Ultrastructural and proliferative features of the ventral lobe of the prostate in non-obese diabetic mice (NOD) following androgen and estrogen replacement associated to insulin therapy

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Evaluation of different periods of estrogen replacement onset in the tibia of ovariectomized rats

Background and aims Estrogen deficiency results in increased bone turnover and can lead to osteoporosis. Hormone replacement therapy (HRT) seems to be the most effective means of reducing bone loss and fractures. However, the effects of the period of HRT onset on bone tissue require further elucidation. This study aimed to evaluate the effects of different periods of HRT onset on the trabecular bone of ovariectomized rats.Methods Seventy-five ovariectomized Wistar rats were divided into five groups according to the onset of treatment. Each group was subdivided into experimental (E; n = 10) and control (C; n = 5), according to treatment with 17-beta-estradiol or vehicle alone (soybean oil), respectively, administered subcutaneously. The first group received treatment immediately post-surgery, while treatment in the remaining groups was initiated 1, 2, 3 and 4 weeks post-surgery. Euthanasia occurred at 9 weeks post-surgery. The left tibias were removed and prepared for histomorphometric analyses. The histomorphometric results were statistically analyzed by the Student's t test (p < 0.05).Results The percentage of trabecular bone was significantly greater in the first (p = 0.002) and second (p = 0.039) experimental subgroups compared with the control for the same period. In the experimental subgroups, the percentage of trabecular bone decreased according to the delay in HRT onset and was statistically significant (t = 3.367; p = 0.0023).Conclusion These findings indicate an increase in trabecular bone loss in tibia at 9 weeks post-ovariectomy. The period of HRT/E onset is important for preventing bone loss; however, despite its preventive effects, HRT/E does not restore lost bone.

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

Objective: To evaluate changes in mammographic density and Tc-99m-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 2 mg of 17 beta-oestradiol continuously combined with 1 mg of norethisterone acetate (E-2/NETA, Kliogest (R), Medley) or Group 2 (G2), which received 2.5 mg/day of tibolone (Livial (R), 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 E-2/NETA than among tibolone users and the controls.Conclusion: In postmenopausal women, HRT with E-2/NETA was associated with increased mammographic density and increased Tc-99m-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. (c) 2005 Elsevier B.V.. All rights reserved.

Influence of estrogen deficiency and its treatment with alendronate and estrogen on bone density around osseointegrated implants: radiographic study in female rats

Objective. This study evaluated the influence of estrogen deficiency and its treatment on bone density around integrated implants.Study design. Implants were placed in female rat tibiae. The animals were assigned to 5 groups: control, sham, ovariectomy, estrogen, and alendronate. The control group was humanely killed to confirm integration of the implant. The others were submitted to ovariectomy or sham surgery. Bone density was measured by digital radiographs at 6 points on sides of the implant.Results. The analysis of radiographic bone density revealed estrogen privation had a negative impact only in the cancellous bone. The estrogen group differed significantly ( P <.05) from the ovariectomy and alendronate groups. The alendronate group presented the highest density for all evaluated regions.Conclusion. Ovariectomy caused a decrease in the radiographic bone density in the cancellous region. Estrogen replacement therapy and alendronate were effective treatments in preventing bone mass loss around integrated implants.

Benefits of soy germ isoflavones in postmenopausal women with contraindication for conventional hormone replacement therapy

Objective: To evaluate the effects of isoflavones on vasomotor symptoms and blood lipids in postmenopausal women with contraindication for conventional hormone replacement therapy (HRT). Methods: This prospective, double-blind and placebo-controlled study included 50 postmenopausal women randomly divided into two groups: 25 women on soy germ isoflavones (60 mg per day, capsules) and 25 women on placebo. Inclusion criteria included: non-vegetarian, non-asian women whose last menstruation dated at least 12 months prior to the beginning of the study, With FSH > 40 mIU/ml, hot flushes and contraindication for HRT, not using tamoxifen or antibiotic and no disease of the gastrointestinal tract. For 6 months, the Kupperman menopausal index (KMI), the vaginal cytological maturation value (MV) and both hormonal and lipid profiles were assessed. The t-test and analysis of variance (ANOVA) were employed to compare the two groups. Results: In both groups, a decreased KI rate was observed. However, isoflavone was significantly superior to placebo in reducing hot flushes (44% versus 10%, respectively) (P < 0.05). After 6 months, the isoflavone group showed increased estradiol levels with unchanged FSH, LH, and vaginal cytology, and a reduction of 11.8% in LDL and an increase of 27.3% in HDL (P < 0.05). In the placebo group, just a reduction in MV was observed after 6 months (P < 0.05). Conclusions: Soy germ isoflavone exerted favorable effects on vasomotor symptoms and lipid profile, showing itself to be an interesting alternative therapy for the postmenopausal women with contraindication for conventional HRT. (C) 2003 Elsevier B.V.. All rights reserved.

Efficacy of hormone therapy with and without methyltestosterone augmentation of venlafaxine in the treatment of postmenopausal depression: A double-blind controlled pilot study

Objective: This study evaluated the augmentation of venlafaxine with hormone therapy in the treatment of postmenopausal depression. The hormones evaluated were estrogen (0.625 mg) in combination with medroxyprogesterone acetate (2.5 mg) and methyltestosterone (2.5 mg). Design: Seventy-two menopausal women (mean age: 53.6 ± 4.27 years) diagnosed with depression (Montgomery-Åsberg Depression Rating Scale [MADRS] scores ≥ 20) were treated with venlafaxine and one of the following hormone therapy combinations, in a double-blind regimen: estrogen + medroxyprogesterone + methyltestosterone (group 1, n = 20); estrogen + medroxyprogesterone acetate (group 2, n = 20); methyltestosterone only (group 3, n = 16); and no hormone therapy (group 4, n = 16). Study duration was 24 weeks. Primary efficacy outcome was remission according to the MADRS, whereas secondary efficacy measures included the Clinical Global Impression (CGI), Blatt-Kupperman Index, and Women's Health Questionnaire (WHQ). Results: Forty-eight patients completed the study. All groups showed significant improvement from baseline. Group 3 demonstrated significant improvement on the MADRS compared with placebo (group 4) at weeks 20 (P = 0.048) and 24 (P = 0.030); effect size 8.04 (0.83; 15.26) (P = 0.029), but also had the highest dropout rate. Groups 1 and 3 had significant CGI improvement rates compared with placebo: 42.23% (P = 0.012) and 44.45% (P = 0.08), respectively. There were no differences in the WHQ or BKI scores among the groups. Conclusions: Methyltestosterone 2.5 mg had the highest effect size compared with placebo, but the high dropout rate prevented its efficacy from being determined. Estrogen plus medroxyprogesterone, combined with methyltestosterone or otherwise, demonstrated a trend toward increased efficacy of venlafaxine. Further larger-scale clinical trials are needed to elucidate the findings of this pilot study. © 2006 by The North American Menopause Society.

Enzyme replacement therapy for Anderson-Fabry disease.

Anderson-Fabry disease is an X-linked defect of glycosphingolipid metabolism. Progressive renal insufficiency is a major source of morbidity, additional complications result from cardio- and cerebro-vascular involvement. Survival is reduced among affected males and symptomatic female carriers. To evaluate the effectiveness and safety of enzyme replacement therapy compared to other interventions, placebo or no interventions, for treating Anderson-Fabry disease. We searched 'Clinical Trials' on The Cochrane Library, MEDLINE, EMBASE, LILACS and the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register (date of the most recent search: 11 September 2012). The original search was performed in September 2008.Date of the most recent search of the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register: 11 September 2012. Randomized controlled trials of agalsidase alfa or beta in participants diagnosed with Anderson-Fabry disease. Two authors selected relevant trials, assessed methodological quality and extracted data. Six trials comparing either agalsidase alfa or beta in 223 participants fulfilled the selection criteria.Both trials comparing agalsidase alfa to placebo reported on globotriaosylceramide concentration in plasma and tissue; aggregate results were non-significant. One trial reported pain scores, there was a statistically significant improvement for participants receiving treatment at up to three months, mean difference -2.10 (95% confidence interval (CI) -3.79 to -0.41); at up to five months, mean difference -1.90 (95% CI -3.65 to -0.15); and at up to six months, mean difference -2.00 (95% CI -3.66 to -0.34). There was a significant difference in pain-related quality of life at over five months and up to six months, mean difference -2.10 (95% CI -3.92 to -0.28) but not at other time-points. Neither trial reported deaths.One of the three trials comparing agalsidase beta to placebo reported on globotriaosylceramide concentration in plasma and tissue and showed significant improvement: kidney, mean difference -1.70 (95% CI -2.09 to -1.31); heart, mean difference -0.90 (95% CI -1.18 to -0.62); and composite results (renal, cardiac, and cerebrovascular complications and death), mean difference -4.80 (95% CI -5.45 to -4.15). There was no significant difference between groups for death; no trials reported on pain.Only one trial compared agalsidase alfa to agalsidase beta. There was no significant difference between the groups for any adverse events, risk ratio 0.36 (95% CI 0.08 to 1.59), or any serious adverse events; risk ratio 0.30; 95% CI 0.03 to 2.57). Six small, poor quality randomised controlled trials provide no robust evidence for use of either agalsidase alfa and beta to treat Anderson-Fabry disease.

Dialysis complications in acute kidney injury patients treated with prolonged intermittent renal replacement therapy sessions lasting 10 versus 6 hours: results of a randomized clinical trial

Prolonged intermittent renal replacement therapy (PIRRT) has emerged as an alternative to continuous renal replacement therapy in the management of acute kidney injury (AKI) patients. This trial aimed to compare the dialysis complications occurring during different durations of PIRRT sessions in critically ill AKI patients. We included patients older than 18 years with AKI associated with sepsis admitted to the intensive care unit and using noradrenaline doses ranging from 0.3 to 0.7 mu g/kg/min. Patients were divided into two groups randomly: in G1, 6-h sessions were performed, and in G2, 10-h sessions were performed. Seventy-five patients were treated with 195 PIRRT sessions for 18 consecutive months. The prevalence of hypotension, filter clotting, hypokalemia, and hypophosphatemia was 82.6, 25.3, 20, and 10.6%, respectively. G1 was composed of 38 patients treated with 100 sessions, whereas G2 consisted of 37 patients treated with 95 sessions. G1 and G2 were similar in male predominance (65.7 vs. 75.6%, P=0.34), age (63.6 +/- 14 vs. 59.9 +/- 15.5 years, P=0.28) and Sequential Organ Failure Assessment score (SOFA; 13.1 +/- 2.4 vs. 14.2 +/- 3.0, P=0.2). There was no significant difference between the two groups in hypotension (81.5 vs. 83.7%, P=0.8), filter clotting (23.6 vs. 27%, P=0.73), hypokalemia (13.1 vs. 8.1%, P=0.71), and hypophosphatemia (18.4 vs. 21.6%, P=0.72). However, the group treated with sessions of 10h were refractory to clinical measures for hypotension, and dialysis sessions were interrupted more often (9.5 vs. 30.1%, P=0.03). Metabolic control and fluid balance were similar between G1 and G2 (blood urea nitrogen [BUN]: 81 +/- 30 vs. 73 +/- 33mg/dL, P=1.0; delivered Kt/V: 1.09 +/- 0.24 vs. 1.26 +/- 0.26, P=0.09; actual ultrafiltration: 1731 +/- 818 vs. 2332 +/- 947mL, P=0.13) and fluid balance (-731 +/- 125 vs. -652 +/- 141mL, respectively) . In conclusion, intradialysis hypotension was common in AKI patients treated with PIRRT. There was no difference in the prevalence of dialysis complications in patients undergoing different durations of PIRRT.

Qualidade de vida em mulheres na pós-menopausa, usuárias e não usuárias de terapia hormonal

OBJETIVO: avaliar a qualidade de vida (QV) de mulheres na pós-menopausa usuárias e São Paulo. MÉTODOS: foi conduzido estudo clínico transversal, com 250 mulheres na pós-menopausa, idade entre 45 a 70 anos, atendidas em uma Unidade Básica de Saúde (UBS), de setembro de 2007 a agosto de 2008. As participantes foram divididas em dois grupos: usuárias de terapia hormonal (TH, n=70) e não usuárias (n=180). Consideraram-se como usuárias de TH aquelas que faziam uso contínuo dessa terapia há pelo menos seis meses. Foram avaliadas as características sociodemográficas e clínicas. Aplicou-se o Índice Menopausal de Blatt e Kupperman (IMBK), para avaliar a intensidade dos sintomas climatéricos, e o Questionário de Saúde da Mulher (QSM), para a avaliação da QV. A análise estatística foi realizada pelo teste do χ2 ou exato de Fisher, teste de Mann-Whitney e de Kruskal-Wallis. RESULTADOS: não foram encontradas diferenças significativas na comparação entre os grupos quanto à idade, menarca, menopausa, paridade e índice massa corpórea. Observou-se que 67,2% eram casadas, 83,2% com ensino fundamental e 53,2% se ocupavam com os trabalhos domésticos, não diferindo entre os grupos. As usuárias de TH relataram menor frequência de sintomas climatéricos (IMBK) de intensidade moderada e acentuada, comparadas a não usuárias (p<0,001). Na avaliação do QSM, verificou-se, entre as usuárias de TH, menor escore médio quanto ao déficit cognitivo (p<0,001), sintomas vasomotores (p=0,04), problemas com o sono (p<0,001) e atratividade (p=0,02), contudo, sem diferença no escore total quando comparadas a não usuárias. CONCLUSÕES: as mulheres na pós-menopausa usuárias e não usuárias de TH, atendidas em UBS, não apresentaram diferenças na QV global.

Effect of 17 beta-estradiol and alendronate on the removal torque of osseointegrated titanium implants in ovariectomized rats

Background: This study investigated the influence of estrogen deficiency and its treatment with estrogen and alendronate on the removal torque of osseointegrated titanium implants.Methods: Fifty-eight female Wistar rats received a titanium implant in the tibia metaphysis. After 60 days, which was needed for implant osseointegration, the animals were randomly divided into five groups: control (CTLE; N = 10), sham surgery (SHAM; N = 12), ovariectomy (OVX; N = 12), ovariectomy followed by hormone replacement (EST; N = 12), and ovariectomy followed by treatment with alendronate (ALE; N = 12). The CTLE group was sacrificed to confirm osseointegration, whereas the remaining groups were submitted to sham surgery or ovariectomy according to their designations. After 90 days, these animals were also sacrificed. Densitometry of femur and lumbar vertebrae was performed by dual-energy x-ray absorptiometry (DXA) to confirm systemic impairment of the animals. All implants were subjected to removal torque.Results: Densitometric analysis of the femur and lumbar vertebrae confirmed a systemic impairment of the animals, disclosing lower values of bone mineral density for OVX. Analysis of the removal torque of the implants showed statistically lower values (P <0.05) for the OVX group in relation to the other groups. However, the group treated with alendronate (ALE group) presented significantly higher torque values compared to the others.Conclusion: According to this study, estrogen deficiency was observed to have a negative influence on the removal torque of osseointegrated implants, whereas treatment with alendronate

Efeito do raloxifeno sobre a densidade mamográfica em mulheres na pós-menopausa

PURPOSE: to evaluate changes in mammographic breast density in postmenopausal women using raloxifene. METHODS: in this clinical trial, 80 women (mean age=61.1 years) were studied prospectively. Forty patients received 60 mg/day raloxifene, and 40 women comprised the non-treated group (control), paired by age and time of menopause. The treated group was composed of patients with osteoporosis of the lumbar spine. Those with history of breast surgery and users of hormone therapy up to six months prior to the study were excluded. The breast density was assessed qualitatively (subjective) and quantitatively (objective) in two moments, initial and final, after a 6-month follow-up. The 320 mammograms (craniocaudal and oblique) were interpreted qualitatively by the Breast Imaging Reporting and Data System (BI-RADS) classification and quantitatively by digital scanning and computer-assisted segmentation. For statistical analysis t-test, Wilcoxon Mann-Whitney, Spearman correlation and the kappa index were used. RESULTS: on the initial statistical comparison, the groups were considered homogenous for the variables: analyzed age, time of menopause, parity, breast feeding, previous hormonal therapy and body mass index. Baseline breast density, by qualitative and quantitative methods, correlated negatively with the age in both groups (p<0.05). Concerning the other variables, there was no correlation. After six months, no alteration was observed in the mammographic breast density in 38 women of raloxifene group and 38 of the control group, by qualitative method. However, by quantitative method, no alteration was observed in 30 women of the raloxifene group and 27 controls (p>0.05). It was observed a weak agreement rate (kappa=0.25) between the BI-RADS classification and digital scanning/computer-assisted segmentation. CONCLUSIONS: in post-menopausal women with osteoporosis, submitted to raloxifene treatment for six months, no alterations were observed on the mammographic breast density.

Adjunctive antimicrobial photodynamic treatment of experimentally induced periodontitis in rats with ovariectomy

Background: The aim of this study is to compare antimicrobial photodynamic therapy (aPDT) as an adjunctive therapy to scaling and root planing (SRP) for the treatment of experimentally induced periodontitis in rats with ovariectomy (OVX) that are or are not treated with estrogen replacement. Methods: A total of 270 female rats were divided into three groups: 1) normal rats; 2) rats with OVX; and 3) rats with OVX with estrogen replacement. Periodontal disease was induced through the introduction of a cotton thread around the mandibular left first molar. After 7 days, the ligature was removed, and the rats were randomly divided into the following treatment groups: 1) SRP plus saline solution; 2) SRP plus low-level laser therapy (LLLT); and 3) SRP plus toluidine blue O irrigation followed by LLLT. Ten rats from each group were euthanized at days 7, 15, and 30 after dental treatment. Bone loss (BL) in the furcation region was evaluated using histometric and immunohistochemical analyses. Results: aPDT treatment resulted in reduced BL compared with SRP treatment at all time points. Additionally, rats treated with aPDT exhibited reduced numbers of tartrate-resistant acid-phosphatase-positive cells and more proliferating cell nuclear antigen-positive cells in all treatment groups regardless of estrogen status. Whereas rats treated with aPDT showed weak immunoreactivity to the receptor activator of nuclear factor-k B ligand at day 7 post-treatment, strong osteoprotegerin immunoreactivity was observed at day 15 post-treatment. Conclusion: aPDT is an effective adjunctive therapy for the treatment of periodontitis in rats with OVX that are or are not given estrogen replacement therapy.

Estrogenic and mutagenic activities of crotalaria pallida measured by recombinant yeast assay and ames test

Background: Crotalaria pallida Ailton is a plant belonging to the Fabaceae family, popularly known as rattle or rattlesnake and used in traditional medicine to treat swelling of the joints and as a vermifuge. Previous pharmacological studies have also reported anti-inflammatory, antimicrobial and antifungal activities. Nevertheless, scientific information regarding this species is scarce, and there are no reports related to its possible estrogenic and mutagenic effects. Thus, the purpose of the present study was to investigate the estrogenic potential of C. pallida leaves by means of the Recombinant Yeast Assay (RYA), seeking an alternative for estrogen replacement therapy during menopause; and to reflect on the safe use of natural products to assess the mutagenic activity of the crude extract from C. pallida leaves, the dichloromethane fraction and stigmasterol by means of the Ames test.Methods: The recombinant yeast assay with the strain BY4741 of Saccharomyces cerevisiae, was performed with the ethanolic extract, dichloromethane fraction and stigmasterol isolated from the leaves of C. pallida. Mutagenic activity was evaluated by the Salmonella/microsome assay (Ames test), using the Salmonella typhimurium tester strains TA100, TA98, TA97 and TA102, with (+S9) and without (-S9) metabolization, by the preincubation method.Results: All samples showed estrogenic activity, mainly stigmasterol. The ethanolic extract from C. pallida leaves showed mutagenic activity in the TA98 strain (-S9), whereas dichloromethane fraction and stigmasterol were found devoid of activity.Conclusion: Considering the excellent estrogenic activity performed by stigmasterol in the RYA associated with the absence of mutagenic activity when evaluated by the Ames test, stigmasterol becomes a strong candidate to be used in hormone replacement therapy during menopause. © 2013 Boldrin et al.; licensee BioMed Central Ltd.

The renin-angiotensin system plays a major role in voiding dysfunction of ovariectomized rats

Aims: The renin-angiotensin system (RAS) plays a major role in cardiovascular diseases in postmenopausal women, but little is known about its importance to lower urinary tract symptoms. In this study we have used the model of ovariectomized (OVX) estrogen-deficient rats to investigate the role of RAS in functional and molecular alterations in the urethra and bladder. Main methods: Responses to contractile and relaxant agents in isolated urethra and bladder, as well as cystometry were evaluated in 4-month OVX Sprague-Dawley rats. Angiotensin-converting enzyme activity and Western blotting for AT1/AT2 receptors were examined. Key findings: Cystometric evaluations in OVX rats showed increases in basal pressure, capacity and micturition frequency, as well as decreased voiding pressure. Angiotensin II and phenylephrine produced greater urethral contractions in OVX compared with Sham group. Carbachol-induced bladder contractions were significantly reduced in OVX group. Relaxations of urethra and bladder to sodium nitroprusside and BAY 41-2272 were unaffected by OVX. Angiotensin-converting enzyme activity was 2.6-fold greater (p < 0.05) in urethral tissue of OVX group, whereas enzyme activity in plasma and bladder remained unchanged. Expressions of AT1 and AT2 receptors in the urethra were markedly higher in OVX group. In bladder, AT1 receptors were not detected, whereas AT2 receptor expression was unchanged between groups. 17β-Estradiol replacement (0.1 mg/kg, weekly) or losartan (30 mg/kg/day) largely attenuated most of the alterations seen in OVX group. Significance: Prolonged estrogen deprivation leads to voiding dysfunction and urethral hypercontractility that are associated with increased ACE activity and up-regulation of angiotensin AT1/AT2 receptor in the urethral tissue. © 2013 Elsevier Inc. All rights reserved.

Avaliação radiográfica e biomecânica da influência da osteoporose induzida em ratas, e seu tratamento com alendronato e estrógeno, sobre o tecido ósseo ao redor de implantes com osseointegração estabelecida

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