Flaxseed (FS) is a rich source of lignans and n-3 polyunsaturated fatty acids (PUFA), compounds that may help preserve normal bone cell function during aging. Understanding the effect of FS alone or combined with lower doses of estrogen therapy on bone and other estrogen-responsive tissues (e.g. uterus) is of particular interest to postmenopausal women who combine dietary bioactives (e.g. FS) with pharmacological agents (e.g. estrogen monotherapy) to attenuate postmenopausal bone loss. The overall objective of my research was to determine the effects and mechanisms of FS, alone or combined with lower doses of estrogen therapy, on bone and uterus health by measuring a comprehensive set of outcomes in the ovariectomized rat model of postmenopausal osteoporosis. The results demonstrated that FS enhances the protective effect of low-dose estrogen therapy (LD) on vertebral bone mineral density (BMD), three-dimensional microarchitecture and strength in ovariectomized rats. Moreover, FS exerts a stronger effect on bone outcomes when combined with LD than when combined with ultra-low-dose estrogen therapy (ULD). These studies also showed that FS feeding results in higher lignans and n-3 PUFAs in vertebrae, tibias and femurs. Histological analyses at the lumbar vertebra (LV) showed that there were no differences in TRAP-5β, CTX, or OPG/RANKL ratio between the FS+LD and LD groups. FS+LD did however result in lower protein expression of osteocalcin, a marker of bone formation and overall bone turnover, and higher expression of OPG compared to the negative control (NEG), while LD did not. While these findings suggest that FS+LD results in greater attenuation of deterioration of bone tissue compared to LD due to a reduction in bone turnover, significant differences between FS+LD and LD were not observed. Elucidating these specific mechanisms of action require further investigation. In the uterus, FS+LD did not induce greater cell proliferation or differences in qualitative indices of uterine morphology compared to LD. These findings suggest that there may be no increase in the risk of endometrial hyperplasia and carcinoma with FS+LD compared to LD. These findings may lead to the development of strategies that combine food bioactives and current pharmacological agents to more effectively normalize bone turnover during aging.

Flaxseed (FS) is a rich source of lignans and n-3 polyunsaturated fatty acids (PUFA), compounds that may help preserve normal bone cell function during aging. Understanding the effect of FS alone or combined with lower doses of estrogen therapy on bone and other estrogen-responsive tissues (e.g. uterus) is of particular interest to postmenopausal women who combine dietary bioactives (e.g. FS) with pharmacological agents (e.g. estrogen monotherapy) to attenuate postmenopausal bone loss. The overall objective of my research was to determine the effects and mechanisms of FS, alone or combined with lower doses of estrogen therapy, on bone and uterus health by measuring a comprehensive set of outcomes in the ovariectomized rat model of postmenopausal osteoporosis. The results demonstrated that FS enhances the protective effect of low-dose estrogen therapy (LD) on vertebral bone mineral density (BMD), three-dimensional microarchitecture and strength in ovariectomized rats. Moreover, FS exerts a stronger effect on bone outcomes when combined with LD than when combined with ultra-low-dose estrogen therapy (ULD). These studies also showed that FS feeding results in higher lignans and n-3 PUFAs in vertebrae, tibias and femurs. Histological analyses at the lumbar vertebra (LV) showed that there were no differences in TRAP-5β, CTX, or OPG/RANKL ratio between the FS+LD and LD groups. FS+LD did however result in lower protein expression of osteocalcin, a marker of bone formation and overall bone turnover, and higher expression of OPG compared to the negative control (NEG), while LD did not. While these findings suggest that FS+LD results in greater attenuation of deterioration of bone tissue compared to LD due to a reduction in bone turnover, significant differences between FS+LD and LD were not observed. Elucidating these specific mechanisms of action require further investigation. In the uterus, FS+LD did not induce greater cell proliferation or differences in qualitative indices of uterine morphology compared to LD. These findings suggest that there may be no increase in the risk of endometrial hyperplasia and carcinoma with FS+LD compared to LD. These findings may lead to the development of strategies that combine food bioactives and current pharmacological agents to more effectively normalize bone turnover during aging.

In this study different bioactive agents were used to investigate their single and combined effects on biomechanical properties of osteoporotic bone. Estrogen, the most common hormon replacement therapy (HRT) agent, was used in single and combined with raloxifen, a well known osteoporosis drug. Despite their high clinical uses, they have not been tried before, in combination. They act as agonist of each other in bone and antagonist of each other in uterus and mammary glands. Hence it was expected to prevent HRT side effects by using combinations while enhancing the healing on osteoporotic bone. So, the study was designed to see the interaction effects of these two agents on bone and uterus, to observe the mechanical behaviour upto fracture, and to investigate the bone mechanical properties by strain gauges and bending theory with ovariectomized rat model. Second approach to osteoporosis treatment, VitK2 was chosen to be used alone or in combination with raloxifen in same model. Although recent studies mentioned the effects of VitK2 on bone, its rebuilding or repair effect was not completely established. So, VitK2-bone relation was aimed to be clarified with the project.VitK2 raloxifen combination was also a new study, that has not been carried out so far. As a result of mechanical tests, it was found that E+R combination is the most effective treatment. All treatment&amp / #8217 / s were resulted in numerically (though not statistically significant) higher values on femur mechanical properties, and significantly better on tibia compared to the untreated controls. VitK2 performs well in energy absorption upto fracture, but worse in others (PL, YL etc.) compared to other treatments indicating that it plays a specific role in modifying bone structure thus, rendering bone stronger under high stress. However, similar to estrogen case, its combination with raloxifen performs better than its individual administration. With combinations it was aimed to reduce the adverse effects of estrogen on uterus and mammary glands by using raloxifen. This idea appears to be achieved with better histological results of uterus in combinations than estrogen groups. Additionally it was observed that direct strain data obtained by strain gauge experiments can be more informative than theoretical model in calculating modulus of elasticity, and shown that shear contribution can be neglected if depth/span ratio and set up dimensions properly chosen. Biochemical analysis of the blood showed an increment in bone formation (ALP activity) compared to both controls. ALP activity was the highest in R group, which was lower in combinations. Thus existence of a different mechanism in osteoporotic bone repair in combinations was suggested.

Objetivo: O propósito desse estudo foi avaliar os impactos isolados e associados da terapia hormonal (estradiol valerate 1 mg orally/day) e do exercício físico (exercício aeróbico moderado, 3h/semana) na qualidade de vida (QV), qualidade de vida relacionada à saúde (QVRS), e sintomas climatéricos entre mulheres histerectomizadas na pós-menopausa. Métodos:Foi um estudo longitudinal, duplocego, placebo-controlado realizado com 44 mulheres histerectomizadas na pósmenopausa. Os 4 grupos estudados de acordo com a terapia e os exercícios foram: exercício físico e terapia hormonal (TFTH, n=9); sedentárias e terapia hormonal (SEDTH, n=14); exercício físico e placebo (TFPLA; n=11) e sedentárias e placebo (SEDPLA, n= 10). A QVRS foi avaliada pela versão brasileira do SF-36, a QV pelo WHOQOL-BREF e os sintomas pelo IMK, no início e no sexto mês de estudo. Resultados: Houve um decréscimo nos sintomas em todos os grupos, mas apenas os grupos que realizaram EF obtiveram aumentos na QV e na QVRS. A ANOVA demonstrou diferenças significativas nos componentes, capacidade funcional (P=0.001) e dor (P=0.012) do SF-36, e nos domínios, físico (P=0,013), psicológico (P<0,001) e relações sociais (P=0,028) após seis meses de estudo entre os grupos que realizaram exercícios em comparação aos sedentários independente da TH. Não foram demonstrados efeitos da TH, nem da associação entre exercícios e TH sobre os escores da QV e da QVRS. Conclusão: Exercícios físicos podem reduzir os sintomas da menopausa, melhorar a QV e a QVRS, independente da TH / Objective: The purpose of this study was to evaluate the isolated and associated effects of estrogen therapy (estradiol valerate 1 mg orally/day) and physical exercises (moderate aerobic exercise, 3h/weekly) on quality of life (QOL), health related quality of life (HRQOL) and menopausal symptoms among women who had undergone hysterectomy. Design: It was a six-months, randomized, double-blind, placebocontrolled clinical trial with 44 postmenopausal women who had undergone hysterectomy. The interventions were: physical exercise and hormone therapy (PEHT, n=9); sedentary and hormone therapy (SEDHT, n=14); physical exercise and placebo (PEPLA; n=11), sedentary and placebo (SEDPLA, n= 10). HRQOL was assessed by a Brazilian standard version of SF-36, QOL by WHOQOL-BREF and symptoms by Kupperman Scale, at baseline and after 6 months. Results: There was a decrease of symptoms in all groups, but only groups which performed physical exercises showed increases in QOL and in HRQOL. ANOVA showed that changes in physical functioning (P=0.001), bodily pain (P=0.012), physical domain (P=0,013), psychological domain (P<0,001), and social relationship (P=0,028) scores over the six months period differed significantly between exercisers and sedentaries, regardless of hormone therapy. There were no effects of hormone therapy, and no significant association between physical exercise and hormone therapy in HRQOL. Conclusions: Physical exercises can reduce menopausal symptoms and enhance QOL and HRQOL, independently of taking or not hormone therapy

Objetivo: O propósito desse estudo foi avaliar os impactos isolados e associados da terapia hormonal (estradiol valerate 1 mg orally/day) e do exercício físico (exercício aeróbico moderado, 3h/semana) na qualidade de vida (QV), qualidade de vida relacionada à saúde (QVRS), e sintomas climatéricos entre mulheres histerectomizadas na pós-menopausa. Métodos:Foi um estudo longitudinal, duplocego, placebo-controlado realizado com 44 mulheres histerectomizadas na pósmenopausa. Os 4 grupos estudados de acordo com a terapia e os exercícios foram: exercício físico e terapia hormonal (TFTH, n=9); sedentárias e terapia hormonal (SEDTH, n=14); exercício físico e placebo (TFPLA; n=11) e sedentárias e placebo (SEDPLA, n= 10). A QVRS foi avaliada pela versão brasileira do SF-36, a QV pelo WHOQOL-BREF e os sintomas pelo IMK, no início e no sexto mês de estudo. Resultados: Houve um decréscimo nos sintomas em todos os grupos, mas apenas os grupos que realizaram EF obtiveram aumentos na QV e na QVRS. A ANOVA demonstrou diferenças significativas nos componentes, capacidade funcional (P=0.001) e dor (P=0.012) do SF-36, e nos domínios, físico (P=0,013), psicológico (P<0,001) e relações sociais (P=0,028) após seis meses de estudo entre os grupos que realizaram exercícios em comparação aos sedentários independente da TH. Não foram demonstrados efeitos da TH, nem da associação entre exercícios e TH sobre os escores da QV e da QVRS. Conclusão: Exercícios físicos podem reduzir os sintomas da menopausa, melhorar a QV e a QVRS, independente da TH / Objective: The purpose of this study was to evaluate the isolated and associated effects of estrogen therapy (estradiol valerate 1 mg orally/day) and physical exercises (moderate aerobic exercise, 3h/weekly) on quality of life (QOL), health related quality of life (HRQOL) and menopausal symptoms among women who had undergone hysterectomy. Design: It was a six-months, randomized, double-blind, placebocontrolled clinical trial with 44 postmenopausal women who had undergone hysterectomy. The interventions were: physical exercise and hormone therapy (PEHT, n=9); sedentary and hormone therapy (SEDHT, n=14); physical exercise and placebo (PEPLA; n=11), sedentary and placebo (SEDPLA, n= 10). HRQOL was assessed by a Brazilian standard version of SF-36, QOL by WHOQOL-BREF and symptoms by Kupperman Scale, at baseline and after 6 months. Results: There was a decrease of symptoms in all groups, but only groups which performed physical exercises showed increases in QOL and in HRQOL. ANOVA showed that changes in physical functioning (P=0.001), bodily pain (P=0.012), physical domain (P=0,013), psychological domain (P<0,001), and social relationship (P=0,028) scores over the six months period differed significantly between exercisers and sedentaries, regardless of hormone therapy. There were no effects of hormone therapy, and no significant association between physical exercise and hormone therapy in HRQOL. Conclusions: Physical exercises can reduce menopausal symptoms and enhance QOL and HRQOL, independently of taking or not hormone therapy

An inverse association between estrogen therapy (ET) and Alzheimer disease (AD) has been reported in some, but not in all studies. We investigated the association between ET and AD in postmenopausal women using a population-based case-control design. Women who developed AD from 1985 through 1989 in Rochester, MN (cases, n=264) were individually matched by age (±1 y) to control women free of dementia from the same population (controls, n=264). ET exposure (≥6 mo after menopause) was ascertained by abstracting the complete medical records archived in the records-linkage system of the Rochester Epidemiology Project. The frequency of ET use was similar in cases (11.4%) and controls [10.6%; odds ratio=1.10; 95% confidence interval (CI)=0.63-1.93]. However, cases who used ET had a suggestive trend for an earlier age at start of ET compared with controls (median, 49.0 vs. 50.5 y; P=0.06). Although smoking (ever vs. never) was not associated with AD overall, we observed an interaction between smoking and ET. The odds ratio of AD in ET users was 4.55 (95% CI=1.33-15.53) among smokers, but was 0.68 (95% CI=0.35-1.32) among never-smokers (P for interaction=0.01). Our findings do not confirm a significant association between ET and AD overall; however, the possible interaction with smoking deserves further study.

Made available in DSpace on 2016-06-02T20:18:07Z (GMT). No. of bitstreams: 1 TeseVFCN.pdf: 4070585 bytes, checksum: 7958766fa01b36832cbe4c73c56a27f2 (MD5) Previous issue date: 2007-02-12 / Universidade Federal de Sao Carlos / The effects of female sex hormones on the cardiovascular system have been the topic of much discussion and controversy in the literature. Nevertheless, many scientists believe that estrogens play an important cardioprotective role in premenopausal women, with their effects being observed directly on blood vessels or indirectly by the promotion of an antiatherogenic lipid profile. In recent years, studies have reported that estrogen hormone levels may also influence autonomic control of heart rate (HR) and exercise tolerance. However, other researches have found no modification of these parameters in function of hormone therapy. Within this context, three studies were conducted to verify whether estrogen therapy (ET) could attenuate the age-related decline in autonomic control of HR under resting and exercise conditions and aerobic capacity of healthy women. Thirteen young women (mean age: 24 years), 10 postmenopausal women undergoing ET (PMET, mean age: 53 years) and 15 postmenopausal women not undergoing ET (PMnET, mean age: 56 years) were studied. Hormonal treatment consisted of 0.625 mg/day of conjugated equine estrogens. In the first study, the effect of age and ET on HR variability (HRV) under resting conditions in the supine and sitting positions was evaluated. HRV was analyzed by time (TD) and frequency domain (FD) methods. In this study, higher values of the temporal indices of HRV were observed for the young group. In the analysis of FD, the PMnET group presented lower values in the indices reflecting vagal activity and higher values in the indices reflecting sympathetic activity compared to the young group (supine position) and to the PMET group (sitting position). These results suggest that HRV decreases during aging and that ET may attenuate this process by promoting a reduction of sympathetic activity on the heart and contributing to the cardioprotective effect of estrogen hormones. In the second study, the effect of age and ET on the autonomic control of HR during dynamic exercise and anaerobic threshold (AT) was evaluated. Dynamic exercise was performed on a cycle ergometer starting at 15 W and followed by 5 W increments, until the loss of HR response stabilization was identified by a semiparametric model, characterizing AT. The autonomic control of HR during exercise was analyzed by vagal withdrawal at the beginning of exercise and by calculating the rMSSD index of the stable interval of each workload level. The vagal withdrawal and the rMSSD index were higher for the young group at the workloads studied. The young group also presented higher workload and HR values at AT compared to the postmenopausal groups. These results suggest that autonomic modulation of HR during exercise and aerobic capacity are strongly influenced by age. Hypoestrogenism and ET had no effect on the variables studied. In the third study, the effect of age and ET on cardiorespiratory responses during a cardiopulmonary exercise test was evaluated. This test was performed on a cycle ergometer with 10 to 20 W/min increments until physical exhaustion. The AT was determined by graphic visual analysis of the curves for carbon dioxide output and oxygen uptake ( O2). Higher workload and HR values both at AT and at the peak of exercise were observed for the young group. HR was similar between groups at AT and significantly higher at peak exercise for the young group. The percentages of AT in relation to peak exercise for O2 and HR values were higher for the postmenopausal groups. These results suggest that ET had no effect on cardiorespiratory responses during the incremental exercise test. In conclusion, the results obtained in the three studies suggest that the vagal-protective effect of estrogen hormones detected at rest is not maintained during exercise. In addition, exercise tolerance does not seem to depend on the physiological levels of estrogens. On this basis, the present findings support the importance of the prescription of physical exercise in the clinical orientation for climacteric women / Os efeitos dos hormônios sexuais femininos sobre o sistema cardiovascular tem sido um tópico de muita discussão e controvérsias na literatura. Apesar disso, muitos cientistas acreditam que os estrogênios exercem importante papel cardioprotetor nas mulheres pré-menopausadas, sendo seus efeitos observados diretamente sobre os vasos sangüíneos ou indiretamente através da promoção de um perfil lipídico antiaterogênico. Nos últimos anos, tem sido reportado que o controle autonômico da freqüência cardíaca (FC) e a tolerância ao exercício também podem ser influenciados pelos níveis hormonais de estrogênios. No entanto, outros pesquisadores não encontraram qualquer modificação nesses parâmetros em função da terapia hormonal. Dentro desse contexto, foram realizados três estudos, com o objetivo de verificar se a terapia estrogênica (TE) poderia atenuar o declínio relacionado à idade no controle autonômico da FC, em condições de repouso e exercício, e na capacidade aeróbia de mulheres saudáveis. Para isso foram estudadas 13 mulheres jovens (média etária de 24 anos), 10 na fase pós-menopausa em uso de TE (PMCTE: média etária de 53 anos) e 15 na pós-menopausa sem uso de TE (PMSTE: média etária de 56 anos). A TE consistiu de 0,625 mg/dia de estrogênios eqüinos conjugados. No primeiro estudo, foi avaliado o efeito da idade e da TE sobre a variabilidade da FC (VFC) durante o repouso, nas posições supina e sentada. A VFC foi analisada no domínio do tempo (DT) e da freqüência (DF). Nesse estudo foram observados maiores valores dos índices temporais de VFC para o grupo jovem. Na análise no DF, o grupo PMSTE apresentou menores valores dos índices que refletem a atividade vagal e maiores valores dos índices que refletem a atividade simpática em relação aos grupos jovem (posição supina) e PMCTE (posição sentada). Esses resultados sugerem que a VFC diminui com o envelhecimento e que a TE pode atenuar esse processo, promovendo uma redução na atividade simpática sobre o coração, e contribuindo para o efeito cardioprotetor dos hormônios estrogênios. No segundo estudo, foi avaliado o efeito da idade e da TE sobre o controle autonômico da FC durante exercício dinâmico e o limiar de anaerobiose (LA). O exercício dinâmico foi realizado em cicloergômetro, sendo iniciado na potência de 15 W e seguido por incrementos de 5 W, até que fosse identificada a perda da estabilização da resposta da FC pelo modelo semiparamétrico, caracterizando o LA. O controle autonômico da FC durante o exercício foi analisado por meio da retirada vagal no início do exercício e pelo cálculo do índice rMSSD do trecho estável de cada nível de potência. A retirada vagal e o índice rMSSD foram maiores para o grupo jovem, nas potências estudadas. As jovens também apresentaram maiores valores de potência e de FC no LA em relação aos grupos na pós-menopausa. Esses resultados sugerem que a modulação autonômica cardíaca durante o exercício e a capacidade aeróbia são fortemente influenciados pela idade. Ambos, hipoestrogenismo e TE, não exerceram qualquer influência sobre as variáveis estudadas. No terceiro estudo, foi avaliado o efeito da idade e da TE sobre as respostas cardiorrespiratórias durante teste de exercício cardiopulmonar. Esse teste foi realizado em cicloergômetro, com incrementos de 10 a 20 W/min até a exaustão física. O LA foi determinado visualmente pela análise das curvas de produção de dióxido de carbono e de consumo de oxigênio ( O2). Foram observados maiores valores de potência e de FC tanto no LA como no pico do exercício para o grupo jovem. A FC foi similar entre os grupos no LA e, significantemente maior no grupo jovem, no pico do exercício. Os valores percentuais do LA em relação ao pico do exercício para os dados de O2 e de FC foram maiores para os grupos na pós-menopausa. Esses resultados sugerem que a TE não teve influencia sobre as respostas cardiorrespiratórias durante teste de exercício incremental. Finalizando, os resultados obtidos nos três estudos sugerem que o efeito protetor vagal dos hormônios estrogênios evidenciado durante o repouso não se mantém durante o exercício. Além disso, a tolerância ao exercício parece não depender dos níveis fisiológicos dos estrogênios. Desse modo, nossos achados reforçam a importância da prescrição de exercícios físicos na orientação clínica das mulheres no climatério