcin and urinary deoxypyridinoline decreased in all groups 1 year after treatment. In groups 1 and 3, the total cholesterol level decreased and the triglycerides level increased. However, there were no definite changes in the total cholesterol and triglycerides levels in group 2. The high density lipoprotein cholesterol (HDL)-cholesterol level increased in groups 1 and 2, but decreased in group 3. As a result, the BMD of the lumbar spine increased and the total cholesterol level decreased in the combined therapy and tibolone groups. Tibolone had no beneficial effect on the BMD of the femoral neck. CONCLUSION: Our results suggest that each therapy has different effects on BMD, biochemical markers of bone metabolism, and lipid profiles. A prospective study involving a larger group, and considering multiple factors, will be required to obtain more clinically meaningful conclusions.

Comparison of the Effects of Hormone Replacement Therapy on Bone Mineral Density, Lipid Profiles, and Biochemical Markers of Bone Metabolism / 대한폐경학회지

OBJECTIVES: To assess the effects of hormone replacement therapy on bone mineral density (BMD), biochemical markers of bone turnover, and lipid profiles in postmenopausal women. METHODS: We retrospectively reviewed the medical records of 199 postmenopausal women who had received care at the Department of Obstetrics and Gynecology of Catholic University Seoul St. Mary's Hospital between January 1994 and December 2008. The patients were divided into the following three groups: group 1 received combined estrogen and progesterone therapy (n = 91); group 2 received estrogen only (n = 65); and group 3 received tibolone (n = 43). We compared the changes in biochemical markers of bone turnover, lipid profiles, and BMD during therapy. RESULTS: The BMD of the lumbar spine increased in groups 1 and 3 by 2.0% and 1.2%, respectively, and the BMD of the total femur increased in groups 1 and 2 by 2.3% and 0.5% from the initial values after 3 years, respectively. However, the BMD of the femoral neck and total femur decreased significantly in group 3 by 4.8% and 1.9%, respectively, 3 years after treatment initiation (P < 0.05). Serum osteocalcin and urinary deoxypyridinoline decreased in all groups 1 year after treatment. In groups 1 and 3, the total cholesterol level decreased and the triglycerides level increased. However, there were no definite changes in the total cholesterol and triglycerides levels in group 2. The high density lipoprotein cholesterol (HDL)-cholesterol level increased in groups 1 and 2, but decreased in group 3. As a result, the BMD of the lumbar spine increased and the total cholesterol level decreased in the combined therapy and tibolone groups. Tibolone had no beneficial effect on the BMD of the femoral neck. CONCLUSION: Our results suggest that each therapy has different effects on BMD, biochemical markers of bone metabolism, and lipid profiles. A prospective study involving a larger group, and considering multiple factors, will be required to obtain more clinically meaningful conclusions.

Simultaneous determination of gestodene, etonogestrel and ethinylestradiol in plasma by LC-MS/MS following derivatization / 药学学报

To establish a sensitive and specific method for simultaneous determination of gestodene, etonogestrel and ethinylestradiol in plasma by LC-MS/MS, plasma samples were extracted and derivatized before injection. An ESI ion source was used and operated in the positive ion mode with multiple reaction monitoring (MRM). Norgestrel was chosen as internal standard and performed on a C18 (100 mm x 2.1 mm, 5 microm) column. The concentrations of gestodene, etonogestrel and ethinylestradiol were measured, using step-gradient mobile phase and step-gradient flow rate. The method was validated over the concentration range of 0.1-20 ng x mL(-1) for gestodene and etonogestrel and 0.01-2 ng x mL(-1) for ethinylestradiol, and showed excellent linearity. The intra- and inter-assay accuracy and precision were below 10.0% and recovery was 93.6%-110.9% over the three concentration levels evaluated. The method was applied in pharmacokinetic study of the compound gestodene patch and the compound etonogestrel patch in rabbits. The LC-MS/MS method was selective, accurate and sensitive, especially the LOQ were 100 pg x mL(-1) for gestodene and etonogestrel and 10 pg x mL(-1) for ethinylestradiol. The method was successfully applied in pharmacokinetic study for contraceptives.

Efeito da tibolona sobre o endométrio de ratas castradas / Effect of tibolone on endometrium of castrated rats

OBJETIVO: avaliar o efeito do uso prolongado de alta dose de tibolona na morfologia do endométrio em ratascastradas. MÉTODOS: foram utilizadas 15 ratas Wistar, fêmeas, com idade de oito semanas e peso médio de 250 g.Todas as ratas foram submetidas à ooforectomia bilateral e 30 dias depois foi coletada citologia vaginal, verificandose o status de menopausa. As ratas foram divididas aleatoriamente em dois grupos: o tratado (n=9) recebeu via oral 1 mg tibolona/dia; o controle (n=6) recebeu apenas solução do veículo carboximetilcelulose. Após 20 semanas de tratamento, todos os animais foram sedados e sacrificados por deslocamento cervical. Os úteros foram retirados e fixados em formol 10% tamponado. Ambos os cornos uterinos foram clivados em três regiões (proximal, medial, distal) e processados para inclusão em parafina. Cortes histológicos corados com hematoxilina-eosina foram submetidos à análise morfológica e morfométrica. Foram avaliados os seguintes parâmetros: espessura do epitélio superficialendometrial, espessura do estroma endometrial, área endometrial, número absoluto de glândulas endometriais e número de glândulas/área endometrial. Os dados obtidos foram comparados mediante o teste t de Student. RESULTADOS: no Grupo Tibolona os úteros se apresentaram bem desenvolvidos e houve aumento significativo (p��0,01) de todos osparâmetros histomorfométricos. Por vezes, o epitélio cilíndrico tornava-se estratificado pavimentoso e recobria porções internas das glândulas bem como a cavidade endometrial. As ratas do Grupo Controle apresentaram útero atrofiado. Havia poucas glândulas de padrão tubular e escassa substância intercelular. As glândulas eram revestidas de epitélio cúbico que se estendia à cavidade endometrial...

PURPOSE: to evaluate the effect of long-term use of a high dose of tibolone on the morphology of the endometriumof castrated female rats. METHODS: fifteen female Wistar rats, aged eight weeks and weighting about 250 g wereused. All the female rats were submitted to bilateral oophorectomy and 30 days afterwards, vaginal cytology was collected, to verify the menopause status. The female rats were randomly divided in two groups. The Treatment Group (n=9) received 1 mg of tibolone/day orally; the Control Group (n=6) received a solution of carboxymethylcellulose vehicle. After 20 weeks of treatment, all the animals were sedated and sacrificed by cervical dislocation. The uterus was removed and fixated in 10% buffer formaldehyde. Both uterine horns were divided in three regions (proximal,medial and distal) and processed to be included in paraffin. Histological sections, stained with hematoxylin-eosin were submitted to morphological and morphometrical analysis. The following parameters have been analyzed: thickness of the endometrial superficial epithelium, thickness of the endometrium stroma, endometrial area, absolute number of endometrial glands and number of glands/endometrial area. The data obtained were compared by the t-Student test. RESULTS: in the Tibolone Group, the uteri were well developed and there was a significant increase (p<0.01) of all the histomorphometric parameters. In some cases, the cylindrical epithelium became stratified, pavimentous and coveredthe internal portions of the glands, as well as of the endometrium cavity. Rats from the Control Group presented uterineatrophy. There were few tubular-like glands and scarce intercellular substance. Glands were covered by cubic epithelium which extended itself to the endometrial cavity...

Effects of estrogen and tibolone on bladder histology and estrogen receptors in rats / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Estrogen deficiency causes atrophic changes within the urogenital tract, and is associated with urinary symptoms. The purpose of this study was to investigate the effects of estrogen and tibolone on bladder histology, and the changes of estrogen receptor alpha and beta (ERalpha and beta) protein expression in the detrusor muscle.</p><p><b>METHODS</b>Forty female rats were separated into four groups of ten each. They received a sham operation (Sham), ovariectomy (Ovx), ovariectomy plus estrogen replacement (Ovx + E), or ovariectomy plus tibolone treatment (Ovx + T). After 12 weeks each rat was anesthetized and the bladders were removed. The bladders' ultra structure, collagen fiber (CF) to smooth muscle (SM) ratio and ER subtypes were studied. Statistical analyses were performed using the one-way analysis of variance test.</p><p><b>RESULTS</b>Ovx resulted in significant degeneration in bladder ultra structure; however, estrogen and tibolone reversed those changes. Ovx increased the CF/SM ratio, estrogen and tibolone resulted in an increase. Two estrogen receptors (ERs) were expressed in the bladder detrusor, with ERbeta the main subtype. Ovx resulted in up-regulation of ERalpha and down-regulation of ERbeta. With estrogen and tibolone treatment, ERbeta showed a significant increase but ERalpha showed no significant difference compared with Ovx.</p><p><b>CONCLUSIONS</b>Estrogen deficiency deteriorates bladder ultra structure and histology. Supplementary estrogen can improve bladder function which may be due to inhibition of collagen hyperplasia and increased SM density. ERbeta has an important role in mediating estrogen function in the bladder. Tibolone has a mild estrogenic action and has an effect on bladder function and structure to some degree.</p>