Effects of low dose of tibolone on steroid receptors and Bcl-2 on the postmenopausal endometrium.

OBJECTIVE: A prospective randomized controlled trial was conducted to evaluate the effect of low dose of tibolone on the histology, expression of estrogen (ER) and progesterone receptors (PR) and Bcl-2 protein, in endometrium of postmenopausal women. METHOD: Forty postmenopausal women consented to treatment and were allocated into two groups of 20 women: Group 1 (Control) without hormone replacement therapy (HRT); Group 2 (Tibolone) treatment at the dose of 1.25 mg/day of oral tibolone administered for a 24-week period. The effect on the endometrium was assessed by histology and the apoptosis marker Bcl-2. The immunoexpression of ER and PR were also measured. RESULTS: Tibolone group showed higher expression of ER, PR and Bcl-2 protein in glandular epithelium and stroma compared to control group. CONCLUSION: Tibolone in a daily dose of 1.25 mg during 24 weeks demonstrated endometrial action that resulted in low proliferation and was shown to lead to atrophic endometrium. It had favorable effects on the postmenopausal endometrium due to its higher immunoexpression of PR and Bcl-2 protein in endometrial glandular epithelium, thereby creating a balance between pro-apoptotic and anti-apoptotic actions.

Morphology and histomorphometry of the bladder and urethra in ovariectomized rats after long-term use of tibolone.

BACKGROUND: This study aimed to evaluate the effect of long-term high-dose tibolone on the bladders and urethras of ovariectomized rats. METHODS: Bilateral ovariectomy was performed in 14 young adult rats randomly divided into 2 groups. Experimental rats (n = 9) received 1 mg/day of tibolone orally; control rats (n = 6) received a placebo. After 150 days, the bladders and urethras were removed. Bladder cell proliferation was analyzed by Ki-67 immunohistochemistry. A histomorphometric analysis was performed for epithelial thickness and the percent areas of collagen fibers and blood vessels. Data were compared using a Mann-Whitney test (significance level at p < 0.05). RESULTS: Urothelial thickness and the percent area of collagen fibers and blood vessels were not significantly different between the tibolone and control groups in the bladder and urethra. In addition, urothelium cell proliferation in the bladder showed a low immunopositivity in both groups. Furthermore, the glycogen and glycoprotein contents in urethral epithelium were slightly modified by tibolone and no change was observed in the bladder. CONCLUSION: Long-term administration of tibolone has no effect on urothelial trophism, collagen fibers, the number of vessels, or cell proliferation in the urethra and bladder of the ovariectomized rat.

Determination of 3-α-hydroxytibolone in human plasma by LC-MS/MS: application for a pharmacokinetic study after administration of a tibolone formulation.

A new method was developed for the quantitation of 3-α-hydroxy tibolone, in human plasma, after oral administration of a tablet formulation containing tibolone (2.5 mg). 3-α-Hydroxy tibolone was extracted by a liquid-liquid procedure, using cyproterone acetate as internal standard and chlorobutane as extraction solvent. After extraction, samples were submitted to a derivatization step with p-toluenesulfonyl isocyanate. A mobile phase consisting of acetonitrile and water (72:28 v/v) was used and chromatographic separation was achieved using Agilent XDB C18 column (100 × 4.6 mm i.d.; 5 µm particle size), at 40°C. Mass spectrometric detection was performed using atmospheric pressure chemical ionization in negative mode for 3-α-hydroxy tibolone and in positive mode for cyproterone acetate. The fragmentation transitions were m/z 510.2 → m/z 170.1 and m/z 417.0 → m/z 357.1 for 3-α-hydroxy tibolone and cyproterone acetate, respectively. Calibration curves were constructed over the range 100-30,000 pg/mL and the method was shown to be specific, precise and accurate, with a mean recovery rate of 94.2% for 3-α-hydroxy tibolone. No matrix effect or carry-over was detected in the samples. The validated method was applied in a pharmacokinetic study with a tibolone formulation in healthy female volunteers.

Comparison of brachial artery vascular responses among postmenopausal women receiving different doses of tibolone.

OBJECTIVE: To compare the effects of low and conventional doses of tibolone in brachial artery flux parameters among postmenopausal women. METHODS: Between March 2011 and September 2012, 24 postmenopausal women attending Gynecology and Obstetrics Hospital Luis Castelazo Ayala, Mexico City, for hormone replacement therapy were consecutively recruited. The women were alternately assigned to receive a daily dose of either 2.5mg (n=11) or 1.25mg (n=13) of oral tibolone. Before and after treatment, all women underwent a brachial artery Doppler ultrasound. The arterial diameter was measured, and the pulsatility index (PI) and the resistance index (RI) were calculated. A hyperemic stimulus was then induced and these parameters were measured again. RESULTS: Among the 24 women, the time since menopause ranged from 16 to 24 months, and the median treatment duration was 3 months. Both groups showed a significant increase in arterial diameter after treatment. There was no significant difference between the groups in arterial diameter, PI, and RI. The arterial diameter after hyperemic stimulus was significantly lower after treatment than before treatment in both groups. CONCLUSION: Low and conventional doses of tibolone induced similar changes in brachial artery flux parameters among postmenopausal women.

[Reasons for abandonment of hormone replacement therapy with tibolone in menopausal women]. / Motivos de abandono de la terapia hormonal de reemplazo con tibolona en mujeres con menopausia.

BACKGROUND: Hormone replacement therapy (HRT) with tibolone used in the management of menopause has low rates of acceptance and compliance in the first year. Few studies analyze the reasons for abandoning the use of tibolone. OBJECTIVE: To analyze the reasons for abandoned tibolone hormone replacement therapy in postmenopausal women and the effects of the drug through the years in the treatment. MATERIAL AND METHODS: In a cross-sectional study, were included 261 menopausal women between 40 and 60 year old who attended their disease control at the Gynaecological Endocrinology serving in the National Medical Center Northwest in Obregon City, Sonora, Mexico during 2010-2011. The variables studied included: age, type of menopause, time of use of HRT with tibolone, abandonment reason, development of hypertension, dyslipidemia, hypothyroidism and diabetes mellitus. RESULTS: A total of 21 women discontinued treatment (8.60%, 95% CI -3 to 19), p=0.0001. The reasons for abandonment included, 42.9% gynecological reasons (23.8% breast disease, 14.3% and 4.8% cervical condition ovarian pathology, p=0.0001). Liver disease and vascular occurred in 28.6%, p=0.050. CONCLUSION: The women studied have adequate adherence to treatment with tibolone (>90%). We don't show an increased risk of cardiovascular or metabolic disease in women studied. Further studies are needed to explore the long-term clinical course, therapeutic response and complications in menopausal patients who use HRT with tibolone.

Osteoporose no climatério II: prevenção e tratamento / Osteoporosis in postmenopausal II: prevention and treatment

A osteoporose é uma doença que pode acarretar um enorme prejuízo na qualidade de vida dos pacientes em função das alterações no tecido ósseo, levando à fragilidade mecânica e consequente predisposição a fraturas e dor. Hoje, dispomos de medidas preventivas, do uso de suplementos e de várias drogas aprovadas para terapia farmacológica da osteoporose, no período pós-menopausa, revisadas neste artigo. Essas drogas apresentam características antirreabsortivas (bisfosfonatos, terapia estrogênica, agonistas seletivos dos receptores de estrogênio - SERM -, calcitonina e denozumabe), anabólicas (teriparatida - PTH) ou ambas, simultaneamente (ranelato de estrôncio). A terapia estrogênica (TE) e a terapia com os bisfosfonatos compreendem as primeiras linhas de medicamentos utilizadas para prevenção e tratamento da osteoporose no climatério. Os medicamentos de segunda linha ficam reservados aos casos com evolução desfavorável com uso de TE e/ou bisfosfonatos, ou quando essas pacientes apresentem alguma enfermidade óssea associada (osteoporose secundária), necessitando de tratamento específico. Na falha ou impossibilidade da utilização dos medicamentos de segunda linha podemos utilizar o ranelato de estrôncio ou o denozumabe, pesando que os riscos dessas drogas precisam ser mais bem estudados

Osteoporosis is a disease that can cause a great loss of quality of life of patients according to the changes in bone tissue leading to mechanical fragility and consequent susceptibility to fractures and pain. Today, we offer preventive measures, the use of supplements and several drugs approved for pharmacologic therapy for osteoporosis in postmenopausal, reviewed in this article. These drugs have anti resorptive characteristics (bisphosphonates, estrogen, selective estrogen receptor modulators - SERM -, calcitonin and denozumab), anabolic (teriparatide - PTH) or both, simultaneously (strontium ranelate). Estrogen therapy (ET) and therapy with bisphosphonates comprise the first line drugs used for prevention and treatment of osteoporosis in the climacteric. The second-line drugs are reserved to cases with unfavorable outcome with the use of TE and/or bisphosphonates, or when these patients have a disease associated with bone (secondary osteoporosis), requiring specific treatment. In the failure or inability of use of second-line drugs, we can use the strontium ranelate or denozumab, weighing the risks of these drugs that need to be further studied

Screening for in vivo (anti)estrogenic and (anti)androgenic activities of Tropaeolum majus L. and its effect on uterine contractility.

ETHNOPHARMACOLOGICAL RELEVANCE: Tropaeolum majus L. (Tropaeolaceae) is a medicinal herb popularly used in Brazil for treatment of inflammatory and cardiovascular diseases. Despite some published data on its efficacy, there are still few toxicological data describing the safety of this plant. The aim of this study was to evaluate the (anti)estrogenic and (anti)androgenic activity of the hydroethanolic extract obtained from Tropaeolum majus L. (HETM), as well as its possible effects on uterine contractility. MATERIALS AND METHODS: Three experimental protocols were performed, (a) uterotrophic assay, (b) Hershberger assay and (c) an ex vivo test to investigate the effects of maternal administration of HETM on uterine contractility at the end of pregnancy. In all protocols three doses of the HETM were administered to Wistar rats: 3, 30 and 300mg/kg. RESULTS: In vivo tests for detection of (anti)androgenic and (anti)estrogenic activities did not show any significant alterations. Similarly, no alterations were observed on uterine contractility induced by oxytocin and arachidonic acid. CONCLUSIONS: HETM was unable to produce (anti)estrogenic or (anti)androgenic activities in the short-term in vivo screening assays performed. In addition, there was no evidence that HETM can affect uterine contractility following gestational exposure of rats.

Influence of estrogen deficiency and tibolone therapy on trabecular and cortical bone evaluated by computed radiography system in rats.

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%. 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.

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.

Safety and efficacy of tibolone and menopausal transition: a randomized, double-blind placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy, safety and tolerability of Tibolone use during the menopausal transition (MT). METHODS: Sixty-five healthy women aged 40-55 years (48.5 ± 3.5 years) were recruited for a randomized, double-blind controlled trial. Thirty participants were recruited to receive oral Tibolone 2.5 mg/day - Tibolone Group (TG), and 35 participants were assigned to the Placebo Group (PG), which received one capsule of lactose/day. Both groups were treated for 12 consecutive weeks. The Blatt-Kupperman Menopausal Index (KMI) and the Greene Climacteric Scale (GCS) were used. The glycaemic and lipid profiles, biochemical measures of hepatic function and endometrial thickness were measured for safety. A daily registry of complaints related to the treatment was maintained, and anthropometric measures were obtained to assess tolerability. RESULTS: A total of 57 women completed the study. After 12 weeks of Tibolone use, the total score and percentage of the KMI and GCS were significantly decreased compared to baseline, which reflected the efficacy of the treatment of climacteric symptoms. The improvement in blood biochemistry, endometrial atrophy and maintenance of the anthropometrical measures reflected the safety of Tibolone use. The absence of serious side effects demonstrated good tolerability for Tibolone use. CONCLUSIONS: The results showed good efficacy, tolerability and safety of Tibolone use during the MT.

Chronic administration of tibolone modulates anxiety-like behavior and enhances cognitive performance in ovariectomized rats.

Hormone replacement therapy (HRT) may be prescribed to prevent the symptoms of menopause. This therapy may include estrogenic and/or progestin components and may increase the incidence of endometrial and breast cancers. Tibolone (TIB), which is also made up of estrogen and progestin components, is often used to reduce the impact of HRT. However, the effect of TIB on the processes of learning, memory and anxiety has yet to be fully elucidated. The aim of this study was to evaluate the long-term effect on learning, memory processes and anxiety in ovariectomized rats caused by different doses of TIB (0 mg/kg, 0.01 mg/kg, 0.1 mg/kg 1.0 mg/kg and 10 mg/kg, administered daily via the oral route for 18 weeks). Two behavioral animal models, the autoshaping and T maze models were employed. The concentrations of acetyl choline transferase (ChAT) and tryptophan hydroxylase (TPH) in the hippocampus were directly measured by Western blot. No significant changes were observed in the autoshaping model and spontaneous activity test. In the T maze, increased latency was observed with TIB doses of 1 and 10 mg/kg compared to the vehicle. We observed that the ChAT content decreased with increasing doses of TIB, whereas TPH content increased with doses of 1 and 10 mg/kg of TIB. These data indicate that high doses of TIB improved emotional learning, which may be related to the modulation of the cholinergic and serotonergic systems by TIB.

Effect of long-time administration of tibolone on vaginal cytology of castrated rats.

PURPOSE: To evaluate the estrogenic effect of tibolone administered at high-dose and long-term through cytological examination of vaginal epithelium of castrated rats. METHODS: 15 adult Wistar rats were submitted to bilateral oophorectomy 30 days before starting the experiment. The rats were then randomly divided in two groups. Experimental rats (n = 9) orally received 1 mg tibolone/day; control rats (n = 6) just received carboxymethylcellulose. Vaginal smears were collected from all rats on days 0, 1-6, 30, 60, 90 and 120 of the experiment. RESULTS: On day 0, smears from all rats were atrophic, classified as anestrus, and remained this type in the control group until day 120. In the tibolone group, on day 3 all the rats had vaginal cytology similar to estrus and maintained the same aspect till day 90. CONCLUSION: Tibolone has estrogenic action in the vaginal epithelium which is already evident after the first dose and remains without major changes over time.

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

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% 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 ingestion by these animals.

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 ...

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

PURPOSE: to evaluate the effect of long-term use of a high dose of tibolone on the morphology of the endometrium of castrated female rats. METHODS: fifteen female Wistar rats, aged eight weeks and weighting about 250 g were used. 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 covered the internal portions of the glands, as well as of the endometrium cavity. Rats from the Control Group presented uterine atrophy. There were few tubular-like glands and scarce intercellular substance. Glands were covered by cubic epithelium which extended itself to the endometrial cavity. CONCLUSIONS: high doses of tibolone, given for long periods of time to castrated female rats, have an estrogenic effect which can be dose-dependent, causing proliferation in the endometrium and causing changes in the cell differentiation (squamous metaplasia), but do not lead to hyperplasia.

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...

Evaluation of mammographic density and (99m)Tc-sestamibi scintimammographic uptake in postmenopausal women on hormone replacement therapy.

OBJECTIVE: To evaluate changes in mammographic density and (99m)Tc-sestamibi scintimammographic uptake in postmenopausal women on hormone replacement therapy (HRT). METHODS: Seventy-five postmenopausal women were prospectively studied and allocated into three groups: 50 women were randomized to either Group 1 (G1, n=25), which received 2mg of 17beta-oestradiol continuously combined with 1mg of norethisterone acetate (E2/NETA, Kliogest, Medley) or Group 2 (G2), which received 2.5mg/day of tibolone (Livial, Organon). The remaining 25 women, who were asymptomatic and had no desire to undergo HRT, constituted the control group (G3). Each patient was submitted to both mammography and scintimammography at baseline and after six months. Mammographic density was evaluated by using the BI-RADS classification system. The classification system of Barros et al. was used in the interpretation of scintimammography. For statistical analysis, the Chi-square test, ANOVA and Pearson's correlation were used. RESULTS: At six months, increased mammographic density was observed in 48% of G1, 12% of G2 and 16% of G3 patients (p<0.001). The increase in sestamibi uptake was 56% in G1, 28% in G2 and 24% in G3 (p<0.001). Increases in both density and uptake were significantly higher in the group on E2/NETA than among tibolone users and the controls. CONCLUSION: In postmenopausal women, HRT with E2/NETA was associated with increased mammographic density and increased (99m)Tc-sestamibi scintimammographic uptakes, suggesting greater mithochondrial activity in the cells of the mammary duct. This was not observed in users of 2.5 mg of tibolone, demonstrating that the effects on the breast were reduced. The same was observed in the control group.