No description available.

Objetivo: Avaliar os efeitos da Sulpirida 50mg/dia comparado a placebo sobre os sintomas vasomotores (frequência e intensidade) e na qualidade de vida de mulheres climatéricas. Métodos: Mulheres climatéricas (N=28), idade entre 47 e 62 anos, com pelo menos cinco episódios de sintomas vasomotores por dia, foram recrutadas em uma clínica especializada de um hospital terciário no sul do Brasil e através de chamamentos na mídia; após os critérios de inclusão e de exclusão, elas foram randomizadas. Placebo (n=14) e Sulpirida 50mg/dia (n=14) foram administrados durante o ensaio. O número e a intensidade dos fogachos foram registrados 1 semana antes e ao longo de 8 semanas após intervenção. Aplicou-se o WHQ – 36 itens para avaliação da qualidade de vida. Resultados: As frequências e as intensidades dos fogachos/dia foram similares em ambos os grupos, observando-se uma redução em ambos os parâmetros durante as semanas de follow-up após a intervenção com Sulpirida (p=0,019 e p=0,009, respectivamente). Quanto à qualidade de vida das mulheres, Sulpirida 50mg/dia reduziu os escores dos problemas com o sono após 8 semanas de tratamento, quando comparada ao grupo placebo (p=0,017). Conclusions: Nossos resultados sugerem que o tratamento com a Sulpirida 50mg/dia se apresentou com tendências significativas na redução dos sintomas climatéricos, se justificando a replicação e outros estudos que investiguem os possíveis mecanismos pelos quais a Sulpirida poderia reduzir os fogachos, de forma segura. / Objective: To assess the effects of Sulpiride 50mg/day compared with placebo on vasomotor symptoms (frequency and intensity) and on quality of life of climacteric women. Methods: Climacteric women (N=28), aged between 47–62 years, with at least five episodes of vasomotor symptoms per day were recruited from a specialized outpatient clinic at a tertiary hospital in the south of Brazil and through a media call after inclusion and exclusion criteria were ensured. Placebo (n=14) and Sulpiride 50mg/day (n=14) were administrated during all trial period. The number and intensity records of hot flushes were evaluated for 1 week before and along 8 weeks after the intervention. The 36-item version Women’s Health Questionnaire (WHQ) was applied to assess the quality of life. Results: The frequencies and the intensities of hot flushes /day happened in a similar way in both groups, with an observed reduction of both parameters during the weekly follow up after the Sulpiride intervention (p=0.019 and p=0.009, respectively). Regarding women’s quality of life, Sulpiride 50mg/day reduced sleep problems scores after 8 weeks of treatment, when compared to placebo group (p=0.017. Conclusions: Our results suggest that the Sulpiride 50mg/day treatment showed significant trends on reducing climacteric vasomotor symptoms, justifying replication and further studies addressing the possible mechanisms by which Sulpiride could safely reduce hot flushes.

Objetivo: Avaliar os efeitos da Sulpirida 50mg/dia comparado a placebo sobre os sintomas vasomotores (frequência e intensidade) e na qualidade de vida de mulheres climatéricas. Métodos: Mulheres climatéricas (N=28), idade entre 47 e 62 anos, com pelo menos cinco episódios de sintomas vasomotores por dia, foram recrutadas em uma clínica especializada de um hospital terciário no sul do Brasil e através de chamamentos na mídia; após os critérios de inclusão e de exclusão, elas foram randomizadas. Placebo (n=14) e Sulpirida 50mg/dia (n=14) foram administrados durante o ensaio. O número e a intensidade dos fogachos foram registrados 1 semana antes e ao longo de 8 semanas após intervenção. Aplicou-se o WHQ – 36 itens para avaliação da qualidade de vida. Resultados: As frequências e as intensidades dos fogachos/dia foram similares em ambos os grupos, observando-se uma redução em ambos os parâmetros durante as semanas de follow-up após a intervenção com Sulpirida (p=0,019 e p=0,009, respectivamente). Quanto à qualidade de vida das mulheres, Sulpirida 50mg/dia reduziu os escores dos problemas com o sono após 8 semanas de tratamento, quando comparada ao grupo placebo (p=0,017). Conclusions: Nossos resultados sugerem que o tratamento com a Sulpirida 50mg/dia se apresentou com tendências significativas na redução dos sintomas climatéricos, se justificando a replicação e outros estudos que investiguem os possíveis mecanismos pelos quais a Sulpirida poderia reduzir os fogachos, de forma segura. / Objective: To assess the effects of Sulpiride 50mg/day compared with placebo on vasomotor symptoms (frequency and intensity) and on quality of life of climacteric women. Methods: Climacteric women (N=28), aged between 47–62 years, with at least five episodes of vasomotor symptoms per day were recruited from a specialized outpatient clinic at a tertiary hospital in the south of Brazil and through a media call after inclusion and exclusion criteria were ensured. Placebo (n=14) and Sulpiride 50mg/day (n=14) were administrated during all trial period. The number and intensity records of hot flushes were evaluated for 1 week before and along 8 weeks after the intervention. The 36-item version Women’s Health Questionnaire (WHQ) was applied to assess the quality of life. Results: The frequencies and the intensities of hot flushes /day happened in a similar way in both groups, with an observed reduction of both parameters during the weekly follow up after the Sulpiride intervention (p=0.019 and p=0.009, respectively). Regarding women’s quality of life, Sulpiride 50mg/day reduced sleep problems scores after 8 weeks of treatment, when compared to placebo group (p=0.017. Conclusions: Our results suggest that the Sulpiride 50mg/day treatment showed significant trends on reducing climacteric vasomotor symptoms, justifying replication and further studies addressing the possible mechanisms by which Sulpiride could safely reduce hot flushes.

Objetivo: Avaliar os efeitos da Sulpirida 50mg/dia comparado a placebo sobre os sintomas vasomotores (frequência e intensidade) e na qualidade de vida de mulheres climatéricas. Métodos: Mulheres climatéricas (N=28), idade entre 47 e 62 anos, com pelo menos cinco episódios de sintomas vasomotores por dia, foram recrutadas em uma clínica especializada de um hospital terciário no sul do Brasil e através de chamamentos na mídia; após os critérios de inclusão e de exclusão, elas foram randomizadas. Placebo (n=14) e Sulpirida 50mg/dia (n=14) foram administrados durante o ensaio. O número e a intensidade dos fogachos foram registrados 1 semana antes e ao longo de 8 semanas após intervenção. Aplicou-se o WHQ – 36 itens para avaliação da qualidade de vida. Resultados: As frequências e as intensidades dos fogachos/dia foram similares em ambos os grupos, observando-se uma redução em ambos os parâmetros durante as semanas de follow-up após a intervenção com Sulpirida (p=0,019 e p=0,009, respectivamente). Quanto à qualidade de vida das mulheres, Sulpirida 50mg/dia reduziu os escores dos problemas com o sono após 8 semanas de tratamento, quando comparada ao grupo placebo (p=0,017). Conclusions: Nossos resultados sugerem que o tratamento com a Sulpirida 50mg/dia se apresentou com tendências significativas na redução dos sintomas climatéricos, se justificando a replicação e outros estudos que investiguem os possíveis mecanismos pelos quais a Sulpirida poderia reduzir os fogachos, de forma segura. / Objective: To assess the effects of Sulpiride 50mg/day compared with placebo on vasomotor symptoms (frequency and intensity) and on quality of life of climacteric women. Methods: Climacteric women (N=28), aged between 47–62 years, with at least five episodes of vasomotor symptoms per day were recruited from a specialized outpatient clinic at a tertiary hospital in the south of Brazil and through a media call after inclusion and exclusion criteria were ensured. Placebo (n=14) and Sulpiride 50mg/day (n=14) were administrated during all trial period. The number and intensity records of hot flushes were evaluated for 1 week before and along 8 weeks after the intervention. The 36-item version Women’s Health Questionnaire (WHQ) was applied to assess the quality of life. Results: The frequencies and the intensities of hot flushes /day happened in a similar way in both groups, with an observed reduction of both parameters during the weekly follow up after the Sulpiride intervention (p=0.019 and p=0.009, respectively). Regarding women’s quality of life, Sulpiride 50mg/day reduced sleep problems scores after 8 weeks of treatment, when compared to placebo group (p=0.017. Conclusions: Our results suggest that the Sulpiride 50mg/day treatment showed significant trends on reducing climacteric vasomotor symptoms, justifying replication and further studies addressing the possible mechanisms by which Sulpiride could safely reduce hot flushes.

No description available.

Introdução: Os sintomas psíquicos e vasomotores são altamente prevalentes na transição menopáusica e na pós-menopausa, e estão relacionados ao hipoestrogenismo decorrente da falência ovariana que ocorre na mulher na meiaidade. Sua exata fisiopatogenia é desconhecida, porém alterações de neurotransmissores, como a serotonina e a noradrenalina, parecem estar relacionados ao aparecimento dessa sintomatologia. A terapia estrogênica geralmente é efetiva em aliviar esses sintomas, no entanto muitas mulheres não podem ou não desejam este tipo de tratamento, por isso, diversas alternativas têm sido estudadas. Objetivos: esta tese teve como objetivo avaliar, em um modelo experimental de climatério em ratas, parâmetros fisiológicos, comportamentais e bioquímicos, visando testar duas novas terapias: a cetamina, um antagonista não competitivo do receptor N-metil-D-aspartato (NMDA) e a eletroestimulação transcraniana de corrente contínua (ETCC) respectivamente, para o comportamento do tipo depressivo e a disfunção termorregulatória. Métodos: Ratos Wistar fêmeas adultas (200 a 250 g) foram randomizadas pelo peso e submetidas a modelo de menopausa por meio de ovariectomia bilateral ou a procedimento sham (falsa cirurgia). No primeiro experimento, os animais foram submetidos ao teste do nado forçado para avaliar comportamento do tipo depressivo e posteriormente receberam uma dose de cetamina 10mg/kg de peso intraperitoneal. No segundo experimento, os animais foram avaliados quanto à disfunção termorregulatória e tratados com ETCC catódica. Resultados: No primeiro experimento, as ratas em estado hipoestrogênico apresentaram comportamento do tipo depressivo que foi revertido pela cetamina. As ratas sham apresentaram um quadro de menopausa precoce indexado por citologia vaginal, provavelmente decorrente da manipulação de anexos. Além disso, as ratas ovariectomizadas apresentaram comportamento tipo ansioso. No entanto, não houve alteração da atividade locomotora e exploratória entre os grupos. No segundo experimento, as ratas ovariectomizadas apresentaram aumento da temperatura retal que foi parcialmente revertido pela eletroestimulação transcraniana de corrente contínua; as ratas ovariectomizadas apresentaram níveis elevados de interleucina 8 no soro, em relação às não ovariectomizadas, sem diferença nos níveis hipotalâmicos; houve aumento dos níveis séricos e diminuição dos níveis hipotalâmicos de BDNF nas ratas ovariectomizadas e interação do modelo com a ETCC em relação aos níveis corticais de BDNF. Nos testes nociceptivos, as ratas ovariectomizadas apresentaram diminuição do tempo de latência de resposta no teste da placa quente e alodinia mecânica no teste Von Frey, parcialmente revertida pela ETCC, no entanto, não houve diferença entre os grupos no teste tail flick. Conclusão: Nossos estudos demonstram que o modelo de ovariectomia utilizado foi eficaz em reproduzir os sintomas apresentados no período perimenopausa tendo, portanto, potencial translacional. Adicionalmente, sugerem que, além dos sistemas serotoninérgico e noradrenérgico, outros sistemas parecem estar associados ao aparecimento de sintomas na transição menopáusica como, por exemplo, o sistema glutamatérgico. Demonstram ainda que a cetamina e a ETCC podem ser eficazes como adjuvantes no tratamento dos sintomas do climatério, respectivamente, farmacológico (nos sintomas depressivos) e não farmacológico (nos “fogachos”). / Introduction: Psychological and vasomotor symptoms have a high prevalence in women during menopause transition and post menopausal years. Though these symptoms are associated to decline of estrogen levels due to ovarian failure, their exact pathophysiology is unknown. Variations on neurotransmitters such as serotonin and norepinephrine seem to be responsible by great amount of these symptoms. Estrogen therapy is usually effective in relieving these symptoms. However, many women have contraindications or do not wish to use this kind of treatment, thus several therapeutic alternatives have been studied. Objectives: This thesis was designed to evaluate, in an experimental model of menopause in rats, physiological, behavioral and biochemical parameters, aiming to test two new therapies: ketamine, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor and transcranial direct current stimulation (tDCS) respectively for the depressive-like behavior and thermoregulatory dysfunction. Methods: Female adult Wistar rats (200- 250g) were randomized by weight and subjected to a menopause model through bilateral ovariectomy or sham (false surgery) procedure. In the first experiment, the animals were subjected to the forced swimming test to assess depressive-like behavior and subsequently received a dose of 10mg/kg of weight of intraperitoneal ketamine. In the second experiment, the animals were evaluated for thermoregulatory dysfunction and treated with cathodal tDCS. Results: In the first experiment, the rats in hypoestrogenic state showed depressive-like behavior that was reversed by ketamine. The sham rats presented a precocious menopause indexed by vaginal cytology, probably due to the surgical handling of the tubes and ovaries. Moreover, the ovariectomized rats showed anxiety-like behavior. However, there was no change in locomotor activity between groups. In the second experiment, the ovariectomized rats showed an increase in rectal temperature that was partially reversed by tDCS. Moreover, the ovariectomized rats showed elevated serum levels of interleukin-8, compared to non-ovariectomized rats, with no difference in hypothalamic levels; there was an increase in serum levels and decreased hypothalamic BDNF levels in ovariectomized rats, and there was interaction of ovariectomy and ETCC in relation to cortical BDNF levels. In the nociceptive tests, the ovariectomized rats presented decreased response latency in the hot plate test and mechanical alodinia in the von Frey test; however, there was no difference between groups in the tail flick test. Conclusion: Our studies demonstrate that the ovariectomy model used was effective in reproducing the symptoms that women present during perimenopause and therefore has translational potential. Additionally, these data suggest that, beyond the serotonergic and noradrenergic systems, other systems seem to be associated with the onset of symptoms in menopausal transition such as the glutamatergic system. Our data also demonstrate that ketamine and ETCC can be effective adjuvant therapeutic tools to the relief of climacteric symptoms, respectively, pharmacological (on depressive symptoms) and non pharmacological (on "hot flashes").

Introdução: Os sintomas psíquicos e vasomotores são altamente prevalentes na transição menopáusica e na pós-menopausa, e estão relacionados ao hipoestrogenismo decorrente da falência ovariana que ocorre na mulher na meiaidade. Sua exata fisiopatogenia é desconhecida, porém alterações de neurotransmissores, como a serotonina e a noradrenalina, parecem estar relacionados ao aparecimento dessa sintomatologia. A terapia estrogênica geralmente é efetiva em aliviar esses sintomas, no entanto muitas mulheres não podem ou não desejam este tipo de tratamento, por isso, diversas alternativas têm sido estudadas. Objetivos: esta tese teve como objetivo avaliar, em um modelo experimental de climatério em ratas, parâmetros fisiológicos, comportamentais e bioquímicos, visando testar duas novas terapias: a cetamina, um antagonista não competitivo do receptor N-metil-D-aspartato (NMDA) e a eletroestimulação transcraniana de corrente contínua (ETCC) respectivamente, para o comportamento do tipo depressivo e a disfunção termorregulatória. Métodos: Ratos Wistar fêmeas adultas (200 a 250 g) foram randomizadas pelo peso e submetidas a modelo de menopausa por meio de ovariectomia bilateral ou a procedimento sham (falsa cirurgia). No primeiro experimento, os animais foram submetidos ao teste do nado forçado para avaliar comportamento do tipo depressivo e posteriormente receberam uma dose de cetamina 10mg/kg de peso intraperitoneal. No segundo experimento, os animais foram avaliados quanto à disfunção termorregulatória e tratados com ETCC catódica. Resultados: No primeiro experimento, as ratas em estado hipoestrogênico apresentaram comportamento do tipo depressivo que foi revertido pela cetamina. As ratas sham apresentaram um quadro de menopausa precoce indexado por citologia vaginal, provavelmente decorrente da manipulação de anexos. Além disso, as ratas ovariectomizadas apresentaram comportamento tipo ansioso. No entanto, não houve alteração da atividade locomotora e exploratória entre os grupos. No segundo experimento, as ratas ovariectomizadas apresentaram aumento da temperatura retal que foi parcialmente revertido pela eletroestimulação transcraniana de corrente contínua; as ratas ovariectomizadas apresentaram níveis elevados de interleucina 8 no soro, em relação às não ovariectomizadas, sem diferença nos níveis hipotalâmicos; houve aumento dos níveis séricos e diminuição dos níveis hipotalâmicos de BDNF nas ratas ovariectomizadas e interação do modelo com a ETCC em relação aos níveis corticais de BDNF. Nos testes nociceptivos, as ratas ovariectomizadas apresentaram diminuição do tempo de latência de resposta no teste da placa quente e alodinia mecânica no teste Von Frey, parcialmente revertida pela ETCC, no entanto, não houve diferença entre os grupos no teste tail flick. Conclusão: Nossos estudos demonstram que o modelo de ovariectomia utilizado foi eficaz em reproduzir os sintomas apresentados no período perimenopausa tendo, portanto, potencial translacional. Adicionalmente, sugerem que, além dos sistemas serotoninérgico e noradrenérgico, outros sistemas parecem estar associados ao aparecimento de sintomas na transição menopáusica como, por exemplo, o sistema glutamatérgico. Demonstram ainda que a cetamina e a ETCC podem ser eficazes como adjuvantes no tratamento dos sintomas do climatério, respectivamente, farmacológico (nos sintomas depressivos) e não farmacológico (nos “fogachos”). / Introduction: Psychological and vasomotor symptoms have a high prevalence in women during menopause transition and post menopausal years. Though these symptoms are associated to decline of estrogen levels due to ovarian failure, their exact pathophysiology is unknown. Variations on neurotransmitters such as serotonin and norepinephrine seem to be responsible by great amount of these symptoms. Estrogen therapy is usually effective in relieving these symptoms. However, many women have contraindications or do not wish to use this kind of treatment, thus several therapeutic alternatives have been studied. Objectives: This thesis was designed to evaluate, in an experimental model of menopause in rats, physiological, behavioral and biochemical parameters, aiming to test two new therapies: ketamine, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor and transcranial direct current stimulation (tDCS) respectively for the depressive-like behavior and thermoregulatory dysfunction. Methods: Female adult Wistar rats (200- 250g) were randomized by weight and subjected to a menopause model through bilateral ovariectomy or sham (false surgery) procedure. In the first experiment, the animals were subjected to the forced swimming test to assess depressive-like behavior and subsequently received a dose of 10mg/kg of weight of intraperitoneal ketamine. In the second experiment, the animals were evaluated for thermoregulatory dysfunction and treated with cathodal tDCS. Results: In the first experiment, the rats in hypoestrogenic state showed depressive-like behavior that was reversed by ketamine. The sham rats presented a precocious menopause indexed by vaginal cytology, probably due to the surgical handling of the tubes and ovaries. Moreover, the ovariectomized rats showed anxiety-like behavior. However, there was no change in locomotor activity between groups. In the second experiment, the ovariectomized rats showed an increase in rectal temperature that was partially reversed by tDCS. Moreover, the ovariectomized rats showed elevated serum levels of interleukin-8, compared to non-ovariectomized rats, with no difference in hypothalamic levels; there was an increase in serum levels and decreased hypothalamic BDNF levels in ovariectomized rats, and there was interaction of ovariectomy and ETCC in relation to cortical BDNF levels. In the nociceptive tests, the ovariectomized rats presented decreased response latency in the hot plate test and mechanical alodinia in the von Frey test; however, there was no difference between groups in the tail flick test. Conclusion: Our studies demonstrate that the ovariectomy model used was effective in reproducing the symptoms that women present during perimenopause and therefore has translational potential. Additionally, these data suggest that, beyond the serotonergic and noradrenergic systems, other systems seem to be associated with the onset of symptoms in menopausal transition such as the glutamatergic system. Our data also demonstrate that ketamine and ETCC can be effective adjuvant therapeutic tools to the relief of climacteric symptoms, respectively, pharmacological (on depressive symptoms) and non pharmacological (on "hot flashes").

Introdução: Os sintomas psíquicos e vasomotores são altamente prevalentes na transição menopáusica e na pós-menopausa, e estão relacionados ao hipoestrogenismo decorrente da falência ovariana que ocorre na mulher na meiaidade. Sua exata fisiopatogenia é desconhecida, porém alterações de neurotransmissores, como a serotonina e a noradrenalina, parecem estar relacionados ao aparecimento dessa sintomatologia. A terapia estrogênica geralmente é efetiva em aliviar esses sintomas, no entanto muitas mulheres não podem ou não desejam este tipo de tratamento, por isso, diversas alternativas têm sido estudadas. Objetivos: esta tese teve como objetivo avaliar, em um modelo experimental de climatério em ratas, parâmetros fisiológicos, comportamentais e bioquímicos, visando testar duas novas terapias: a cetamina, um antagonista não competitivo do receptor N-metil-D-aspartato (NMDA) e a eletroestimulação transcraniana de corrente contínua (ETCC) respectivamente, para o comportamento do tipo depressivo e a disfunção termorregulatória. Métodos: Ratos Wistar fêmeas adultas (200 a 250 g) foram randomizadas pelo peso e submetidas a modelo de menopausa por meio de ovariectomia bilateral ou a procedimento sham (falsa cirurgia). No primeiro experimento, os animais foram submetidos ao teste do nado forçado para avaliar comportamento do tipo depressivo e posteriormente receberam uma dose de cetamina 10mg/kg de peso intraperitoneal. No segundo experimento, os animais foram avaliados quanto à disfunção termorregulatória e tratados com ETCC catódica. Resultados: No primeiro experimento, as ratas em estado hipoestrogênico apresentaram comportamento do tipo depressivo que foi revertido pela cetamina. As ratas sham apresentaram um quadro de menopausa precoce indexado por citologia vaginal, provavelmente decorrente da manipulação de anexos. Além disso, as ratas ovariectomizadas apresentaram comportamento tipo ansioso. No entanto, não houve alteração da atividade locomotora e exploratória entre os grupos. No segundo experimento, as ratas ovariectomizadas apresentaram aumento da temperatura retal que foi parcialmente revertido pela eletroestimulação transcraniana de corrente contínua; as ratas ovariectomizadas apresentaram níveis elevados de interleucina 8 no soro, em relação às não ovariectomizadas, sem diferença nos níveis hipotalâmicos; houve aumento dos níveis séricos e diminuição dos níveis hipotalâmicos de BDNF nas ratas ovariectomizadas e interação do modelo com a ETCC em relação aos níveis corticais de BDNF. Nos testes nociceptivos, as ratas ovariectomizadas apresentaram diminuição do tempo de latência de resposta no teste da placa quente e alodinia mecânica no teste Von Frey, parcialmente revertida pela ETCC, no entanto, não houve diferença entre os grupos no teste tail flick. Conclusão: Nossos estudos demonstram que o modelo de ovariectomia utilizado foi eficaz em reproduzir os sintomas apresentados no período perimenopausa tendo, portanto, potencial translacional. Adicionalmente, sugerem que, além dos sistemas serotoninérgico e noradrenérgico, outros sistemas parecem estar associados ao aparecimento de sintomas na transição menopáusica como, por exemplo, o sistema glutamatérgico. Demonstram ainda que a cetamina e a ETCC podem ser eficazes como adjuvantes no tratamento dos sintomas do climatério, respectivamente, farmacológico (nos sintomas depressivos) e não farmacológico (nos “fogachos”). / Introduction: Psychological and vasomotor symptoms have a high prevalence in women during menopause transition and post menopausal years. Though these symptoms are associated to decline of estrogen levels due to ovarian failure, their exact pathophysiology is unknown. Variations on neurotransmitters such as serotonin and norepinephrine seem to be responsible by great amount of these symptoms. Estrogen therapy is usually effective in relieving these symptoms. However, many women have contraindications or do not wish to use this kind of treatment, thus several therapeutic alternatives have been studied. Objectives: This thesis was designed to evaluate, in an experimental model of menopause in rats, physiological, behavioral and biochemical parameters, aiming to test two new therapies: ketamine, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor and transcranial direct current stimulation (tDCS) respectively for the depressive-like behavior and thermoregulatory dysfunction. Methods: Female adult Wistar rats (200- 250g) were randomized by weight and subjected to a menopause model through bilateral ovariectomy or sham (false surgery) procedure. In the first experiment, the animals were subjected to the forced swimming test to assess depressive-like behavior and subsequently received a dose of 10mg/kg of weight of intraperitoneal ketamine. In the second experiment, the animals were evaluated for thermoregulatory dysfunction and treated with cathodal tDCS. Results: In the first experiment, the rats in hypoestrogenic state showed depressive-like behavior that was reversed by ketamine. The sham rats presented a precocious menopause indexed by vaginal cytology, probably due to the surgical handling of the tubes and ovaries. Moreover, the ovariectomized rats showed anxiety-like behavior. However, there was no change in locomotor activity between groups. In the second experiment, the ovariectomized rats showed an increase in rectal temperature that was partially reversed by tDCS. Moreover, the ovariectomized rats showed elevated serum levels of interleukin-8, compared to non-ovariectomized rats, with no difference in hypothalamic levels; there was an increase in serum levels and decreased hypothalamic BDNF levels in ovariectomized rats, and there was interaction of ovariectomy and ETCC in relation to cortical BDNF levels. In the nociceptive tests, the ovariectomized rats presented decreased response latency in the hot plate test and mechanical alodinia in the von Frey test; however, there was no difference between groups in the tail flick test. Conclusion: Our studies demonstrate that the ovariectomy model used was effective in reproducing the symptoms that women present during perimenopause and therefore has translational potential. Additionally, these data suggest that, beyond the serotonergic and noradrenergic systems, other systems seem to be associated with the onset of symptoms in menopausal transition such as the glutamatergic system. Our data also demonstrate that ketamine and ETCC can be effective adjuvant therapeutic tools to the relief of climacteric symptoms, respectively, pharmacological (on depressive symptoms) and non pharmacological (on "hot flashes").

Introduction: Hormone therapy (HT) has been considered as a safe treatment for menopausal symptoms. Use of HT increased dramatically in the 1980s and 1990s. Results from large randomized clinical trials (RCT) could, around the turn of the century, however not find evidence for long-term benefits with HT. These results attracted great attention from media and the scientific community leading to changed treatment guidelines and decreased use of HT. Aim: The overall aim of this thesis was to explore Swedish women’s conceptions, knowledge, management, and attitudes regarding the menopausal transition and HT. Material and methods: To explore and describe women’s conceptions of the menopausal transition women seeking medical advice due to climacteric symptoms were interviewed (n=20) and their statements were analyzed with a qualitative method (paper I). In 1999 (n=1760) and 2003 (n=1733) attitudes to (paper II) and knowledge of (paper III) the menopausal transition and HT among 53- and 54 year old women were investigated with a cross-sectional design using postal questionnaires. We also analyzed if attitudes differed before and after new scientific findings were published on risks and benefits of HT and if knowledge differed between educational levels. Since many women try to abandon use of HT a RCT was performed to study the effect of two different methods to discontinue HT, on recurrence of hot flushes, resumption of HT and on health related quality of life (HRQoL). Women (n=87) with vasomotor symptoms before initiating HT participated. Results: We found that the majority of the middle aged women in our study viewed the menopausal transition as a natural process the nature of which is affected by both hormonal changes and by ageing. Each woman seems to experience a set of psychological and physical symptoms that are in some sense unique to her experience. Women’s answers to the questions about HT demonstrate that attitudes towards HT held by women going through menopause have changed rather dramatically between 1999 and 2003. These changes probably reflect the influence on the women of media reports based on research that identified risks associated with HT that had not been identified before 1998. Women’s knowledge of the effects of HT seems to be unsatisfactory from a clinical perspective. No differences in hot flush frequency and resumption of HT were found between the women randomized to two different modes of discontinuation of HT. Almost 50 % of the women restarted HT within one year after discontinuation. Deteriorated wellbeing and severity of hot flushes were important predicting factors for resumption of HT. Conclusion: It is important to be aware of the individual woman’s conceptions and attitudes about and knowledge of the menopausal transition and HT to be able to individualize the counselling situation. Women who initiate HT due to hot flushes may experience recurrence of vasomotor symptoms and deteriorated HRQoL after discontinuation. A great proportion of them may resume HT. At present knowledge of possible advantages for the taper-down method when discontinuing HT is still lacking.

Background: Interest in alternatives to hormone therapy (HT) for menopausal symptoms increased following its association with serious health risks. In terms of phytotherapeutic interventions, while traditional use supports a range of herbs for treating menopausal symptoms, evidence from rigorous scientific trials is limited, and has largely focused on the phytoestrogenic plants. Because of some safety concerns over long-term use of isoflavones, the present study focused on two non-estrogenic herbs, Hypericum perforatum and Vitex agnus-castus, also employed in this context in the Anglo-American and European traditions. Both herbs have shown effectiveness for the alleviation of symptoms of premenstrual syndrome (PMS), which is reported to be more severe during the perimenopause, and may account for many of the so-called 'menopausal symptoms' at this time. Research on menopausal vasomotor symptoms is prone to substantial placebo responses. There has been much interest in increasing our understanding of the placebo response with a view to controlling it in clinical research and harnessing it in clinical practice. Methods & Results: A double-blind, randomised controlled trial (RCT), with a 16-week treatment phase, was conducted on 100 late-perimenopause and early postmenopause women. The herbal combination (Hypericum and Vitex) was not found to be superior to placebo for any of the endpoints - daily weighted flushing scores, overall menopausal symptoms (on the Greene Climacteric Scale) and depression (on the Hamilton Depression Inventory). However, significant improvements across the treatment phase were observed in both arms for all of these outcome measures. No significant change was found for either group on the Utian quality of life scale. The effects of the herbal combination were also examined on PMS-like symptoms in the small sub-population of late-perimenopausal women, and found to be superior to placebo for total PMS-like symptoms and the sub-clusters, PMS-D (depression) and PMS-C (cravings). The active treatment group also showed significant improvements on PMS-A (anxiety) and PMS-H (hydration), although these effects were not superior to placebo. Predictors of the placebo response were investigated and found to include study-entry anxiety for the outcome measures of flushing, depression and overall menopausal symptoms, and improvement during non-treatment run-in for depression and overall symptoms. Because no difference had been found between 'active' and placebo groups in the menopause RCT, it was hypothesised that the same predictors would predict the response to the study treatment. However, low anxiety was significantly associated with improvement in this group. None of the other variables that predicted the placebo response was relevant to the study treatment response. This finding is discussed with reference to the possibility that 'drug' effects and placebo effects are not necessarily additive, and that the same magnitude of effect in both arms might not necessarily imply activity via the same pathways. Conclusions: This research contributes to the growing body of scientific knowledge about evidence-based complementary therapies that informs the community, health-care providers and regulatory authorities. The findings may facilitate identification of potential placebo responders in future research. The need for more research in the area of mechanisms of placebo versus active responses is supported.